Recurrent Implantation Failure Treatment in India for Failed IVF Implantation

As a reproductive immunologist and fertility specialist, I understand that few experiences in the IVF journey are more disheartening than a failed cycle.

When this happens repeatedly, it leads to a condition we call Recurrent Implantation Failure, or RIF.

I am Dr. Jay Mehta, and at our dedicated Recurrent Implantation Failure (RIF) Clinic in Mumbai, my team and I focus on managing complex implantation challenges with a structured, scientific approach.

RIF is not a final diagnosis—it is a clinical situation that signals the need for deeper evaluation.

Recurrent Implantation Failure (RIF) is a clinical condition where a patient fails to achieve a successful pregnancy after two or more consecutive embryo transfers. 

This diagnosis is specifically applied when Top Quality Embryos (TQE) or genetically tested, chromosomally normal euploid embryos are used, and no other clear medical reason for the failure has been identified.

It is the “unexplained” gap between a perfect embryo and a successful pregnancy.

1. The Technical Definition vs. The Emotional Reality

While the medical definition requires two or more failures, we recognize that the journey of anxiety begins the moment the first IVF cycle fails.

Most patients enter IVF expecting success; when it doesn’t happen, it creates a trauma that needs specialized attention.

2. The Search for “Fine Points”.

As a dedicated RIF clinic in Mumbai, we don’t just “try again.” We look for the subtle details that may have been missed in previous standard IVF cycles:

• Minor Anatomical Issues: Small polyps or filmy adhesions.

• Hormonal Syncing: Misalignment between the embryo’s age and the uterine lining’s readiness.

• Micro-inflammation: Silent infections in the uterine lining.

A careful, case-specific analysis is the only way to move from a generic “failure” to an individualized “success.”

3. The “No Single Answer” Warning

Despite rapid advancements in reproductive science, it is often impossible to give one singular answer to every patient. RIF is usually a multifactorial puzzle.

Success comes from optimizing several small factors rather than looking for one “magic” reason.

4. The Role of Reproductive Immunology

This is one of the most misunderstood areas of RIF. While immunology is a powerful tool, it is often overused.

• The 30% Rule: Out of every 100 patients we evaluate for RIF, only 30% actually warrant specialized immunotherapy.

• Targeted Therapy: We warn against “blind” immunotherapy. We only use these treatments when specific diagnostic markers show that the mother’s immune system is actively rejecting the embryo.

Expert Advice: RIF is not a dead end; it is a signal to stop and look closer. As a fertility expert, my job is to find those ‘fine points’ that standard protocols miss. We focus on truth and data, ensuring you only get the treatments you actually need.

RIF basically stands for recurrent implantation failure, and it is classified as a condition, where the patient has experienced two or more attempts, of IVF failure after the embryo transfer, which has been performed for a top quality embryo (TQE) or a genetically tested chromosomally normal embryo, also called as a EUPLOID embryo.

This becomes extremely important because majority of the times we wish to make sure that these are the patients who experienced the highest success rates. A detailed evaluation of the patient as well as all the other factors which may be even responsible for a slight chance of giving an implantation failure is warranted in all of these situations.

In a vast majority of the situations, finding the exact cause may be a technically challenging issue and as a result of this, a deep dive into the technical understanding of the subject is mandatory as a clinician to give the outcomes to the patients. All the patients must hear also understand that the age of the female partner is one of the most important diagnostic factors to give rise to implantation failure.

Because as the age of the female partner increases, there is a definitive reduction in the quality of the Oocyte or the EGG, and as a result of which the probability of forming genetically normal embryo greatly reduces serially as the age of the female partner keeps on increasing.

As far as the technical definition is concerned, having two or more failed, IVF cycles are considered to be recurrent implantation failures, especially if the IVF embryo transfer for the patient has been done with the help of a top quality embryo or preferably, a genetically tested chromosome, normal embryo also called as a EUPLOID Embryo.

However, quite a lot of patients are extremely sensitive in this subject because the emotions are running extremely higher as a result of which quite a lot of patients come forward for evaluation, Even after their first IVF cycle has failed.

Another problem which occurs in this situation, is that there is a lack of standardisation of the procedure of IVF across a variety of IVF clinics which have mushroomed across India, as a result of which the technique of the embryo freezing, embryo thawing as well as the type of embryo which is transferred, is not yet certain and standardised across India.

Addressing this issue on a case to case basis usually fetch the answer in approximately 50% of the cases in India, who present to our clinic with a diagnosis for a recurrent implantation failure.

One has to also understand that the facility and the technique for performing PGT-A, is currently not available at more than 85% of the clinics who are practising fertility therapies in India.

As more and more people opt for fertility treatments in India. The diagnosis and patients who end up with recurrent implantation failure also keeps on going up.

Another important reason why this has gone up because the average age of seeking fertility treatment in India has gone up drastically in the last one decade.

Just to give you an example of our Clinic more than 85% of the patients whom we end up treating have an average age of more than 37 years for the female partner.

So definitely, it is getting more and more common and probably from here onwards. It is only bound to increase.

I would always like to classify recurrent implantation failure or RIF as a description for a particular case. That is because the true reason if in case we are able to find out for the RIF ultimately leads to the diagnosis and once the diagnosis has been firmly established correction of the diagnosis from there onwards allows the patient to have a conception.

The patient should understand the fact that in majority of the cases where there is recurrent implantation failure, a deep technical understanding of the subject is important and most of the times we will be able to find out one particular cause which has given rise to an implantation failure for that particular patient.

This becomes very easy if you are specialist in this subject, especially in a country like India, where even today more than 80% of the fertility treatments and IVF cycles are carried out in clinics, which do not have the necessary or the advanced equipment to perform any type of advanced fertility procedures, which once when it is offered to the Patient, completely solve their problem of having repeated or recurrent implantation failures.

A dedicated RIF clinic or a Recurrent Implantation Failure clinic, was the need of the hour for a country like India, where a specialist is able to sit down with the patient and evaluate and at least try to identify one of the most probable causes which would have given rise to an implantation failure in their case.

The reason why the Clinic works so efficiently is very simple. In a country like India, major majority of the times after there is a single IVF cycle failure., more than 85% of the couples are going to be recommended to go ahead with a cycle with a donor program, as ridiculous as it sounds, it is absolutely true for a country like India, as a result of which majority of the patients were educated enough.

This switch out from the Clinic, where they are currently doing the treatment and move forward, looking forward to options where a better perspective in a better diagnosis for their disease is available in order to make sure that they are able to have a conception using their own sperms and own eggs, which is also called as a SELF Cycle IVF.

Back in 2023, we started our dedicated OPD both in the clinic but predominantly online, to make sure that couples across India can come to us and seek our expert opinion to make sure that we are able to offer them a protocol based approach to lead to an effective diagnosis to put an end to the multiple and repeated IVF failures, by giving them the necessary confidence and a scientific backup to allow them to have a conception using their own sperms and own eggs.

When we started this, we were the first in India to do it., on a dedicated level across the country. In just two years, the Clinic has grown from strength to strength having offered guidance online to more than 3000 couples already, and we have helped majority of them to address a diagnosis and ultimately achieve a conception.

The beauty is this allows us to make sure that the couples receive the treatment in their own home city and are allowed to travel to Mumbai only if there is a requirement for performing a specific procedure during the course of their entire journey, this makes the entire journey smooth and logistically convenient for the couple.

An IVF cycle can fail due to a lot many reasons that is precisely the reason whenever a single IVF cycle fails, especially in a country like India, where there is a mushrooming of small fertility clinics without any standardisation of the techniques as well as of the machinery, it becomes extremely difficult for us to go ahead and explain to the Patient.

The reason why a particular IVF cycle failed because many types if you are a patient in India, you would have understood and recognised the fact that there are certain amount of discrete marketing practices which are happening in the country of India, where a patient is wooed, into doing their primary IVF cycle at a particular Clinic to start off with in the hope of a plenty of false promises.

One of the most common promise being an exaggerated success rate, which may or may not be true for that particular case. RIF or recurrently plantation failure should only be considered in those situations when the patient has failed at least two or more embryo transfers with top quality embryos in the absence of any other known and detectable cause.

Patient should be labelled as a patient who is having RIF or a recurrent implantation failure, only in those situations where two or more embryo transfers have failed with top quality embryos, preferably with embryos, which have been genetically tested and have been found to be chromosome normal called as EUPLOID embryos.

They should also happen in preferably a pelvis which was completely free of any types of diseases, especially the ones which may create a trouble infertility like fibroids, polyps, endometriosis, and Adenomyosis.

This is precisely the reason why the science of implantation failure is a very technically challenging science and there are a lot of promising and upcoming advancements in this field which are predominantly trying to solve the entire enigma of implantation.

Maybe in one decade or so, studies like proteomics, metabolomics and transcriptomics may change the entire science positively and benefit a lot many patients who are undergoing through this situation.

This is a very important and a key differentiating point as far as the patient is concerned. In a vast majority of the situations, I be a failure typically occurs either due to the age factor of the female partner or it occurs due to a cause which gives rise to a poor quality or recurrent, but poor embryo quality or if there is an inherent Pathology, which is present in the pelvis, for example, endometriosis or multiple fibroids or a very chronically thin idiopathic endometrium or Adenomyosis.

These are the situations where there is IVF, which is persistently failing for the patient where a diagnosis is available right in front of you because there is a Pathology which is available right in front of you, and as soon as the surgical expertise or the necessary technical expertise set in in order to treat that Pathology, the patient experience is a smooth ride ahead.

No one can ask that if the Pathology is well defined, why was that Pathology not treated earlier? The answer to that is again very very simple. It is because maturity of the fertility clinics which have currently mushroomed in the country of India.

Do not have the technical operation theatre which is available to address any of these diseases which cross a particular challenge limit, also in a vast majority of these clinics, the fertility specialist are themselves not trained into performing any type of surgical management and majority of them do approach Endoscopic Surgeon or ghost surgeons from outside to do their surgical work.

If you are a patient, and if you are from India, you will 100% relate to this what I’m trying to tell you., this is because if you have had a fertility failure due to your past treatments, this is something which you would have category.

Koli established in the fertility clinic where you went to wear that type of a standalone Clinic did not have the Hospital backup or the technical backup in order to perform any type of advanced procedure.

All of this only accounts for the failed IVF cycles., the situation of a Recurrent Implantation failure comes truly into the picture when there are more than 2 attempt at embryo transfer of a Top quality Embryo or genetically tested EUPLOID Embryo which has failed, in the absence of all the other visible factors.

This is the thing which absolutely differentiate is a repeated IVF failure from a repeated implantation failure.

This is one of the most important reasons why dedicated recurrent implantation failure, Clinic like ours, which is a referral unit for majority of these patients from across the country also ends up seeing a lot of patients who have had a failed IVF cycle.

There is a lot of technical understanding of the subject of IVF, implantation embryology and the laboratory environment which is required in order to make sure that the patient has an excellent development of the embryo Iyer female partner as well as the sperm parameters which are existed for the male partner.

The most important reasons why a particular treatment in IVF food and as a failure is because some of the situations would not have been interested in this situation typically indicate the pelvic pathology which are present inside the pelvis. For example, fibroids or endometriosis or Adenomyosis, the reason is that many of the routine fertility clinics which have mushroom at various locations across the country.

Do not offer such type of advanced facilities in order to make sure that these diseases in the pelvis can be handled by an expert because most of them are run by fertility specialist, who are not trade in the art of endoscopic surgery, and as a result of which they rely on calling surgeons from outside or ghost surgeons in order to get the surgical work done.

In a lot of clinics which call themselves to be for clinics in India, there is a great lack of having a trade biologist or a trade Embryologist who is required as a mandatory asset in order to make sure that the aspect of embryology for a particular couple is handled thoroughly and with a lot of precision, more than 80% of the fertility clinics which are currently present in India as we speak dependent on freelancing or travelling Embryologist in order to get their entire embryology work done for a particular batch of Patients.

In a situation like this recurrent implantation failure, presence a completely different situation to the Clinic as well as the patient where a dedicated service is required in order to make sure that the entire case gets evaluated with some amount of microscopic precision so that the most probable factor which would have caused a failure to implantation is initially attempted to be diagnosed and then attempted to be sold and in order for this to happen, the Clinic should possess a lot of advanced facilities.

For example, facilities like performing the biopsy of the embryo and the facility in order to culture, the embryo on the Time lapse as well as advanced facilities to handle the entire situation of the Oocyte culture. This is the case where the role of a super specialised recurrent implantation failure.

Clinic comes into the perspective because the Clinic would have incorporated all the necessary facilities which would be required in order to make sure that the diagnosis of the disease for the patient occurs correctly, and then the patient and the family is given a viable solution in order to make sure that they achieve their best fertility potential with a lot of ethics as well as a lot of honesty..

There is a big role of the science of reproductive immunology in a patient who has had multiple implantation failures and in this type of a situation as a patient, I want each and everyone of you to understand the fact that immunology is a very promising science in fertility out of every hundred patients whom we see with implantation failures.

Only 20% of the patients actually are going to be needing any type of immunological support. Majority of the fertility clinics in the country of India because they are not trained to handle. Such type of cases, Dev would go ahead and randomly offer immunological support to the patient, especially in the form of plasma injections or intralipid or give the patient pattern null, lymphocyte immunisation therapy, even if the therapy is not indicated by complicating the cases further rather than simply referring them to a recurrent implantation failure clinic

This is not going to be a very exciting statement because our purpose here is to absolutely not criticise anybody, our purpose is also not to criticise a fellow IVF clinic, however, being an IVF consultant and being into the industry for the last 20 years, almost, I am sure of the fact that majority of the fertility clinics which are doing fertility practice in India, do not have the necessary high end equipment to end up handling each and every case which comes to them, especially patients who have had multiple previous failed, IVF cycles and multiple cycles where there have been implantation failure.

Now this is because majority of the IVF centres are currently set up with a perspective of catering to extremely simple and straightforward cases.

However, because the total number of IVF clinics has gone up drastically, especially in a country like India due to a massive mushrooming of the clinics, what has begun to happen is that even a decent clinic does not get enough patients in order to make sure that they have enough income to cover up for their expenditures, and as a result of which they simply do not wish to let go any case which comes across to them.

This is one of the most important reasons why there is a deficit of proper referral system for referring patients who have had implantation failures due to unsupervised and unscrutinized marketing tactics, which are prevalent, many of the patients and typically getting confused as to whom they should believe and whom they should not, this could be one of the most important reasons.

Why in a routine IVF clinic patients with RIF, do not get the deserving justice., it is also important to not hear that majority of the doctors would be trying their level best in order to make sure that they keep their patients happy.

However, due to the severe corporate policies in India, especially in IVF clinics which are run by corporate chains, they simply do not allow the doctor to make a referral outside their system.

This is one of the ground realities and as a result of which majority of the patient who is an end user end up suffering. This is one of the most important reasons.

Why if you are a patient who has had a previous implantation failure with your IVF cycle or if you have had a failed IVF cycle then in that situation, it is absolutely mandatory that you choose a doctor of expertise rather than choosing a clinic, which is close to your home.

A routine IVF clinic, which is basically a fertility clinic carries out all the fertility procedures which are mentioned in the level two proceedings as far as the fertility act of India is concerned.

Once they have been approved to carry out those particular procedures, usually they will appoint a particular set of doctors in order to make sure that the procedures are carried out smoothly for the best interest of the patient.

However, the technical requirement for handling recurrent implantation failure, cases and failed. IVF cycles are beyond the purview of a routine IVF clinic because they require a heavy investment in the machinery as well as the technical expertise of the subject, which may include investment in machines like time, lapse imaging., spindle assays, pre-implantation, genetic testing, as well as non-invasive chromosomal studies and many other things which are routine clinic may not be interested in investing because they may or may not get the return returns for the same.

A specialised and dedicated recurrent implantation failure. Clinic would also go all out and invest in therapy which are useful for immuno modulation., this also requires a heavy amount of training and technical expertise.

This is why patients who have had multiple IVF cycles failed or who have experienced recurrent implantation failure. Despite having excellent quality embryos in the past, should ideally go ahead and consult a Doctor Who specialise in recurrent implantation failures or with reproductive immunology because that is something which may help the doctor pinpoint the poised of concern.

As far as the surgery over the medical history of the patient is concerned and correct it. It necessarily as and when required so that the patient gets the desired outcome of undergoing any type of future therapy.

Unfortunately, the problem in India is such that if you have had a single IVF cycle failed rather than referring you to a dedicated clinic majority of the routine IVF clinics will make sure that you undergo donor cycle., where your gametes are switched.

A strong amount of caution is to be exercised by the patient prior to agreeing for donor Gametes and the patient strongly encouraged to do their research and meet a Doctor Who specialises in recurrent implantation failures.

The biggest problem with recurrent implantation failure is their mismanagement because most of the patients are managed by routine, IVF routine fertility clinic do not have the necessary expertise.

This leads to a lot of fragmented testing where a stepwise testing is not initiated for the patient and a lot of unindicated tests which are extremely expensive or performed over the patient, and a lot of unnecessary immunological therapy is provided to the patient, certain situations in India are such where this immunological therapy is provided as a part of the type of a particular fertility clinic with a particular immunology consultant, where both the parties do not specialise in the management of implantation failure, this can lead to a lot of unnecessary testing and a lot of wasteful expenditure to the patient, one has to remember that in India, it is the patient who bears the cost for doing their fertility treatment and as a result of which unless sound medical advice is not provided by the time, patient visits, a current implantation failure specialist, most of their finances are completely exhausted.

This is the reason why a country India required a dedicated recurrent implantation failure clinic and we are glad that we set it up., where we have already benefited more than 3000 couples already in their journey, the beauty is, this allows us to do the entire procedure for the patient online without the patient having to physically visit the clinic and this brings in a massive relief to the patient.

The importance of going to a dedicated recurrent implantation failure, clinic like ours is that primarily we look at the technical understanding of the case. Now why is it extremely important for the patient?

Let us try and understand this with a lot more clarity now if you are a patient who has had a fail IVF cycle, then the first thing which we want to study is that why did it particularly fail? Was it an issue as far as the sperm was concerned or was it an issue as far as the egg-quality was concerned or was an issue which was related to the development of the embryo or the laboratory technique in which the embryo was formed.

Step-by-step the clinic will also like to look into what was the grade of the embryo was a top quality embryo or was it not simultaneously?

The clinic will also want to study why the genetic testing for the testing of the embryo was performed or not performed. After all. This analysis has been done.

We would definitely want to evaluate the pelvis for the female partner in order to make sure if there is any abnormality in the pelvis which has been missed out or not.

It is very common for a routine IVF clinic in India to go ahead and do the IVF cycle for the patient, irrespective of the presence of pelvic Pathologies like multiple fibroids or endometriosis or Adenomyosis, and if any of them are actually present in the patient, then they would warrant a form of a surgical correction.

Now, after having evaluated all of this and let assume everything is normal, then the recurrent implantation failure clinic would want to go ahead and evaluate the patient for an endometrial immune profiling, which is basically a biopsy of the endometrium which is taken in order to study the microscopic factors which may help in implantation to the patient.

For example, factors like MUM-1, uNK, IL-18, BCL-6. After a study of the immune markers of the endometrium is carried out, then the clinic would simultaneously also want to proceed for testing for immunological factors, especially the HLA matching and the CDC Cross Matching.

After having a detailed overview of all the factors, usually the stuff which has been missed out in the previous cycles, for example, edition of advanced techniques like Oocyte Spindle Assay, Time Lapse Imaging or a change in the stimulation protocol compared to the stimulation protocol, which was previously used by the patient, might be warranted in order to make sure that the patient does not experience an implantation failure.

No one has to distinctly understand her as a patient that despite doing everything right, these are some of those situation where, the patient may still experience an implantation failure because the success rate in such situation is still in the range of approximately 45%. One has to also understand that out of all the causes of implantation failure, approximately 40 to 60% of the people still do not end up with a diagnosis., however, it is the recurrent implantation failure clinic, which gives the patient almost all the clarity which they need.

In a typical situation in India, majority of the patients who are referred would have at least failed one or two IVF cycles with their own eggs and own sperms and at least 1 to 2 IVF cycles using donor Gametes.

The patient has to typically understand that replacement of the gametes is not considered to be the treatment of choice for recurrent implantation failures because there are so many patients who undergo donor cycles and still end up with a failure.

This is why as the chief consultant for probably India’s largest recurrent implantation failure clinic. We keep on telling patients that the science is still enigma to us until and unless there is more research and commercial testing available for advanced things like transcriptomics, metabolomics, proteomics.

The key benefit of visiting a structured IVF clinic, especially a structured recurrent implantation failure clinic is that as a patient, you will come to know what was the probable reason why your treatment failed, and you will have a reasonable expectation as to what to expect in the future course of your treatment.

This is widely important because in a country like India major majority of the patients who have at least one or two failed IVF cycles would commonly end up doing treatment with donor Gametes, where they end, passing a completely different lineage and inheritance to their children.

I am definitely not trying to tell you here that by visiting a recurrent implantation failure clinic, your case will end up with 100% success rate because a patient has to categorically. Remember that out of every 100 patients whom we see as a part of our recurrent implantation failure clinic around 40-60% of them will still be left without any type of a definitive diagnosis, however, majority of them would know in a very concrete manner as to what best can be done in their situation, and how to avoid any type of unscientific immunological therapies, which are going to be usually prescribed to them out of desperation by a routine IVF clinic in order to make sure, that somehow Patient achieves a conception.

Simultaneously, the patient also has to understand that like how we operate online. Majority of our patients come to us through online appointments only and as a result of which it is important to note that you may not be put at an inconvenience of leaving your city and leaving your work and making a logistical arrangement, just to visit recurrent implantation failure clinic, majority of the care is provided to you at the comfort of your house, and this is one of the reasons why clinics like ours who are dedicated to recurrent implantation failures have seen a lot of success

Majority of the times, the diagnosis for a patient who has an implantation failure is actually very straightforward because if you look at the technical understanding of an IVF cycle,

Tthere could be certain find points regarding the monitoring of a particular cycle or regarding the development of the embryo or regarding the laboratory conditions or regarding the health of the sperm or regarding the overall health of the pelvis in order to correctly diagnose and identify conditions and Pathology, like fibroids or Adenomyosis or endometriosis, and once we correctly latch upon this, we can usually offer a particular diagnosis to the patient end up, correcting it for the patient, and then making sure that the patient undergoes the correct protocol with the correct treatment in order to get the desired outcome

However, there are still certain things which are beyond the scope of the science as the science is still evolving, and the concerned with implantation of the human embryo is still an enigma, which is why, if in case, we typically try the trial and error method.

We may try a lot of unindicated and unnecessary therapies for the patient, and the patient may not experience any benefit of the same, this may also cause the patient to be grossly distended with the treatment, and it can also result into a severe financial loss for the patient as majority of the treatments in a country like India are self financed.

I must confess here that though the science of implantation failure is still a big time, enigma slowly and steadily, we have begun to realise that a chromosomally normal embryo also which is called as a EUPLOID embryo, would have a significant impact on the crosstalk between the embryo and the endometrium, and it will make sure that if the implantation window is correct, the implantation for that particular embryo is going to be successful, however, that is not always the case along with this, there is going to be a absolute right mix of the genes which are responsible for the implantation, as well as the local factors which are present in the endometrium have to be absolutely perfect.

Recurrent implantation failure is typically characterised when we have at least two or more unsuccessful attempt of top quality embryo, preferably them being a genetically tested embryo and that is when we actually begin to scratch our heads as to what would have gone wrong for the patient. So basically as a recurrent implantation failure specialist, I would like to divide this into two or three categories, primarily the first category would be. Is there something in the pelvis or in the uterus which we have missed out?.

the common causes for the same in India being idiopathic, thin endometrium, fibroids, endometriosis, and Adenomyosis, after this has been rolled out, we definitely want to do and roll out the microscopic factors which are responsible for the implantation to occur, and for us to do that a luteal Phase guided hysteroscopy for the patient is extremely important, along with an evaluation of all the microscopic factors.

These microscopic factors predominantly include testing for chronic endometritis like MUM-1, uNK, BCL-6 and when needed IL-18. No, after the implantation factors of the endometrium have been sorted out, and if still, there is no clue, then we would definitely want to shift our Attention towards the immunological aspect of the implantation. Here we would like to do certain blood investigations as well as genetic testing for the couple which would predominantly indicate either an HLA typing along with whole exome sequencing.

After looking into all these factors, we may want to come to a particular conclusion as to what may benefit the couple the most. in these situations we do understand and realise, that out of every hundred couples whom we want to see for having a recurrent implantation failure, a correct diagnosis and answer will only be obtained in approximately 40 to 60% of them.

I want to explicitly mention to the patient that in this situation, you are not supposed to confuse a recurring implantation failure with your failed IVF cycle, which can occur due to a poor embryo quality or a poor equality or a poor sperm quality or a poor laboratory infrastructure.

As a recurrent implantation failure, Clinic for across the country, we to entertain a lot of patients who have had their IVF cycle failed because it is very easy to interact with us online because majority of the patients who we treat for recurring implantation failure as well as for failed, IVF cycles are the ones whom we are seeing and treating online, but there is a key difference between handling a failed IVF cycle and recurrent implantation failure.

However, both of these sciences require a very strong and technical understanding of the entire IVF process, which is currently an expertise which is not available across the country.

At this moment, whether recurrent implantation failure is caused by the embryo or if it is caused by the uterus is not clearly understood by anyone of us because this is still evolving science.

However, we definitely would want to evaluate the uterus much more significantly because the basis of our recurrent implantation failure is to have a top quality embryo or a genetically tested embryo, which is normal as a result of which I want to state explicitly that the role of a well done hysteroscopy is extremely important in the diagnosis of a patient where we are trying to strike and understand the problem which could have happened in the implantation, especially in the uterus.

However, there are many things in the science which are currently not well understood and there is a lot of development which is happening in order to study the molecular biology and the embryo and endometrium cross talk.

This is being studied by variously research laboratories across the world in the form of development of transcriptomics- the study of the genes which are necessary for implantation OR proteomics- the study of proteins, which are responsible from the embryo and endometrium for a successful implantation OR metabolomics- the study of various constituents, which are secreted close to the embryo in order for the patient to achieve a successful implantation, however, all of these are currently sciences which are under investigation, and currently, there is no clinical testing, which is available for one of them in India.

However, it is very important for a patient with recurring implantation failure to go to a laboratory of excellence where a lot of advanced machinery is available because it is these types of machines which may actually play a very important role in solving the hidden problems, which we are otherwise, unable to diagnose, for example.- machines like time, lapse imaging or Spindle Assays, though not extremely beneficial for a routine, patient are widely important to be incorporated for a patient who is having cricket and implantation failures and failed IVF cycles.

This is one of the most important reasons because of a technically upgraded IVF laboratory. We are able to entertain patients who have had implantation failures from across the world.

I truly believe for a fact that till the exact diagnosis for a particular patient is not made a reccurrent implantation failure should be treated as a multi diagnostic and multifactorial condition.

This is because it allows us to give the necessary answer to the patient and their relatives as to what would have probably gone wrong as far as their case is concerned simultaneously.

This also gives us fantastic answers to the patient as to what type of things should a patient not be doing in a country like India. You will often see a patient who has had a singular IVF cycle which has failed probably due to a patient factor would very strongly be recommended to go ahead with a donor programme.

Simultaneously, these are also the patients who would be very very strongly recommended by a fertility clinic to go ahead with immunotherapy maturity of the times because the patients are self sponsored as far as doing their fertility treatment in India is concerned carrying out wasteful procedures like immunotherapy, lymphocyte, immunisation therapy, and others can be an extremely wasteful expenditure for the patient without any stable or proven benefit in clinical science.

This is why though the aetiology may be multifactorial, we desperately want to make sure that we are giving the correct diagnosis to the patient so that then the patient and their family can come to us and take a sound clinical decision which is in the best interest of the reproductive potential rather than simply doing a treatment which may or may not work in their situation.

At this moment, I have categorically explained that the science of recurring implantation failure, especially the science of implantation is something which is unknown to a lot of us despite making our best efforts in the advancements of the implantation sciences.

So till we do not come to know about that, we would really want to have a broad spectrum evaluation of the embryo as well as a broad spectrum evaluation of the uterus as well as look at all the other possible factors in the overall pelvic health which can get mixed out,

for example, fibroids and endometriosis and make sure that a patient who has gone through recurrent implantation failure follows a particular proper well scheme diagnostic protocol, though I completely understand that for every hundred patients who we evaluate only 40 to 60% of the patient will actually come out with a proper diagnostic, but still it gives this patient a wonderful opportunity to understand as to what could have technically gone wrong in their situation and simultaneously, it gives them a return overview as to what all treatments would not work so that the patient does not end up spending money needlessly in their situation.

I want to specifically mention one of the most important causes which is often missed out in evaluation for recurrent implantation failures, especially in a country like India and that is silent endometrial tuberculosis.

This is one of those entities which actually goes and causes severe amount of fibrosis in the endometrium and it can severely affect the implantation.

Usually people come to know about this only when they do a diagnostic hysteroscopy in order to make sure that the uterine factor is perfectly normal.

The most common cause for having a recurrent implantation failure in India is going to be idiopathic. That means we do not exactly know why did it happen.

However, some of the most common known causes are thin endometrium, untreated endometriosis and Adenomyosis, presence of multiple fibroids in the uterus, chronic endometritis and some amount of immunological factors.

The answer to this question is a glaring, yes. An embryo which is seeming to be a top quality embryo also called as a good embryo may also fail to implant.

In fact, we often see in clinical practice that even a genetically tested embryo, which is normal also called as a EUPLOID embryo, may also have a failed implantation, and in that situation, it becomes extremely difficult for the clinician to go ahead and explain to the patient, and her family has to what went wrong.

Because the routine and typical observation is that if everything was right, then why did the patient did not become pregnant?. the answer to that lies in for the research of the implantation science.

Even if the embryo has tested out to be genetically normal., we do not really know if the genes which are necessary for the correct implantation to occur for that particular embryo were regulated at the time of implantation or not.

This is where there is a fast emerging role of the science of TRANSCRIPTOMICS, though this is a science currently under evaluation, a lot of research is being done under clinical research settings, and hopefully, within a decade, we should be having answers for why does a genetically normal embryo also failed to implant despite having the optimal transfer conditions and optimal conditions of the endometrium.

Adding to the science, there are also further factors which may be related to embryo exhaustion which are typically marked out by the science of.

METABOLOMICS, which studies the metabolism of the embryo as well as the factors which are crucially important for implantation like the proteins which has to be secreted by both the embryo and the endometrium which is being actively started by the science of PROTEOMICS.

So once we are able to have more answers to this, we shall be definitely able to answer this question as to why does a good embryo also failed to implant.. of course, friends.

Here we are definitely trying to make sure that the embryo transfer which is a critically important step during the IVF procedure is being carried out by a Doctor Who is well and performing the procedure, preferably under the guidance of the ultrasound.. here we are also trying to make sure that all the embryo transfers which are done for the patient are done under a well prepared endometrial preparation protocol, and we are also, assuming for a given that the technique of freezing and throwing for the embryo was carried out absolutely correctly.

Believe me my dear friends, if you are a clinician, then one of the most difficult questions which are clinician phases and which they have to answer to the patient is why did this particular event happened to them, unless an realistic picture of this entire presentation is not provided to the patient, the patient may end up losing a lot of confidence from the system and may actually not pursue fertility treatments further

PGT-A basically involves taking a biopsy of the embryo, preferably, which is a Blastocyst embryo or a Day five embryo, typically approximately 3 to 5 cells are extracted at the time of the biopsy from the trophectoderm, which is also the outer layer of the embryo, these cells are than cultured and cultivated in order to express out the DNA from there, and then the DNA studied in order to give the genetic report of the embryo, what we predominantly study here is the number of genes and quite a lot of times

We also end up studying the architecture of the genes. As a substitute to PGT-A, a new alternative, which has come up is non-invasive chromosomal study (NICS).

Which basically ends up testing the fluid which is surrounding the embryo where the embryo has let out its genetic material.

However, this requires absolutely strict culture conditions in an IVF laboratory and it is not something which is very easily possible to achieve in majority of the fertility clinics in India, and as a result of which in India, we need to strongly evaluate if the laboratory is optimised for performing non-invasive testing or not.

The procedure to perform the PGTA, also requires a tremendous amount of expertise, because this is one of those situations which can be very technically challenging, and if the procedure goes wrong, it can cause permanent and reversible damage to the embryo, as a result of which it has to be carried out very meticulously and under strict aseptic precautions.

Receive this very very often in a country like India, where a lot of patients would have their embryos cryo- preserved with a particular Clinic, and the patients are the ones who are contacting as per a second opinion because they have had at least one or two embryo transfer failed, now in majority of these situations, we may recommend genetic testing to those frozen embryos, and the biggest doubt which I want to answer her is that it is absolutely fine to unfreeze a particular embryo, carry out the biopsy and refreeze that particular embryo as long as the time limit, which is maintained is less than 54 minutes. This is something which is easily achievable.

If you have a highly trained embryology unit which you are heading, and this is something which will very routinely due at our laboratory., majority of these patients, in a situation like this, are pretty desperate because the Clinic where their memory was frozen may or may not have the optimal facility in order to perform the embryo biopsy or PGT testing. However, if a patient has had one or two IVF cycles one or two embryo transfer, which have failed in them, then genetic testing is very very strongly recommended in those patients.

Embryo morphology is a very important topic because quite a lot of time the morphological grading of the embryo is done manually by the Embryologist, or by the biologist who has been studying the embryo as it has been growing.

In a lot of advanced IVF clinic like our especially because we are dealing with a lot of patients with failed IVF as well as patients with multiple recurrent implantation failures.

We have completely replaced the system of morphological grading of the embryo rather than a manual system to a completely AI based system., this AI based system is actually available with a lot of time lapse incubators, these are special incubators were continuous photographs of the embryo are being taken almost at every 20 minutes and then at the end of it, a beautiful one minute video is presented to the clinician to take their final informed choice.

There are a lot of checkpoints and annotations where the AI actually guides us as to how to select the perfect embryo for the patient. There is also a traditional classification which is available for grading of a particular embryo based on a particular score of the development of the inner cell mass (ICM) as well as the trophectoderm (TE), and in the absence of an AI based algorithm, this standard classification is followed by most of the fertility units.

One has to clearly remember that there could be an embryo which is not perfect as far as the looks of the embryo or the morphology of the embryo is concerned. However, it may turn out to be a chromosome normal embryo, which actually ended up having a successful implantation.

There could also be certain embryos, which look absolutely beautiful for morphologically perfect, and they do not end up having an implantation because genetically they end up having chromosomal abnormalities, this is precisely why, we very strongly encourage genetic testing for all the blastocyst or day 5 embryos which are formed.

Usually, unless and until we do the genetic testing for the embryo, we need to make sure that the embryo which is being selected for implantation is a top quality embryo based on the morphological characteristics and though there are limitations, we can usually tell the patient that a single morphological top quality day 5 embryo would usually have an implantation potential of approximately 45 to 50%. But because the science is currently limited, we cannot cross that threshold of 45 to 50% and give a higher guarantee to the Patient.

Mosaicism of the embryo is basically a genetic abnormality which is identified upon the genetic testing of the embryo which classical divides the embryo into two more further categories, which could be low mosaic and high Mosaic embryos.

If the chromosomal abnormalities are in the range of approximately 30 to 50%, then we categories these embryos as low mosaic embryos. If the chromosomal abnormalities are in the range of between 50 to 70%, then they are classified as high mosaic embryos, as such one has to understand that there is no science which currently tells that we cannot undertake the embryo transfer for a mosaic embryo.

At our clinic, we categorically leave this choice to the patient after giving them a crystal clear instruction as to what can happen after the embryo transfer of a Mosaic embryo., this is because we have seen a situation.

It is also been improved in science that even if the embryo is a Mosaic embryo, it can still undergo something called as an auto correction by the implantation occurs and it can give rise to a successful live birth., however, one has to also explain to the patient that there is a high probability of having an abortion, if the genetic rearrangement does not occur in that particular embryo.

It is the informed choice, which then the patients selects and then the patient decides for themselves. At this moment in India, there are no particular guidelines., to state that the embryo transfer for an embryo which is classified as a Mosaic embryo can, or cannot be performed.

yes, the uterus is primarily also responsible for having an implantation failure, this is because, apart from the endometrium, which is the inner lining of the uterus, the implantation is also heavily independent upon the entire uterus, muscular as well as the size of the uterus and the affecting pathology in the uterus, this is one of the most important reasons why we always tell a patient, the tiffin case we have to diagnose a reccurrent implantation failure.

Primarily we have to make sure that the uterus is absolutely normal. An altered uterus can give rise to an alter endometrium, which can heavily affect the implantation potential of the embryo., simultaneously, the uterus, as well as the muscular of the uterus, have contractions, and these contractions can be very abnormal if the patient is having diseases like endometriosis our fibroids or Adenomyosis, and as a result of which these conditions very strongly and negatively affect the implantation potential of a particular embryo inside the endometrium.

Simultaneously, we also need to understand that in India, there could be a lot of diseases, especially diseases like tuberculosis, which go ahead and affect the endometrium in a silent manner and cause a permanent damage to the endometrium, thereby completely destroying the implantation potential of that particular endometrium.

This is why we are so desperately wanting to study the inner lining of the uterus, and to do a decisive ultrasound on each and every patient to as presented to us with either failed IVF cycle or recurrent implantation failure.

Correction of the uterus from this pathology is one of the most important thing to make sure that the patient does not really have a failed. IVF cycle again., in fact, this is the thing which is majorly avoided by most of the fertility clinics in our country in India because quite a lot of them do not carry the technical expertise to make sure that, they have a well equipped operation theatre to handle surgery, either laparoscopic or robotically with these procedures and as a result of which quite a lot of of them, try to do IVF, either indicated or an indicated in the presence of severe pelvic pathology

, in fact, the patient will be surprised to note that as soon as the pelvic pathology is correct. For example, if the fibroid and the endometriosis is correct for the patient, then more than 60% of them would actually end up conceiving naturally in the next one year of the surgery, without even having to require to go ahead with IVF.

At this moment, the science of endometrial receptivity and the manner in which the implantation markers is so unique and so different that currently we have not been able to completely evaluate the integrity and define nuances of science.

But definitely the receptivity of the endometrium plays a widely important role towards the acceptance of a chromosomally tested embryo which is EUPLOID.

We do have certain test which are available for endometrial receptivity, especially called endometrial receptivity Array (ERA), this test was widely promoted by European group once upon a Time because the statistics and the data were predominantly European, however, over a period of time, we have begun to realise that ERA does not really hold any significant clinical benefit to the patient in vast majority of the situations, unless there is a very specific situation like a severely Obese patient or a patient who is having extreme PCOS only in those situations do now recommend the patient to undergo ERA, for all other practical purposes, we have actually stopped doing this test since 2023, because it did not add any clinical benefit to the patient outcomes for having recurrent implantation failure, apart from adding a cost to the Patient.

Many of the reputed fertility clinic across the world and many of the clinics where there is a government intervention has completely stopped doing this test.. it has to be also noted by the patient that the outcome which comes is only valid for the next subsequent cycle, and it is best done on an HRT preparation for the endometrium.

In India, the approximate cost of ERA, comes to approximately ₹40-₹50,000. And this is a very heavy cost burden for a patient who is self financing, the IVF cycle like majority of the IVF patients of India, I strongly encourage a lot of caution and further detailed discussion regarding the technical understanding of this test with your fertility consultant.

If you’re a patient who is considering to do this test, just because you have certain frozen embryos, which are lying down with a particular Clinic., much more viable option for you as a patient would be to consider to get those genetically tested.

If in case you have not done them already. I also encourage a lot of these patients who wish to consider this test to get a strong consultation and opinion with a second reference done from a reproductive immunologist or fertility specialist.

Typically, from what the studies have shown as far as the natural cycle embryo transfers are concerned, the window of implantation is usually for 24 hours, however, inside that what exactly is the window of implantation is currently unknown.

This window of implantation would drop down to approximately 6 to 8 hours for a patient who is undergoing an embryo transfer on an HRT protocol., the window of implantation can get displaced, especially in situations where the uterus is experiencing, any type of pelvic pathology, typically endometriosis, and very, very commonly in chronic inflammation of the uterus as well as acute inflammation in the pelvis.

This displaced window of implantation can also occur if the patient is having some hormonal deficiency or if the patient is extremely obese., as a result of which, in all these situations, if you are a consultant who is dealing with a patient who is having a recurrent implantation failure, it is very important that the patient undergoes hysteroscopy in order to rule out any type of chronic endometrial pathology.

Majority of the times, the infection and inflammation inside the endometrial lining can be corrected by administration of antibiotics for approximately 21 days to the patient, followed by a course of probiotics which can be required to be taken over early for the next three months., it is this which completely restored the endometrial microbiome, and usually once the cavity is restored back to normal, the window of implantation also comes back to normal.

When a chromosome tested normal embryo is inserted inside the correct window of implantation for every single embryo, which is implanted, the clinical pregnancy rate is approximately 45 to 50%., Which itself is massive and as a result of which correct calculation of the drugs in order to match the window of implantation for every patient who is undergoing an embryo transfer in IVF is widely important for the success of the cycle.

The endometrium is one of those topics which continues to impress each and every fertility practitioner across the world and simultaneously also virtually kills their head because there is no definitive answer to the management of thin endometrium, especially because in our vast majority of the cases it is going to be an idiopathic thin endometrium., nothing endometrium is typically when the thickness of the endometrium refuses to go above 5 mm despite the best possible efforts which are taken by the clinical team by administration of drugs or by performing therapy inside the endometrium typically in India, which is called as the PRP therapy or by performing various types of hysteroscopic surgeries

The biggest part of this frustrating problem which occurs is that despite massive efforts by the scientific community, there is hardly any breakthrough which allows the endometrium to consistently grow beyond 5 mm in a vast majority of the situation due to which ultimately a lot of patients have to actually give up on this and consider options which are alternative options like surrogacy.

We also tried to perform autologous burn marrow stem cell therapy inside the endometrium, but we have seen over our worst experience that it benefits the patients only in approximately 55 to 60% of the situations. There are some set of women in whom the endometrium persistently and chronically stays thin without no identifiable cause and actually it is these women who benefit the most because in these women, it is very easy for them to achieve an implantation despite having a persistent thin endometrium. In an Indian situation, a persistent thing, endometrium predominantly occurs due to a history of silent endometrial tuberculosis.

This is the most common cause for having this thin endometrium problem in India. The other common cause in India is having a surgical trauma due to the procedure of dilatation and currettage, which occurs to cause adhesions inside the endometrial cavity, intrauterine adhesions also called as Asherman syndrome, is a condition which is extremely difficult to be treated and despite repeated surgeries carried out in the endometrial cavity, the usual success rate of having an implantation following these surgeries is going to be less than 20%. On top of it, many of the young girls undergo repeated hysteroscopic surgeries, in Asherman syndrome, which gives rise to even more surgical trauma.

There is a lot of literature which is available which consistently questions the roles of tablets like Sildenafil, as well as high doses of estradiol as well as intrauterine injections of GCSF, and all the therapist which are widely available for the treatment of thin endometrium should then be used with a strong amount of caution.

The patient and their family and their relative should be given a realistic situation as to what to expect in this situation., though we see that an honest counselling usually encourages the patient to change the Clinic and go to the doctor, who is promising the moon to them, ultimately it is seen that the patients come back to referral units like us who specialise in handling recurrent implantation failures because they know that what we told to them at the primary level was the absolute truth.

There are women who have thin endometrium and they also undergo repeated abortions as well as having preterm deliveries., also it is very important to note that for a patient who is having persistent thin endometrium, one must try to rule out causes, which affect the uterus musculature like Adenomyosis, which can cause a severe distortion of the endometrial-myometrial Junction, and again this condition is extremely difficult to treat in a clinical situation.

This is the reason why having persistent and idiopathic thin endometrium, is considered to be one of the toughest aspects to treat in a fertility consultants, professional journey

One of the most common and irritating conditions to treat in the aspect of reconnect. Implantation failure is a patient who is having chronic endometritis.

Now this is predominantly because a patient with chronic endometritis does not usually present with any typical symptoms and as a result of which it may become extremely difficult to pick up unless you perform a hysteroscopy or you do a hysteroscopic guided biopsy in order to rule out the presence of microscopic chronic endometritis.

Typically, the findings will demonstrate themselves as strawberry coloured patches present along the endometrium., however, histopathological and microbiological diagnosis of the same is extremely important for the patient in order for us to initiate them on any type of antibiotics, typically try to test the sample for the presence of concentration of cells, which are isolated using MUM-1, this is a highly specific marker for plasma cell, and it helps us identify the diagnosis of chronic endometritis, the patient who usually have a chronic endometritis are subjected to a antibiotic for approximately 21 days which is then followed by an oral probiotic for approximately 90 days.

Repeat biopsy may not be warranted in a situation like this after the antibiotic protocol has been completed for the patient., usually once the antibiotic is completed, the patient may experience a significant benefit as far as the implantation is concerned as well as in the development of the endometrium is concerned.

In certain situation and early diagnosis to chronic endometritis can be made, especially when the endometrium is staying persistently thin or if it is becoming hazy very early upon exposure of the oestrogen., however, I must tell you that once it is correctly diagnosed, then the treatment is absolutely smooth and simple and more than 90% of the patients in whom the diagnosis for chronic endometritis has been established.

They experience a significant benefit as far as their fertility and their implantation failure is concerned, making it one of the most satisfying treatments. Once upon a Time, people used to do CD138., which has now completely been replaced by MUM-1, as MUM-1, is way more specific for the demonstration of plasma cells in the endometrium.

Along with this, one can always get the endometrium also tested for the presence of uNK cells, as they play a vital important role in the coordination between the embryo and the endometrium at the time of successful implantation.

The uNK have to be present in the endometrium matter a specific concentration when the embryo is set for implantation because they play a vital role in the development of spiral arterial, which allow for a successful continuation of the pregnancy for the patient.

Adenomyosis and endometriosis, are very important causes for having recurrent implantation failure in India because predominantly in India, there very few units of excellence for endometriosis, and as a result of which what typically happens is that the fertility specialist do not want to refer the patient to a specialised the unit because of their insecurity of holding onto the Patient, quite a lot of the fertility specialist would want to initially start the IVF cycle, irrespective of the presence of Deep endometriosis as well as the presence of Adenomyosis.

Now this is something which is extremely dirty because that cycle never sees it end, as there can be a lot of problems as far as doing the egg pick up or doing the embryo transfer is concerned in a patient who is having grade 4 endometriosis and Adenomyosis.

A patient should hear categorically note that as a referral unit for advanced endometriosis for across the country. If you get a successful surgery done by an endometriosis specialist like us, then the possibility of the disease coming back to you is less than 5% and simultaneously more than 60% of the patient and up conceiving spontaneously or naturally, within the first one year of the surgery.

However, treating the ADENOMYOSIS, either with the help of flap surgery, or with the help of microwave ablation, or a combination of both when it is required to treat the lateral wall Adenomyosis, is considered to be extremely important, and when it is that correctly, it genuinely enhances the success rate for implantation for the patient.

We typically request the patient to go and get their surgery done from a specialist and wait for at least 4 to 6 months after the surgery has been performed so that the embryo transfer can be carried out with a lot of success.

We have typically noticed that after a successful surgery has been done the implantation rates go up to as much as 20% in this situation., also lot of patients are very, very fearful that having this surgery for endometriosis is going to weaken their uterus, this is absolutely incorrect information, and that is the reason it is important that you go to a super specialist for getting your surgery done.

From the average which I know on an average, we do more than 2000 surgeries for patients with endometriosis and Adenomyosis, in a single year across India, and that is the reason why I have so much confidence and stating what I have stated above

Out of all the procedures which are considered to be extremely important in the clinical application and diagnosis of recurrent implantation failure, probably hysteroscopic diagnosis, what stand out as one of the most important things which we need to carry out, as simple as it may seem a well done, hysteroscopy, something so widely important for the Clinic as well as for the patient because it gives both of us adequate diagnosis in order to make sure which test do we need to perform in the future as far as the patient treatment is concerned.

Hysteroscopy is a procedure which is typically done by us in an office setting. That means the patient typically does not require any form of anaesthesia. It is a very quick procedure and the patient usually goes home within approximately two hours after getting the procedure done.

This is also considered to be a procedure which is easily available at multiple locations with our country of India and as a result of which this can be easily done by the patient in their hometown.

We usually encourage the patient and the fertility practitioners to give the video of this surgery to the patient so that the patient can keep it with them as record and for future use one can easily refer that video, so that based on that further procedure, if at all they are indicated can be carried out for the patient.

This is a great topic because this is a topic which is under a lot of research. Definitely, the vagina microbiome has been extremely well established.

However, the establishment of endometrial microbiome is extremely difficult because the concentration of the microbes which are present inside the endometrium are typically very low, which makes them very unsuitable for taking a biopsy and then allowing further culture inside an incubator for us to decipher, which exactly are the microbes which are required to sustain the endometrium very nicely, however, there are certain things which are indispensable as a part of this knowledge and which we want to share here is that administration of oral probiotics is considered to be way better than administration of vagina probiotics as far as replenishment of the endometrial microbiome is concerned,

this is predominantly because there is a dominant gut pelvic axis, which exists in the human body, which has been improved out and need doubt, and as a result of which replenishment of the gut bacteria is way more important as compared to the replenishment of the vagina bacteria, through trans migration from the anus, quite a lot of of the gut bacteria, any which ways undergoes seeding inside the vagina, the endometrial microbio, typically distorted, and disturbed in cases of vagina infection, as well as in cases of chronic endometritis, and they are also disturbed in cases where there is an infection of the cervix, this is one of the key reasons why examination of the cervix forms a primary part in the consultation and examination visit for a patient who scheduled to undergo for deleted treatment or a patient who has undergone fertility treatment but has experienced current implantation failure, this is actually considered to be a very simple thing as far as examination in Gynaecologist concerned,

but it is often missed out, treatment of the vagina infections, as well as treatment of the unhealthy cervix, definitely go long way in the replenishment of the endometrial microbiome, and this should be a very important.

Take home point, if you are a patient., because quite a lot of time, there are many many patients who want to get tested for an endometrial microbiome by undergoing an expensive biopsy, and careful planning and decision making should be done by the patient before spending their resources over such type of investigations, which may not prove to have any type of clinical benefit to the patient.

The typical immune causes which can give rise to a recurrent implantation. Failure are actually best studied after the pelvis is established on a confirmatory ultrasound to be absolutely normal.

A variety of immune testing is available in order to test the couple for having any immune mismatch and it is absolutely certain and clearly understood that there are certain biological conditions especially antiphospholipid, anti nuclear antibodies, anti cardiolipin antibodies, HLA concordance and absence of blocking antibodies, all of whom may some responsible for spoiling the micro environment, which is present in the endometrium and thereby affecting the implantation of a particular embryo.

Now it is pretty certain that majority of them can be easily treated by giving very basic immune modulation to the patient, either in the form of tablets of aspirin or along with injections of low, molecular weight heparin, as and when it is indicated.

Certain situations may also involve the administration of drugs like prednisone or steroids along with HCQ-s, and this is usually more than sufficient to almost take care of all the types of immune causes, there are certain immune causes which are going to be extremely resistant to treat by the basic treatment and in that situation, we may warrant to use intra lipids as injections in order to make sure that the endometrial response is taken care of, and in certain highly special situations, we may consider to use reserve drugs like IVIG, Tacrolimus and Thymosin Alpha.

In very rare situations, basically in less than 10% of the cases where there is a persistent CDC cross match, we may want to use paternal lymphocyte immunisation therapy also called as LIT to be administered to the patient. However, it has to be noted with a great amount of caution that the overall benefit which LIT therapy offers to the patient is not more than 10% as far as the clinical pregnancy rates are concerned as a result of which not many people use LIT therapy very aggressively in clinical practice.

Unfortunately, in a country like India immune therapy are grossly commercialised and as a result of which their administered to the patient who have had even a single IVF failure without any evaluation or without any justification and we strongly urge the patient to do their research before they actually give the consent for administration of any of these therapies

What matters in a patient who is undergoing an implantation failure? Is the presence of uNK cells in the endometrium at the time of implantation.

NK cells otherwise called as natural killer cells, are of two main types- the peripheral NK cells and the uterine NK cells, we are predominantly concerned about the uterine NK cells only because they are predominantly responsible for the spiral arterial development as well as for implantation of the embryo, now this is very important for us to understand because this involves a very complex molecular play between the embryo and the uterine natural killer cell where, a particular type of HLA-C is expressed by the embryo which then interact with the KIR receptors,

which are present on the uterine NK cells, this ultimately decide if that particular embryo will get implant or if it will not get implanted, fortunately, the activity of the uterine and K cells can easily be tested by performing an endometrial biopsy between day 17 and 22 of the menstrual cycle and the concentration of the uterine NK cell should be between 10 to 30%, in order to be good enough for implantation of the embryo.

There are certain types where the presence of uterine NK cell is grossly reduced, and this typically occurs in patients who are immunocompromised?, As a result of which it severely affects the implantation of these patients., the immunity here can be boosted by addition of immuno modulators, which allow for further establishment and development of the uterine natural killer cells in the endometrium.

The uterine natural killer cells are also completely dependent upon hormones like oestrogen and progesterone for their development and growth. There are also certain situations where the presence of uterine NK cells is overly active., this typically occurs in situations where their chronic endometritis has set an inside the endometrium setting up, exaggerated inflammatory response.

This type of situation is best handle by administration of antibiotics to the patient to whenever it is indicated followed by a long course of probiotics in order to make sure that the uterine NK activity comes back to normal. This delicate balance between the uterine natural killer cells and the embryo is really widely important in the study of implantation

We typically try to perform the immune testing for the patient. After all the other causes for implantation failure have been ruled out for that particular case.,

the typical test which we perform are testing for all the anti nuclear anti antibody, antiphospholipid antibodies, anti cardio antibodies, HLA typing of the couple and the CDC cross match.

These are only to be performed after there is a confirmatory evidence on ultrasound that the pelvis is absolutely normal.

We do not perform a lot of peripheral blood investigations because we are predominantly reliant on the uterine micro environment for us to take immune therapy based decisions for a particular patient and as a result of which we may also go ahead and perform endometrial immune profiling, which involves taking a biopsy from the endometrium, preferably between the day 22 of the menstrual cycle in order to look at the microscopic factors which are responsible for implantation along with that concentration, which is present in the endometrium at that particular moment.

Though there are a lot of other complex testing which are available beyond this, we do not recommend any other testing for any other patient.

Recurrent implantation failure due to a known thrombophilia is very rare because, usually a thrombophilia, gets diagnosed pretty soon in life, and most of the patients would have had an event of thrombosis or clotting, which would have put them on anticoagulant medication long before they even think of trying the IVF.

This patient should be managed very very meticulously in combination with haematologist and only if there is appropriate permission which is available from, then should the patient be considered to go ahead and do any type of fertility treatments, otherwise, as such fertility treatments are considered to be pretty safe in these women provided they are maintained on anticoagulation, even the thrombolytic or therapeutic dosages of anticoagulant, especially of low, molecular weight heparin, does not majorly add to any added risk of bleeding during the pregnancy as long as it is monitored very nicely, the combination as to how much anticoagulation is to be provided to the patient is to be worked up with enclose monitoring with a cardiologist even prior to doing the embryo transfer because that is critically important to make sure that the implantation of the embryo is going to occur correctly.

When this is not monitored correctly, it can give rise to recurrent implantation failure and as a result of which we have a very good cardiology team in our unit to look into these types of patients and trust me once a cardiologist calibrate the dose for the particular patient, then the usually end up having an excellent outcome as far as the pregnancy is concerned because managing a recurrent implantation failure with thrombophilia is extremely simple as long as the Dose correction is correctly established for that particular patient.

I am not here discussing all the specific variant of the thrombophilia because that is beyond the scope of discussion in this chapter.

One has to remember that usage of blood thinner or low, molecular weight heparin, he is now no longer considered to benefit all the patients that means the empirical usage of these drugs need to be very strongly avoided because this adds to the unnecessary burden of injection in the patient.

In some type of situation, these drugs are administered simply to jack up the pharmacy sales, this is a practice which is carried out by a lot of commercial for profit fertility establishment across the country, and some of them, go to the extent that they forced the patient to buy the drugs from their own pharmacy only.

Such type of practises unfortunately, go unchecked in a country like India where the regulatory backup is simply not available to make sure that the treatment is performed on the patient in an ethical manner.

. low molecular weight heparin is justifiable in a patient who has had multiple IVF failed cycles is age more than 38 has had multiple abortions in the past, has added a history of pre-eclampsia in the past, has had a history of previous preterm births, or is having elevated uterine artery PI during the early pregnancy scan, or is having any type of a thrombophilia, where in the haematologist has recommended the continuation of low molecular weight heparin during the pregnancy.

For a prophylactic use, the low molecular weight, heparin is typically administered to the patient in subcutaneous manner in the dose of either 40 or 60 mg., this dose is best decided in combination with a cardiologist.

I think this question answer is what typically happens in India without any type of evaluation. Majority of the patients are subjected to immune therapy. One of the most useless and heavily abused.

Therapist in India is paternal lymphocyte immunisation therapy (PLIT) which is done at even a single abortion or a single IVF failure without a proper evaluation by many commercial establishment across the country, it is very important to understand that the basis of reproductive immunology is to ensure that the embryo is absolutely normal.

That means it is preferably genetically tested as well and the pelvis is absolutely clean. Only then can we resort to using any form of immunotherapies in order to make sure that the patient does not have future recurrent implantation failures.

Unfortunately, in India, major majority of these therapy are given to the patients without their knowledge, despite having pelvic pathology like endometriosis and fibroids and Adenomyosis, this is why many patients believe that despite doing their immune therapy, their entire treatment has failed, whereas actually in their situation that immune therapy was not even recommended, simultaneously in India.

A lot of patients are injected with unnecessary injections of intralipids without even doing any type of testing for the patient, this is the reason via a lot of patients ultimately lose hope from the treatment and end up getting frustrated.

We sincerely encourage each and every of the patient who has had a failed IVF cycle or who has gone through a recurrent implantation failure to strongly go ahead and consult reproductive immunologist across the country because majority of the reproductive immunology colleagues like ourselves consult the patients online and as a result of which the patient can access the care from their own city without having any type of logistical issues and I think the patient is strongly encouraged to do this consultation before they say yes to any type of immune modulations therapy.

Certain therapies like Tacrolimus, IVIG, Thymosin Alpha, all of them are to be used extremely sparingly, because all of them have extremely specific set of indications and are to be used only as reserve therapies.

Though we have device the specific protocol for the usage of thymosin Alpha, at this moment, the clinical utility of this drug and the necessary positive effects still remain questionable, and as a result of which we want to use it only as a reserve drug that in Patient, who have had multiple abortions or multiple biochemical pregnancy after embryo transfer.

In some of the situations we make sure that the immune protocol which we are recommend is also gets verified by the nephrologist because some of these drugs are very sensitive to the renal tissue.

Most of the times when we try to study the causes for recurrent implantation failure, we only end up studying the female partner that is one of the biggest mistakes. People do in their implantation failure.

Practice one has to categorically understand that embryo formation is a combination between the sperm factor and the egg factor as a result of which equal and undivided attention has to be provided to the male partner as well.

What otherwise, look to be a normal semen analysis report when evaluated carefully, especially for factors like abnormal morphology of the sperm, abnormal liquefaction of the sperm, and then advanced sperm testing, which allows for testing of DNA fragmentation index is widely important in order to make sure that sperm integrity is good and correct before having a repeated implantation failure,

often One should realise that the age of the male partner is also very important in order to decide the quality of the embryo, the overall semen parameters may look good, but the DNA of the sperm can deteriorated typically in males after the age of 45 and as a result of which this has to be carefully to the patient who is experiencing implantation failure due to this factor.

Administration of the necessary lifestyle modifications as well as anti-oxidation therapy can be of benefit as when it is indicated.

DNA fragmentation index of the sperm is one of the critical factors which decides the quality of the embryo inherently, thereby either increasing the risk or reducing the risk of developing a recurrent implantation failure with the patient is undergoing and IVF cycle.

The DNA fragmentation index is a very commonly done semen analysis parameter, which is a part of the advanced semen analysis.

A lot of the good fertility Clinic across the country, have the facility to perform this test, which takes approximately four hours for the outcomes to be produced. This can be done irrespective of the male partner, having any form of abstinence or not.

A typical DNA fragmentation index of less than 15% is considered to be good., any value of DFI more than 25% warrant further intervention and treatment. The treatment is usually given by modification of lifestyle parameters for a period of approximately three months where invisible benefits can be seen along the DFI.

However, there does exist certain situations where the DFI does not go down despite giving the particular treatment in that situation.

If the patient has experienced implantation failure in the past, despite having good quality embryos, then it is prudent to consider and council, the male partner to undergo a testicular extraction of the sperm in order to make sure that the sperm which is available has the least amount of DNA fragmentation to give the best amount of outcomes to the patient.

Apart from the gross semen parameters as well as the sperm DNA fragmentation, which be mentioned about, the sperm which is chosen for performing the ICSI is widely important because, the entire embryo development is also dependent upon the genomic activation where in the sperm plays a vital role,

as a result of which if the inherent quality of the sperm sample is poor in form of either motility or morphology, then that can play a very important role in the development of the embryo and this is best studied on Time lapse imaging of the incubator, where the embryo is culture, we often see that in severely compromised male factor in fertility, there could be a large amount of fragmentation which can develop inside the embryo.

Where is the male factor is typically responsible and correction of this is vitally important before making sure that the patient does not have repeated failed, IVF cycles,

it is important that we understand that the quality of sperm is very very important in undergoing the Genomic shift which occurs in the embryo and this shift is widely important for the formation of a good quality blastocyst And Only once a good quality blastocyst has been formed, can it have a successful implantation.

As a result of this, the inherent quality of the sperm is extremely important for a patient to achieve a good implantation and then carry on the pregnancy smoothly and as a result of this, it is very important for us to know that a patient who is undergoing any type of fertility treatment also undergoes a complete evaluation of the male factor.

The only advanced sperm testing, which is recommended and suggested in all the patients who have undergo a recurring implantation failure is to make sure that the patient undergoes sperm DNA fragmentation testing here. The patient should clearly understand that there are certain advanced techniques which are available for the diagnosis and future therapy in the form of micro fluid chip.,

this is an excellent addition to the armamentarium of the fertility specialist in the IVF laboratory because it allows for excellent, separation of the good quality sperms, which are available from the sperm sample with the sperms having the least DNA fragmentation index.

Though this is not a subject which has been thoroughly understood and evaluated, it is absolutely clear that paternal epigenetic is a very important role in the implantation failure.

However, there is no crystal clear testing which is available for the diagnostic of which type of paternal epigenetic may play a disturbing role in causing embryo development. However, one thing is for absolutely certain and clear that the age of the male partner is very important and males who are age more than 45 years despite having excellent overall semen analysis may have a detrimental sperm DNA quality giving rise to excellent embryo,

which may have a consistent implantation failure. There needs to be more research in this subject of Paternal Epigenetics and I am confident that in the next decade or so there would be a lot of studies which would be available in order for us to pinpoint the exact causes which may help us identify and probably also modify the paternal epigenetics.

Definitely in a patient who is experiencing insulin resistance and that is going to happen, predominantly because the patient may have either a severe PCOS either thin or thick, or the patient may be having diabetes inherent, in both the situations, one has to categorically, you understand that there is a high probability of having a recurrent implantation failure, unless and until the insulin resistance is correctly controlled.

There is approving scientific reason for this and that is that there is going to be an alteration in the window of implantation. A patient is having insulin resistance and despite having excellent quality of embryos which are formed, the patient may end up having an implantation failure in a situation like this.,

as a result of this, if in case you are experiencing any type of insulin resistance, it is important that along with your fertility specialist, you stay in close contact with your endocrinologist as well and make sure that you are undergoing correct therapy, especially in the form of oral therapy, and sometimes you may have to switch to insulin in order to make sure that your resistance is well and care of

PCOS is one of the most Rampant causes for having infertility in India, and the biggest problem with PCOS is that, especially in women who are very obese, it may cause a severely altered window of implantation simultaneously.

PCOS is also responsible for extremely poor egg quality., as a result of which there can be many eggs which are obtained during the stimulation with very limited blastocyst embryos which are developed and these blastocyst embryos, which are then developed me or may not have the optimal quality, as a result of which making the necessary correction with whatever is required in order to treat the PCOS is very important for the patient.

One also has to understand that in a patient with PCOS, the stimulation protocol for IVF, especially if there is been a previous failed, IVF cycle or previous implantation failure can be started on almost any day of the menstrual cycle as majority of the follicles would be heavily suppressed due to a micro environment, which is present in the ovary, which gives rise to an excessive androgen component inside.

But the discussion of the entire PCOS is beyond the preview of this, and as a result of which I will be restricting only to giving the impact of PCOS on recurrent implantation failure.

There will be a lot of Obese PCOS women who will be very strongly recommended to undergo weight loss therapy and at least to lose approximately 10 to 15% of their body weight in order to make sure that the window of implantation comes back to normal.

There is a clear link between thyroid dysfunction, especially in the presence of anti TPO antibodies and recurrent implantation failure, in all of these situations, one has to be absolutely clear about the fact that thyroid supplementation is mandatory for a patient who is having an anti TPO titre of more than 1:40,

because almost all of these patients would have some amount of inherent thyroid dysfunction, and as a result of which, making sure, that these patients have their TSH values in the optimum range prior to doing the embryo transfer is vital to make sure that the patient does not experience any form of recurrent implantation failure. This is simply one of the most easily correctable things which we see in our practice.

It is very important that every fertility practitioner as well as every patient understands that obesity is a single most important detrimental factor to achieve a good implantation in any Lady.

If the BMI of the patient has exceeded more than 30, then definitely the role of a bariatric surgeon as well as an endocrinologist along with a fertility specialist is very important either to administer the drugs which are required as anti obesity drugs to the patient or to make sure that the patient is a candidate for undergoing bariatric surgery because long-term effect of obesity and especially the altered hormones which are present in the body due to obesity, have a massive damage to the window of implantation of the patient due to which patient can experience consistent implantation failures.

Never drugs, which are available in the market like ozempic and Mounjaro, have revolutionise the treatment of weight loss for a patient and they are to be given on a maintenance basis to the patient for a prolonged period of time. However, one has to understand that before doing the embryo transfer, we try to stop these drugs, at least for three months and only then undergo the embryo transfer.

After the bariatric surgery is performed, the patient has to wait at least for one year prior to undergoing the embryo transfer.

A weight loss of approximately 10 to 15% of the original body weight or reversal of BMI into a category of less than 26 is considered to be very important in order to achieve a successful implantation in all these patients who are fighting with severe obesity.

It is also important to not hear that the weight of the male partner is also critically important in achieving a good implantation. Obese males are known to have extremely poor sperm quality and quite a lot of them also have as per which mayor may not get reversed, despite doing any type of weight loss therapy, or bariatric surgery because of the prolonged chronic exposure of the altered estrogen from the peripheral conversion of the fat which goes and causes severe irreversible damage to the development of the sperms in the seminiferous tubules.

However, obesity units early forms is one of the most easily treatable lifestyle changes which is recommended to the patient so that the patient can undergo a very safe fertility treatment.

To be very honest with everybody, we do not calculate the value of serum progesterone as a routine investigation in patient in whom the IVF cycle is being planned, even at the time of embryo transfer, nor do we consider to do it for documentation purposes.

However, it is important to understand if that if the progesterone value is between 10 and 80, it is considered to be normal in an embryo transfer window. During the situation of a natural cycle, the progesterone values should ideally be more than 25 at the time of implantation..

however, there is no concrete documented study, which says that if the value of the progesterone is less than it can have a severe impact on the implantation for the patient. There is also something called as a luteal Phase defect, which may be one of the causes for having recurrent abortions in a patient who has conceived naturally,

however, it can be very easily corrected by administration of external progesterone in the Luteal phase of the menstrual cycle, in an IVF cycle, there is almost always addition of external progesterone on which is provided to the patient and as a result of which the possibility of having a reduced progesterone on simply does not arise

Vitamin D supplementation is considered to be almost standardised in every patient who is undergoing and embryo transfer because it has been proved without doubt that extremely low and chronically, low values of vitamin D are going to negatively affect the implantation of an embryo by affecting the response of the endometrium to accepting the embryo inside the system, and as a result of which almost all for fertility clinics across the World,

give vitamin D supplementation as an empirical therapy to almost every patient without causing any additional burden of testing for the value of vitamin D in the patient.

In this situation, I would like to advise and write down that there is main or may not be any particular cure as far as recurrent implantation failure is concerned. However, the medical team can take its maximum efforts in order to make sure that the next implantation failure is typically avoided as I have mentioned even before out of every 100 patients whom

we see approximately 40 to 60% of them will end up reaching a diagnosis. The remaining 40% who do not reach a diagnosis are still going to go by the virtue of the experience of the treating physician, and as a result of which patient who have previously experienced to failed IVF cycle or have experience to recurrent implantation failure, are strongly recommended and suggested to always go to a specialist or a dedicated recurrent implantation failure.

Clinic, where all these problems can be categorically discussed, and a diagnostic protocol based evaluation can be done in order to treat the patient rather than simply giving them some random treatments in order to take care of their problem.

In most majority of the situations, the diagnosis is going to be established such that the diagnosis is correct. For example correction of the fibroid and the endometriosis is extremely easy by sending the patient to a dedicated team to do the surgery for them as soon as it is done, the problem is taken care of and the patient does not experience an implantation failure after that.

A similar situation also arises when the patient has had some form of an immunological disease which can easily be managed and combination by the fertility specialist and the rheumatologist, and in both the situation, the patient can be very easily treated by giving the corrective medication or the drug whatever maybe mandatory and necessary in order retreat.

The problem for the patient so that the patient does not then experience any form of implantation failure. The actual problem comes in patients who do not reach a diagnosis and there could be certain empirical therapy, which may be used as well as certain reserve therapies, which can be used by the patient in order to ensure that they reduce their chances for further failures.

These therapist typically include protocols, which are a combination of thymosin alpha and Tacrolimus, to be given in a very appropriate dose, and and when it is deemed necessary. In our unit, we always seek advice of the nephrologist before we administer any of these drugs to the patient because they are much more well versed with the immunosuppressants protocols.

It is important to understand that just changing the IVF protocol probably helps a treat a patient who has had a failed IVF cycle. It does not really help us treat a patient who has undergo recurrent implantation failure because in quite a lot of these patients forming a good quality embryo is actually happening.

In fact quite a lot of these patients would have also formed a genetically tested normal embryo before they are referred to a Recurrent implantation failure, Clinic, and as a result of which, unless there is a very specific requirement, we do not end up changing the IVF protocol for most of these patients.

Doing a freeze, all therapy is almost absolutely mandatory. All patients who are undergoing treatment for recurrent implantation failure because majority of these patients would require genetic testing of the embryo to happen and if in case we want a genetic testing of the embryo to happen, then we have to keep in mind that., freeze all therapy for all the embryos is absolutely mandatory.

now, as a specialist, who runs a recurrent implantation failure, Clinic, one thing is absolutely clear in my mind, for this particular procedure, patients undergo a lot of emotional trauma, as they are already completely exhausted, mentally, physically and emotionally.

By the time they are undergoing the entire procedure.. this really requires a lot of support, especially in the form of the counselling, which is provided to the patient and a very realistic expectation as to what they should be expecting in their case situation rather than simply giving them some type of fun promises.

I think one of the reasons why so many patients really appreciate us is because no matter how bad the situation is, we are pretty honest to the patient and in the long-term the patient realises and understands that that medical team was extremely considerate to them.

Sometimes I feel in a country like India support from the family is also very important in these types of situations to be very honest with you.Now

Really, I mean, I will always pray to God that the patient is mentally, emotionally, physically and financially strong to cope up with so much problem, which happens when a couple is undergoing recurrent implantation failure, now, unfortunately, most of the couples who are undergoing the treatment with us ultimately and becoming our friends and as a result of which we understand how strong they are, but I very strongly believe that there has to be a dedicated support group which has to be initiated and started by some of our patients.

Quite a lot of whom we have really encouraged in order to go ahead and do so so that they can give the necessary guidance to all the patients who are undergoing these types of treatments and can probably end up benefiting from their guidance so that they can take some concrete decisions as and when they are required, however, of course the final owner for taking all these medical decisions is to be based upon the sound clinical judgement of the medical team only

Needless to say there is a lot of anxiety as well as depression, which is associated when a patient undergo treatments for recurrent implantation failure because because of the best efforts of the medical team as well as the best efforts which are done by the patient, nature has a final role to play and as a result of which quite a lot of times it can happen that the patient doesn’t really end up achieving the type of outcomes which they have dreamt of achieving and as a result of which there is a lot of depression and anxiety, which is associated with these forms of treatments now fortunate the best way to correct.

All of this is to make sure that we give correct and honest counselling to the patient. Whenever something like this happens, what happens is that initially the patient may feel a little bad as far as the honesty which is reflected by the counselling team, but in the long run, the patient realises that that was in the best interest of the patient quite a lot of times in a situation in India.

It is also better to provide the patient written documentation for the same, so that the patient can go and check the written documentation whenever they are in doubt, and this really helps them reduce the anxiety which is associated with the treatment otherwise.

So at our unit, we have a counsellor who gives the patient, psychological counselling and support as and when it is required and quite a lot of.

Our team members are also trained in psychological counselling because a lot of patient who come to us have gone through a lot of stress and emotional trauma before they actually build up the courage to start the treatment, one time more in a hope that this time around the treatment will give them a positive outcome. Of course,

it is important to give the scientific information and fact through the patient as well so that they have a realistic expectation of what they are going to undergo and what is going to be there probable outcome.

Recurrent implantation failure is basically an emerging science and Patient should remember that it is not a hope based treatment.

As a result of which there is so much trauma which the patient is undergoing mentally before undergoing any such therapy, and I would really like to tell each and every patient that as long as you have visited a specialist, and if you have consulted a specialist, then you genuinely should leave the rest on the clinical expertise and the medical knowledge of the expert in order to make sure that they give the appropriate guidance to you, simply by making sure that you undergo the therapy which is something which is of most benefit to you as far as your case based situation and your individual approaches concerned.