Implantation failure – what are the causes?

Implantation failure is determined when embryos of good quality fail to implant. This can happen for different reasons, including embryonic, uterine, endometrial and tubal causes. Successful implantation needs specific “cross-talk” between a good embryo, a receptive endometrium and a functional uterus. In fact, the latter, being the “natural incubator”, is the most forgotten cause of failures in IVF treatments, being it either with own or donor eggs. During this live webinar, Dr Nadia Caroppo, the Head of the International Medical Team at Equipo Juana Crespo, revealed what factors enable successful embryo implantation followed by a clinical pregnancy. Reproduction itself is like an orchestra. If the latter does not sound good, it is because one or a few of the instruments are failing. The same with human fertility. Dr Caroppo admits that it is one of the most complex issues in the field of medicine. Mainly, because there are so many variables that should be handled to assure the final success. However, a lot of things in reproduction are still unknown. Dr Caroppo quotes her boss and mentor, Dr Juana Crespo Simó, who even claims that an implantation failure as itself does not exist. It should be rather perceived in terms of several problems that doctors sometimes just do not know how to diagnose.

Implantation failure and personalised medicine

There are several definitions of ‘implantation failure’, depending mostly on the fertility society forming it. Generally, it is understood as the impossibility to obtain a clinical pregnancy with the transfer of at least 4 good quality embryos during at least 3 cycles in women under the age of 40.  However, the criteria is not strict and it depends mainly on a patient’s individual case and the cycles she has had before. Dr Caroppo says medicine should always be personalised. It is necessary to adapt medical treatment to individual characteristics and the history of each patient. The correct diagnosis is the first step towards the correct treatment – meaning the right plan and strategy for a patient. It also refers to the embryo transfer itself. The gold standard for reproduction is natural conception. According to the study conducted on 1,000 postpartum women, the conception period for natural pregnancies is 3 months in the case of 65% of women. The rest have to wait for a successful outcome for up to 18 months. In comparison, 65% of egg donation patients need to have 5 embryos transferred to achieve a live birth. According to Dr Caroppo, these results demonstrate that the implantation success is not the result of good quality eggs and embryos. There are other factors affecting the process – both in case of own and donated eggs.

The role of the uterus in implantation

There is one thing that all conceptions (both natural and through IVF) have in common – and this is a woman’s uterus. Dr Caroppo compares it to the most important incubator – however, it is also, the most forgotten one.

Embryo implantation is not a passive process. The endometrium and the embryo exchange messages have a kind of a ‘cross-talk’ between each other. It has been proved that a good quality embryo is able to positively change the environment inside the uterus. In the same way, it seems that even a poor quality embryo can improve its performance if the uterus and the endometrial lining are functioning correctly. Women with hyper-fertile uteruses get easily pregnant with any type of an embryo – either normal or abnormal. Of course, the latter generally results in a miscarriage. According to Dr Caroppo, these are the ‘easy patients’. In their case, the treatment protocols require to adjust only one factor, namely the embryonic one. At the opposite end, there are patients with the hostile uteruses, characterised by very poor receptivity. Such uteruses will always fail, no matter how good embryos they receive. These are the most difficult cases (called ‘low responders’) that have to be treated in a very specific way. However, it has to be highlighted that woman’s age makes a significant difference here. If a ‘low responder’ patient is very young, her chances of getting pregnant are much higher as the quality of her eggs is much better.

Preimplantation Genetic Testing

Dr Caroppo says there is always a certain percentage of patients who have to undergo preimplantation genetics testing (PGT / PGS) for abnormal embryos. This includes women who need to have chromosomal problems ruled out for the implantation failure. Dr Caroppo presents the results from the Equipo Juana Crespo clinic showing that, in case of PGT-tested embryos, clinical pregnancy rates increase a lot – up to 70.6% in cycles with own oocytes and to 75% in cycles with egg donation.

Using PGT – PGS – genetic embryo diagnosis clinical pregnancy rates increase a lot – up to 70.6% in cycles with own oocytes and to 75% in cycles with egg donation

This is another reason that accounts for the personalisation of reproduction medicine. In Dr Caroppo’s clinic, doctors usually suggest PGT to women who are 42 years old or above, just to assure they have got normal embryos. However, around 90% of all the clinic’s patients suffer from endometriosis. So even if PGS testing is indicated, it has to be remembered that the embryos belonging to endometriotic patients will suffer a lot when taken up to the blastocyst stage and tested. Dr Caroppo says that in such cases, the doctors’ main task is to provide those embryos with the best opportunity to implant. To do so, they have to place them in the correctly treated and well-conditioned uterus.

Studying the causes

Having assessed each case individually and ruled out other causes (e.g. thrombophilia or blocked fallopian tubes), doctors can focus on the uterus. They have to study not only its anatomy but also functionality. Dr Caroppo differentiates two types of tests conducted on the uterus: morphological and functional ones. The former includes 2D and 3D ultrasounds and pelvic MRI that are used to rule out pathologies that are not easily seen. The uterus functionality is, on the other hand, assessed by using hysteroscopy (to rule out endometritis, adenomyosis or fibrosis), subendometrial Doppler (to see vascularisation in the sub-endometrium) and contractility tests (made with video MRI to assess peristalsis).

According to Dr Caroppo, the most important part of the uterus to assess is the fundal one. It is the functional part and it is where embryos attach. As the uterus is a functional and hormonal dependent muscle, its changes depend on multiple factors – both acquired and congenital. These factors include painful periods throughout a woman’s life, altered menstruation patterns, previous C-sections, long labours or myomectomies – in other words, anything that can harm the inner muscle walls and change the uterus functionality. Fortunately, most of these changes can be repaired to restore the uterus functionality. It is an important fact to consider when ruling out factors that affect implantation. Choosing the treatment According to Dr Caroppo, making the diagnosis is the easiest part. However, it is useless if you do not know how to treat different types of uteruses. Fortunately, doctors have many treatment options available, including medical and surgical ones. First, there are a lot of medications that can be used before proceeding with surgical treatment, such as e.g. anti-estrogens, progestogens, dopaminergic agonists, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs) and antibiotics.

When it comes to surgery, the most important treatment is laparotomy. However, it is best avoided and used only when it is highly needed, assuming that other techniques have failed. Dr Caroppo mentions that open laparotomy may in some cases result in some of the most serious pregnancy complications following surgical treatment, such as uterine ruptures, premature births or an intrauterine restrain of fetal growth. This is why Dr. Caroppo Caroppo’s principal advice for all fertility patients who are to undergo any type of surgery is look for an experienced and trained reproductive surgeon. Only such specialists know exactly what should be restored in each case to give the uterus its functionality back. Making it work Although the range of treatment possibilities are wide, Dr Caroppo reminds us that doctors do not use all of them in each case. The choice of treatment depends on the type pathology that is observed, the strategy that should be adopted and – most importantly – on the patient’s past failures and medical history. The main endpoint of all these efforts – apart from getting a patient pregnant – is making her uterus work. However, there are no secrets to the final success. It is always the result of thorough preparation, hard work and learning from failures.