Uterine factor infertility relates to abnormalities of the uterus that can make it difficult to conceive or carry a pregnancy to term. In this webinar, Prof. Luciano Nardo, MD MRCOG, Consultant Gynaecologist & Specialist in Reproductive Medicine, explains the uterine factors that have an effect on embryo implantation in IVF treatment.
It is a fact that successful embryo implantation is dependent not only on how good the embryo is but also on the normal endometrial and uterine environment. In this case, implantation failures are similar to miscarriages – some factors could be shared between both of them. To minimise the risk of an implantation failure or an early pregnancy loss, it is very important to prepare for upcoming IVF in a thorough and individualised way.
Before using any assisted reproductive technique (ART ), one should investigate a few issues related to their reproductive health. These include ovarian reserve, semen performance/analysis, normal appearance of the uterus and ovaries and embryo quality – both in a morphological and a genetical sense. In prof. Luciano Nardo’s opinion, investigating the uterus is as important as investigating everything else we do before commencing a cycle of assisted conception. In his practice, he always individualises the diagnostic tests offered to patients with a plan to minimise unnecessary risks and the time to pregnancy as well as to maximise the chance of success in the shortest possible time.
When conducting fertility treatments, doctors and patients are often faced with the dilemma of something being unexplained. It can be highly frustrating as fertility issues are hard enough to deal with when we understand what’s causing the problem. Prof. Luciano Nardo says that doctors need to be in a position to explain why subfertility occurs, why the transfer failed or why a miscarriage took place – and the only way to explain it is by looking into the possible causes.
One of the most important technological developments and significant progress in the field of reproductive medicine is surely the possibility of investigating embryos, from the early stage to the blastocyst (day 5 or 6). Data published in the literature demonstrates that pre-implantation genetic testing for aneuploidies in embryos increases the chances of live birth and reduces the risk of miscarriages. However, relying entirely on this improvement may entail some surprising consequences. Prof. Nardo admits that – if the embryo test results come back as normal – there is a tendency to assume that everything is fine and patients may embark on an IVF journey. And it is often wrong as IVF itself doesn’t help to overcome the underlying infertility problem.
Prof. Luciano Nardo does not share the view that everything that is not successful is unexplained. He says that at his clinic, they always start with investigating the uterus at a very early stage of the fertility program to ensure that it is possible to shorten the time to pregnancy, reduce the risk of miscarriages and increase the chances of successful embryo implantation. There are a lot of gynaecological problems known to impact on normal endometrium environment that, in turn, will affect the ability of embryos to implant.
One of the most common gynaecological problems encountered in women trying to conceive is the presence of fibroids. These are generally benign lumps that can grow within the uterus, in the layers of the uterus and outside the uterus. Prof. Nardo admits that the impact on fertility and implantation is significantly different depending on the fibroid’s location. While the subserosal fibroids (located on the outside of the uterus) are of no importance to conception and pregnancy, fibroids within the uterus and those within the layers of the uterus will affect normal fertility performance. In early pregnancy, they are the causes of miscarriages and in women trying to conceive, they can lead to subfertility. It is enough to say that fibroids can impact tubal patency and normal endometrial activity and they may also cause abnormal blood supply to the uterus as well as inflammation.
Fibroids that are present within the uterus and inside the endometrial environment are called submucosal. They can easily be seen on a transvaginal two-dimensional ultrasound scan. They are divided into type 0, type 1 and type 2, depending on how much of the fibroid protrudes within the endometrial cavity. Submucosal fibroids have to be removed in women trying to conceive. And, what prof. Nardo stresses heavily, it is not to be done after a failed IVF cycle or a miscarriage but proactively before first conception attempts. There is strong published evidence that fibroids within the uterus cavity significantly affect the success of IVF treatment. Surprisingly, removing fibroids is sometimes enough to conceive naturally, without the need of starting an IVF treatment cycle at all.
According to prof. Luciano Nardo, it is equally important to look at the fibroids that are not within the uterus but which are within the layers of the uterus and may be close to the endometrium. These are the intramural ones and they are close to the junctional zone – the area between the endometrium and the myometrium. There is evidence that fibroids affecting or impinging the junctional zone cause inflammation, affect blood supply and induce contractions. Therefore, they should be removed to give the uterus the best chance of success. The best way to assess if fibroids are impacting the junctional zone will be by an MRI scan.
Polyps, being another common type of benign lumps, can be the result of prolonged hormonal treatment. As they are considered to be foreign bodies within the uterus, they can cause spotting and bleeding as well as impact the ability of a blastocyst to implant successfully. Polyps are generally soft and fleshy and can be very easily removed by hysteroscopy. Doctors can differentiate them from fibroids with the use of ultrasound scans. Prof. Nardo says that polyps, just like fibroids, should be removed before a woman’s conception attempts, before starting IVF treatment or in any case when there is a history of miscarriages.
When looking for causes of subfertility, miscarriages or implantation failures, one cannot ignore intrauterine adhesions. They usually occur following intrauterine surgery or curettage, insertion of coils or previous sexually transmitted diseases. They are often associated with painful periods and can be diagnosed and treated with a hysteroscopy. According to prof. Luciano Nardo, the worst-case scenario of intrauterine adhesions is Asherman’s syndrome (AS) when there is the complete obliteration of the inside of the uterus by what looks like cotton wool. In such a case, surgery is challenging and can only be performed by experienced surgeons. It should be followed with at least eight weeks of hormone therapy to induce a rapid and significant growth of the lining of the womb. There is scientific evidence that the removal of adhesions improves fertility, the ability of an embryo to implant and the pregnancy rates.
Congenital uterus abnormalities are something that women are born with – and the septum is the most common example of them. It is like a partition wall within the uterus and it can occupy either the entire cavity of the uterus (a full septum) or a proportionate percentage of the cavity (a partial septum). There is some evidence that a septate uterus can impact the ability of a blastocyst to implant and can cause a miscarriage, a pre-term delivery as well as increase the probability of a caesarean section. The presence of a septum will also affect placentation, reduce the size of the uterine cavity and harm the presence of growth factor receptors which are important for normal endometrial function. Prof. Nardo says that removing the septum improves the outcome: lowers the miscarriage rate and improves the pregnancy rate of women with unexplained infertility.
Prof. Nardo admits that only recently doctors have acquired information about how important the endometrial environment is for successful embryo implantation and pregnancy. In women with a history of recurrent implantation failures and – at the same time – good embryo quality, it is recommended to analyze the endometrium. It is a genetic test called endometrial receptivity array (ERA) which is performed after taking a biopsy of the endometrium. It uses the latest genetic technology – next-generation sequencing (NGS).
The biopsy is performed at a certain time in the cycle and gives doctors information based on the analysis of some gene expression of the endometrium. Generally speaking, it provides data about the best time when to transfer the embryo. It defines the endometrium as being either in the pre-receptive phase (not ready), the receptive phase (ready) or the post-receptive phase (past the optimal state). In prof. Nardo’s opinion, the information gained from the ERA test is extremely important to personalise the time of the embryo transfer. What doctors do next is to conduct the so-called ‘mock’ cycle which means mimicking what happens during a frozen embryo transfer either in a natural cycle or a hormonally controlled cycle. It helps them to see whether there is an adequate endometrial environment to support successful blastocyst implantation. In case the endometrium seems not to be prepared, the decision about prolonging progesterone exposure is made.
Apart from the ERA test, there is also the ALICE test that identifies the abnormal endometrial environment. It is known that up to 40% of patients undergoing IVF treatment present abnormal vaginal microbiota. Unfortunately, the abnormal microbiome in the uterus is not symptomatic – unless, of course, we take the implantation failure as a symptom. Prof. Nardo highlights that bacterial vaginosis (BV) is not only responsible for implantation failures but it also increases the risk of late miscarriage and premature rupture of membranes, so premature labour. The most important bacterial species within the endometrium is called lactobacillus. The lack of lactobacillus or, on the other hand, the dominance of others types of bacteria will affect the chances of an embryo to implant successfully.
Prof. Luciano Nardo admits that fertility patients are often told that their subfertility is unexplained. However, what he claims is that ‘unexplained’ is not the right word it means that the patients’ inability to become pregnant has not been investigated enough or the causes have not been found. Embarking on the IVF journey is not the right solution in such cases as the treatment itself is not going to overcome the problems, such as e.g. the abnormal endometrial environment or the presence of a fibroid or a septum. It will only move patients from the problem of unexplained subfertility to the problem of an unexplained implantation failure. The administration of the right medications or surgical removal of infertility causes before IVF treatment may significantly increase the ability to achieve a successful pregnancy and live birth.- Questions and Answers