If you are looking for answers to questions above, check the webinar and live Q&A session with Dr Nataliya Kushniruk from FertiCare Prague, in the Czech Republic.
Egg donation is often considered to be the best chance at achieving pregnancy for many patients. As the treatment is time-consuming and expensive, it’s no wonder both patients and doctors recommend taking every precaution possible in order to boost the chances of success. One of the precautions is correctly estimating the implantation window – that is, the period of time during the natural cycle during which the uterus is at its most receptive towards new embryos.
To help us understand just how important the implantation window is – and how exactly it works – we invited Dr Nataliya Kushniruk from FertiCare Prague to share her knowledge and experience. She began her presentation by setting out some basic requirements for egg donation in the Czech Republic – namely, the patient must not be older than 49 years of age on then day of the transfer, must have no contraindications for pregnancy and her BMI must be under 35.
To ensure no complications arise during the pregnancy, prospective mothers undergo detailed testing – from ultrasounds and bloodwork, through mammography’s, to pap smears and hormonal analysis. The results of these tests allow doctors to ascertain whether or not a viable pregnancy can be sustained by the patient. Establishing a general health baseline for the patient mitigates possible complications during the gestation phase of pregnancy.
Partners of patients don’t need to feel left out of the fun – they also should undergo testing. Blood serology, genetic testing, and semen analysis provide information especially important to the fertilisation and implantation processes. In cases of recurrent implantation failure, DNA fragmentation analysis may help reveal the culprit behind the issue.
The general health of the intended father has a real impact on pregnancy; health and lifestyle factors greatly impact the sperm quality, which in turns has an effect on embryo quality and implantation. Couples hoping to find success in IVF should make an effort to improve sperm quality.
Once these tests are concluded and both prospective parents pass, the egg donation process can begin. Dr Kushniruk quickly brought us to speed by explaining egg donation step by step. Following the initial request, a medical coordinator sends a basic questionnaire to the patient interested in egg donation. Once the patient completes it, the first medical consultation can be scheduled. During this consultation, the doctor chooses the best path to proceed based on the patient’s medical history. Additional tests can be scheduled at this point if necessary. After the initial consultation, the clinic sends consent forms to the patients. Once these are signed and once a donor is matched, the egg donation process begins in earnest.
Cycle synchronisation is one of the most important parts of egg donation and it fulfils a twofold role; firstly, it stimulates the growth of follicles within the donor’s ovaries in order to generate more eggs at once. Secondly, it helps grow the recipient’s endometrial lining; this lining is what is ultimately responsible for the endometrium’s receptivity towards embryos. As an added benefit, the embryo transfer can be performed in the same cycle as the oocyte retrieval, requiring only a single visit to the clinic.
The effectiveness of egg donation programmes is dictated by several factors. Embryo quality is one of them and that, in turn, is dictated by the quality of eggs and sperm. In egg donation scenarios, oocyte quality is assumed to be good, as donors are universally young and healthy. Laws and regulations also set out rigorous criteria that potential donors need to match, ensuring that the eggs they provide are healthy and of good quality. Sperm quality, as we discussed, is mostly affected by lifestyle and health factors; in case of male factor infertility, sperm donors can also be used; like egg donors, they undergo screening and must meet certain criteria, which means their sperm is of good quality.
Endometrium quality and receptivity is another factor. Uterine quality is judged primarily by the thickness of its lining – ideally, it should be over 7.5 millimetres thick at the mid-point of the menstrual cycle. This can be measured through a simple ultrasound. The ultrasound also provides other valuable information about endometrial health – it can be used to defect abnormalities such as polyps, fibroids, myomas, et cetera. Endometrial receptivity is another topic entirely. Two types of receptors inside the uterine cavity are regulated by hormones – oestrogen and progesterone. High enough levels of both hormones signify the endometrium’s readiness to accept an embryo.
This brings us to the implantation window – the most optimal point for embryo transfer. During the implantation window, the uterus presents the best possible environment for the embryo. For most patients, this window occurs between days 19 and 24 of the menstrual cycle. For some patients, this window may be displaced – that is, it could occur earlier or later when compared to the majority of the population. An endometrial biopsy is helpful in determining whether or not that is the case and is a common test ordered for patients suffering from recurrent implantation failure.
On a closing note, Dr Kushniruk shared with us the story of a couple she treated. The couple were of advanced reproductive age – the wife was 44 years old, while her husband was 46. Their diagnosis was primary infertility in addition to adenomyosis. The woman was also a poor responder – which means she was a patient who did not respond as well as others to hormonal stimulation. Her partner suffered from poor quality of sperm.
At first, the patients attempted three cycles of IVF using their own eggs, which didn’t work. Following that, the couple made a decision to start an egg donation programme. Three fresh egg donation cycles resulted in just one biochemical pregnancy – not a clinical one. The patients didn’t give up however. They had one frozen embryo left from the previous programme. Unfortunately, it still didn’t result in a pregnancy.
After seven unsuccessful cycles, the couple decided to make the switch to donated embryos. Embryos in donation programmes come from other couples who completed their IVF journey and had surplus embryos; when a couple decide they do not want more children, they can donate the embryos to other couples. Alternatively, embryos for donation can be created using egg and sperm donors. In either case, the process results in high quality embryos being available to the patient. Our patients decided to go with the second route.
Embryo donation did not bring immediate effects. The first four cycles resulted in no pregnancy, the fifth resulted in a biochemical pregnancy, while the final – the sixth – resulted in an actual, clinical pregnancy. That’s thirteen attempts in total before a successful pregnancy. So, what went wrong?
An ultrasound of the patient’s uterus revealed that visually, there was no real difference between the endometrium and the myometrium. The patient suffered from adenomyosis – a condition in which endometrial cells grow within the myometrium. Adenomyosis is very tricky to diagnose; a simple ultrasound is often not enough; often, a laparoscopy or a biopsy is required. As a result, her uterus was enlarged and her uterine cavity was not up to the challenge.
However, perseverance paid off; adenomyosis does not mean pregnancy is impossible. By not giving up, these patients eventually achieved their goal and had a healthy child.
Sometimes, higher DNA fragmentation percentage may occur even when the semen test comes back as normal, so yes, I would recommend it.
Let’s start from antibiotics – yes, they will be recommended in case you have some problems with microorganisms or inflammation in the vagina or cervical channel. It would be reasonable to start with a thorough checkup – it would be beneficial to do some extra tests, not just the pap smear that is recommended routinely, but also to take the vaginal culture and to check for Ureaplasma or Chlamydia trachomatis etc. in the cervix. If there is an imbalance in bacteria or bacterial vaginitis, then you should definitely cure it, but even with vaginosis it will be beneficial to normalise the biocenosis in your vagina. Whether you should use antibiotics depends on if the microorganisms present are pathological or semi-pathological, and if they are, then you should take antibiotics. If there are no microorganisms, no inflammation, your leukocytes are within the normal range and your pap smear shows a normal result, then probably antibiotics should not be used.
We may use these sorts of medicine because when we are talking about the egg donation programme, it means the embryo which is implanted has no genetic links to your organism, and then it might be reasonable to take prednisolone to depress your body’s immune response to it.
If you are talking about the ERA test, where we test the estrogen and progesterone receptors in the uterine cavity, it may be helpful to find the implantation window. Sometimes it will be enough to make the transfer one or two days later according to the test result, so your body may be using progesterone for one or two more days, and it may be beneficial. But, it doesn’t mean that only this will help in 100%. The most important thing is to have an individual approach to each patient, and to find what is the cause of implantation failure in each precise case. Sometimes it is enough to simply give one or two days more of progesterone, but in other cases we might have to change something else, or to change the whole protocol. So, each procedure or method may be helpful to some extent.
ERA tests show the concentration of estrogens and progesterone, and the best time for implantation. When we are talking about ectopic pregnancy, if your ERA test was positive, and your implantation occurred at that exact time, then it doesn’t mean that the next time it will lead to ectopic pregnancy as well. An ectopic pregnancy is a possible complication of embryo transfer, and it actually doesn’t relate to the ERA test. If the ERA test showed you that at that precise time, LH peak + 7 days or LH peak + 6 days, then your uterine cavity is ready to accept the embryo – it should be the same in each cycle. So, you probably shouldn’t repeat the ERA test if the first one was positive. If the first ERA test told you your lining was pre-receptive, then please repeat the ERA test until it helps you find the result with receptivity. If the ERA test showed you that you were post-receptive, then definitely the embryo transfer should be done earlier, or if you want to prove that you are on the correct day, then you should repeat the ERA test in the next cycle to ensure that in that particular period, your endometrium is receptive.
As I said previously, every test that we are using is good for some reason. If your doctor has recommended you to take this test, it means by the means of this test, the doctor would like to prove or exclude some kind of pathology, and find the best option for your couple to figure out some problems which may be taking place, and to prepare them in the best way for further IVF attempts. Nobody wants to go through unsuccessful attempts, and the doctors are suffering as well if there is no pregnancy, not only the patients.
It’s reasonable to do an ERA test to find the best day for the possible implantation. When you have day 3 frozen embryos, you have 2 possibilities. The first is to thaw the embryos and let them grow in the laboratory until day 5 until they become blastocysts – these blastocysts will then be transferred corresponding to the implantation window found in the positive ERA test. If there is no possibility to culture these embryos into blastocysts, then we can presume your embryos will be alive after thawing, and they will develop inside the uterine cavity. We need to make the transfer according to the calculation of when your embryos will reach 120hours, so day 5 (blastocyst stage), and this should be within the implantation window which was found in the ERA test. If both the positive ERA test and the calculated transfer of the day 3 embryos correspond, then this can result in a successful pregnancy.
In literature, there are several things described. There are articles stating that on the one hand, it may afflict the implantation window, but mostly, in the latest retrospective research, there is data stating that increased numbers of NK cells in the endometrium are linked to recurrent miscarriages. So, the women become pregnant, but these pregnancies may terminate at different stages, but mostly they terminate before 10 weeks of gestation.
Some patients don’t have a triple lined endometrium, and this means that although pregnancy may happen, the percentage of successful pregnancies in this category of patients is much lower in comparison to patients with a normal, trilaminar endometrium.
We have several kinds of progesterone, and definitely, when we are talking about IVF programmes, we need to have good support of the luteal phase. Utrogestan is not the only option to support it. We have several kinds of this medicine, and we have several routes of administration of this progesterone to substitute internal progesterone in your body. If you are allergic to Utrogestan, then you may change it to Crinone gel – this is one option. There is also another medicine, mostly available in the UK, called Cyclogest – it has two routes of administration, either vaginally or rectally, so you may try and use it rectally. Or, we have a good number of intramuscular or subcutaneous progesterones as well, such as Gestone and Gesglutin (intramuscular), or Prolutex (subcutaneous). So, your doctor will select the best option for you, and can definitely substitute Utrogestan. Without the support of the luteal phase with progesterone and without an adequate concentration of progesterone inside the uterine muscle, it’s not possible to imagine a good, progressive pregnancy.
DHEA is recommended in patients who have low concentration of DHEA inside the body. You can use probiotics as well – there are no contraindications for this. If you mean local probiotics, to aid normal biogenesis inside the vagina, it’s reasonable to use them in the stage of preparation and then when you’re at the stage of having the procedure, continue taking the probiotics orally.
You’re talking about the so-called endometrium biopsy, which is an investigation by pathologists, where they look at the sample on a glass slide under the microscope and give us their view on if there is chronic inflammation inside the endometrium or not. If there is a chronic inflammation process inside the uterus, it’s reasonable to use antibiotics, and it should be a broad-spectrum antibiotic. Not only Doxycycline can cure this kind of inflammation. But, to answer your question, yes, it’s reasonable to both check the inflammation and cure it with antibiotics.
The uterine cavity should be clear of bacteria. Lactobacillus should be inside the vagina, and yes, it’s good if it is at the correct concentration and balanced. Definitely, you may take lactobacillus or probiotics orally, but the concentration of probiotics is more important in your vagina than in your gut.
There are several ways that we can improve the endometrium thickness. We can change the concentration of estrogens inside the body – it means that the dose of estrogens should be adjusted. There are several routes of administration of estrogens into your body – it depends on your initial endometrium thickness, and we need to see how it will change. Then, we can try to improve the vascularisation, as it plays a very important role in the development of the endometrium. We can do this by working on the thickness of your blood – there are some medications we can give for better blood flow inside the vessels supplying the endometrium, which can to some extent improve its thickness.
6.7mm – it seems like you may have some previous history of inflammation or some manipulation of your endometrium which has affected its thickness. However, 6.7mm is not an extremely poor endometrium. It would probably be reasonable to add some medicine that will help the vascularisation process, and even with this, you need to see how it will grow and develop. It is very interesting to see your lining and its thickness in a completely natural cycle, without any type of estrogens. Before the embryo transfer, you could try to do some sort of insignificant uterine injury, to try and change the developmental/reparative process inside your uterine cavity. So, it would be reasonable to think about endometrial scratching if you haven’t done it previously, and to start to adjust the dose of the transdermal patches and oral medications – adding a regional route of administration of medicine may be helpful as well.
However, not everything depends on the lining. If you had embryos, but failed implantation, then next time, if you decide to go ahead with IVF again, you should check the genetics and full chromosome count of the embryos as well, along with good preparation of your lining. Sometimes, with the type of lining that you have, it may be a good idea to do a number of cycles with estrogen support before you do the transfer of the embryo. You should think about all of this, discuss it with your doctor, and make a decision with how you would like to continue.
When we are talking about chronic inflammation, it doesn’t make a difference on which day the biopsy is performed. The best time to do it would be after menstrual bleeding finishes, and then do a hysteroscopy and/or endometrium biopsy in the first part of the menstrual cycle, collecting a sample of the functional layer of the endometrium and also a part of the basal layer, which would show the inflammation.
Post-receptive means that you should do the transfer one day earlier. When you did the ERA test, it means it was done on the same cycle you used for the embryo transfer – the same amounts of estrogens and progesterone, and the same protocol. Now you need to calculate on which day of your menstrual cycle your ERA test was performed. Then you have several options. You could try to transfer the embryo one day before the day on which your previous ERA test was done, or to repeat the ERA test one day earlier than it was previously done. In your case, it will probably be enough to take 4-5 days of progesterone intake before the embryo transfer – it’s very individual. Post-receptive means you put the embryo in when the implantation window was closed, and you have to put it in when it is open.
Pre-receptive means the opposite of what I said before. It means you need to do the transfer one or two days later than you did before. In my experience, when I had patients who were pre-receptive, it was simply enough to transfer the embryo one day later, and that was it. However, in rare cases, we gave one more day of progesterone and repeated the ERA test and it was still pre-receptive – so, then we would need to give one more day of progesterone. It would be best to repeat the ERA test one day after you did previously and see if it becomes receptive or not.