In this webinar, Dr Valentina Denisova, an Obstetrician-Gynecologist, and Fertility Specialist at Next Generation Clinic, located in St. Petersburg, Russia talked about all the factors that can influence your IVF chances after previous failed attempts.
Low prognosis patients
The low prognosis patients are classified into 4 groups according to the results of ovarian reserve markers like antral follicle count (AFC), female age and the number of oocytes retrieved in previous cycles of conventional stimulation in cases where this information is available. According to this classification, we can divide patients, predict low response or poor prognosis and suggest some pre-treatment options and stimulation protocols. This classification aims to individualize the treatment approaches and optimize ovarian response and the number of retrieved oocytes and euploid embryos to obtain to give the highest implantation potential.
Several investigators proposed using different options to achieve euploid embryos in low prognosis patients, for example, high FSH doses, LH supplementation, double stimulation, and so. In one of the cohort studies which included more than 500 low-prognosis patients at the age of fewer than 44 years old who started their first IVF cycle and were treated with a fixed dose of FSH, and cumulative live birth rate in this group was, on average, 56% within 18 months of the treatment cycle. The variations of results are primarily determined by female age, which reflects the importance of oocyte quality.
Impact of lifestyle changes
Fruit and vegetable consumption is considered an excellent source of essential nutrients such as vitamins, and minerals that support the balance between reactive oxygen species and antioxidants. Lifestyle choices including smoking, alcohol, and other nutrition can promote chronic low-grade inflammation and oxidative stress in various organs. Therefore, lifestyle factors may eventually impact IVF outcomes and have an effect on the reproductive system in both men and women. In women, smoking, active or passive, causes an increased risk of miscarriage during pregnancy, which is potentiated by the number of cigarettes smoked per day. Smoking can also introduce perturbations in the menstrual cycle, promoting short and irregular cycles. It can also decrease ovarian reserve, which is shown by a lower antral follicle count and lower AMH level.
Several studies have demonstrated a decrease in sperm density and sperm motility in smoking individuals. Smoking has also been shown to affect sperm DNA fragmentation and some morphological parameters. Alcohol consumption should be ceased during pregnancy because it has been well-documented that it has a detrimental effect on fetal development, and there is no safe level of alcohol consumption during pregnancy. In males, alcohol was found to be harmful to sperm motility and morphology and it can impair the development and maturation of sperm, it has a detrimental effect on semen quality and the levels of male reproductive hormones.
High levels of caffeine consumption have been associated with decreased fertility. High doses during pregnancy may increase the risk of miscarriage, but it doesn’t affect the risk of congenital abnormalities. Elevated levels of cortisol, which is also called the stress hormone, leading to a greater chance of miscarriage in the first 3 weeks after conception compared to patients with normal cortisol levels.
In 2016, almost 40% of adults were overweight and among them 13% were obese. Most of the world’s population lives in countries where overweight and obesity kills more people than underweight. We need to remember that obesity is preventable. Raised BMI is a risk factor for several diseases, like cardiovascular disease, which is the main reason for death, diabetes, and even some kinds of cancers (including endometrial, breast, prostate, and liver cancers).
In women, obesity may cause some inflammatory responses, lowers the chance of pregnancy following IVF, increases the risk of pregnancy loss, and reduces rates of implantation, such women require higher dosages of gonadotropins and increased level of cycle cancellation. In males, obesity operates through different pathways. It creates epigenetic changes which can lead to some disorders in offspring, and it alters male androgenic hormones influences the host of our new hormones, and rises insulin levels. Finally, it has been linked to erectile dysfunction, causes of stress inflammation, and sleep disorder and all of these can lead to further reduction of male fertility.
PGT-A indications
Aneuploid embryos are the most frequent reason for implantation failures. Aneuploid embryos may increase the risk of first-trimester pregnancy loss. For patients under 42 years old, the overall live birth rate per oocyte was about 18%, so we need about 5–6 oocytes to produce 1 baby. For women over 42 years of age, every oocyte has only a 4% chance to become a baby, therefore, we would need more than 22 oocytes to produce a baby.
The indications for PGT-A are still arguable, and in 2018, according to ASRM (American Society for Reproductive Medicine), the value of PGT-A as a universal screening test for all patients is yet to be determined because some studies have demonstrated a higher live birth rate, however, the studies have limitations. Other important considerations about PGT-A must be addressed by further research, including costs, the role, and effect of cryopreservation time to pregnancy, etc.). It was also concluded that for patients with more than 1 embryo, PGT-A reduces healthcare costs, shortens treatment time to pregnancy and reduces the risk of failed embryo transfer. PGT-A increases implantation rates and decreases clinical pregnancy loss because the embryos can be selected.
Some investigators have expressed concerns that PGT-A adds cost to already expensive treatment and that it is an embryo diagnostic, so it never improves reproductive potential. According to this group, it’s more cost-effective to simply transfer all the embryos and let nature sort it out.
ESHRE recommendations that were published, at the beginning of 2020, suggest that PGT-A should be offered to patients of advanced maternal age, with previous recurrent miscarriage or recurrent implantation failures and severe male factor. It’s important to mention that in some cases, the only solution is egg donation.
Endometrial factor
Implantation relies on the crosstalk between an embryo and the endometrium. The optimal environment usually lasts for only a few days and begins around 6 days after ovulation. One of the possible mechanisms involved in recurrent implantation failures is the change in endometrium receptivity. One of the changes in receptivity involves the shift of timing of the window of implantation, which is previously assumed to be the same in all women. ERA test is used to identify the window of implantation, and this change is based on more than 200 genes. It was first introduced for patients with recurrent implantation failures, and so the day of the embryo transfer was changed based on the data from the ERA test, and a good pregnancy rate was achieved. However, further studies are still needed in larger samples and randomized control trials to identify its effectiveness.
Another important aspect is chronic endometritis. Among the patients with recurrent implantation failure, about 45% had chronic endometritis. This pathology can be diagnosed through histological examination, hysteroscopy, and sometimes by bacterial culture, there are some treatment options, such as antibiotics that have to be taken before your IVF cycle.
Regarding endometrial thickness, the guidelines from 2019 say that thin endometrium is commonly encountered in patients undergoing ART, and it may impact pregnancy and live birth rates in the fresh and frozen embryo transfer. However, there is insufficient evidence for the use of any adjuvants to increase the pregnancy rate in patients with thin endometrium. They also claim that endometrial thickness should be measured at the thickest portion of the endometrium. Fresh embryo transfer should be performed when the thickness is more than 8 millimetres, and frozen embryo transfer should occur when the thickness is 7 millimetres.
Other pathologies, such as uterine myomas (fibroids) and adenomyosis. Uterine myomas are the most common uterine tumours, and adenomyosis is another benign uterine disease characterized by the invasion of the endometrium into the myometrium. Myomas can lead to infertility and some reproductive problems through different mechanisms and sometimes they should be treated before IVF. There are a few treatment options, both conservative and surgical. Surgery is not always necessary before IVF. Adenomyosis may also impact implantation and even lead to some complications during pregnancy. It can be treated, but not through surgery when you are planning pregnancy.
Take-home messages
- Before planning IVF, modify your lifestyle (lose weight if you are overweight, stop smoking, don’t drink alcohol, decrease caffeine intake.
- Look for possible reasons for failures and try to correct them.
- The main factor of success is the female’s age, so remember that egg donation might be an indication.
- PGT-A can shorter the time of pregnancy and increase your chances.
- Assess your chances accordingly to the current situation.
