A well attended Campus meeting in December organised jointly by the ESHRE SIGs Implantation & Early Pregnancy and Endometriosis & Endometrial Disorders considered the conditions and diseases associated with recurring loss of pregnancy, and the interplay between endometrial and embryonic factors.
Highly regenerative and complex, the endometrium’s role in recurrent implantation failure (RIF) and pregnancy loss (RPL) is still poorly understood. Against such a challenging backdrop, a December Campus meeting in Vienna, organised jointly by the SIGs Implantation & Early Pregnancy and Endometriosis & Endometrial Disorders, sought to expand on this elusive topic despite evidence gaps.
What first became apparent during this two-day meeting was the need for a universally accepted definition of recurrent implantation failure. One (definition) does exist for recurrent pregnancy loss (clearly stated in ESHRE’s updated guideline for RPL), and, while ESHRE is now finalising its latest guideline for RIF, speakers agreed that consensus was needed on a definition in order to improve the management and treatment of this serial inability to achieve a successful pregnancy.
RIF definitions aside, a comprehensive overview of the factors behind RIF in IVF cycles - such as abnormal trophoblast invasion - was provided at the meeting along with insights into conditions and diseases likely to increase the risk of RPL. Endocrine dysfunctions, autoimmune diseases and coagulation disorders, congenital uterine anomalies, dysbiosis, endometriosis and endometritis were among those analysed as associated with RPL and for potential treatment.
Poorly controlled thyroid disease has been implicated in pregnancy loss, said Kilian Vomstein, Innsbruck Medical University, citing thyroid peroxidase antibodies (TPO) as a marker for increased risk of miscarriage. Hypothyroidism is linked with RPL and subclinical hypothyroidism with sporadic pregnancy loss but evidence for the efficacy of levothyroxine has proved negative to date. Vomstein presented data from a randomised controlled trial showing that levothyroxine did not result in higher live birth rates than placebo, and a recent study had to be stopped.(1) As such, he called for international research collaborations to obtain more robust data.
While screening is recommended for RPL in women with abnormal levels of TPO and thyroid-stimulating hormone, screening is not recommended in PCOS; the ESHRE guideline cites a lack of evidence on how insulin resistance can result in pregnancy loss.(2) Instead, Vomstein said clinicians should keep lifestyle factors in mind, such as BMI, and also called for larger studies into metformin as a potential treatment for RPL in PCOS.(3)
In her presentation on the microbiome, SIG co-ordinator Henriette Svarre Nielsen from the University of Copenhagen said dysbiosis – characterised by loss of lactobacillus dominance and other factors – is more common in miscarriages with competent (euploid) embryos, which suggests the problem lies with the environment, not the embryo. Small scale studies indicate a possible link between endometriosis and lower microbiome diversity but the evidence is as yet inconclusive. A collaborative study project in which Svarre Nielsen is involved aims to shed more light on the microbiome and reproductive health in women.(4)
Probiotics and antibiotics have been investigated as potential treatments for dysbiosis but both have been found wanting: antibiotics remove pathogens in up to 70% of cases but recurrence occurs in up to 50%, and lactobacillus levels don’t increase; and Svarre Nielsen said that no convincing data has yet emerged for probiotics. Vaginal microbiome transplantation is a new exploratory approach involving fluid donated by women with high lactobacillus; an exploratory study in 2019 showing a marked improvement in a majority of patients.(5) Details were outlined by Svarre Nielsen of another pilot study she and colleagues are conducting in 32 transplanted patients and 16 controls; she also presented a case history at her clinic of a highly dysbiotic patient who received a transplant on compassionate grounds after experiencing pregnancy loss and who has just delivered a healthy baby.
One clear message from sessions on therapeutic approaches in women with RIF was that any surgery for endometriosis patients should be in those experiencing pain and that clinicians should not operate before ART. Describing implantation as a ‘good dance’ which requires the right steps at the right time, Ron Van Golde from UMC Maastricht said the good news is that RIF is often self-limiting with nearly half (49%) of patients getting pregnant anyway without treatment. He argued against endometrial receptivity tests on the grounds that the concept was unproven but said lifestyle factors must be taken into account. What would also improve understanding of RIF was a model of the endometrium, he said, to mimic implantation.
For RIF patients who do become pregnant and achieve childbirth, data are lacking on links with potential complications. Angela Koniger from Germany said women with endometriosis face an increased risk of several adverse pregnancy outcomes, including pre-eclampsia (although aspirin can reduce this risk by 80%) and potentially very rare complications such as spontaneous hemoperitoneum and bowel perforation as outlined in a meta-analysis.(6) Koniger argued provocatively that obstetricians may be partly responsible for endometriosis and RIF by pointing out that focal adenomyosis can form in caesarean scar defects and act similarly to endometriosis, which may lead to subsequent implantation failure. Closing all the layers of the peritoneum post c-section is vital, said Koniger, who is carrying out a research project on this question with the aim of reducing risks.
Whether the causes of RPL and RIF relate to the endometrium or the embryo (or both) is still up for debate. What is apparent from this meeting is that patients who are affected face a bewildering number of possible causes for their inability to become parents but very few answers, which is why larger scale studies are still needed.
1. Dhillon-Smith RK, Middleton LJ, Sunner KK, et al. Levothyroxine in women with thyroid peroxidase antibodies before conception. N Engl J Med 2019; 380:1316-1325
3. One such trial (the LOCI study in the UK) is under way: https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/loci-letrozole-or-clomifene-for-ovulation-induction/
4. Krog MC, Madsen ME, Bliddal S, et al. The microbiome in reproductive health: protocol for a systems biology approach using a prospective, observational study design. Hum Reprod Open 2022; https://doi.org/10.1093/hropen/hoac015
5. Lev-Sagie A, Goldman-Wohl D, Cohen Y. Vaginal microbiome transplantation in women with intractable bacterial vaginosis. Nature Medicine 2019; 25: 1500-1504. https://www.nature.com/articles/s41591-019-0600-6
6. Breintoft K, Pinnerup R, Henriksen TB, et al. Endometriosis and risk of adverse pregnancy outcome: A systematic review and meta-analysis. J Clin Med 2021; 10: 667. https://doi.org/10.3390/jcm10040667