Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please can you give a brief introduction to miscarriage?
Miscarriage is defined as the spontaneous loss of pregnancy before the baby reaches viability. Besides the physical trauma, miscarriage causes considerable anxiety, stress, and depression.
Importantly, miscarriage – especially recurrent pregnancy loss – also increases the risk of adverse outcome of a subsequent ongoing pregnancy, including preterm delivery, premature preterm rupture of membranes, low-birth weight and congenital malformation.
How common are miscarriages?
Miscarriage is the most common complication of pregnancy. One in seven recognized pregnancies end in miscarriage during the 1st trimester and 1-2% fail between 13 and 24 weeks gestation. When taking into account very early (unrecognized) losses, the true incidence of miscarriage is between 50-60% of all pregnancies.
Because miscarriage is so prevalent, medical investigations and treatment tend to be reserved for those women who suffered recurrent pregnancy loss (RPL). In many European countries, RPL is defined as 3 or more consecutive miscarriages whereas in the US the diagnosis is made after 2 or more consecutive losses. RPL is a particularly distressing disorder and affects between 1 and 2% of couples trying for a baby.
What was previously known about the causes of miscarriage?
Miscarriage research is not well funded and there has been little progress over many decades. Early pregnancy loss is still blamed on either chromosomal abnormalities in the implanting embryo or on some ‘maternal’ factor, such as an exaggerated immune response to placental cells. Consequently, couples suffering RPL are routinely tested for various anatomical, endocrine, immunological, clotting and genetic risk factors.
In a majority of cases no underlying associations are found. As a result, many RPL patients will receive no treatment whereas others are treated empirically with a variety of immunomodulatory and blood-thinning drugs. Several of these interventions have shown to be ineffective or even detrimental; and none as yet effective.
How did your research into the molecular signals that make some women prone to miscarriage originate?
Before joining the University of Warwick, Siobhan lead a dedicated miscarriage clinic in Liverpool and I was doing the same in London. We both became very frustrated by the obvious lack of insights in early pregnancy failure and the absence of effective treatments. As mentioned, the recommended standard laboratory investigations are by and large uninformative. Even when a standard test is positive in a RPL patient, for example revealing a subclinical clotting defect, the same abnormality will be present in 50 to 100 women with uncomplicated pregnancies.
Three major observations in recent years completely altered our view of the mechanisms behind miscarriages. Firstly, it became established that most – if not all – human embryos exhibit some chromosomal abnormality before implantation. This can range from abnormalities in 1 or 2 cells to the embryo being genetically chaotic. This was a very important realization as it implied that there must be some kind of quality control process that enables the mother to reject invasive but unwanted embryos. Together with our Dutch collaborators, we then discovered that endometrial cells are exquisite biosensors of poor quality embryos but only when properly prepared for pregnancy, a process termed ‘decidualization’. Finally, we were able to see that this process of decidual transformation of endometrial cells is grossly impaired in RPL patients.
Put differently, to be successful, the lining of the womb (endometrium) must be ‘receptive’ to implanting embryo but also ‘selective’. In RPL women, the lining of the womb appears excessively receptive (‘super-receptivity’) but insufficiently selective. Hence, many of our patients report that they find it very easy to become pregnant (‘super-fertile’) but then fail to hold onto the pregnancy. Because ‘receptivity’ and ‘selectivity’ are opposing uterine traits that require constant balancing, our model also explains why a woman with 3 or 4 healthy children is likely to also have experienced 1 or 2 miscarriages.
What did your research involve?
We established in 2012 a Biomedical Research Unit in Reproductive Health with the support of Warwick Medical School and University Hospitals Coventry and Warwickshire National Health Service Trust. This enables us to recruit women suffering from miscarriages to a specialist research clinic for in-depth assessment of the endometrium. We now routinely culture endometrial cell from individual patients, which we study by preparing them for pregnancy in the laboratory.
We also use various mouse models. In the current study, we exposed the wombs of mice to signals from human endometrial cells and then assessed the impact on early pregnancy events. Rather remarkably, brief uterine exposure to endometrial signals from RPL patients prior to embryo transfer was sufficient to trigger early pregnancy failure in mice.
What did your research find?
We made several important observations in the present study. First, we showed that endometrial cells mount a profound but transient inflammatory response in preparation of pregnancy (decidualization).
Second, we found that the duration of this inflammatory response determines how long the womb will be receptive to an implanting embryo; the so-called ‘implantation window’. Limiting this window of implantation is very important as it aligns the environment in the womb to the needs of the implanting embryo.
Further, we demonstrated that this inflammatory response is driven by simultaneous release of interleukin-33 (IL-33) and expression of its transmembrane receptor ST2 on decidualizing endometrial cells.
Finally, we showed that IL-33/ST2 activation is both prolonged and disordered in endometrial cells from RPL patient. As aforementioned, exposure of mice uteri to these signals prolonged the implantation window in these animals, allowing out-of-phase implantation and resulting in early pregnancy loss.
Are these molecular signals involved in any other diseases?
IL-33 is abundantly present in various mucosal tissues. It’s considered to be an ‘alarmin’; a danger signal released primarily upon tissue injury or infection. By binding to the ST2 receptor on immune cells, IL-33 strong activates innate immune responses, leading to tissue inflammation. Our observations suggest that endometrial cells should be viewed as being part of the innate immune system as they transiently release IL-33 and express the ST2 receptor in preparation of pregnancy.
Interestingly, the IL-33/ST2 pathway is considered a major novel target for therapeutic interventions across a range of diseases, including infections, cardiovascular disease, obesity, asthma and other autoimmune disorders. Our findings suggest that targeting the same pathway in the uterus is a promising strategy to regulate endometrial receptivity.
What impact do you think your research will have?
Our observations have several important clinical implications. First, our data demonstrate that the cause of miscarriage, especially RPL, lies in the preparation of the womb before pregnancy. Consequently, it is possible to develop tests that predict prior to conception the likelihood of pregnancy complications.
Pregnancy is a feed-forward system with each developmental stage impacting on the next stage. Hence, a pre-pregnancy testing may also identify women at risk of obstetrical complications, such as fetal growth restriction and pre-eclampsia. The corollary is that interventions designed to prevent pregnancy complications are likely to be effective only if initiated before or around the time of embryo implantation.
Do you think it will be possible to develop a treatment to prevent miscarriages?
Yes of course; and we are working on this!
Where can readers find more information?
More information can be found on the website of the Division of Reproductive Health, University of Warwick: http://www2.warwick.ac.uk/fac/med/research/reproductive/
During this interview, we referred to the following research papers:
Salker MS, Nautiyal J, Steel JH, Webster Z, Šućurović S, et al. (2012) Disordered IL-33/ST2 Activation in Decidualizing Stromal Cells Prolongs Uterine Receptivity in Women with Recurrent Pregnancy Loss. PLoS ONE 7(12): e52252. doi:10.1371/journal.pone.0052252
Salker MS, Christian M, Steel JH, Nautiyal J, Lavery S, Trew G, Webster Z, Al-Sabbagh M, Puchchakayala G, Föller M, Landles C, Sharkey AM, Quenby S, Aplin JD, Regan L, Lang F, Brosens JJ. Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure. Nat Med. 2011 Oct 16;17(11):1509-13. doi: 10.1038/nm.2498.
Salker M, Teklenburg G, Molokhia M, Lavery S, Trew G, et al. (2010) Natural Selection of Human Embryos: Impaired Decidualization of Endometrium Disables Embryo-Maternal Interactions and Causes Recurrent Pregnancy Loss. PLoS ONE 5(4): e10287. doi:10.1371/journal.pone.0010287
Teklenburg G, Salker M, Molokhia M, Lavery S, Trew G, et al. (2010) Natural Selection of Human Embryos: Decidualizing Endometrial Stromal Cells Serve as Sensors of Embryo Quality upon Implantation. PLoS ONE 5(4): e10258. doi:10.1371/journal.pone.0010258
Would you like to make any further comments?
We would be delighted to hear from anyone interested in supporting our work. Further, women wishing to take part in our research should email Kerri Geraghty (Kerri.Geraghty@uhcw.nhs.uk), the Secretary of the Biomedical Research Unit in Reproductive Health at University Hospital Coventry and Warwickshire NHS trust.
About Jan Brosens and Siobhan Quenby
Jan Brosens is Head of the Division of Reproductive Health, Professor of Obstetrics and Gynaecology at the University of Warwick, and Honorary Consultant at University Hospital Coventry and Warwickshire NHS trust. His research centers on the role of steroid hormone signalling in the human endometrium, especially in the context of prevalent reproductive disorders, such as infertility, endometriosis and endometrial cancer. His major translational interest is focused on improving the management of miscarriage, the most common complication of pregnancy. He obtained a PhD from the University of London in 1999, working on the mechanisms underpinning the preparation of the lining of the womb (endometrium) for pregnancy, a process called decidualization. He was awarded a Wellcome Trust Clinical Scientist Fellowship in 1998, then joined Imperial College London as Chair of Reproductive Sciences in 2004 and became Chair of Reproductive Medicine in 2008. He has written over 125 papers as well as numerous chapters on clinical and molecular aspects of reproduction and cancer.
Siobhan Quenby is the Director of the Biomedical Research Unit in Reproductive Health, Professor of Obstetrics at the University of Warwick, and Honorary Consultant at University Hospital Coventry and Warwickshire NHS trust. Siobhan has twenty years of experience in translational research into recurrent miscarriage and dysfunctional labour. She published over 75 original articles and numerous book chapters on this subject. She serves on several international and national committees; European Society for Human Reproduction and Endocrinology Early Pregnancy Special Interest Group, MHRA Expert Advisory Panel for women’s health, Scientific Advisory Committee of the Royal College of Obstetricians and Gynaecologists (RCOG), RCOG Preterm Labour Clinical Study Group, RCOG Early Pregnancy Clinical Study Group. She is currently an Associate Editor for BMC Pregnancy and Childbirth and has served as an Associate Editor for Human Reproduction. Her work has received considerable media interest, including from national newspapers, BBC radio and TV, ITV and Channel 4 news. She is also a media spokesperson for the RCOG.