LONDON – For a healthy pregnancy to have the best chance of surviving, the cells lining the uterus must undergo a short-lived burst of inflammatory activity about five days after ovulation, which must come to a halt 48 hours later, researchers have found. The discovery suggested new ways of treating women who suffer recurrent miscarriages.
A pilot randomized controlled trial in which women who previously had several miscarriages were treated with an anti-inflammatory drug or with a placebo several days after ovulation already has shown promising results.
Jan Brosens, professor of obstetrics and gynecology at the University of Warwick, told BioWorld Today: "We have reached the point in our studies of the causes of recurrent miscarriages where we need to use all the data and work toward improving therapies. What is unequivocally clear is that, to be effective, treatment needs to start before a pregnancy begins. We are currently testing various strategies to see what is most effective."
Brosens is working with Siobhan Quenby, of the Biomedical Research Unit in Reproductive Health, which has been established as a joint venture by the University of Warwick Medical School, the University Hospital Coventry and Warwickshire NHS Trust. They are recruiting women who have histories of recurrent miscarriages to clinical trials that will help them evaluate different therapies.
Brosens' team has spent many years studying the differences in gene expression by cells in the uterus between women with normal fertility and those with a range of infertility problems. For the current study, which was published in the Dec. 28, 2012, issue of PLoS ONE, the researchers focused on what happens in cells from the human endometrium (the lining of the womb) during decidualization – the process by which the endometrium gets ready to allow an embryo to implant in its wall.
The paper is titled "Disordered IL-33/ST2 Activation in Decidualizing Stromal Cells Prolongs Uterine Receptivity in Women with Recurrent Pregnancy Loss."
Given the important impact of a pregnancy on a woman, including the risk that she could die as a result, it is not surprising that the cells that will receive the embryo are a bit fussy about whether they will permit the pregnancy to go ahead. "We knew that, normally, there is a window of a couple of days during which the lining of the uterus is receptive and will allow attachment of the embryo," Brosens said. "Once that happens, the embryo is surrounded by the decidual cells, which are like biosensors of the embryo's quality. If the embryo is abnormal, then, most of the time, the decidual cells will not allow it to implant."
In addition, in a previous study, published in Nature Medicine, Brosens' team demonstrated that this kind of biosensing does not occur in women with recurrent miscarriages. The endometrium is both super-receptive but not sufficiently receptive. Abnormal embryos can implant and, following development of the placenta, will result in miscarriage. That observation chimes with the experience of many of Brosens' patients, who become pregnant very easily but also suffer repeated miscarriages.
In the PLoS ONE paper, Brosens and his colleagues take the research a step further, by showing that when the decidual cells start to prepare to receive the embryo, they mount an inflammatory response which includes production of interleukin-33 (IL-33). Furthermore, the inflammatory response lasts for just two days, and is then shut down.
"We found, however, that in cells from patients with a history of recurrent miscarriage, the expression of IL-33 was much more prolonged and disordered than in cells from patients who had normal fertility," Brosens said.
In further experiments, the team set up laboratory cultures of endometrial cells from patients who had experienced recurrent miscarriages. The scientists then took the culture fluid and flushed it through the uteri of mice, before adding embryos.
"The surprising finding," Brosens said, "was that when we transferred the mouse embryos, we found that we got implantation over a much longer period than normal, and that the vast majority of these embryos failed. Our conclusion is that the lining of the uterus in women with recurrent miscarriage is receptive for far too long, allowing implantation of both good and bad embryos, and that, even if a good embryo does implant, it will do so in an unsupportive environment and will lead to a miscarriage."
The discovery points to some "really interesting" treatment options, Brosens continued. "It should be possible to switch off the inflammatory response at exactly the time when the window for implantation should be closing."
He and Quenby already have completed a pilot study in which women took prednisolone for its anti-inflammatory properties when trying to get pregnant. The timing was very precise: The women took the drug on the seventh day following ovulation (which they detected using a commercial kit) because the implantation period is known to occur between five and seven days after ovulation.
"We are currently writing up the pilot study, but I can say that the pregnancy rate among the women taking part did rise," Brosens said. "It may be the case that prednisolone on its own is not the most effective therapy, so we will continue to investigate different treatment options."