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Miscarriage could be caused by too many ageing cells and a fluctuating immune response. This finding suggests that carefully timing a pregnancy could prevent miscarriage and increase a woman’s chances of delivering a baby.

“All the ‘treatments’ we’ve been giving to women who miscarry haven’t been effective at all,” says at Homerton University Hospital in London. “We haven’t been getting to the root of the problem,” he says. “But this idea is particularly clever.”

A quarter of pregnancies end in miscarriage within the first 23 weeks. There are some known risk factors, such as being older or overweight, and some embryos miscarry because of genetic abnormalities. But we don’t really understand what causes miscarriages, especially in the 1 per cent of women who experience three or more in a row.

It’s not that these women are infertile – some women who’ve had as many as 12 miscarriages in a row still go on to have a perfectly healthy baby, leaving researchers wondering what’s going on.

at the University of Warwick, UK, thinks the balance between stem cells, ageing cells, and immune cells could be to blame.

Immune imbalance

In a healthy uterus, stem cells enable the endometrial lining to build up by about 10 millimetres over the course of 10 days, after every period. Some cells in the endometrium then senesce – they stop dividing, and trigger inflammation. A group of immune cells, called natural killer cells, answer the call, clearing out the ageing cells. This process creates a kind of honeycomb mesh, with holes just the right size for an embryo to embed, says Brosens.

But something seems to go awry in women who miscarry. When Brosens’s team took samples from the uteruses of women who haven’t had miscarriages, they found that the number of natural killer cells cycled in a predictable manner throughout the month. But in women who have miscarried several times, the numbers of natural killer cells varied every month, continually rising for several months in a row, before disappearing, and then beginning to accumulate again.

This could be because they have too few stem cells. “Forty per cent of [recurrent miscarriage] patients had no stem cells at all,” says Brosens. As a result, more cells enter the tired “senescent” state, attracting larger numbers of natural killer cells, leading to bigger holes in the endometrium.

If this is the case, it may explain why women who frequently miscarry can find it very easy to get pregnant. The large holes in the endometrium may make it easy for an embryo to implant at first, but eventually the structure will collapse in on itself, says Brosens.

Natural window

However, as natural killer cells rise in number over time, eventually a woman should have very low numbers of senescent cells, minimising the effects of having relatively fewer stem cells. “We should have windows where things are completely normal,” says Brosens, who presented his work at the Nordic Fertility Innovation meeting in Stockholm, Sweden, earlier this month.

This could be why women can experience multiple miscarriages before having a healthy baby – they may have been conceiving at times when the uterus was not receptive to a pregnancy, before chancing on the optimum conditions.

It’s possible to test the levels of natural killer cells, and Brosens and his colleagues have begun offering this test to women who’ve had recurrent miscarriages, to help them identify the best time to get pregnant. So far, they have advised around 150 women.

They have already had some success stories. One woman recently told Brosens that she is now 26 weeks pregnant.

However, these stories are anecdotal. The team can’t be sure if their strategy is working until they have run a clinical trial. “They obviously need more evidence, but the basis is a very strong argument,” says Homburg.

at Copenhagen University Hospital in Denmark is also impressed. “There’s been a lot of research into causes of miscarriage, but there has been no consensus on what’s going on,” he says. “Brosen’s theory is well justified, but it’s too early to declare whether it will work.”

If it does work, the approach could also be useful for women undergoing IVF, says Homburg. “We could learn how to get the ideal endometrium, or implant embryos when the endometrium is ready,” he says.