For those who’ve experienced recurrent miscarriages, the devastation can be immense. While around one in five pregnancies end in miscarriage (defined as losing the baby before 24 weeks), this remains an isolating and under-discussed issue.
If the miscarriage happens early in the pregnancy, it’s usually down to chance. However, for women who lose their baby during the second trimester – or who experience three or more miscarriages in a row – it’s important to investigate the cause. Unfortunately, recurrent miscarriage affects around one in a hundred women, and it isn’t always possible to say why.
One potential culprit is endometriosis, a common condition affecting around 10% of women of reproductive age. It occurs when tissue similar to the uterine lining grows outside the womb, and can cause heavy periods and searing pain (some women, it should be noted, experience no symptoms at all).
The condition is also linked to recurrent miscarriage. While this link bears further exploration, there are two large databases (one from Sweden and one from Scotland) that suggest women with endometriosis are more likely to miscarry than those without. In fact, many women with the condition don’t get their diagnosis until they start experiencing fertility problems.
Trialling antibiotics for recurrent miscarriage
Now a trial is underway at the University of Warwick, in partnership with University Hospital Coventry, to see whether a simple course of antibiotics might solve the problem.
The randomised controlled trial will recruit over 3,000 women who have experienced two or more early miscarriages, and will use a specially optimised test to see if they have endometriosis. Those who do will be given a 14-day course of the antibiotic doxycycline, or a placebo, and will be advised to start trying to conceive once they have finished the course.
Warwick Medical School’s Professor Siobhan Quenby, principal investigator on the trial, said: “This is potentially a new treatment for up to half of people with recurrent miscarriage… Instead of just having your blood tested to look for causes of miscarriage, as is current practice, you will have the lining of the womb tested too so that we can identify those who will benefit from this treatment.”
The trial will seek to answer a number of questions, rather than just one as in a typical clinical trial. It will explore what degree of inflammation in the womb is needed to cause miscarriage, and how this mechanism might work. It will ask whether doxycycline actually succeeds in reducing inflammation, and whether it reduces rates of miscarriage overall.
Another pertinent question is whether the drug alters the microbiome (the balance of bacteria) in the reproductive tract. It has been speculated that endometriosis might be caused by a bacterial imbalance, which could in turn make the womb lining less hospitable to a growing foetus.
“Our aim is to try to improve the womb before you get pregnant,” said Quenby. “Most miscarriages occur within the first trimester (12 weeks) of pregnancy and our aim is to see a reduction in these early miscarriages.”
The trial has received £1.9 m in funding from the Efficacy and Mechanism Evaluation (EME) Programme, and will be recruiting participants over the next two years. If successful, it could help up to 7,000 prospective parents every year.
Antibiotics treat endometriosis in mice
Dr Ramakrishna Kommagani, an assistant professor of obstetrics and gynaecology at Washington University School of Medicine, is conducting his own research in this field. Earlier this year, his team found that antibiotic treatment could reduce the size of endometrial lesions in mice.
“A few studies have indicated that mice with endometriosis have different gut bacteria and a different uterine and cervical microbiome,” says Kommagani. “We decided to use antibiotics to wipe out the gut bacteria in mice and see how that affected the progression of the disease. The antibiotic metronidazole inhibited the growth of the lesions. So, our research suggests the bacteria itself can promote this disease.”
If the same applies to humans, it wouldn’t come as too great a surprise. Many women and girls with endometriosis also suffer with inflammatory bowel problems, and one 2016 study suggested the gut bacteria might be a “puppet master in the pathogenesis of endometriosis”.
Kommagani’s contention is that the balance of gut bacteria can indeed promote, or protect against, the development of lesions.
“After I published our work I got many emails from patients who had taken this particular antibiotic for some other issue, and suddenly the pain associated with endometriosis stopped,” he says. “This is very encouraging, although of course we have to do a clinical trial to confirm it.”
He is currently in talks with a number of companies and institutes to set up a small preclinical study.
“We hope to test the drug in at least 20 or 30 women, but because metronidazole is not a new molecule that can be patented, companies aren’t interested – they’re not going to make a profit,” he says. “So we’re struggling to initiate the trial in a very swift manner, but we are trying and I really hope it will happen.”
Getting to know the gut bacteria
It’s worth mentioning that Kommagani’s team actually tested four antibiotics in the mouse study. Only metronidazole made a difference.
“This antibiotic only kills gram-negative bacteria that are anaerobes, and we think some of those bacteria promote lesion growth in endometriosis, as well as in inflammatory bowel disorders,” Kommagani says. “We are now conducting research to identify the specific bacteria involved, so we hope to have some good data very soon.”
His team is also trying to pinpoint bacteria that may protect against endometriosis. In the mouse study, mice with endometriosis displayed very low levels of a protective type of gut bacteria. This implies probiotics, as well as antibiotics, could play a role in treating in the disease.
On top of that, understanding sufferers’ microbiome could help with diagnosis.
“At the moment, endometriosis is diagnosed via an invasive laparoscopy investigation, but hopefully we could use the lessons learnt from our work to come up with a simple non-invasive diagnostic tool for early detection,” Kommagani says.
His research makes an interesting counterpoint to the Warwick trial, which will use the broad-spectrum antibiotic doxycycline. Doxycycline is active against many different types of bacteria (both aerobic and anaerobic, gram-positive and gram-negative). It is already being prescribed as an endometriosis treatment – and is also being given to some women experiencing miscarriage – but has not yet been thoroughly tested.
For the millions of women worldwide who are affected by either issue, research of this nature may seem long overdue.
“More than 176 million women in the world are affected by endometriosis, but the amount of research going on is very limited compared to cancer and it receives only a fraction of the funding,” says Kommagani. “Endometriosis needs more attention – it’s a very under-studied, underappreciated, underfunded area.”