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Pregnancy procedure associated with increased risk of preterm birth and neonatal loss

Imperial College London

Researchers are urging surgeons to reconsider using a particular type of thread for a procedure to prevent premature birth, after new research found this thread was associated with an increased rate of premature birth and baby death compared with a thinner thread.

In a new study, researchers at Imperial College London analysed 671 UK women who received a cervical stitch procedure to prevent miscarriage or premature birth.

The procedure, which is performed on around two million women a year globally, is offered to women deemed at high risk of miscarriage or premature birth. The process involves surgeons placing a stitch in the cervix to hold it closed and delay labour. The closed cervix also acts as a barrier to infection, and so shutting it with a stitch prevents bacteria passing through the cervix and into the womb.

Surgeons use one of two types of thread for the stitch - the majority use a thicker woven thread, and around 20 per cent use a thinner thread.

The study results, published in the journal Science Translational Medicine, suggest the thicker thread is associated with a three-fold increase in rate of baby death in the womb when compared to the thinner thread, and is associated with an increased rate of premature birth. It's thought the thicker woven structure of the thread encourages the growth of dangerous bacteria.

The team suggest switching to the thinner thread for all procedures could prevent 170,000 premature births globally every year, and 172,000 intrauterine baby deaths every year across the world.

Professor Phillip Bennett, lead author of the study from the Department of Surgery and Cancer at Imperial, said: "Although the cervical stitch procedure still holds benefits for women overall, our results suggest the thicker thread may encourage the growth of potentially dangerous bacteria in the cervix. This may lead to premature birth or even loss of the baby. We strongly advise that the thicker thread - which is currently used in the majority of procedures - only be used in a research setting whilst we thoroughly investigate the risks this may hold."

Around 50,000 babies are born prematurely ever year in the UK. Defined as birth between 24 and 37 weeks of pregnancy, premature birth is the leading cause of neonatal death in the UK. It is triggered by the cervix opening too early in the pregnancy, causing the baby to start moving down the birth canal. The causes are unknown, but infection in the birth canal is thought to be a factor.

Women are recommended to undergo the cervical stitch procedure if they are deemed at high risk of late miscarriage or premature birth - for instance if they have had a previous miscarriage later in pregnancy or a baby who was born too early.

During the procedure, also called cervical cerclage, surgeons use one of two types of thread to close the cervix. One is a thin nylon thread, around 1mm think and very similar to fishing line, called monofilament. The other is a thicker thread - around 5mm thick - that is comprised of smaller threads woven together like a shoe lace. The thicker woven thread - called multifilament - is used in around 80 per cent of procedures as surgeons believe it to be stronger, and more efficient at holding the cervix closed.

In the new study, the team looked at 671 women who had the procedure at five UK hospitals over the last ten years. Around half had the thinner 'fishing line' thread, while the other half had the thicker 'shoe lace' thread.

The results revealed the thicker thread was associated with increased rate of intrauterine death compared to the thinner thread (15 per cent compared to 5 per cent). The rate of intrauterine death in a normal pregnancy is around 0.5 per cent.

The thicker thread was also associated with an increased rate of preterm birth rate compared to the thinner thread - 28 per cent compared to 17 per cent. The rate of preterm birth among the general population is around 7 per cent, but the cervical stitch procedure is only performed on women already deemed at high risk of premature birth.

To understand the difference in outcomes between procedures using the two threads, the team conducted a second study with 50 women who were due to have the cervical stitch procedure. Half received the thinner thread, while half received the thicker thread.

The team then monitored the women at 4, 8 and 16 weeks after the procedure through ultrasound scans and analysis of bacteria collected using vaginal swabs.

The results suggested that women who received the thicker thread had increased inflammation around the cervix. There was also increased blood flow, which is associated with the cervix opening before labour.

Crucially, the team also found women who received the thicker thread had more potentially harmful bacteria in the vagina and around the cervix.

Dr David MacIntyre, scientific lead of the study, also from the Department of Surgery and Cancer at Imperial explained: "At the beginning of the trial, all women had similar types of naturally-occurring bacteria, called Lactobacillus, in their birth canal and around their cervix. However four weeks after the procedure 45 per cent of the women who received the thicker thread had these harmless bacteria replaced with potentially dangerous bacteria that have previously been associated with poor outcomes during pregnancy, like preterm birth and infection in babies. Women who received the thinner thread maintained normal levels of harmless Lactobacillus bacteria in the birth canal or cervix."

The team also performed lab-based experiments to examine how easily bacteria grew on the two types of thread. Dr MacIntyre added: "We found potentially dangerous bacteria grew more easily on the thicker thread. This may be because bacteria can latch onto the woven structure of the thick thread more easily than the smooth thin thread. "

There is a randomised clinical trial of 900 patients currently underway, organised by University of Birmingham, which is looking at the comparative risks of the two threads.

Professor Bennett added: "Our current study suggests the thick multifilament thread is associated with increased risk of complications. Even after factoring in the age and overall health of the patient, this effect still existed. However there are other factors that may influence the risks, such as surgical technique. Only by performing a large randomised clinical trial can we confirm whether the thicker thread itself is triggering complications, to ensure this procedure is as safe and effective as possible for the mother and baby."

Professor Bennett added that anyone concerned about the cervical stitch procedure should speak to their healthcare team.

Professor Jeremy Nicholson, head of the Department of Surgery and Cancer at Imperial, explained the research also provides insights into how a women's naturally occurring bacteria may influence pregnancy: "This research showed that all 50 women in the second part of the study had a higher level of potentially dangerous bacteria in their birth canal than a healthy pregnant woman - even before undergoing the cervical stitch procedure. This links to our ongoing work that suggests a woman's bacterial mix in the birth canal - called the microbiome - has an important role in pregnancy. It also shows, for the first time, that treatments that change the bacteria in the vagina may lead to bad outcomes in pregnancy. We need to further investigate the role of a woman's vaginal microbiome in pregnancy to help ensure more babies are born healthy, and at the right time.

"This is part of a much broader work programme in our department aimed to understand the normal microbial composition of the body, and how changes to this may link to a range of non-infectious diseases."

Jane Brewin, chief executive of the charity Tommy's, added: "The really good news is that a safe and proven treatment to prevent pre-term birth has just been made safer by this new finding. A treatment which has been around for many years has been shown to prevent pre-term birth but no-one really understood why it seemed so effective in some people but not in others; now we have a plausible explanation and success rates should improve as a result of this work. It's important that women who have this procedure ask their obstetrician about what stitch they will receive because clinical practice can take time to catch up with research findings."

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The research was funded by the Genesis Research Trust and the NIHR Imperial Biomedical Research Centre. Dr David MacIntyre was supported by a Career Development Award from the Medical Research Council.

For more information:

Kate Wighton
Research Media Officer - Medicine
Imperial College London
k.wighton@imperial.ac.uk
+44(0)20 7594 2410

Notes to Editors:

1. "Relationship between vaginal microbial dysbiosis, inflammation, and pregnancy outcomes in cervical cerclage" by L.Kindinger et al is published in the journal Science Translational Medicine.

2. Images of the two threads are available to download on link below. The images show the thick multifilament thread (top), and the thin monofilament thread (bottom).

A short three-minute video of the researchers discussing the trial and its implications is available for re-use - contact k.wighton@imperial.ac.uk for the link.

3. A Q&A about the study by lead researcher Professor Bennett is available for re-use:

starts

Professor Philip Bennett from the Department of Surgery and Cancer at Imperial explained why the procedure is used, and what this research means for women.

What is a cervical stitch procedure?

The cervical stitch procedure, also called cervical cerclage, involves surgeons placing a stitch into the cervix - the small channel at the base of the womb. The idea is this strengthens the cervix and prevents it opening too early in the pregnancy. Around 80 per cent of procedures are performed with a thicker thread - which resembles a tape - and the rest are performed with a thin nylon thread, like fishing line.

Why is the procedure needed?

Some women have a weakened cervix, which means it opens too soon in the pregnancy. This triggers premature birth. Around one percent of all pregnancies are affected by a weakened cervix. The cervical stitch procedure is offered to women deemed at high risk of premature birth - for instance if they have had a previous miscarriage later in pregnancy or a baby who was born too early.

At the moment there aren't any other options available to such women, although much of the work we do in my group is focused on trying to understand what causes premature birth and how we can prevent it.

There was a review into the cervical stitch procedure in 2012, conducted by the renowned Cochrane Review, which looked at the existing research on the cervical stitch. It found the procedure reduces the incidence of preterm birth in women at risk of recurrent preterm birth, although it did not find a statistically significant reduction in stillbirth or health effects on the baby.

What did your new research find?

Our new research analysed 671 UK women who received a cervical stitch procedure to prevent miscarriage or premature birth. We found that the thicker thread is associated with a three-fold increase in rate of baby death in the womb when compared to the thinner thread, and is associated with an increased rate of premature birth. We think that the thicker woven structure of the thread could be encouraging the growth of dangerous bacteria.

We believe that globally, switching to the thinner thread for all procedures could prevent 170,000 premature births and 172,000 intrauterine baby deaths every year.

Although no data is kept on how many women in the UK receive the cervical stitch procedure, we estimate around half of all women with cervical weakness receive the procedure - that's about 1 in every 200 pregnant women, or roughly 3250 women every year. Around 80 per cent receive the thicker thread - but if this proportion were to be given the thinner thread, this may prevent around 280 preterm births, and result in 260 fewer baby deaths per year in the UK.

Based on what we found in our study, we recommend the thicker thread is only used in a research setting until we have more evidence about the potential risks.

A clinical trial is currently underway, called C-Stitch, that is comparing the two types of thread.

If anyone is thinking of having this procedure, what should they do?

Anyone concerned about this procedure should talk to their healthcare team. Each patient has different risk factors and circumstances, so it's important patients speak to their midwife or doctor about what might be right for them.

The charity Tommy's provide information and support for anyone affected by premature birth or stillbirth - Tommys.org.uk. They also have a support line open 9am-5pm Monday-Friday - 0800 0147 800.

4. About Imperial College London

Imperial College London is one of the world's leading universities. The College's 16,000 students and 8,000 staff are expanding the frontiers of knowledge in science, medicine, engineering and business, and translating their discoveries into benefits for society. Founded in 1907, Imperial builds on a distinguished past - having pioneered penicillin, holography and fibre optics - to shape the future. Imperial researchers work across disciplines to improve health and wellbeing, understand the natural world, engineer novel solutions and lead the data revolution. This blend of academic excellence and its real-world application feeds into Imperial's exceptional learning environment, where students participate in research to push the limits of their degrees. Imperial collaborates widely to achieve greater impact. It works with the NHS to improve healthcare in west London, is a leading partner in research and education within the European Union, and is the UK's number one research collaborator with China. Imperial has nine London campuses, including its White City Campus: a research and innovation centre that is in its initial stages of development in west London. At White City, researchers, businesses and higher education partners will co-locate to create value from ideas on a global scale. http://www.imperial.ac.uk

5. About the NIHR

The National Institute for Health Research (NIHR) is funded by the Department of Health to improve the health and wealth of the nation through research. The NIHR is the research arm of the NHS. Since its establishment in April 2006, the NIHR has transformed research in the NHS. It has increased the volume of applied health research for the benefit of patients and the public, driven faster translation of basic science discoveries into tangible benefits for patients and the economy, and developed and supported the people who conduct and contribute to applied health research. The NIHR plays a key role in the Government's strategy for economic growth, attracting investment by the life-sciences industries through its world-class infrastructure for health research. Together, the NIHR people, programmes, centres of excellence and systems represent the most integrated health research system in the world. For further information, visit the NIHR website (http://www.nihr.ac.uk).

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