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Charm Research Project

Charm is a small charity with an even smaller infrastructure, which means that the overwhelming majority of the funds donated are spent directly on the research.

We now know that the most important treatable cause of recurrent miscarriage are disorders of pregnancy haemostasis or blood clotting problems.

Our team have shown that women with antiphospholipid antibodies can be helped to have a successful pregnancy by treating them with blood thinning drugs such as aspirin and heparin. But we also realise that there are many other blood clotting problems that can lead to miscarriage and we are always trying to identify new tests to identify those women who are at risk and offer them appropriate treatments during pregnancy.

The thromboelastogram (TEG) is a machine that analyses blood samples and can provide us with much information about the speed of clot formation in the blood, the strength of the blood clots formed and the rate at which the clots are dissolved in the blood stream. We have found it enormously helpful in identifying women with recurrent miscarriages who may respond to different treatments. For example, those women with raised clot strength who can be identified before they become pregnant are advised to start taking aspirin tablets as soon as their next pregnancy test is positive. On the other hand, it appears that when the problem is a reduced ability to dissolve the clots, that it is more likely that heparin treatment is the drug of choice. However, it now appears that some women with normal TEG results before pregnancy go on to have abnormal test results when they become pregnant. Presumably the pregnancy switches on a pro-inflammatory or pro-clotting tendency that cannot be identified beforehand and by repeating the TEG test as soon as they become pregnant we can offer these women treatment to save their pregnancies from miscarrying.

The great advantage of TEG testing is that it is relatively inexpensive and the results are available within a few hours of the blood sample being taken, so we can really respond quickly when we know that one of our patients has become pregnant. This has been a real breakthrough in terms of advancing the care of the woman and her unborn child and potentially represents huge savings for our hard pressed health service budget.

During the next 6 months we want to carry out several new research projects using the TEG in order to identify further sub groups of recurrent miscarriage women who may benefit from novel treatments during pregnancy. We also think that the TEG results may help us to predict which women are at greater risk of heart attacks and strokes in later life. If we can identify these women when they are relatively young, we can offer them the opportunity of preventative health care for the future and this would have an enormously beneficial impact on women’s health.

Polycystic ovaries (PCO) are common. A quarter of all women have this type of ovary but amongst those with recurrent miscarriage more than 40% of women have PCO. Women with PCO have a higher miscarriage rate in future pregnancies compared with those without PCO. Over the last 25 years, a variety of hormonal abnormalities seen in women with PCO have been thought to be the underlying cause of the pregnancy losses. However, a number of studies, including those from St Mary’s, have shown that there is no relationship between several different hormones and future pregnancy outcome.

More recently, we have been investigating whether the link between PCO and repeated miscarriages could be explained by disorders of blood clotting. Our studies have shown there is a relationship between PCO, raised insulin levels and a genetic abnormality in the gene that controls the break down of blood clots and hence implantation of the tiny embryo in the uterine lining. This work is funded by a project grant from Wellbeing of Women but we were only able to apply for this funding because we had pilot data to show that our research was likely to be successful. And yes it was Save the Baby (Charm’s predecessor) that gave us the money to get this project up and running and ensure that the research work would be carried out. We have recruited over 200 women to this important study and we have already presented our preliminary data at an international meeting in Florida earlier this year. If our findings are confirmed it will open a potentially new avenue of treatment for the large number of women with PCO who have experienced recurrent miscarriage.

Fortunately only 1% of pregnancies that have reached the second trimester are at risk of miscarrying. However, in the recurrent miscarriage clinic at St Mary’s, as many as 1 in 4 of the couples we see have suffered the trauma of a “late” miscarriage. We have developed considerable experience looking after these tragic cases and now recognise that very often the woman has more than one underlying cause for the late miscarriages. She may have a weakened cervix (neck of the womb) which starts to shorten and open as the pregnancy advances; she may be prone to infection which ascends the vagina and cervical canal to reach the membranes around the baby, causing the waters to break and uterine contractions to start prematurely; or she may have a prothrombotic disorder that results in blood clots developing in the placenta which prevents the baby from receiving vital nutrients. Sometimes she has all three problems and needs treatment for all of them simultaneously: – aspirin and heparin, antibiotics and the insertion of a special cervical stitch to keep the cervix closed throughout the second and third trimester of pregnancy.

At St Mary’s we have developed a modified version of the Shirodka cerclage or stitch, which we insert at about 12 weeks in the operating theatre under an anaesthetic. We believe that it is particularly successful because it is placed much higher in the cervix and also because we bury the stitch material under the vaginal skin. Since ther is no foreign body or suture material sitting in the vagina, the woman does not develop a chronic discharge during her pregnancy. This together with the use of heparin for prothrombotic problems and antibiotics for any infection that we identify has resulted in us having a 97% live take home baby rate – a success rate that has been maintained over several years now because we only allow the stitch to be inserted by senior consultants who have lots of experience of the technique.

When a couple is suffering from recurrent miscarriage doctors usually focus their attention on the woman to find the cause. However recently researchers have started to look into factors in men. Sperm has an important role in the development of a healthy placenta to provide oxygen and nutrients to the baby. The DNA of the sperm is the important instructions which pass on the father’s genes. A recent study in Imperial College London revealed that sperm from men whose partners had suffered from recurrent miscarriage had twice as much DNA damage compared to the sperm of men whose partner hadn’t. It was also found that molecules called ‘reactive oxygen species’ were four times higher in men with sperm DNA damage. These reactive oxygen species are produced naturally in small amounts in the semen to protect sperm from infection but in higher concentrations they can damage the sperm’s DNA. Factors such as obesity, ageing, alcohol, smoking and infection are being investigated as potential causes of increased levels of reactive oxygen species and therefore DNA damage. If we can find exactly what causes these affects in men then we may be able to find treatments to reduce it.

 

The first study was the PROMISE trial which studied 836 women who had experienced three or more miscarriages. In their next pregnancy, half of the women were given progesterone pessaries and the other half were given a placebo. The study found that overall, there was not a significant increase in live births for the women who had progesterone compared to those who had the placebo. There was however some evidence that the more miscarriages a woman had experienced, the more likely progesterone was to be beneficial. It was concluded that this finding required more research.

The subsequent study investigating the role of progesterone further was the PRISM study. This was a larger study where 4153 women were given either progesterone or a placebo when they presented to the hospital with bleeding within the first 12 weeks of pregnancy. The study showed no benefit in taking progesterone for women who were bleeding who had no previous miscarriages. There was some benefit in taking it for those who had experienced one previous miscarriage and a strong benefit seen for those who had experienced three or more miscarriages. 

In summary, for women who have experienced three or more miscarriages and have bleeding in early pregnancy taking progesterone supplementation is recommended as there has been shown to be a strong benefit. For women who have had one or two miscarriages and experience bleeding in early pregnancy there may be some benefit in taking progesterone. For women who are not bleeding in pregnancy but have experienced a higher number of miscarriages, there may be some potential benefit in taking progesterone.

(Reference: Coomarasarmy, A., Devall., A.J., Brosens, J.J. et al. (2020) Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence. American Journal of Obstetrics and Gynaecology. 232 (2) pp. 167-176. Doi:10.1016/j.ajog.2019.12.006.)

 

the major London hospitals, but instead of just looking at Recurrent Miscarriage couples and their babies, Some years ago the Recurrent Miscarriage team at St Mary’s started collecting a tissue bank of blood samples from the many couples that were referred to the unit. We wanted to ensure that we would be able to utilise every opportunity to carry out further research to improve pregnancy outcomes for these couples. We recognised that to do this we needed to establish an archive of tissue that we could refer back to at a later date, with the benefit of new and improved technology and laboratory techniques. At the time it was considered quite unusual to collect samples from the father, but we felt that this was essential since 50% of the fetus or baby comes from the father. Soon after, we extended the collection to also include samples of the cord from the newborn baby and pieces of placenta from those pregnancies that sadly went on to miscarry. This was how our tissue bank of “trios” (mother, father and baby) started and in no space of time, we found that it was a really valuable resource for our research projects. Instead of having to wait to collect samples for each project, we could now turn to the samples we had carefully stored and undertake the laboratory experiments much more swiftly.

Our idea has really caught the attention of others interested in research into later pregnancy complications and recently Professor Lesley Regan and Professor Gudrun Moore from University College London were awarded a large grant from Wellbeing of Women to set up the Baby Bio Bank. This is a collaborative collection of Trios from all the Baby Bio Bank is including trio samples from the other major complications of pregnancy: preterm birth, fetal growth restriction and pre-eclampsia. So an idea that started here and was funded by our supporters has really taken off and been adopted nationally. Another example of how our research is really making a difference.



Important research projects that Charm would like to fund in the future

Longitudinal study of the long term health in women with antiphospholipid antibodies who make their first medical presentation when they suffer recurrent miscarriages.

Not much is known about the long term effects of antiphospholipid syndrome on women’s general health. In theory they may be at greater risk of thrombosis in later life but we do not know how great this risk is and who is most likely to be affected. These women may benefit from taking anti-thrombotic precautions and avoiding additional risk factors like smoking, hormone therapies, prolonged periods of immobility and long haul travel. We hope to follow up our many patients over the next 10 to 20 years so that we can offer them the very best advice to stay healthy in later life.

Pregnancy: the healthcare opportunity of 2 lifetimes – mother and baby.

We know that many events that occur during a woman’s pregnancy are predictive of her future health and that of her baby. In some ways pregnancy can be viewed as a trial run or road test for the future rather than an event that ends after the delivery of the baby. Furthermore, we know that women who have suffered recurrent miscarriage appear to be at greater risk of a variety of medical problems in later life. We want to develop new tests and more robust ways of identifying those women and their babies at greatest risk in order to offer them preventative interventions that will improve their future health.

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Charm Foundation UK, St Mary’s Hospital, Department of Obstetrics and Gynaecology, Ground Floor, Mint Wing, South Wharf Road, London W2 1NY

Registered charity number 1133659.