20
Preterm Birth Committee
Corrected oral evidence: Preterm birth
Monday 26 February 2024
3.05 pm
Members present: Lord Patel (The Chair); Viscount Colville of Culross; Baroness Cumberlege; Lord Hampton; Baroness Hughes of Stretford; Baroness Owen of Alderley Edge; Baroness Seccombe; Baroness Thornhill; Baroness Watkins of Tavistock; Lord Winston; Baroness Wyld.
Evidence Session No. 5 Heard in Public Questions 62 - 67
Witnesses
I: Professor Anna David, Professor in Obstetrics and Maternal Fetal Medicine, University College London; Professor Mark Johnson, Clinical Chair in Obstetrics, Imperial College London; Professor David MacIntyre, Professor of Reproductive Systems Medicine, Imperial College London; Professor Sarah Stock, Professor of Maternal and Fetal Health, University of Edinburgh.
Professor Anna David, Professor Mark Johnson, Professor David MacIntyre and Professor Sarah Stock.
Q62 The Chair: I welcome all our witnesses. Thank you very much for coming. To put on record who you are, would you please introduce yourselves and then we will get on with the questions.
Professor David MacIntyre: I am professor of reproductive systems medicine from Imperial College London.
Professor Anna David: Good afternoon. I am a consultant in obstetrics and maternal fetal medicine, and director of the Institute for Women’s Health at University College London.
Professor Mark Johnson: I am a professor of clinical obstetrics at Imperial College.
Professor Sarah Stock: I am professor of maternal and fetal health at the University of Edinburgh.
The Chair: Thank you very much indeed. Before I ask Baroness Wyld to kick off the questions, I say to you, Professor Johnson, particularly because you were instrumental in working with Baroness Bertin, who instigated this inquiry, that, unfortunately, she was unable to join the committee because she got a tougher job to do than this one. We acknowledge that you were involved in drawing attention to the subject of preterm birth. I hope we do justice to that work.
Q63 Baroness Wyld: Good afternoon, everybody. Could we start by you telling us what validated techniques are available to determine the risk of preterm birth? Within that, we are very interested in whether those could then be applied to screening for all women. Shall we start with Professor Stock?
Professor Sarah Stock: Thank you. In terms of predicting the risk of preterm birth, the main tests we have in secondary prevention revolve around measuring the length of the neck of the womb or cervical length. These are part of the guidelines from NHS England for secondary prevention of preterm birth, where women with identified risk factors are coming into specialist services, when the neck of the womb is shortened, and having treatment for that.
On whether the techniques could be applied to all pregnancies, I think the answer is yes, they could. The question is whether that will be effective and cost effective. They are not recommended as part of screening at the moment in the UK. The reason is that, if a short cervix is detected on scan in a low-risk population, only three in 10 of those with a positive test would actually go on to give birth preterm. That would mean that we are overtreating seven in 10 women with treatments to prevent preterm birth. If it is introduced, we need to think very carefully about how we would collect the data from all those receiving treatment to make sure that we record the outcomes and can assess them.
The second thing is that the tests detect only a small proportion of the women who give birth preterm. About 10% of all preterm births are in women screened with a short cervix. It may help to predict in those women, but there will be a lot of women for whom these tests would not work.
My third point is that we may be able to learn from other countries. The Australian Preterm Birth Prevention Alliance has a government-funded initiative, where it is rolling out a programme that includes offering these screening tests to low-risk women and the general population. Those results will be reported later this month to the Australian Government. I think they have shown a small absolute reduction in preterm birth locally. We are waiting to see whether it would be useful as a national programme.
Professor David MacIntyre: I am a non-clinician, so I come at this from a different perspective. The only thing I would add to what Sarah has already mentioned is the fact that a lot of the tests that are currently being used for screening detect risk at quite a late stage of the process of the events that would lead to a preterm delivery. That indicates that, if we can come up with better methods of detecting women at risk earlier in pregnancy, the current treatments available to us might be far more effective. That is an important point to consider.
Professor Anna David: I think of preterm birth in a very holistic way. It is not just women who have a short cervix, but women who have placental insufficiency or develop early onset pre-eclampsia, where they get high blood pressure and protein in the urine. Although many of them are delivered, or have an indicated delivery, because they have raised blood pressure, and they have a caesarean section, quite a proportion of them go into labour early.
There is a relatively effective screening test called the Fetal Medicine Foundation algorithm, which has been developed by Professor Nicolaides. It incorporates obstetric history, blood pressure—mean arterial pressure assessing the blood flow in the uterine arteries—and looking at two blood tests, PAPP-A and placental growth factor. He has done a randomised control trial, and if you put all those together, it has been demonstrated that in women who screen high risk and are given low-dose aspirin, which has to be done early, before 16 weeks of pregnancy, and with a good enough dose, probably at least 80 mg daily, you reduce the risk of preterm birth. It is preterm birth due to early onset pre-eclampsia, but that still means you are reducing the risk of preterm birth.
Of course, to roll that out nationally you would need to make sure that everybody could do that screening test in practice, which would mean you might need to extend the length of the ultrasound that you do and that women have blood tests. A recent health technology assessment from Ontario, published a couple of years ago, demonstrated that that is probably cost effective, but it would need some investment of funding and time at the time that you do the screening test, at around 11 to 14 weeks of pregnancy. That may well reduce the risk of preterm birth in a cost-effective manner.
Baroness Wyld: If you were of the view that that should be rolled out across the NHS, where do you see the main blocker? If it is around 11 to 14 weeks, is it about time and resource or workforce or money?
Professor Anna David: I think it is both time and resource. I think you would have to increase the number of sonographers available to do the ultrasound—the uterine artery dopplers. It would take at least half an hour to 45 minutes, so it would tack an extra 15 minutes on to the dating scan that all women are offered. Then you would have to make sure that people were taking low-dose aspirin. That is one of the issues. Low-dose aspirin is a good drug for reducing the risk of early onset pre-eclampsia, but, of course, women go to pharmacies and are told, “Oh, you’re not supposed to take low-dose aspirin in pregnancy because it’s risky”, so not everybody is actually advised to take it. There are barriers. Finally, I do not think that everybody will respond to it. We know that for nine out of 10 women it has an effect, but for probably at least 10% of the population it has no benefit.
For women who are at risk of spontaneous preterm birth, more data is needed. I refer to Professor Stock, who wrote a very good article about this recently, which was a comment on a trial suggesting that low-dose aspirin might reduce the risk of spontaneous preterm birth. We need more data, but certainly for women at risk of early onset pre-eclampsia, leading on to preterm birth, we have some good evidence. We need to evaluate it and see whether it is cost effective.
The Chair: Can we be clear on what you have just said? This is a test that identifies women at risk of pre-eclampsia and therefore the number of preterm deliveries, but that would be because those mothers, when they develop pre-eclampsia, will need to be delivered early because of the pre-eclampsia. It is not that it prevents spontaneous preterm labour.
Professor Anna David: Some women who develop pre-eclampsia go into labour early. It is very difficult to tease out whether it is a spontaneous preterm birth due to a short cervix or due to a placental pre-eclampsia cause. That is one of the problems that we have with this whole area. There is such a mixed bag of causes.
The Chair: What numbers are we talking about as a percentage for the totality of preterm births? I know you will be the one who has that data.
Professor Anna David: Just looking at the ASPRE trial, which was the original trial that Professor Nicolaides did, the preterm pre-eclampsia rate reduced from 4.3% to 1.6%.
The Chair: It was a reduction. Please continue, Lady Wyld.
Baroness Wyld: Thank you very much. Do you want to add anything, Professor David?
Professor Anna David: No, thank you.
Baroness Wyld: Professor Johnson?
Professor Mark Johnson: I have little to add. There have been studies proving that if you introduce the 12-week screening test it is, money-wise and staff-wise, unchanged because you reduce the risk of the need for serial growth scans. That is work by a professor from St George’s whose long name I cannot pronounce.
Professor Anna David: Thilaganathan.
Professor Mark Johnson: Exactly. You said it beautifully. I think it would be cost neutral. The first step is to go to the screening committee. I was discussing it with it recently. It says that it is close to approving it. Once it is approved, I think the existing data would be sufficient for us to start using the test.
In terms of the cervical length screening, some data pick up slightly higher rates than 10%, but there is so much data in this field. At King’s, where they have introduced this, they saw a 10% reduction in preterm birth before 32 weeks by doing this and giving progesterone to low-risk women who had a short cervix. There is an effect; 10% is 10%, but it is not as large as the 40% we might have hoped from the studies on progesterone and short cervix.
The Chair: Are these studies well validated and controlled, or are they ad hoc?
Professor Mark Johnson: The cervical length screening tests?
The Chair: No; the one that you just mentioned that King’s uses.
Professor Mark Johnson: The King’s study is only, I am afraid, an evaluation of what introducing the service did. It was not a randomised study; it was an observational study.
The Chair: It is an early-phase study that indicates that there might be a possible benefit, which may then lead on to properly conducted research, which requires funding.
Professor Mark Johnson: Absolutely.
The Chair: That is an important point because our job is to identify areas of possible research that may benefit.
Q64 Lord Winston: Thank you all very much indeed for turning up today to help us with this difficult inquiry. My key question is about the molecular and cell biology research that may be going on, or that you feel is either missing or available, and what is being undertaken to try to look at the mechanisms of preterm labour. One thing that is very clear to all of us is that preterm labour is an unknown mechanism. It seems to me that we should try to get much more of a handle on that mechanism. David, could you start that discussion?
Professor David MacIntyre: I could not agree more with your suggestion that we need to understand more about the mechanism. It is not just one mechanism. That is the place to start the conversation. Preterm birth can be caused by many factors. We are still trying to get a handle on the various underlying aetiologies of preterm birth. For example, giving aspirin to women to deal with issues around placental function is likely to be effective in reducing later preterm births, but issues around early preterm births—when babies have the most need for care and have the worst outcomes—are probably more associated, we think, with an infection or an infectious aetiology in preterm birth.
A lot of the work that is currently being done on cellular and molecular mechanisms of understanding preterm birth comes all the way back to what you commented on in an earlier committee session. It was work that was largely being done 30 years ago trying to understand the fundamental science of what causes the uterus to start to contract at the time of labour, the cervix to become soft and ripened, and the fetal membranes or the amniotic sac to rupture.
We are also trying to understand whether the pathways that are involved with switching on those types of events are consistent with or similar to what happens in preterm birth. There are some similarities, but there are also several differences. It is quite challenging to tease that apart. Good advancements are being made in certain areas, which, if you give me the time, I can highlight very briefly—for example, understanding the role of certain microbes in the lower reproductive tract and how that might shape immunological responses in the reproductive tract that are very relevant to the pathways that switch on preterm labour.
Similarly, there is evidence indicating that senescence, or ageing, of cells in and around the placenta and the fetal membranes could be another mechanism, which would tie in again with mechanisms involving inflammation signalling at the time of labour. That differs from term labour where inflammation is involved, but we are not quite so sure that it is a trigger of labour itself. I could go on for a lot longer, but I fear that I would take up all the time of the committee.
Lord Winston: I wish you would, but the committee would get very fed up with me asking you further questions. I will ask you about one or two related issues. There is a lot of interest at the moment in, for example, the biome. The response to inflammation is clearly of great interest. Would you like to comment on those two areas and whether we are barking up the wrong tree?
The Chair: When you answer the question, can you, for the benefit of the rest of the committee, briefly say what you mean by “biome”?
Professor David MacIntyre: The microbiome refers to the collection of microbes. These are the bacteria, viruses and fungi that colonise the reproductive tract. Like many other body sites, we now understand—largely from the new developments in technology that have happened over the last couple of decades—that a woman’s reproductive tract is full of those microbes, which are collectively called the microbiome. Work, not just from our own lab but from others around the world, indicates that certain communities of bacteria in particular are likely to shape immunological responses that are very relevant to the onset of preterm birth. Some of the bacterial communities are actually protecting against adverse inflammatory activation of the reproductive tract, whereas others are probably perturbing it.
We are getting more and more data from datasets throughout the world to indicate that this is actually quite a convincing potential route of investigation. Importantly, it is a modifiable risk factor of preterm birth. What I mean by that is that there are therapeutics and treatment interventions that we can use to try to modulate and change the microbial composition in the reproductive tract.
Lord Winston: I do not want to bang on about this but do different populations have a significantly different biome? Does that appear therefore in the incidence of preterm birth?
Professor David MacIntyre: There are several confounders of the composition of the microbiome. There is some evidence to indicate that different ethnic populations have different compositions of microbes. However, even when we take that into consideration there still seems to be a signal that the microbiome is a risk factor for preterm birth. It also links to some other things that have already been discussed in the community. We know that women who are of lower socioeconomic status and women who are perhaps not optimising their health in certain ways can have suboptimal microbial communities that could increase their risk of preterm birth.
Lord Winston: Mark, do you want to add to any of that stuff?
Professor Mark Johnson: We are doing more in the charity that I founded back in 2013. We started to do the BUMP analysis—the Borne uterine mapping project—to see whether we can use cutting-edge technologies such as single cell or single nucleus sequencing to find out what is going on with the onset of labour.
We lack pharma involvement in preterm labour. The absence of it is—
Lord Winston: Which single cells would you look at?
Professor Mark Johnson: The myometrium, the decidua, the choriodecidua, the fetal membrane—each single cell from the reproductive tract. It is essential that we understand what is going on at the cellular level so that we can find the mechanism, in order to have treatments that might stand a success of treating it.
Lord Winston: I am in difficulty here, Professor David and Professor Stock. Obviously, you are coming at this from very different academic angles. Clearly, the impact that you have made has been much more profound in many ways than the obstetricians’ impact because neonatal research started with gatherings of really good paediatricians who started to look at neonatal medicine. I came from the Hammersmith, where there were four consultants, and a pathologist, Jonathan Wigglesworth, doing the post-mortems, which, of course, led to much of the work that is going on. Do you feel that there are areas where you could make more input into the obstetric management, such as seeing the patients together, for example? Would you comment on that, Professor David?
Professor Anna David: I am an obstetrician and maternal fetal medicine specialist, but I have lot of liaison with neonatologists. It is really important that we think with the neonatologists about what is the best care for a woman, and a couple, about to have a baby, going into labour—for example, all the work that has been done on optimising giving timely magnesium sulphate to reduce the risk of the baby having a fit after birth, and timely steroids. We know, for example, that giving steroids too early probably has a detrimental impact on the long-term development of the baby. That is why it is quite difficult. Many of the tests—you were talking about the fetal fibronectin test—to predict preterm birth are not that good. We need to time the steroid dose to be given preferably 24 to 48 hours before the woman goes into labour, but it is actually very difficult to do that.
One way that we can have an impact for couples is to improve the counselling that we do about the potential risk of the woman going into labour and the potential impact for the baby. It is particularly around women who have a risk of very early delivery. For example, Ciara Curran was talking about early, preterm, pre-labour rupture of the membranes at 22 weeks. I do a lot of work on fetal growth restriction, which means that we are delivering babies very early because they are very tiny.
We have some evidence to show that we can actually predict what will happen, but this has occurred only because we have been looking at the natural history of somebody presenting with ruptured membranes or a very small baby, and then taking their blood and following them through in very detailed ways, collecting all the information. We look at the placenta and do long-term follow-up studies on the baby until two years of age, identifying the key outcomes. For parents, the key outcome is, “How will my baby be at two years of age?” It is very expensive; to do that kind of natural history study requires a lot of investment. That is what we really need to do. It is not just, “When will the baby deliver? What is the gestational age of delivery?” It is, “What is the outcome for the baby at two years of age? Will the baby have cerebral palsy, lung damage, or will they have a good, healthy life?”
The Chair: Professor Stock, as a maternal/fetal medicine expert, you are also highly involved in molecular- and cellular-level studies. Going back to Professor Winston’s original question, do you have any comments?
Professor Sarah Stock: I would like to tie both together. There is an absolute need for fundamental research, and that research has to be in humans because we do not have good animal models. What we can do is tie into some of the clinical studies that we need. We can collect samples that feed back to improving our molecular knowledge.
As Professor David said, it is not only about prediction from an early stage. It is about monitoring and diagnosis, and making sure that we can time therapies that we know can be lifesaving and illness sparing for preterm babies. We need better measures and early detection of changes that happen around the time of parturition—the time of labour. We need to collect high-quality samples to feed into the fundamental research. Building our expertise in that is very important.
The Chair: Do you have any supplementary questions, Lord Winston?
Lord Winston: No. I think that is a good start; thank you.
Q65 Baroness Watkins of Tavistock: Clearly, there is a range of challenges in undertaking obstetric research. We cannot replace humans, as we have just been told. Can you talk about the challenges and difficulties but also the opportunities for translating what we know now into clinical practice across the multi-professional team, and how you think further investment could enable us at least to do that, as well as conducting new research?
Professor Anna David: I would sum it up by saying that, because we do not do clinical trials of drug treatment in pregnancy, we do not do clinical trials in pregnancy. It is almost that because we do not do them we do not have the tools to be able to do them.
I will give a few examples. I have been part of what is called the Birmingham Health Partners Commission, which produced a report. We interviewed insurers and asked, “Why is it so difficult to get insurance for a clinical trial of a new drug?” Part of the reason is that they do not know how to cost out the premium. They are concerned about the risk of litigation because it is incredibly expensive. A baby damaged in utero could cost upwards of £37 million.
We know that babies have fetal anomalies. The risk of fetal abnormality is probably about one in 47 or one in 50. It is risky, but if you do not know how much it will cost you cannot say what the premium should be. I have been very fortunate. I am developing a treatment for fetal growth restriction, where the baby is very small. We are trying to improve growth and blood flow. An example of a premium cost would be about £85,000, which we got for another trial. That was cheap. That was because the university, the academic institution, added the premium on to its existing premium for insurance trials for the whole of the academic institution. That is the sort of cost. When you say to insurers, “But look, all the women I will recruit to this trial have a baby who will be unwell. I can identify in a trial and include women who have a 50% chance of having a stillbirth and a 50% chance that their neonate who is born preterm will have a very poor outcome”, then it starts evening up. It starts becoming much easier for them to say, “Actually, we can work out what the premium is”.
One of the suggestions from the Birmingham Health Partners consideration was, “Would the Government consider developing a short-term pot of money that would be used to insure clinical trials in pregnancy, which would then kick-start the process and allow insurers to come up with information about how risky it is to do a trial of a drug in pregnancy?” I think that is a really important area, and I hope that something could come through this.
Baroness Watkins of Tavistock: Presumably, in such a strategy there is always the option—not that one wants to do it—that they had with some of the breast cancer trials when it was clear that results were really positive and that continuing with the trial would not be ethical. You could do the same thing in these trials if the Government acted in that way.
Professor Anna David: Of course, you really want to try to get to the endpoint of the trial and not intervene too early, otherwise you might end up with an error.
Baroness Watkins of Tavistock: I completely understand that. It is ethically challenging sometimes, is it not?
Professor Anna David: It is very ethically challenging.
Baroness Watkins of Tavistock: Mark, what could we do about interdisciplinary teams taking on the current findings? We know that is not universal across the country.
Professor Mark Johnson: No, it is not universal. Looking at the analysis of the data, you could probably reduce preterm birth rates by 0.5% if you did everything you could possibly do perfectly. In our current knowledge base, we have very little capacity to achieve the government target of a 25% reduction in preterm birth rates. We need to look at how we approach preterm birth differently. The screening tests of the low-risk population, as this is where by far the majority of people who deliver preterm come from, is the only way we will start achieving that 25% reduction in risk.
Baroness Watkins of Tavistock: Right—much wider populations.
Professor Mark Johnson: I think we have to screen the whole population for that risk.
Baroness Watkins of Tavistock: At 12 weeks?
Professor Mark Johnson: At 12 weeks for the pre-eclampsia screen, and then at 20 weeks for a short cervix. Where we have data currently, we do not know whether there will be better times to screen or intervene for either of those tests, and whether we could do something pre-conceptually, which would obviously be ideal, to identify who would be at risk. We do not have that information yet.
Baroness Watkins of Tavistock: When a woman goes to see a midwife, a GP or an obstetrician, how much does a really good assessment at that point indicate whether people need further screening?
Professor Sarah Stock: A good first assessment is key for antenatal care. It is a busy first assessment and many risks are looked at. Again, to echo Professor David’s point, and the point that Professor MacIntyre made as well, there are many risk factors that could lead to preterm birth, but there are different pathways for that. Screening for diabetes, for example, may help reduce preterm birth from complications in pregnancy from diabetes.
We have to think about how that is done well. I think you are thinking about screening for high-risk spontaneous preterm birth. At that point, risk factors are looked at, and then people should be fed into the appropriate services for further assessments. It is absolutely key that those are done comprehensively and, I guess, robustly. To do that we need good information systems so that there is standardisation of risk and you understand, as patients move around, the risk factors that may have come from their health and from other settings.
Baroness Watkins of Tavistock: David, do you have anything to add?
Professor David MacIntyre: It is only a little more relating to your original question about the challenges of getting some of these obstetric research findings into clinical practice. It has been touched on, but maybe I can reiterate that we have so many different causes of preterm birth that when we are doing the basic research, we are often not comparing apples with apples and oranges with oranges. We still see a lot in obstetrics research a situation where different types of preterm birth, with different causal mechanisms, are basketed together and compared against a control group. That clouds the data and prevents us teasing out the mechanisms, coming back to Lord Winston’s earlier point.
If we can start to use methodologies and cutting-edge techniques that enable us to stratify our patients and identify the likely underlying causes, it will help us start to get resolution of the types of information that we need to be able to understand better mechanisms for specific forms of preterm birth.
Baroness Cumberlege: I want to ask about the hard-to-reach women. When you were talking, it gave the impression that you could do something for everybody, but clearly there are some people who are very hard to reach. Do you have any mechanisms for those people?
Professor Mark Johnson: The hard-to-reach population have the same risk of preterm birth as the high-risk group identified by screening. In the same study from King’s, the people who refused cervical length screening had the same risk as the high-risk group.
How do you get those hard-to-reach people to take part? Jonathan Valabhji was talking about diabetes. Forgive me for the digression. He tried to introduce a diabetes prevention programme. He found that 30% of people actually went through to completion of the diabetes prevention programme. He then used you and I—normal humans—to approach those who would not complete. They could say, “We can see that this person has not completed”, but if they got a person to speak to those people, they got the completion rate up to 50%.
The answer to the question is that different things work for different people. There is a very clever chap at Imperial who can film you as I am talking to you now and say, “You will do as I say”, or, “This person will completely ignore what you’re saying”. Perhaps we need to find a different way to get our message across. You are absolutely right that the hard to reach are the trickiest people to help, but we need to do research to know how to help them.
Baroness Cumberlege: Let me take that a tiny bit further. Do you have ambassadors or people who are very accessible to the people who do not want to take part?
Professor Mark Johnson: Influencers. We are doing a lot more work with those sorts of online techniques. If I were to speak to somebody, you can monitor in that population how often they are going online to look at the subject that you are trying to convince them on, be that diabetes or whatever. You are absolutely right that we will have to do that, and that is why we try to involve celebrities in just about everything we do with the charity because they carry so much more weight. When Darcey Bussell tells people about her terrible experience with pre-eclampsia, you see a spike and people’s awareness is raised. Raising awareness is absolutely key.
Baroness Cumberlege: I was a Minister for a while and at that time we were quite seduced by celebrities—great mistake. It all came to grief. The people you thought would be really good at it were not. I just want to say that this needs a lot of judgment.
Professor Mark Johnson: Absolutely.
The Chair: To go back to serious matters, Baroness Watkins asked a question, and a detailed answer would be better. How do you make sure that the first contact with the mother in early pregnancy gets the history taking right, to identify any risk factors she may have for subsequent preterm labour? Whether it is a doctor, a nurse or a midwife, including a community midwife, they have to be aware and ask the questions; for instance, “Have you had previous cervical surgery?” That might be a risk factor for a subsequent preterm birth. Do we get that right?
Professor Mark Johnson: I do not think so. That is the quick answer. I think we need a better way of taking that booking history. I would like to computerise it so that if anybody says “cervix” they get sent to the preterm labour clinic. Anybody who says, “My mum had preterm birth”, will get sent to the preterm birth clinic. If you had a computer doing that, it would be far more reliable. Speaking for myself, I sit in my lovely high-risk clinic and if somebody rolls up at 20 weeks, it is too late.
The Chair: We have to make sure that the computers, and the people, are available. We have to have some kind of strategy so that the person taking the first history is knowledgeable enough to get it right.
Professor Mark Johnson: Yes.
Baroness Wyld: To pick up on that, Lord Chairman, I want to ask about the NHS app. I know it is relatively early days, but in theory surely you ought to be able to log on and hand that over to your midwife at your booking-in appointment, if you so wish.
Professor Mark Johnson: I agree. It is invaluable, potentially, as long as you can get it to work at that time. It has only just come in. That is my experience of it. Time will tell whether you can get your history from that, and it will pick up those factors. I bet it does not tell you about your mother’s preterm birth history.
Baroness Wyld: No. I am not making the case for purely an app. I told my own midwife my life story, but you are dependent on a combination of them. We should be quite far ahead in that now.
The Chair: The question, therefore, is whether an app, appropriately developed and with all the information, would be beneficial or not.
Professor Mark Johnson: Yes, I agree.
Q66 Baroness Owen of Alderley Edge: We have already touched on the subject of perinatal funding and its comparatively low levels. Do you agree with the assessment of the low levels of funding, and why do you think that is the case?
Professor Anna David: There is definitely an inadequacy of healthcare funding for pregnancy. Personally, I think that a number of other specialties do not appreciate that your health when you are pregnant is so key to your later life health. Cardiovascular health risks and risks of dementia and cancer are increased if you have a preterm birth. If your baby is born preterm, it does not just affect the baby, it affects the mother. It is absolutely critical that those disciplines appreciate that healthcare starts before you are born.
For every £1 spent on pregnancy care in the NHS, only 1p is spent on research, whereas we have a huge litigation bill. There is absolutely a need to emphasise the joined-upness of research in improving care in pregnancy and the effect that it has on your later life. If you end up investing a lot of your money in treating cancer or cardiovascular disease, it is an important thing to do but maybe it is much more cost effective to improve your diet when you are pregnant, or even your diet pre-pregnancy. We have not talked a lot about this, but pre-pregnancy diet and health are so important. Some of the investment needs to be in those areas. That will require a lot of money. It requires a complete systems approach, similar to the way they have done it in the Netherlands, for example, with the Rotterdam study run by Professor Steegers.
We were talking about communities that are hard to reach. In the Netherlands, they have developed a system of buses that are painted pink. They go round the city and educate people about how you get healthy before you get pregnant. They have shown that that improves the health in pregnancy of the women and the health of the babies. They are now rolling it out across the Netherlands. They are able to reach communities that are difficult to reach. For example, they provide support at weekends on how to cook. They teach people how to cook a good meal when you do not have a lot of money. They share those meals with them so that they can see what is the right food to eat. Sorry, I am rambling a little bit, but I am very passionate about this. I think pre-conception health is very important. We do not invest enough money in that area of our healthcare system.
Baroness Owen of Alderley Edge: Is there a bias against funding for perinatal research?
Professor Anna David: Yes. I would say it is a lack of understanding.
The Chair: I am surprised that you were hesitant. Most academics would have jumped at that question.
Professor Mark Johnson: We find it difficult to describe a pathway to impact. You get a researcher who says, “We will save N million lives by doing X”. We say, “Well, we need to do the basic research, which will tell us what we could do in order to achieve that”. There are few pharmaceutical companies that can actually help us achieve it. The absence of pathway to impact makes our grants less attractive. That would be my feeling. I do not know what everybody else thinks.
Professor Sarah Stock: I was going to say something similar. We need enablers for the whole pipeline of research, to take it from the fundamental stage through to translation. The lack of investment by industry is a real problem. We need to enable that, to have a clear pathway that we can see to the translation of the fundamental science research. Enabling that will help the fundamental research be more attractive as well, and will have solutions that can feed back in. There are certainly ways. We have touched on insurance, and improving the industry funding, as well as the public health funding, is key.
The Chair: Professor Stock and Professor MacIntyre, you engaged with Lord Winston earlier on the importance of cell biology research. What are other countries doing on this? Where is the United States? Where are Australia and Germany, if there is a gap in understanding the fundamental molecular and cellular mechanisms that distinguish term labour from preterm labour, and you are making a plea for more investment before the pharmaceutical industry can engage to develop treatments?
Professor Sarah Stock: I can tell you a little bit about a global programme I am involved in, the Wellcome Leap in Utero programme. One of the key things that we are developing in that are toolkits, so that we can measure, model and predict what happens normally in gestational development and see what happens when it goes wrong.
There are definitely technologies now that are being applied in different countries. With wearables, we can monitor maternal health and apply them to pregnancy. We can develop advanced imaging techniques that can look at things inside the uterus. Can we measure placental oxygen, for example? Can we look at cells from inside the womb that circulate rarely in maternal circulation? There are markers of infection—non-invasive markers of what is happening in the uterus. Those are the key things that we need. The toolkit would then be able to generate data about the cellular and molecular biology techniques.
There are some fundamental things that we need to apply the technology. It really is becoming multidisciplinary, perhaps working with teams that have not been inspired to work in pregnancy before but could see this as the next challenge. It would be applying technologies to pregnancy that we might apply to cancer, for example. The work is starting to happen, but it needs co-ordination, which would be very useful. It needs a kind of grand challenge approach: “We don’t know why humans go into labour, and we don’t know why it happens early. Can we use new technologies and tools to get a window into this?”
Professor David MacIntyre: Perhaps I could quickly add a couple more numbers to build up the case even further. The US and other places are also guilty of not investing enough money into preterm birth research and women’s health research. For example, in the UK and the US, despite around 10% of reproductive-age women falling pregnant at any given time, only 2% of all medical research is going in that direction to investigate research in the pregnancy space and early life space. That is exemplified here in the UK. It comes back to an earlier point made by Professor David; there was a publication in Nature a couple of weeks ago highlighting the deficit of funding in the US and in the UK for women’s health. It highlighted the fact that the MRC, from 2014 to 2019, invested around £90 million in all areas of women’s health. Of course, preterm birth and perinatal research is a small fraction of that.
To give you some context, that is the investment that the MRC made over the same period just in cardiovascular research. We need more money into the basic research and the questions that we are all highlighting. Professor Johnson’s comment about engaging industry as part of the success in funding these types of global challenge approaches is critical. It would be really great if the committee had an opportunity to discuss that with some industry representatives, but they will be hard to find.
The Chair: We will find them.
Lord Winston: David, it is the obvious question: is this lack of funding due to the lack of really good applications for funding or is it due to a lack of money? Surely funding is competitive. Therefore, one of the issues is the number of people in women’s health who are capable of putting together decent project grants and applications for funding.
Professor David MacIntyre: We have more than enough people who are very capable scientists and clinical academics who have the ability, if given the resources, to make large strides in this field. One of the problems is that we have such a reduced, small pool of funding to do this type of research that we are all, essentially, trying to out-compete one another to get access to that funding. If we are able to increase that funding pool—it needs to be increased substantially—we will start to make progress.
I will give you another quick example as to why I think that is a good way forward. One of the issues that you have at an earlier career stage is that you are contemplating where your career security lies: “As a talented young scientist, do I want to follow my passion into preterm birth research and try to solve some of these very highly complex problems or, knowing that I risk not receiving funding and knowing that I will not get access to that funding, do I move towards other areas such as cardiovascular research or cancer biology where I know there will be much more consistent funding available to me?” We have almost a brain drain effect of highly talented young scientists who do not stay in the field. It is a problem.
The Chair: I thought your initial answer to Lord Winston was good. You ruined it by the answer you just gave, by saying that it is more attractive for me to give up preterm research because it takes longer, and to move to cancer research where there is more funding. We could make a plea for more funding for reproductive health research, but to suggest that they give up is defeatist. That is my view.
Professor David MacIntyre: I will clarify that, if I may. It was a hypothetical. What I was suggesting is that that is a scenario that many young researchers are faced with. That is the reality of their situation.
Lord Winston: I am sorry to come back, but it is important. Are you really suggesting that UKRI is not open-minded to any decent research, or are you saying that it will concentrate predominantly, for example, on cancer research? I feel that is not significantly true because, of course, we know that cancer research is increasingly being funded in alternative ways and not by the research councils.
Professor David MacIntyre: I do not think it is the case that, if UKRI sees a good application and a good project, it will not fund it. That is not the case. If we really want to make a difference in preterm birth, which is what I think this committee ultimately wants to do—
Lord Winston: Do we have data on the number of women’s health applications to the research councils? If not, we should get them.
Professor David MacIntyre: I suspect that that data would be available, but I do not have it.
Professor Mark Johnson: I was on the scientific advisory board of Action Medical Research, and sometimes we did not have applications for our preterm birth grants. I feel there is another problem, which is that the numbers of people working in that field are very small. Borne is now trying to get more people into the field by funding, with the MRC, training fellowships.
Lord Winston: I have a bit of a problem here because I have just been arguing with our clerk about this issue and whether it is the people or the money. Maybe there is a bit of both.
Professor Mark Johnson: It is both.
The Chair: We will have to tease it out.
Baroness Watkins of Tavistock: I would like to come back on one thing. I thought I heard earlier that preterm birth was often associated with cancer and dementia later in life for some women. Is there a hypothesis around working with people who are doing research in those areas to find, in fact, whether there are underlying genetic issues around those two, particularly cardiovascular disease leading to dementia, that actually may not be caused because of the preterm birth but may contribute to the preterm birth?
Professor Anna David: You are right. It is about the revealing of a genetic potential to develop cardiovascular disease later in life. You can consider pregnancy as a stress test. There is work being done on that. With Tommy’s, Genomics England is going to invest money to do duo tests, mother and baby, looking at whole-genome sequencing of women who deliver preterm. One of the inclusion criteria will be spontaneous preterm birth.
Of course, that will be infection related. It will not be related to their cardiovascular risk, but some of them will be. There may be the opportunity to extend it to iatrogenic preterm birth; for example, for early onset pre-eclampsia. There is work that will be done on it. That will, I hope, enthuse people in other disciplines to explore the overall causes of preterm birth and its long-term consequences.
The Chair: Perhaps we could move on to Viscount Colville’s question because it fits in well with this discussion.
Q67 Viscount Colville of Culross: Good afternoon. We, as a committee, will have to come up with some recommendations for priority areas for further research to improve obstetric care and the prevention of preterm birth. Professors MacIntyre and Stock, you talked about research at the molecular level to understand the mechanisms of birth. Professor Johnson, you talked about the single cell that we need to understand better. If I could take you in turn, Professor MacIntyre, is that where you think we should concentrate the research, or do you think there are other areas we ought to be looking at?
The Chair: What are the four grand challenges that you would like to see?
Professor David MacIntyre: Fundamental understanding of the mechanisms leading to preterm birth is critical, for two main reasons. First, it will give us insight into new druggable targets to prevent preterm birth, which are currently lacking. It will also give us the ability to identify potential strategies for better biomarkers and screening procedures that we can employ earlier in pregnancy. That would therefore mean that the existing treatments, or treatments that will be developed in the future, could be more effective if given to women in a more targeted way.
The other thing I would make a plea for—Professor Stock made mention of this earlier—is that randomised control trials are fantastic but I think we are missing a trick by not bolting on a mechanism and taking them as an opportunity to investigate and work with the participants in those trials to understand how these types of interventions might actually work, when they work, and in whom they work. Currently, we still do not understand the two treatments that are being given to women to prevent preterm birth and how they might work in some women and not in others.
Professor Sarah Stock: I agree with the point on fundamental research. To add to that, one of the challenges is understanding how human labour starts, even at term, because then we can understand the triggers better. That is really important, remembering—we have touched on this before—that preterm birth is the final common result of a number of different pathways. We have to be realistic about the scale of data and research that needs to be done on these individual pathways if we are to make headway. We need to address multiple different pathways and understand those, rather than thinking about preterm birth as a whole, if we are to drive down the numbers.
Professor Mark Johnson: I am sorry, I am not going to give you a quick answer. We have to study the whole of pregnancy. Yes, we can look at mechanisms at the point and that is what we are doing with BUMP. There are bits of evidence. We find that people who are depressed have a 50% higher risk of preterm birth. Preterm birth fell during Covid, which does not fit with what I would have expected. There is so much that goes into causing preterm birth that we will be able to understand only by looking at the whole of pregnancy, starting before pregnancy, what we can learn in early pregnancy and then, yes, when we go into labour.
If I could ask the committee to do anything, it would be, “Please, let’s understand pregnancy”. Pregnancy has a huge impact. The NHS says, “Start well, live well, age well”. Start well is when we are in the womb. If we make the environment correct in the womb, we will have benefits throughout the life course for that baby. I think we are at a Manhattan Project moment. We should put all the scientists and all the clinicians into a room, lock the doors and say, “Until you come out with a plan that will address all the different aspects of people’s”—
The Chair: Why has that not happened?
Professor Mark Johnson: It is so important.
The Chair: Why has that not happened? You are a persuasive chap.
Professor Mark Johnson: I am a persuasive chap. I have got the Borne collaborative together, but charity can fund only so many flights to America to get everybody in the same room. We have produced recommendations for how we can manage or start to research preterm birth. The BUMP initiative is one of those. We are looking at different ways for treatments that we can use. Even if we treat infections causing preterm labour, those babies still have disability because the inflammation related to that infection persists. It will not be as simple as giving an antibiotic, I am afraid.
Viscount Colville of Culross: That is a failure of all of us to go off to Los Alamos. Are there particular points that we ought to be looking at, if we are not able to bring the whole field together?
Professor Mark Johnson: Absolutely. David referred to treatments such as progesterone. We have no idea how we should give it or the dose we should give. It is unbelievable that we do not know fundamental facts.
If you asked me to focus on two areas, I would want to focus on how we screen appropriately, because I think that will give us the most bang for our buck in the short term. Then I would say, “Let’s focus on preterm labour. Let’s understand what we can treat. Infection is something we can treat. Can we diagnose it?” We have another study called PROMPT. We do an amniocentesis. We take amniotic fluid. What is the bug there? We give the right antibiotic in combination with something that will repress inflammation. Those are the two areas I would focus on. That is what BUMP is about, understanding that all together.
The Chair: That is a pretty invasive test.
Professor Mark Johnson: Amniocentesis at that stage will increase your risk of preterm delivery by 0.1%. If you look at getting the right antibiotic, in some of the animal models, you can increase latency by two weeks. That is a huge difference to a baby.
Viscount Colville of Culross: Professor David, you have talked about the difficulty of doing clinical trials in pregnancy and the various ways of trying to mitigate that. That is obviously one of your top priorities. We have not talked about this at all, but I have been doing quite a lot of work in the digital ecosphere in different parts of my work here. Does AI technology have anything to offer to improve the way that trials are carried out?
Professor Anna David: AI definitely has a use, for example, in silico modelling. That is putting in data about what happens when a woman takes a drug, for example, in pregnancy; it is putting all the factors in and seeing what effect it might have. You are avoiding doing animal studies. You have all the human data in the computer. It definitely has a role there.
One of the groups that we have not really talked about is the pharmaceutical industry. The pharmaceutical industry is interested in doing drugs trials, but finds it very difficult, because it is incredibly risky for it to invest in them. If there was an option to put the scientists, the clinicians and the pharmaceutical companies together in one room, that would be very helpful. More funding is definitely needed to encourage them; it could be similar to the paediatric investigational pathways, which have revolutionised children’s drug development. Perhaps we ought to consider having some kind of obstetric or maternity investigation or pathways for when new drugs are developed.
Yes, AI will be very helpful if we can get lots of data in and apply data to electronic patient records. It could pick out, for example, particular diseases or targets that drug companies could use. We have to engage with them, but it will take more money and incentives for them to really want to invest in this area.
Viscount Colville of Culross: Would that be one of your top priorities for our recommendations?
Professor Anna David: It would, absolutely. It would be to have some kind of investment opportunities for them. When looking at a drug in pregnancy, imagine that you identify the risk of preterm birth at 20 weeks. Women will take that drug only for another four months. It is not cost effective for a company to spend huge amounts of money developing a drug that somebody will take for only four months. You have to work out the cost benefit of the drug, how you position it in the market and what you will charge the NHS. All that information about economics also needs to be collected when you do your study. Big data is needed.
The Chair: The chances are that the industry does that kind of modelling, but before you get to that point you have to have a treatment. To get to the point of getting a treatment, you have to understand the mechanism of the disease. No treatment is developed without first understanding the molecular and cellular biology that leads up to that disease. I take your point about the importance of modelling and what effects, good or bad, the drug might have, but before that we need the evidence. Is that correct?
Professor Anna David: We need the evidence, but we also need information from pregnant women who have a condition, and the actual biochemistry, haematology and blood markers, so that we can put that into the model and then potentially see whether there are—
The Chair: We are even one step further back. We need the data collection first before you use the AI to do the modelling.
Professor Anna David: I think there are some drug targets; for example, drug targets looking at thrombosis. That may be a druggable target. We need to encourage pharma to—
The Chair: To prove that thrombosis has a role in preterm labour.
Professor Anna David: Yes.
The Chair: First.
Professor Anna David: Yes.
The Chair: We have three minutes and there is one question that I would like to nail in the evidence. It is about the importance of the timing of cord clamping. Among the things that we know already, that makes a difference. We have not had arguments based on properly conducted research. I understand that properly conducted, randomised research shows that the timing of cord clamping is important in significantly reducing poor outcomes for babies’ neonatology. We have a session next with neonatologists, and we will try to confirm that.
Professor Sarah Stock: Yes, I think that is right. There is very good evidence, most recently two papers in the Lancet, reviewing all the trials on cord clamping in preterm babies; when a baby is born, the cord is clamped and cut immediately so that the baby can be resuscitated. There is a period of time when the cord is not clamped and resus can be done, if needed, and the support that the baby needs can be done at the bedside, so that there is a delay of at least 60 seconds before the cord is cut. That can reduce mortality by up to half. That is something that there is evidence for. It does not cost very much. It involves training and implementation, but it is something that we should be doing. Some areas do it very well, but it is not done consistently across the country.
The Chair: Should it be mandatory for all maternity units?
Professor Sarah Stock: I think it should be routine practice, yes.
The Chair: Do any of the other three want to add anything to that, or do you agree?
Professor Mark Johnson: I agree.
The Chair: Thank you very much indeed. It has been a most fascinating session. You batted well for your cause. Thank you for taking the time out of your busy services. Despite it being years later, it is nice to see you all.