Michal Elovitz, MD, Director, Maternal and Child Health Research Center, Vice Chair of Translational Research at the University of Pennsylvania talks about a study examining how the microbiome in the cervical/vaginal space might be related to preterm birth.
Interview conducted by Ivanhoe Broadcast News in August 2017.
What was it that you discovered with this study?
Dr. Elovitz: We did a study that we called the Motherhood and Microbiome or M&M for short. We enrolled two thousand women during pregnancy and we collected vaginal swabs at three time points in pregnancy. The grant was actually in response to a call from the National Institutes of Health to investigate how the microbiome might be involved in preterm birth, which fit exactly what was happening in our research program. So we were very excited to apply for that grant and very fortunate to have received it. We accomplished this and in about two and a half years we enrolled two thousand women. We have now have the preliminary data looking at the microbiota in the cervical vaginal space and its association with preterm birth.
This happens to a lot of women and traditionally they’re pretty far along before they even determine all this. So this is going to detect it sooner? And the traditional medical means of diagnosing this has really not worked?
Dr. Elovitz: The biggest problem with preterm birth is those with spontaneous preterm birth as opposed to those with maternal or fetal reasons to be delivered early. Women who spontaneously go into labor at twenty three, twenty eight, or thirty one weeks —we have no idea who is going to do it. We do know that women who have had a preterm birth before are at significant risk: twenty to fifty percent depending on which study you read… We know they are at higher risk and we have some interventions that work to some degree but we do not know how they work and they only work for about 1/3rd of the women at risk. But even though they are at such higher risk, they don’t make up the majority of women who ultimately have a preterm birth. So if you really want to make a public health impact you can’t just target them. You have to target all these millions of women but you don’t know why they are at risk. So how do you determine risk? Right now the only thing we really have in our clinical armamentarium is measuring cervical length by ultrasound, and we’ve done this for years. We know that a short cervix by ultrasound is associated with high risk of a preterm birth, so that’s great. We also know from a large study that if you have a short cervix and you get a specific therapy (vaginal progesterone); you reduce that risk of preterm birth. But, there is a problem to this approach… We just showed in a National Institute of Health study, which was an eight center study called NuMOM2b, that this time of screening does not identify the majority of women at risk for preterm birth. We looked at ten thousand women and at their cervical length in the second trimester. In those women who ultimately had a preterm birth, only 9% would have been identified by having a d a short cervix in the 2nd trimester… So while those nine percent were identified that means ninety one percent of women with the spontaneous preterm birth are going to be missed if we use this tool to identify them as being at risk.
So where do you go from here in terms of really getting it out there where everybody is utilizing it and you hit the other ninety one percent?
Dr. Elovitz: First we have to figure out why it’s happening. I have looked at preterm birth for seventeen years now, and we created mouse models to actually try to figure out what mechanisms are involved in this process. One of the things that have been missing in obstetrics for decades is the idea of understanding what’s happening in this adverse outcome. What goes wrong in a woman who has preterm birth? If we don’t understand those mechanisms, we can try all day long but we would be guessing at therapies. So what we did, and I think this is fairly unique to our research program, probably now four to five years ago is we started saying; what is this same about reproductive tissues and other tissues. What are we missing? What can we learn from other organ systems in the body? Where might there be some redundancy that could help us understand preterm birth? The cervix and the vagina are an epithelial mucosal barrier and then they connect to the uterus which is a smooth muscle. If you look at what happens in the gut which has mucosa and epithelial and then smooth muscle in the intestine, we knew that we should start talking to people who worked in the gut. We asked them, what do you know in your world, what causes Crohn’s disease, what causes inflammatory bowel disease, talk to us. The more that they talked to us the more lightning bolts were going off everywhere. There’s a lot of rich data that has emerged in the GI world if you will about the microbiota, about immunology, and about how immunology and microbiology interact. How it relates and how it leads to disease states and then how we can change those mechanisms leading to the disease state. We kind of borrowed from them and we started thinking more about the vagina and cervix instead of about the uterus—which has been the focus, specifically how contractions might cause preterm birth. We asked what if the accepted paradigm of preterm birth is wrong and the focus should not be on the uterus? What if the uterine contractility happens second, what if the cervical vaginal space which is open to the environment looks like the gut? What if it acts like the gut? So we started asking what are the microbial communities there, what is the immune response there, how does that change the properties and the structure of the cervix? And that’s how we got started looking at this kind of new paradigm of preterm birth.
So what are you going to look at next in terms of is it colonies of bacteria that get out of control or what might it be? Just speculating here of course.
Dr. Elovitz: We’re not completely speculating because we have data now. Some of the data that we have shown from that Motherhood and Microbiome study is that there are very specific bacteria that are not only associated with an increase risk of preterm birth, but interestingly they’re very specific bacteria that are protective. We now are trying to create almost a risk scoring system. Right now, I tell a woman with prior preterm birth some ambiguous risk for a recurrent preterm birth, somewhere between twenty to fifty percent. And for a women in her first pregnancy, well the national average for preterm birth is about twelve percent, so, good luck, right? The goal would be to say, I don’t think we’re ever going to be able to say you’re at a hundred percent risk or you are at a zero percent risk. But if I can tell a first time mom you’re not twelve percent but based on the bacteria colonizing your cervical vaginal space, your risk for preterm birth is forty percent, that’s dramatically different. Then the real important step is once I do that, once I can better risk stratify can I offer treatment, right? What we’ve learned, without going into too much detail, there’s good and bad bugs. The bugs that are there, the composition, the colonies make a difference. If you have a bad bug but you have a lot of good bug with it, it may modify that effect. Just as important, we found that certain immune responses modify the bad and the good bugs, but we’re just learning this. We assumed to some degree we were right to mimic the gut and to some degree we were wrong, because the immune responses in the cervical/vaginal space we’re finding are very unique. In some ways we have to do discovery; what immune responses are normally there, when do they change in response to the microbial communities and when do they help and when do they hurt. All of that together will help us be able to develop, we believe, a risk stratification profile to identify with much better accuracy than cervical length, who is at risk for preterm birth.
Do you have any idea how it might be treated? I’m sure you speculated on that or maybe you’ve already got data on that.
Dr. Elovitz: We don’t have data but we have a lot of speculation. We think that there is a common denominator if you will. That if you have enough good bugs, or get rid of the really bad bugs; you might be able to prevent preterm birth.
How would you do it?
Dr. Elovitz: As far as treatment options, similar to the gut, we believe there are different ways to manipulate the bacterial populations. We don’t have any data yet that we’re able to do that. In the gut we know that they have been able to right? One of the best examples from the gut is a disease where people get this very bad bacterial colonization. The FDA approved not an antibiotic but a fecal transplantation. So people take a little bit of a pause when they hear this, but what it means is by taking the microbial communities from a healthy person and giving them back without the risk of antibiotics you get rid of the disease. If that’s possible in the gut, we think that kind of therapy, maybe not a vaginal transplantation but the idea of giving the better bugs back might be one therapy. The other idea that we don’t know yet since we only know association and not mechanism are the bugs just a marker of something else? We still need the basic and translational research in the lab to say, are the bugs sufficient to cause the cervix to change, if they’re just a marker we need that next step so that can be the target of therapy.
Do you know when a woman comes in now; is there a way to tell there’s this bacteria and that bacteria? Or how do you properly diagnose that?
Dr. Elovitz: We have not done that yet but that is the goal of our next trial. Our goal is to make this really more point of care testing so that you can test these bugs by doing a simple test, looking at very specific bugs. That will one day, if we are correct, be a hospital based test that you would be able to screen someone and get a test back in a week or so saying are you at low or high risk.
What can happen to the preterm child, they have difficulties too?
Dr. Elovitz: The issue that is the biggest problem with a preterm birth is the earlier in pregnancy happens the worse the outcomes. Our neonatal colleagues have done so well at improving survival. Long-term adverse neurobehavioral development has not gotten better. A twenty four weeker may survive but its chance of having really severe neural development disability is quite high, and that is a lifetime impact, not just for that child but for those parents and the family as a whole. The other problem is as you get further in gestation while some of those more acute diseases that are part of being new, being premature, are lessened, the long-term are not dissipating. So what we’re finding now is kids that are born even at thirty or thirty two weeks, or thirty four weeks have neurobehavioral problems as well. They may not be as severe but they are present. They also have executive function disorders. They have issues when they get to school. But, we also know that ex-preterm children have decreased life spans compared to a non-preterm kid. Their chance of having long-term medical conditions is dramatically increased. So it’s not just you were born preterm, you’re talking about a life time sentence of medical and neurological disability for that child.
Can you summarize just in one statement in layman’s terms what you’ve found out with this study?
Dr. Elovitz: What we’ve found out with our Motherhood and Microbiome study is that there are certain bacteria that live in the cervical/vaginal space that either are protective or associated with an increased risk of spontaneous preterm birth.
END OF INTERVIEW
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