sMater | Preterm Births: Progesterone | Dr Sarah Janssens

Welcome back for episode two of sMater, where Dr Sarah Janssens, Director of Obstetrics and Gynaecology at Mater Mothers' Hospitals, delves into the role of progesterone in preterm births. 

How does it work? Who does it benefit? How effective is it really? And are there any long-term risks for mother or baby?

Tune in to find out. 

GP Education activity log:

•   Podcast title - sMater: Preterm Births: Progesterone
•   Provider - Mater Misericordiae Ltd 
•   Date published - November 24, 2023
•   Certificate of completion - Download here

To learn more about Mater, visit https://www.mater.org.au/

Transcript

Hello and welcome to this episode of sMater. A podcast by clinicians for clinicians brought to you by Mater, an Australian leader in healthcare for more than a century. My name's Jillian Whiting and I'm Katherine Cooper Clinical Specialty Coordinator for Mothers Babies and Women's Health at Mater and we're coming to you from Meanjin the land on which this podcast is being recorded.

Today we are joined by associate professor Sarah Janssens. Director of Obstetrics and Gynecology at Mater Mothers Hospitals. Sarah has been a specialist obstetrician and gynecologist at Mater Mothers for more than 10 years and has been heavily involved in Education and Training particularly simulation. Sarah is an associate professor at the University of Queensland and she recently received her PhD in teamwork and leadership in maternity teams but today she's joining us to talk about progesterone's role in preventing pre-term birth.

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Back to basics - what is progesterone and what role does it play? Well progesterone is a hormone that the female reproductive tract creates it's usually made in our ovaries when we ovulate but it's got a really important role in maintenance of a pregnancy and how we know this is that initially when we get pregnant our Corpus Luteum or the little area from which the egg has been released produces the progesterone and then after about 7 to 9 weeks the placenta takes over production of that and in that critical time if you take the Corpus Luteum away we know that the pregnancy will fail so it's really important for pregnancy maintenance and what we also know about progesterone is it helps to keep the uterus quiet throughout the pregnancy and the very high levels of progesterone that we see in pregnant women's bodies fall precipitously as labor starts so we that's how we guess we know that it's got a really important role in the initiation of labor. 

So I was going to ask about you know what made us think to use progesterone in prevention of preterm birth. You've kind of answered that a little bit is that just a linear progression that we thought this has a role so will use it to prevent labor happening? Yeah I guess there's been a lot more science behind it I hope and studies on what exactly that role of progesterone is so it's a really interesting hormone because it actually has multiple effects so within the uterus itself it helps to prevent the formation of what we call gap junctions and so they're the

connections between the myometrial cells which help to propagate contractions in a coordinated fashion so it stops them sort of being formed. It also has some pretty important immune modulation type effects that probably prevent initiation of inflammatory pathways which again can initiate labor so it probably acts on multiple levels to prevent labor starting early. 

How does it work once it's in the patient system?

Well that's a very interesting question because in fact we would think that it worked by increasing our natural levels of of progesterone hormone but in fact later in pregnancy our own hormone levels of progesterone are actually really really high and so it is questioned how I guess the addition of progesterone to our already naturally high levels which are probably saturating our receptors actually works. So there are some theories that perhaps it might work more locally within the vagina and be altering the vaginal microbiome or the inflammation or actions directly within the cervix that might be what its main mechanism action is so there's a lot we still don't know about it.

So Sarah we use progesterone for treatment of other things like breast cancer and endometriosis even birth control does that work on the body in the same way?

You're talking about maybe two different chemicals. One is natural progesterone's and the stuff that we take to treat um endometriosis or what's in the contraceptive pill a more synthetic form of progesterone and they're called progestogens so they act in a different way and probably don't have any actual mechanism with respect to pre-term birth prevention.

If someone had been taking progesterone prior to conception would that have a residual effect? Not really we don't think because we think that the half life and the bioavailability is actually quite short which is why we tend to use daily dosing.
In Australia progesterone has approval from both the Therapeutic Goods Administration and pharmaceutical benefits scheme for prevention of pre-term birth in singleton pregnancies where there is a short cervix or a history of spontaneous pre-term birth a streamline Authority is available for a daily 200 milligram pessary and must be commenced no earlier than 16 weeks gestation. Sarah what types of progesterone are there? So you can take progesterone in a number of ways so you can take it orally although that's not used in Australia for this purpose and there were actually lots of studies in America where they used an injectable form of progesterone 
so intramuscular daily injections. Unfortunately the studies have shown that that actually is not as effective and that's that was never actually available in Australia anyway but it's actually been withdrawn from use for that purpose in America due to its lack of efficacy so vaginal progesterone is now what is used here in Australia and is what is most effective.

So what would a typical progesterone regime look like for the prevention of preerm birth?

So typically would be starting around 16 weeks gestation or later if the diagnosis of a short cervix occurred later and generally continue up until about 34 or 36 weeks most of the studies have shown  and usually just a nightly vaginal pessary of 200 milligrams. So stopping at 34 to 36 weeks. Why that point?

Yeah I guess at that stage the risk of delivery at that gestation is much less for the mother and I guess that's what the studies or for the mother and the baby and that's what the studies have generally used so that's a funny thing about research isn't it like we kind of this is how the protocol was in the research protocol so we would use it up until then yeah and I guess your progesterone levels are going to be really high at that stage anyway. 
So Sarah so any woman has been identified as having a need for progesterone where does she get it and who prescribes it? 
Well recently it's been listed on the PBS for women with both a indication as a history of pre-term birth or asymptomatic short cervix so a GP can prescribe this  a woman doesn't have to come into hospital if a short cervix has been identified or she has that risk factor so I think it's important because we believe that early initiation is probably going to be most beneficial so whoever sees the woman first can prescribe the progesterone but of course if she's identified at high risk then by a GP she needs to be referred in for 
review at a hospital.
So what's the efficacy of progesterone in preventing or delaying preterm birth?

Yeah it's quite effective but it's not 100% effective of course and there's lots of different causes for pre-term birth so we don't understand all of the mechanisms so progesterone is probably just one thing that's affecting one of those pathways that leads to pre-term birth but the studies have shown about a risk reduction of 0.6

consistently so for pre-term birth say less than 33 weeks we're talking about a difference between and this is in women with a known short cervix so we know that they're at high risk so reducing that pre-term birth before 33 weeks from about 22.5% down to 14.5% so it's pretty effective and then the consequent I guess complications for the babies being preterm are all of similar magnitude and reduction so low
birth weight, respiratory distress, needing to be in the NICU. They all come down I guess in concert with that reduction in the rate of early delivery. The meta analysis from the same randomized trials demonstrated that in pre-term births less than 28 weeks the risk was reduced from 11% to 8%.

Looking at the patients who would benefit from progesterone and who wouldn't?

Yeah that's a great question and I think we're still finding our way with that to a certain extent. The indication for it is women with an asymptomatic short cervix so that this is women who are not experiencing symptoms of pre-term birth like contractions or they've broken their waters already or they're bleeding and that's the indication so 
with the asymptomatic short cervix and that's less than 25 millimeters on a trans vaginal scan I'm sure someone's already gone through that so I won't go over that again so that's the one the group that definitely has benefit the other indication and listed on the PBS for progesterone is women with a history of pre-term birth but the benefit in that group of women is actually a little bit more controversial and a recent meta analysis demonstrated no benefit for women

with a without a short cervix I guess at diagnosis and only a history of pre-term birth but it gets a little bit murky so you know certainly we would advocate that if you've got a history of pre-term birth that maybe you should have cerclage or you could have progesterone but certainly monitoring the cervical length is really important because we know that's the group of women who are going to benefit from progesterone having said that not everyone has access to regular cervical length monitoring. In rural or regional areas or women who are socially disadvantaged for example so we certainly don't think that it would be wrong to put women on progesterone simply because they had a history of pre-term birth but we would certainly advocate for serial cervical length monitoring because progesterone will only help up to a certain point and when your cervix then is shortening despite progesterone like it's getting less and less and say it's less than 10 mm now that's a group of women you don't want to miss because they may benefit from a cerclage at that point. 

Are there any risk factors that would rule someone out completely? There's no absolute contraindications I would say to to it certainly we don't tend to give it in women who have already ruptured their membranes or are in active labor or showing signs and symptoms of pre-term labor because I think the point
however it's working you've probably missed the boat once women get to that point. How would the administration progesterone change if we were talking twins or higher order multiples?

Well as you know they much higher risk of having a pre-term delivery. The data on twins is actually much the same but much smaller numbers so there have been some meta analysis that have done that have looked at all the randomized control trials and then pulled out those small numbers of women with multiples to look at that and there does seem to be an effect. Some centres
tend to use a different cut off like a 20 mm cervix. We tend not to use that here we still tend to go with a 25 but I think certainly with twins you're just on high alert anyway but we don't think again that progesterone is going to be harmful but they've got such a high rate of pre-term birth already you imagine if your baseline risk is much higher you might still get a relative risk reduction of 0.6 but you'll still have an overall high rate of pre-term birth even if you use progesterone.

Talking of risk what about any short or long-term effects for the mother.

Well it's kind of annoying having to put a vaginal pessary every night would be the one thing but the things that women mostly report are just irritation of the vagina and certainly they get vaginal discharge from the from using the pessaries that would be the most commonly reported side effects. 
So an irritation what about the infant any side effects for them?

I guess we know that because of the reduction in the risk of pre-term delivery that the short-term outcomes for the babies are much better. The longer term studies are smaller because we haven't really done a lot yet but there was some look at some studies again at meta analysis that looked at outcomes from 6 months through to 8 years and there was no detected difference in neuro development outcomes but there's a lot of outcomes that have not been looked at and we certainly haven't seen yet the results of these studies going on into adolescence or adulthood so there's a few unknowns there for sure.

So would that be something that we would want to consider looking into the future of using progesterone?

I mean I think always safety is always at the back of our mind whenever we're using a new therapy. I think natural progesterone we've got no reason to believe that would be unsafe but you never know and so we must continue to do those long-term follow-up studies and check that there's no increase in risk of you know cancers in people who were born to mothers who had progesterone when they were pregnant or any other problems like reproductive tract abnormalities or fertility issues for example.
We don't think there will be but it's that's what we need to be doing in the longer term. Absolutely, well Sarah thank you so much for joining us on sMater. Thnk you. Before we go we'd like to introduce you to a little segment we call The Checkup. So this is about the medical professional but also Sarah the human, the person. We've got 

five quick questions. I'll do my best. Deep breath. You ready to go. Yeah okay okay.  What TV show best portrays your profession? Oh goodness. Can I say in my younger years Scrubs? Fantastic. How would you describe your handwriting? How would you describe my handwriting? I'll say no more I chose that question especially for you. Barely legible. What's on your surgery playlist? Oo you know it's funny I don't tend to listen to music too much when I'm operating but I don't mind if other people listen to music. I have this terrible verbal tick that I do lots of and so whatever the registar feel would drown out my that freaks them out a little bit when we're operating together. Who do you admire? Oh gosh. I admire everyone in our profession who and who really dedicates their lives to what we do and makes working with all my friends enjoyable. 
And final question if you had a day off today what would you be doing? Cleaning and

organizing. That doesn't sound fun at all Sarah. 
Well thank you so much for that Sarah. Thanks for joining us on sMater. Thank you for having me. And also to those who've tuned in from home or the hospital please join us for our next episode where we talk about cervical cerclages with Dr Adam Bush. See you next time on

sMater.