IBD Drive Time: Updates on the PIANO Study of IBD and Pregnancy

IBD Drive Time Hosts Millie Long, MD, and Raymond Cross, MD, discuss new recommendations for managing inflammatory bowel disease among pregnant patients or those wanting to conceive, resulting from updates to the landmark PIANO study. 

Raymond Cross, MD, is director of the IBD Center at Mercy Medical Center in Baltimore, Maryland, and professor of medicine at the University of Maryland. Millie Long, MD, is a professor of medicine, vice chief of education, and director of the fellowship program in the Division of Gastroenterology and Hepatology at the University of North Carolina at Chapel Hill.

TRANSCRIPT:

Any views and opinions expressed are those of the authors and or participants, and do not necessarily reflect the views, policies, or positions of the A IBD network or HMP Global, its employees and affiliates.

Dr Cross: 

Hello everyone. I'm Raymond Cross from Mercy Medical Center in Baltimore, and I'm delighted to have my cohost here as a guest, Millie Long from UNC, and we're going to talk about pregnancy and IBD. Millie, welcome as a guest to IBD Drive

Dr Long:

Time. Thank you. It's fun to be here in the other chair.

Dr Cross:

So Millie, I wanted to talk about the PIANO registry. I think this is one of the biggest and most important collaborative projects that we've done in IBD. And can you just describe the registry for the listeners who may not be familiar with it?

Dr Long: 

Sure, absolutely. So this registry is really the brainchild of Dr. Uma Mahadevan at UCSF. And over the years she has really developed an amazing resource to help us to understand novel therapies in pregnancy and inflammatory bowel disease. And not only can we understand what happens during the pregnancy for enrolled patients, but we also follow the child. And in this fashion we're now even following the children out to 18 years of age. So this really allows us to get quite a full picture of outcomes for mother as well as baby, to help us to provide hopefully reassuring evidence to our patients about the safety of medications, whether during conception, pregnancy, during breastfeeding, and outcomes for their children. It's really a unique design where obviously, Ray, you have been a part of this for some time, as have I, as a site where UCSF is kind of the central site.

And then there are a number of sites really across the country that recruit from their patient population. But also just so our listeners know, any pregnant woman with IBD anywhere in the country can actually be enrolled because through UCSF, there's actually a direct enrollment. So you as a referring provider can actually tell your pregnant patients to reach out to the PIANO registry. We have a website, it's www.piano study.org, and they can directly link there to contact the lead coordinator and enroll.

Also the website's really important because we actually have it linked to real-time results. And so it actually shows right now there are over 1700 women enrolled that have been enrolled in the study and what their outcomes are on various medications. So it can be used even as a discussion tool in the clinic room with the patient when they mention concerns about the therapies that they may be on in pregnancy.

Dr Cross: 

Yeah, we're going to be a site at Mercy. We're super excited. At Maryland, when I was there, it was super easy to do external referrals. I just had a smart phrase that would put into my after-visit summary, and we had a number of our patients that participated and UCSF really did everything. They were really phenomenal and the children, they get cord blood and blood from the babies and UCSF arranges all of that. So even for the active sites, there's very little burden. So it's really a well-oiled machine at this point in time.

Dr Long: 

Yeah, it really is. And it could pivot to really novel information. For example, risankizumab, an IL-23 agent, has been relatively recently approved in Crohn's disease and ulcerative colitis. Now we all think of that mechanism as an IgG-based biologic. It's not going to cross in the third trimester. We know it's likely safe, but we've already been able to capture a number of moms and have their outcomes and it's just reassuring data even when something new comes out. We actually even just published a small series of about 3 patients and cord blood levels, so you can actually measure levels of RZA and mom and baby and talked a little bit about that. Actually the levels were actually a little lower than we anticipated, but overall, this ability to pivot when a new drug is released really provides great information for the community.

Dr Cross: 

That's where I was going to go next, but you started with novel biologics. So before novel biologics, we had anti-TNFs and thiopurine. So what has PIANO taught us about the safety of those classes of medications in pregnancy?

Dr Long: 

This is huge. I mean, as you well know, right? TNFs really have transformed the care of inflammatory bowel disease, so imperative to the management of both Crohn's disease and ulcerative colitis. But early on, when these therapies were approved in really 1999, right, like late nineties, there was no data on pregnancy and there were huge concerns based on this class. And so the PIANO registry actually started in 2007. And so within that registry, we have captured over 15 years of data. And so we really have long-term outcomes of the use of various medications, including anti-TNFs, and back in the day—we're both older, so we even at times used to hold anti-TNFs during part of pregnancy to try to minimize exposure to the baby. But what PIANO has taught us is that we should not do that. That in fact it's active disease in the mom that increases complications for the baby and by holding an TNF in the third trimester, mom can flare and can cause adverse outcomes for baby, whereas continuing the TNF actually has no adverse outcomes on the infants. And so not only do we know the medications are safe, but we don't need to limit and we actually should be using them and we should be starting them if needed during pregnancy. All of these questions that we didn't have an answer to that, through the generous donation of their data to patient participants, we now can provide a lot of reassurance and hopefully improve outcomes for moms and babies.

Dr Cross: 

And just remind me if I'm remembering this incorrectly, Millie, but the only signal with anti-TNFs and thiopurines was combination therapy and ulcerative colitis, and that was NICU admissions and I think it was infection. And I thought that that has mostly been attributed to increased disease activity in those patients. Am I remembering that correctly?

Dr Long: 

Yes. And remember that as you cut it, you get to smaller and smaller subgroups, the numbers do get smaller even though this is the largest registry in the US. But I think when you look more globally, there have not been significant complications associated with thiopurine use. And so we do know that actually levels in mom during the course of pregnancy probably do go up, of thiopurines. And at one point there has been seen some transient anemia, even in offspring, associated with higher levels of thiopurines. We don't necessarily recommend modifying treatment, but in my practice, what I do is if I'm starting TNF de novo during pregnancy, I use monotherapy. I don't use combo therapy. Part of that rationale is that the thiopurines can rarely be associated with pancreatitis and you don't want to give a pregnant mom pancreatitis. And so I do proactive therapeutic drug monitoring and use monotherapy for a mom who needs an initiation of a therapy during pregnancy.

If someone is on combination therapy, they're often on it in my practice for a reason. They may have complex perianal disease; there's a reason why they're still on combo therapy. I use a lot of combination therapy upfront and then reduce to mono if appropriate. So for those individuals, I keep them on their combo therapy. There's some data from Australia now that say that maybe we could think about reducing the dose of the thiopurine in the third trimester. I generally use lower dose anyway if I'm doing it for synergy and for immunogenicity. So I think that the take-home message is we should just monitor. We haven't seen adverse outcomes in our babies or the moms who are on combo therapy. Don't start a new thiopurine during pregnancy, but maintain them and monitor. And I think that those are the key outcomes and we have a lot of great data that this can keep mom in remission, which is what really helps the outcomes for baby.

Dr Cross: 

And you mentioned risankizumab. So you opened the door for novel biologics and we're not going to have a bunch of those patients yet in the registry, but what about vedolizumab and ustekinumab? I presume to be safe, I think confirmed in PIANO?

Dr Long: 

Exactly. So we did have a recent publication just last year in the American Journal of Gastroenterology that looked at vedolizumab and ustekinumab. And these outcomes were very reassuring. We did not see adverse outcomes for infants or for moms. There were no increased risks of congenital malformations, no increased infectious complications, and babies met developmental milestones normally. So that those data are quite reassuring as to the outcomes on biologics. And I think generally we're all pretty comfortable with biologics right now. I mean, for example, even though there's not a lot of data specifically on risankizumab, I'm very comfortable with risankizumab during pregnancy and I think our audience should be as well. But this is just another way to obtain more data as to that effect that specifically we're not seeing anything attributable to the medication. If our listeners want to go to pianostudy.org, they can see exactly the number on each drug that are enrolled. We are specifically looking for more individuals on the novel biologics, meaning the new IL-23 agents that have recently been approved such as mirikizumab, risankizumab, or guselkumab. But we're also really trying to get more information on the JAK inhibitors, which I'm sure you want to talk about as well. And the

Dr Cross: 

Going to…

Dr Long: 

Small molecules are a different beast here.

Dr Cross: 

So we don't have enough information on S1P receptor modulators and the JAK inhibitors.

Dr Long: 

Yeah, exactly. And I think generally my impression is that an S1P receptor modulator is usually used in a more moderate population. And so generally those patients may have lots of other choices. And so in my practice, if I have someone who's contemplating pregnancy and they are on an S1P, we may actually switch them to an alternate agent such as one of the novel biologics. The small molecules cross the placenta immediately, whereas this occurs later associated with the biologics. And there are some data in animals as to detrimental effects when used at higher doses. And so it's not necessarily that we have bad data in people and that the data thus far in people published out of the clinical trials, for example, with JAK inhibitors have been reassuring. But that said, if you have another option, I would do that. For example, with S1Ps, it's a harder ball game with those on JAK inhibitors because often they're on the JAK inhibitor because they have failed other therapies. And so we have to really have an individualized one-on-one discussion about how to approach pregnancy for individuals on JAKs.

Dr Cross: 

I think with JAK inhibitors, if we can somehow get them through the first trimester when the organs are formed and then potentially start in the second or third trimester if needed. We don't know that that's safe, but I think that many of us, that would be the goal is get pregnant, try to get through the first trimester, and then get back on the JAK. And fortunately there's no, of course, immunogenicity with small molecules. So you can in theory, do pulse therapy.

Dr Long: 

Exactly. What I've done in my practice, too, Ray, I'll often start them on perhaps there's one of the novel biologics that they haven’t seen yet like an IL-23 and I'll start them on that, kind of keep them on the JAK right up until they attempt a pregnancy and then leave it in my backpack with the thought that if I need to use it in second or third trimester, I'm going to, because you've got to, we do know the PIANO has taught us that it is the active disease that is associated with preterm delivery and that's associated with small for gestational age that's associated with infectious complications for the infant. There are just so many complications tied to active disease.

Dr Cross: 

Before I ask you a couple more questions, Millie, just a reminder to the listeners that were sponsored by the AIBD Network and that we are on Spotify and Apple Podcasts, so please subscribe.

So Millie, transitioning to, we talked about maternal and fetal outcomes. Let's think about more longer term outcomes in newborns and kids. So anything we've learned there.

Dr Long: 

So we actually follow the developmental milestones, which is great. There's some physical developmental milestones. There's kind of personal social developmental milestones or cognitive developmental milestones. And these are measured in kind of a standardized fashion through a survey instrument called the ASQ, which for those of you who are parents, this is what you're filling out in your pediatrician visits for kids at various ages. And so we are tracking those developmental milestones. Initially in PIANO we had them out to 4 years and we showed no difference with biologic exposure or combination therapy exposure. And now we're additionally following children out with at least annual assessment out to age 18. We're also capturing, for example, new diagnoses of autoimmune diseases, other diagnoses in children as they get older. We even had a really interesting case report where there was a young boy who was diagnosed with inflammatory bowel disease, but he had been, when he was in utero, his mom had been on infliximab. And the question was, well, he was kind of exposed before and will it work? And someone who's 10 years down the road needs infliximab and at least in this case report, there was no issue. He didn't develop any antibodies, did well, and got into remission. So you can follow interesting scenarios like that where because you have long-term follow up,

Dr Cross: 

What the anti TNFs, what's really interesting when you and I were learning this years and years ago, is that we know these drugs stay around in your system for a while, but in babies they stay in their system for months at a time, sometimes going out to 6 months. And fortunately in the US none of the vaccines early are live vaccine except for the rotavirus. So we were telling mothers to not give their infants the rotavirus vaccine. But what have we learned from people in the registry or babies in the that were inadvertently given the vaccine?

Dr Long: 

So we actually, as you know, there are lots of people, even though we counseled that, there are a lot of people that accidentally got rotavirus vaccine in the PIANO registry and there were no adverse outcomes with that. No acute infections, really only what would be expected in the general population in terms of some people after they get a vaccine you have a low-grade fever and some of that sort of stuff, but there were no differences. And so those data are very reassuring about accidental use in the PIANO cohort. But importantly, there was a really nice very high-level study out of Canada that was recently published where they actually did immunophenotyping of the kids and they actually gave rotavirus vaccine intentionally. And essentially what they found is there are no adverse outcomes. And so now with a really large population, I think we can say much more definitively that rotavirus vaccine is okay in patients on biologics.

And so recently I was a part of kind of an international global consensus conference and we used the GRADE process to evaluate the literature and came up with a recommendation that we can now give rotavirus vaccine to individuals on biologics and so to individuals whose mom was on a biologic. Let me clarify for the infant. And so I think this is going to make it a lot easier because now it's very simple—baby gets all vaccines in the US. Now I want to emphasize that internationally there is a live vaccine, the BCG vaccine, this is a much more potent vaccine. This is an antituberculosis vaccine that is live and this vaccine definitively should not be given to infants born to moms on biologics. There have been cases—a case—of disseminated TB with that live vaccine. And so that is a different ballgame than the rotavirus vaccine. But again, that BCG vaccine is not to typically given in the US and so at least here in the US all vaccines on schedule. The one caveat is that international BCG vaccine.

Dr Cross: 

So I only have a couple more questions Millie, but I remember that there was a statement from Europe that about children should not go to daycare for, I thought it was a year because of concern of biologics in their system and possible infection. And I remember that the investigators in the US were scrambling to use the registry to try to address that. So what did PIANO teach us about that?

Dr Long: 

Okay, this is really important. So I live in the US, typical maternity leaves in the US are actually pretty short—around 6 weeks if you're lucky. And so in Europe they have much longer maternity leave. So I think it was they were being protective and saying children shouldn't go to daycare, but there was more coverage for that. And so we felt it was really important to understand if that really caused issues. And so the answer is it does not. And so we followed babies born to moms on biologics and babies born to moms not on biologics who went to daycare early in life, when in theory the biologic-exposed babies would still have a level in their system, and there was no increased difference in serious infection between the 2 groups. Now when you compare kids who go to daycare versus kids who stay at home, all kids who go to daycare have a little bit more upper respiratory infections, some diarrheal illnesses, things like that. But the important part is there was no difference between those exposed to biologics and those not, so moms and dads, they can feel confident that if their child needs to go to daycare that they can even if they've been exposed to biologics.

Dr Cross: 

So for the listeners, this is just an advertisement for the national Advances in IBD course December 9th to December 11th at the Dolphin Resort in Orlando.

Millie, it doesn't have to be PIANO-focused, but any other new recommendations for pregnant women with IBD that's important for the listeners. We could talk probably for an hour about this, but any new things?

Dr Long:

Yeah, let me give you 3 quick pearls. The first is that this is true in the general population as well, but any pregnant mom with risk factors for preterm pre-eclampsia—and autoimmune disease is one of those risk factors—at week 11 of pregnancy should go on a low-dose aspirin. So all of my patients with IBD I am now recommending a low-dose aspirin because that is a risk factor for preterm pre-eclampsia. This dramatically reduces the risk and is really important for maternal fetal health. And I will say that there was a nice study that Uma Mahadevan did out of UCSF that showed a low-dose aspirin does not cause flares of inflammatory bowel disease during pregnancy. And so we can feel confident in that as well. So that's number 1.

Number 2, vaccination and prevention. There is now recommended in the general population that RSV vaccine be given to women in their third trimester of pregnancy. This is because RSV actually causes increased mortality in infants. And so by giving mom the vaccine in third trimester, obviously infant will have antibodies when they're born and it helps prevent this terrible outcome. So all moms with IBD, just as those in the general population, should get RSV vaccine in the third trimester. This is an inactivated vaccine, is perfectly safe for mom and baby. Actually a very large, very nice study done in pregnant women that showed the efficacy and safety.

And then finally just that one comment that we discussed about the Global Pregnancy Consensus Conference, that for infants in the US all vaccines can be given on schedule, including rotavirus vaccine. If the baby was exposed to a biologic during pregnancy, that is no longer a contraindication.

Dr Cross: 

Great. Millie, this has been wonderful. I usually ask a fun question, but instead I'm just going to give a congratulations. So I've known Millie maybe for 15 years now. We've been close friends and we've done a lot of cool things together, research and education. And in this podcast, and for those of you not aware, Millie is this year's Sherman Prize winner, which I view as sort of a career recognition award and it's long overdue. And Millie, as a friend and colleague, I was so delighted to hear that you won the award and I'm going to be so excited to see you accept this in Orlando. So congratulations on behalf of me and your many fans in the IBD world.

Dr Long: 

Oh, well thank you so much. Such an honor and what a wonderful prize from the Sherman family. And I'll tell you what, I am so thrilled for my other awardees this cycle who are so deserving. We have Jordan Axelrad from up at NYU, who's one of your mentees, who is our Emerging IBD Sherman Prize winner. And then we have Dermot McGovern up from Cedar-Sinai, who's such an amazing translational scientist. And so we really have a fantastic awardees this season and I look forward to hearing their stories as well. So thank you so much for the congratulations.

Dr Cross: 

Agreed. And even more reason for the listeners to come to the national meeting.

Dr Long: 

Exactly, exactly. I truly do believe this is the best clinical IBD conference really definitively in the US and I would argue potentially internationally. So I do hope our listeners will come and enjoy some of the most up-to-date IBD content. This is the time the therapeutic options are exploding. So this is a really good time to come learn about all the new options we have.

Dr Cross: 

Alright, great Millie, we'll talk next time when we're co-hosting.