IBD Drive Time: Uma Mahadevan, MD, on Pregnancy With IBD and the PIANO Study

In this episode of IBD Drive Time, our host Dr Cross discusses the PIANO study and treating pregnant patients with inflammatory bowel disease (IBD) with the study’s lead investigator, Dr Mahadevan.

Uma Mahadevan, MD, is the director of the Colitis and Crohn's Disease Center at University of California at San Francisco Medical Center.
 

For more insights from experts like Dr Mahadevan, click here.

TRANSCRIPT:

Dr. Raymond Cross:   Welcome, everyone, to IBD Drive Time. I'm Raymond Cross from the University of Maryland School of Medicine. I'm delighted to have my friend and colleague, Uma Mahadevan, from University of California, San Francisco, to talk to us today about pregnancy.

Uma, welcome to IBD Drive Time.

Dr. Uma Mahadevan:  Thank you, Ray. Thank you for having me.

Dr. Cross:  Let's jump right in. Question, when a woman comes to the office for preconception counseling, what variables, what information are you considering when giving a patient a green light to conceive? Tell us what your thought process is.

Dr. Mahadevan:  The first thing is if she's coming for preconception counseling, you've already won. What we don't want to see happening is that a patient gets pregnant, sees a provider, stops all her medicines, and then comes to see you in a flare. The fact that she's coming for preconception counseling is a big win.

I do tell my patients, whatever medication I start them on, "You can or cannot get pregnant on this. When you're ready to conceive, come talk to me," so that they've been primed. When she comes in, the questions you want to ask primarily go around how her inflammatory bowel disease is doing.

Is she in remission? Is she off steroids? Is her remission stable and documented? All of those are important, and then we go through our healthcare maintenance checklist. Has she had a recent Pap smear, because cervical dysplasia can impact fertility? Has she had children before? How old is she? What other medical comorbidities does she have?

With respect to the inflammatory bowel disease, I would make sure their medicines are optimized. If they're on a biologic, I will check a level, make sure it's where it should be. I will almost always do a scope to confirm remission and also do baseline labs along with vitamin levels and confirm they're in remission. Those are all very important things.

You want endoscopic remission, clinical remission before you give a green light. Not everyone can get there, but that's the goal.

Dr. Cross:  I completely agree, Uma. I started to smile when you said that the fact that the patient's there for preconception counseling, you've already won at least half the battle. I completely agree. In my experience, the bad outcomes, the very premature infants have been in flaring patients that happen to get pregnant. It's very good that they're coming to see you.

I'm going to push you a little bit on the remission. I struggle with this. The old data we used to quote from the '80s was all based on patient symptoms. It basically suggested that if a woman felt well, she was going to do well. If a woman didn't feel well, it was the rule of thirds, a third do better, a third stay the same, and a third do worse.

That was all based well before treat to target. Let's say you do do a baseline scope and the patient has endoscopic activity. How much do you try to push that before telling them it's OK to conceive? Do you have any kind of threshold there? It's a tough question.

Dr. Mahadevan:  It depends on the patient. If this is someone who this is their first biologic, they recently started, they're now three or four months into it, I will definitely optimize. I'll even consider changing meds.

We all have patients who've been through multiple therapies, and the one they're on is the only thing that's ever worked for them. That patient, I would give more leeway and say, "OK, this is the best we're going to get. Let's go," for most patients, particularly with ulcerative colitis.

There's been a lot of data from our pregnancy registry, PIANO, from European registries. Women with ulcerative colitis are statistically more likely to flare than women with Crohn's disease. In that patient with UC who has active inflammation, the chances of them having a significant flare in pregnancy is more than a third. We do see that in practice.

Most of our patients who flare in pregnancy are UC patients. The other caveat is that if you have active inflammation, you're less likely to conceive. You're less likely to conceive, more likely to have a miscarriage, and more likely to have complications of labor and delivery.

All of that put together, I do push for endoscopic remission in most patients, not everyone, in most patients.

Dr. Cross:  We've been talking a bit about pregnancy outcomes that go poorly. Do you recommend that all your patients see a high-risk OB-GYN, or is it select patients?

Dr. Mahadevan:  I do recommend all my patients see a maternal-fetal medicine specialist. A MFM specialist is what we think of as a high-risk OB. There may be OB practices where they have somebody who sees "hig-risk patients," but that is not an MFM. An MFM has done additional training in perinatology.

The Society for Maternal-Fetal Medicine has joined with the American Gastroenterology Association to come up with a joint guideline on the management of these patients. They recommend, as do I, that every IBD patient see an MFM.

When I refer my patients to an MFM, depending on how sick they are, they may completely take over the care and do everything for the patient, including the delivery, or they may work with the local OB and monitor at certain time points. The intensity of how they're followed varies on the patient's history.

Just because someone's young, and healthy, and has no other issues, they still have an increased risk of complications of labor and delivery compared to other patients who get pregnant. Also, they will do things like start patients on aspirin, because that's been shown to reduce preeclampsia in patients with immune-mediated disease.

They will monitor them for placental issues. There are a lot of things that can go wrong in any pregnancy, more so in someone with IBD.

Dr. Cross:  Best practice is refer all your patients to maternal-fetal medicine specialist?

Dr. Mahadevan:  Yes, I do that. I'm lucky I have access to that. I realize not everyone does.

Dr. Cross:  Not a long list, but for our listeners, what medications can't they use during pregnancy?

Dr. Mahadevan:  The FDA got rid of the A, B, C, D, and X because people were misusing that, and sometimes your OBs wouldn't give your patient azathioprine because it was a D. Now, we have the PLLR, which gives information, and you use that information as a provider to make a decision.

The only medication I say a patient cannot be on that's related to inflammatory bowel disease is methotrexate. That is a known abortifacient and teratogen. I also don't use thalidomide, though, I don't use that anyway, but some people have used that for Crohn's disease in the past.

Everything else is a risk-benefit ratio, and that would include ciprofloxacin. There are some reports of bone developmental abnormalities in animals with exposure to cipro, but the studies done in OB literature on cipro does not show increased risk, and something that can be used short-term, same with metronidazole short-term, because that's what they study.

They don't look at it for the entire pregnancy like someone may use in IBD. My antibiotic of choice in pregnancy is amoxicillin/clavulanic acid for pouchitis and for perianal disease.

Dr. Cross:  That's a good segue into patients that are worsening. If you have a patient that flares during pregnancy, do you manage them any differently than a patient who's preconception or postpartum?

Dr. Mahadevan:  Yes and no. Obviously, there's some things that you wouldn't want to do in a pregnant patient, but the management is the same. If somebody flares or has symptoms of flare, the first thing I do is get blood work. I will examine them.

If it's significant and I think I need to change their therapy, I will do a flexible sigmoidoscopy in the ulcerative colitis patient. We published on that, and it's low-risk. There's no increased risk of harm to the infant or the mother with the flexing. For ulcerative colitis, that's great, because you get all the information you need.

In our study, 10 percent of patients with symptoms had a normal flexing. Remember that pregnancy itself can give you hematochezia from hemorrhoids and can give you GI symptoms. Not everything GI in pregnancy is a flare. If I'm going to change therapy, I want to look.

A colonoscopy, I've rarely had to do a colonoscopy in pregnancy. If I need imaging, I will try to avoid a CT, but the amount of radiation in CT is pretty minimal. I tend to do an MR enterography without gadolinium because the radiologists have panic attacks if you even write the word gadolinium and pregnancy next to each other.

I will do a flex, I will do imaging with an MR without gad. I will do labs, but remember, labs are different in pregnancy. They're going to have low albumin. They're going to have an elevated sed rate. They're going to have an elevated alk phos, including in lactation, but it gives me an idea of where they are.

In terms of treatment, I do try to avoid steroids if I can. You don't always have that choice. I would rather go straight to infliximab in someone having a UC flare if I can get it right away than I would go to corticosteroids.

The only thing I don't do in pregnancy is I won't start azathioprine 6-MP for the first time in pregnancy. I'll continue it if they're on it, but I don't like to start it for the first time, because you can't predict who's going to get pancreatitis and everyone who's going to get bone marrow suppression.

I have used tofacitinib in pregnancy. I have sent patients to colectomy in pregnancy. There are reports of cyclosporin in pregnancy. All of those things that you would do, you can do in the pregnant patient. I absolutely have the MFM involved at that point.

Dr. Cross:  To summarize some of that, clearly, a pregnant flaring patient is a high-risk patient. Once you confirm that there's active inflammation, whether it's imaging endoscopy, or if you have a reliable biomarker for that patient, it sounds like there's a definite preference.

You want to use the most rapid-acting agent, and that's why your preference is infliximab. Many of us use Prednisone. The point is you want to get them better fairly quickly because they're high-risk.

Dr. Mahadevan:  Correct. There was some work we did out of PIANO that showed patients on steroids in pregnancy had higher rates of complications. Of course, that's very tightly tied to disease activity.

Don't think that, "Oh, we'll put them on steroids, get them through the pregnancy, and then start something," because that is not correct. You want the mother to be healthy.

Dr. Cross:  Before we talk about PIANO, I want to remind everyone that IBD Drive Time is sponsored by the Gastroenterology Learning Network and Advances in IBD.

Uma, can you give us a high-level summary of the PIANO registry and the results?

Dr. Mahadevan:  Sure. PIANO stands for Pregnancy and Inflammatory Bowel Disease in Neonatal Outcomes. This is a prospective pregnancy registry in the United States, and it's done through the Crohn's & Colitis Foundation Clinical Research Alliance.

We started enrolling in 2007, and in 2019 or 2020, we published our major results, where we had 1,490 women who were pregnant with IBD, 379 not on a thiopurine or biologic, 242 on a thiopurine, 642 on a biologic, and 227 on both. There are 1,431 babies with no increase in birth defects, spontaneous abortion, preterm birth, low birth weight, or infections in the first year of life.

You'd think now, "OK, well, that makes sense," but remember when we started in 2007, people were stopping the biologics, and still, within the last couple of years people were stopping biologics when a woman became pregnant.

If they had active disease, there was more spontaneous abortion. We also looked at developmental milestones which were good up to four years of age, despite whatever medication they were exposed to in utero.

Dr. Cross:  We know that neonates will have drug in their system when they're born and that in many cases, this can last for months. For mothers that have just delivered, any precautions for their infants that they need to think about?

Dr. Mahadevan:  There's a difference between the TNFs and the newer biologics. Infliximab was the one that had the highest transfer, where babies were born with almost two-and-a-half times the amount of drug as mom. It can be detectable in very low levels out to nine months.

In PIANO, most of it was gone by six months. There was a case report of a baby who had a live vaccine, BCG, in Europe and developed disseminated BCG and died. With that, we say no live vaccines if they were exposed to a biologic in utero.

In the United States, the only biologic we give in the first six months is rotavirus, so we say to skip that. However, in PIANO, we had 40 babies exposed to rotavirus despite getting exposed to a biologic in utero and they were fine.

There's been data from other sources, too, with biologic exposure in rotavirus. It's probably overkill. We still recommend no live vaccine in the first six months. All other vaccines should be given on schedule. If you need to give MMR at six months, which is a live vaccine if it's an issue where you live, that's fine. BCG after six months is fine.

They can go to day care — this was a study that Millie [Long, MD] did — without any increase in infections compared to other kids in day care. There aren't restrictions, but, of course, especially in the first couple of months, these babies have a significant amount of biologic on board. If you have any infections, etc., you need to alert your pediatrician as you would anyway.

Dr. Cross:  Any breastfeeding precautions in our patients on biologics or small molecules, they're getting a procedure, they're asking about pumping and dumping? Anything they need to be aware of?

Dr. Mahadevan:  They can breastfeed on any of the biologics. We looked at that, and there's very minimal transfer and no harm that was noted. They can breastfeed on thiopurines. Methotrexate is not recommended for breastfeeding.

The other small molecules, tofacitinib and ozanimod, are also not recommended in breastfeeding, because they're small molecules, they will transfer, you take them every day, and there is a potential for immunosuppression in the infant.

On those, the thought is that you don't. It also could be that we have such little data. We are where we were with azathioprine 20 years ago when we also said don't breastfeed, and now it's OK. We just need more information, but for now, small molecules, no, methotrexate, no.

Antibiotics, metronidazole is a no. Cipro is OK. There's a resource called LactMed, which is a very good resource for checking any drug and whether the mother can breastfeed on it. You asked about pumping and dumping.

Pumping and dumping doesn't make physiologic sense for these medications, because as the levels go up in the serum, they go up in breast milk. As they go down in the blood, they get pulled out of breast milk. Pumping and dumping has no utility for any of the biologics or other medications we use in IBD.

If a patient comes for a procedure, propofol is great, because it's gone so quickly, so that's preferred. If you're using fentanyl, meperidine, or midazolam, what anesthesia says is if the mom is awake enough to breastfeed, it's fine. I generally tell them to wait 12 hours if they can.

Dr. Cross:  Let me summarize. No methotrexate, no metronidazole, no oral small molecules, the new small molecules, and no pump and dump?

Dr. Mahadevan:  Correct. Are you saying I'm using too many words? [laughs]

Dr. Cross:  No, I just want to make sure everyone gets the high-level points. C-section seems to be over-utilized in our patients. Which patients should have a C-section?

Dr. Mahadevan:  As a gastroenterologist, the only time I say someone should have a C-section is if they have active perianal disease at the time of delivery or a rectovaginal fistula. Everything else is at the discretion of the obstetrician. Ileoanal J-pouch is somewhat controversial.

Most of our J-pouch patients do get a C-section. Ideally, they should get it in the light of day, somewhere with surgical backup, because they may have scarring, etc. There is data from Mayo and Cleveland Clinic showing these women can have successful vaginal delivery.

The concern is not so much damage to the pouch, but damage to the sphincter and increasing incontinence, which patients with J-pouch already have higher rates of.

Dr. Cross:  Before I get to the fun question, I want to say congratulations on PIANO. As a clinical researcher, it's very infrequent that you can publish research that's going to change clinical practice. You've certainly done that, so congratulations, and thanks from all the providers that take care of these patients.

Dr. Mahadevan:  Thanks for everyone who sent their patients in. I couldn't have done it without that.

Dr. Cross:  Fun question. Tell us something about yourself the audience would not know.

Dr. Mahadevan:  You know this, but others may not. I am a huge football fan. My week rises and shines based on how the 49ers are doing, so this is not a good week for me. I'm happy how the team did and look forward to next year.

Dr. Cross:  Next year's promising, right?

Dr. Mahadevan:  Yeah.

Dr. Cross:  Uma, thanks so much for joining us on IBD Drive Time. We hope to have you back soon.

Dr. Mahadevan:  I would love that. Thanks, Ray.