Issue: May 2020
Source/Disclosures
Disclosures: Afzali reports acting as a consultant for AbbVie, Celgene, Janssen, Takeda and UCB; and receiving speaker fees from AbbVie, Janssen, Pfizer, Takeda and UCB. Mahadevan reports consulting for AbbVie, Janssen, Pfizer and Takeda and receiving a research grant from Pfizer. Regueiro reports financial ties with AbbVie, Amgen, Celgene, Janssen, Miraca Labs, Pfizer, Salix, Shire, Takeda and UCB.
May 22, 2020
8 min read
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‘Education is Power’: Pregnancy and IBD

Issue: May 2020
Source/Disclosures
Disclosures: Afzali reports acting as a consultant for AbbVie, Celgene, Janssen, Takeda and UCB; and receiving speaker fees from AbbVie, Janssen, Pfizer, Takeda and UCB. Mahadevan reports consulting for AbbVie, Janssen, Pfizer and Takeda and receiving a research grant from Pfizer. Regueiro reports financial ties with AbbVie, Amgen, Celgene, Janssen, Miraca Labs, Pfizer, Salix, Shire, Takeda and UCB.
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Inflammatory bowel disease is somewhat unique compared with other immune-mediated diseases. Its closest cousins, like rheumatoid arthritis, usually affect patients later in life.

While all immune-mediated diseases can have a dramatic impact on a person’s life, IBD can come very early and patients may undergo decades of therapy. Additionally, for many patients, a diagnosis coincides with a time in life complicating not only their lives but also the management of their disease; the child-bearing years.

Uma Mahadevan, MD, co-director of the Colitis and Crohn’s Center at the University of California, San Francisco, told Healio Gastroenterology and Liver Disease that pregnancy makes management of IBD tricky and vice-versa.

“You have multiple people involved in the care and the [obstetricians] are concerned about the IBD and the GIs are concerned about the pregnancy and don’t always have all the knowledge to address those issues,” she said. “It’s out of their wheelhouse in general. That creates a lot of fear.”

One of the leaders in the management of pregnancy and IBD, Uma Mahadevan, MD, co-director of the Colitis and Crohn’s Center at the University of California, San Francisco, said knowledge and proper communication are key to proper care.
One of the leaders in the management of pregnancy and IBD, Uma Mahadevan, MD, co-director of the Colitis and Crohn’s Center at the University of California, San Francisco, said knowledge and proper communication are key to proper care.
Source: Uma Mahadevan, MD.

Healio Gastroenterology and Liver Disease spoke with several IBD experts about the consequences of those fears, as well as what progression is needed in the area of research and data.

Miguel Regueiro, MD
Miguel Regueiro

Miguel Regueiro, MD, chief of gastroenterology, hepatology and nutrition at Cleveland Clinic, told Healio Gastroenterology and Liver Disease that some of the difficulty comes down to the simple fact that providers are juggling two very important factors.

“Pregnant women and IBD present some unique challenges,” he said. “One is always trying to account for the safety of medicine in pregnancy and maintaining remission of IBD when pregnant. Then, number two is the health of the mother and the baby, which, obviously, is of paramount importance.”

Fears

When there is fear or uncertainty about how IBD medications could impact a pregnancy, the default decision is to take the patient off their therapy, even if it was working.

“That has been the biggest challenge,” Mahadevan said. “To have people understand that the risk of the disease-causing complications in pregnancy is far more than the risk of the majority of medications we use.”

According to Anita Afzali, MD, medical director of the IBD Center at The Ohio State University, this thinking comes from an older mindset where biologic therapy could be held if the mother was doing well at the time they became pregnant.

Anita Afzali, MD
Anita Afzali

“Especially come the second or third trimester we said, ‘they’re doing well, so let’s try to reduce any potential exposure to the baby, hold their next dosing or their next infusion until after the baby is delivered, and then let’s resume therapy.’”

However, more recent findings show that the strategy of taking patients off their biologic therapy puts them at risk for flare, which can lead to greater complications for both mother and baby.

“Now the mother is flaring, her disease is out of control, and she’s going to require additional management, whether that’s steroids, hospitalization or surgery,” Afzali said. “There is no increased risk for infection to the newborn, there’s certainly no risk for congenital malformations, and therefore we recommend biologic therapy be continued throughout.”

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While some physicians take a more conservative approach, Afzali said newer evidence has shown that there is no harm to the mother or the baby if there is ongoing exposure to biologic therapy and more doctors are becoming comfortable with keeping women on therapy throughout their pregnancy.

“There is still a minority that may not, but let the evidence speak for itself,” she said. “Recent studies show no harm in continuation of biologic therapy, in fact, there’s potential risk if we discontinue, hold or delay therapy.”

Lack of Data

The older, more conservative approach remains because data in the area of pregnancy and IBD are still lacking. Limitations on clinical trials mean that the efficacy and safety of drugs in pregnant women cannot be studied as easily as in other settings.

“There will probably not be FDA registration studies designed in pregnancy,” Regueiro said. “It’s difficult to do a study in which some pregnant patients are randomized to placebo, especially if you think that the mother needs the medicine for IBD and could harm the mother and fetus without the medication. As for the safety of the medicine, it’s difficult to do a safety study on a medicine if you think there’s a chance that it could harm the fetus.”

Pictured left to right: Fernando Velayos, MD, Aline Charabaty, MD, David Rubin, MD, Millie D. Long, MD, Uma Mahadevan, MD, Adam Cheifetz, MD, Miguel Regueiro, MD, Edward V. Loftus Jr., MD, and Christina Ha, MD, all leaders in the management of IBD were among the faculty at the recent GUILD meeting in Maui.
Pictured left to right: Fernando Velayos, MD, Aline Charabaty, MD, David Rubin, MD, Millie D. Long, MD, Uma Mahadevan, MD, Adam Cheifetz, MD, Miguel Regueiro, MD, Edward V. Loftus Jr., MD, and Christina Ha, MD, all leaders in the management of IBD were among the faculty at the recent GUILD meeting in Maui.
Source: Uma Mahadevan, MD.

As soon as a woman in a clinical trial becomes pregnant, they are excluded from the study and taken off the drug, Mahadevan said. Patients would not know safety data until after a drug is released, and many are just afraid to use those drugs, she said.

“So, there’s even less data as people don’t actually get exposed to it during pregnancy,” Mahadevan said. “We end up relying on observational studies, and most of them have been retrospective, which means that you don’t always capture the information you need.”

For patients to become comfortable with newer IBD drugs in the realm of pregnancy, Afzali said it can feel like playing catch up.

“We’re always going to be behind,” she said. “All these new drugs are going to be coming onto the market at some point, but it’s going to take 5 or 10 years for safety data to be released.”

There has been some limited research into outcomes for mother and child, Mahadevan said.

“The EVASION study of a large number of women who were exposed to anti-TNF therapy during pregnancy, showed that there were no increased adverse outcomes in the kids,” she said. “However, if the mother discontinued the drug before the third trimester, which is a European recommendation, they were more likely to flare. Additionally, if they had disease activity in the third trimester, then the kids actually had more infectious complications. So, it really confirmed that disease activity is the biggest predictor of a negative outcome, and controlling disease is important.”

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Most medicines prescribed for IBD can and should be continued during pregnancy, Regueiro said. However, there are two exceptions, Xeljanz (tofacitinib, Pfizer) and methotrexate.

“Methotrexate is known to cause an abortion and has known teratogenic effects to fetus. The concern for tofacitinib is based on animal studies that raised some questions for concern for teratogenicity in the first trimester. This has not been shown in humans, so, until we have more data, we recommend avoiding tofacitinib in pregnancy.”

Prospects for Data

Our experts stressed the need for more prospective data on pregnancy in IBD, and it appears as though some might be on its way. Mahadevan has taken the lead on establishing A Multicenter National Prospective Study of Pregnancy and Neonatal Outcomes in Women with Inflammatory Bowel Disease, otherwise known as the PIANO registry, which is set to track approximately 1,700 mothers with IBD.

“They are followed prospectively, and it will also follow their children out to 4 years,” she said. “In its final publication, it will provide a lot of safety information that would help reassure us that what we’re doing is correct.”

Specifically, the registry will determine how the rates of birth defects, miscarriages, premature births and other outcomes are different between women with IBD taking azathioprine or biologic therapy and women with IBD not taking those medications. Now in its 13th year, the PIANO registry has already demonstrated several findings.

Researchers have found that corticosteroid use was associated with gestational diabetes, preterm birth and low birth weight. However, they found no significant increase in infant infection in the first 4 months of the babies’ lives.

Uma Mahadevan, MD
Uma Mahadevan

Mahadevan said the American Gastroenterological Association care pathway for pregnancy in IBD recommends that women on biologics maintain therapy through the third trimester. This care pathway was published jointly with the Society for Maternal Fetal Medicine, so both obstetricians and gastroenterologists can be on the same page.

“Something that people do, myself included, is we try to manipulate the dose so that the patient is at trough at the time of delivery. If someone gets a drug every 8 weeks, we try to give it somewhere between week 30 to 34, so that when they deliver, they don’t have the highest amount of drug in their body. If they’re on a 2-week drug, give the last dose around week 37 or 38, and then after delivery, assuming no infection.”

As more data come out, Afzali thinks it will give a lot of patients with IBD some peace of mind.

“I think it will be interesting to see what story it shares,” she said. “Half our patient population are females, and they want that information. They want to know. Maybe not all 50% of them, but it’s going to be very helpful for the patients and the providers to understand that this is an ongoing concern.”

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What Next?

The PIANO registry has the potential to be an invaluable source of knowledge for physicians treating patients with IBD who become pregnant, Regueiro said. However, more data in other areas are still needed to build a solid foundation for care.

“We absolutely need what [Mahadevan] has done,” he said. “It’s a fantastic registry. We also need more fundamental studies where we’re measuring pharmacodynamics in pregnancy, and, if possible, the neonate. It’s difficult, but we need more of the prospective biologic information studies on the mother, fetus, and neonate, that we just don’t have right now.”

Afzali hopes that having more prospective registries will provide women with more assurance and more confidence so they will not have to question choosing between becoming a mother and staying on their IBD medication(s).

“I think we’re slowly getting there,” she said. “We need longer term data on the babies beyond a year to give reassurance to the mother and family. We need to make sure the infant is meeting the developmental milestones, without impact to their immune system.

“With what these newer registries are tracking, that’s going to add a bit more ease and comfort for the mother.”

One of the most important steps of managing pregnant women with IBD is providing proper preconception counseling, Mahadevan said. When a patient does not have access to the right information, it can have a negative impact on their disease and pregnancy outcomes.

“Education is power,” Mahadevan said. “What we don’t want to see is a woman who gets pregnant and sees a friend or sees a doctor who’s not as informed and is told to come off all her medications.”

The potential for flares presents too big a risk for mother and baby.

“I tell all my patients, ‘When you’re ready to conceive, come talk to me first,’ so that we can have that conversation,” Mahadevan said. “Even if they’re far from considering conception, I tell them what can or cannot be continued through pregnancy.” – by Alex Young

Disclosures: Afzali reports acting as a consultant for AbbVie, Celgene, Janssen, Takeda and UCB; and receiving speaker fees from AbbVie, Janssen, Pfizer, Takeda and UCB. Mahadevan reports consulting for AbbVie, Janssen, Pfizer and Takeda and receiving a research grant from Pfizer. Regueiro reports financial ties with AbbVie, Amgen, Celgene, Janssen, Miraca Labs, Pfizer, Salix, Shire, Takeda and UCB.