EXPERT ANALYSIS FROM RWCS 2016
MAUI, HAWAII (FRONTLINE MEDICAL NEWS) – The consensus among gastroenterologists with expertise in inflammatory bowel disease is that continuation of biologics or immunomodulators in affected women throughout pregnancy and breastfeeding poses no increased risks to the fetus – and therein lies a message for rheumatologists and obstetricians, Dr. Uma Mahadevan said at the 2016 Rheumatology Winter Clinical Symposium.
“The risk of uncontrolled disease must be weighed against the risk of medical therapy. And this is something that is often missed,” according to Dr. Mahadevan, professor of medicine and co–medical director of the Center for Colitis and Crohn’s Disease at the University of California, San Francisco.
Gastroenterologists – at least, those whose practices focus on inflammatory bowel disease (IBD) – have led the way within medicine in terms of establishing the safety of biologics and immunomodulators such as azathioprine in pregnant women with chronic inflammatory diseases and their babies. And having accomplished that, they have been ahead of the curve in terms of continuing such therapy throughout pregnancy and breastfeeding. That’s because active Crohn’s disease and ulcerative colitis are particularly common in women during their childbearing years. And a disease flare during pregnancy is associated with a markedly increased risk of preterm birth and other adverse outcomes.
Gastroenterologists’ longstanding interest in the safety to mother and fetus of continued use of effective, potent medications throughout pregnancy was the impetus for the ongoing prospective U.S. Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes ( PIANO ) study, now in its ninth year, with an enrollment of roughly 1,500 women with IBD. The study has included comparisons of outcomes of women on different medications during pregnancy versus unmedicated women.
In multiple publications, Dr. Mahadevan and other PIANO investigators have established that increased IBD activity adversely affects pregnancy outcomes, and that stabilization of disease and effective maintenance therapy throughout pregnancy is important. The PIANO group has demonstrated that IBD medication exposure well into the third trimester in patients in sustained remission was not associated with an increase in congenital anomalies, spontaneous abortions, intrauterine growth restriction, or low birth weight.
To the surprise of many gastroenterologists, the PIANO study has shown that women with Crohn’s disease generally have smoother pregnancies than do those with ulcerative colitis, who tend to get sicker and have more complications.
Since PIANO data show an increased rate of preterm birth and low birth weight in IBD patients on combination therapy with azathioprine plus a biologic throughout pregnancy, Dr. Mahadevan and others try to discontinue the azathioprine, even though the need for combination therapy is a marker for patients with more severe disease.
Anti-TNF-alpha use during third trimester
Of particular interest to rheumatologists, who rely heavily on many of the same biologic agents gastroenterologists use to treat IBD, the use of anti–tumor necrosis factor–alpha biologics in the third trimester was not associated with an increase in preterm birth or maternal disease activity in the third trimester or the first 4 months post partum. When women on certolizumab pegol (Cimzia) during the third trimester were excluded from the analysis, since this biologic uniquely does not cross the placenta at all, the most recent PIANO data show a modest yet statistically significant 35% increase in infections in infants at age 12 months whose mothers were on other biologics in the third trimester. But Dr. Mahadevan said she doesn’t yet consider this finding definitive.
“It’s still a small group of patients, and every year when we update the results the infant infection risk goes back and forth from statistically significant to nonsignificant. I think there’s a signal here; we just need to keep collecting more data,” she said.
Particularly reassuring is the finding that the offspring of PIANO participants who had in utero exposure to biologics and immunomodulators didn’t have any developmental delay, compared with unexposed babies, according to the validated Ages and Stages Questionnaire at ages 1, 2, 3, and 4 years and Denver Childhood Developmental Score at months 4, 9, and 12.
“These kids do great later in life. Actually, they have better scores than unexposed kids. Not to say that biologics make your kid smarter. It probably has to do with better IBD control,” Dr. Mahadevan said.
Effects while breastfeeding
Breastfeeding while on biologics or azathioprine didn’t adversely affect infant growth, infection rate, or developmental milestones. More specifically, levels of biologics in the mothers, babies, or cord serum were not associated with the likelihood of a neonatal intensive care unit stay, an increase in infant infections, or achievement of developmental milestones.
“Almost all the agents are detectable in breast milk, but only at the nanogram level. We tell all our patients on biologics they can breastfeed. It doesn’t matter when their last dose was, don’t worry about it,” the gastroenterologist said.
Importance of preconception counseling
Key practical lessons she has learned in taking care of large numbers of patients with severe IBD referred to her tertiary center include the importance of preconception counseling. A woman should stop methotrexate at least 3 months prior to conception. Providing information on medication safety and the risks of poorly controlled disease helps in adherence.
It’s best to communicate with the patient’s obstetrician about the importance of continuing her IBD therapy during pregnancy before she becomes pregnant.
“It’s better to have this discussion ahead of time and have a plan in place. Once a patient is pregnant it’s very difficult if her doula or someone else has told them to stop a medication to convince them to continue it,” said Dr. Mahadevan.
All women with IBD should be followed as high-risk pregnancies. Mode of delivery is at the discretion of the obstetrician unless the patient has an open rectovaginal fistula; even if it’s inactive, cesarean delivery is preferable in that situation, she said.
Steps taken in the third trimester
In the third trimester, she routinely sends a letter to the patient’s pediatrician requesting no live virus vaccines in the coming baby’s first 6 months – in the United States, that’s the rotavirus vaccine – if the infant was exposed in utero to a biologic other than certolizumab pegol, but that all other vaccines can be given on schedule. She also asks that the pediatrician monitor an exposed baby for infections.
“That being said, there have been 20-plus exposures to rotavirus vaccine in the first 6 months of life recorded in the PIANO registry in the infants of mothers on biologics and we haven’t seen any adverse events. So maybe the CDC is overstating the risk, but at this point the rule is still no live virus vaccines,” she said.
She tries to time her last dose of biologic agents during pregnancy as follows: at week 30-32 for infliximab or vedolizumab and week 36-38 for adalimumab or golimumab. As for certolizumab pegol, “they can take that on their way to labor and delivery,” she quipped.
“I give the next dose of a biologic agent soon after delivery, often while the patient is still in the hospital, 24 hours after vaginal delivery and 48 hours after a C-section, assuming no infection,” Dr. Mahadevan said.
The elements of her approach to management of the pregnant patient with IBD are in accord with a recent report, The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy, in which she participated ( Gastroenterology. 2016 Mar;150:734-57 ).
Rheumatologists’ habits with biologics in pregnancy
Dr. John J. Cush rose from the audience to observe that the situation in rheumatology with regard to biologics in pregnancy is quite a bit different from what’s going on in gastroenterology.
“I think a lot of rheumatologists don’t let their patients get pregnant on biologics for fear of what may happen. And that’s because they don’t know the data. I think you’ve shown very clearly that you can get pregnant on biologics and do well. But for many of us who do allow our patients to get pregnant on biologic monotherapy, the practice is to stop it once they get pregnant. The idea is we want them to be in a very deep remission to increase the odds of getting pregnant and having a successful pregnancy, but then we stop the drug and we assume the disease state is going to stay the same. Often, though, it doesn’t stay the same, it gets worse. Yet this is a common practice in rheumatology. What’s your response?” asked Dr. Cush, professor of medicine and rheumatology at Baylor University Medical Center, Dallas, and director of clinical rheumatology at the Baylor Research Institute.
“I think in IBD it’s very clear that patients with active disease in pregnancy do much, much worse,” Dr. Mahadevan replied. “They have preterm birth, they get very sick, they’re hospitalized and placed on steroids. So for us, the benefit is very clear. I don’t know the data in rheumatoid arthritis – whether active disease leads to increased complication rates – but I do know from colleagues that in the postpartum period women with poorly controlled rheumatoid arthritis can’t take care of their baby because their hands are so damaged. And that’s a big deal.
“So when you see that the drugs are not associated with an increased risk of birth defects and on monotherapy there’s no increase in infections and other complications, you’d think that in the right patient continuing treatment until the late third trimester would be the way to go, especially since if you’ve put the patient on a biologic it must mean she has severe disease,” the gastroenterologist observed.
Dr. Roy Fleischmann of the University of Texas, Dallas, asked why gastroenterologists don’t put all IBD patients of childbearing age on certolizumab pegol if they need biologic therapy, since it doesn’t cross the placenta.
“Maybe IBD is different, but our biologics don’t necessarily have the longest persistence,” Dr. Mahadevan replied. “If you start a woman on certolizumab pegol at age 20 the chances of her still being on it at 28 are probably pretty low.”
Conference director Dr. Arthur Kavanaugh, professor of medicine at the University of California, San Diego, asked if the message regarding management of IBD in pregnancy being put forth by Dr. Mahadevan and the IBD in Pregnancy Consensus Group has gained wide acceptance by gastroenterologists across the country.
“I think the people who do IBD as a concentrated practice, whether in private or academic practice, are very aware of this literature,” she said.
“In general, IBD has become more and more centered among a group of people who want to take care of IBD. If you look at the big private practices, they have a hepatitis C person, an IBD person, and everyone else just wants to scope. I think the message is getting across to non-IBD gastroenterologists, but there is some confusion because the Europeans are very firm about stopping biologics at 22 weeks’ gestation if the patient is in deep remission and we in North America continue treatment,” said Dr. Mahadevan.
Her work with the PIANO study is funded by the Crohn’s and Colitis Foundation of America. In addition, Dr. Mahadevan disclosed ties to more than half a dozen pharmaceutical companies.