Patient Selection and Safety With TNF Inhibitors - Episode 10
Marla Dubinsky, MD: The main things that we then turn our attention to, which are priorities for women who come to see me in my preconception clinic, are how will IBD [inflammatory bowel disease] affect pregnancy and how will pregnancy affect IBD?
It all goes back to the theme of inflammation control being king. We break it down into each trimester. In the first trimester, the bigger emphasis is on answering their question of, “Does inflammation affect my ability to stay pregnant?” “Is the miscarriage rate higher in the face of active inflammation?” In the high-risk world, they talk a lot about the role of inflammation and its impact on the rates of miscarriages. So we do explain to our female patients that control of inflammation is very important in the first trimester, because we want to minimize the risk of losing a baby.
The focus for a lot of women during that first trimester is on medications and the risk of congenital malformations. The baby is formed within 10 weeks. By the time they come to us reporting pregnancy, the baby has often been exposed to the medications they were on if they present in pregnancy to me, for example, a question around the safety of their medication. They’re most concerned about the risk of biologics since they’re newer, and we spend a lot of time talking about that. And so the malformation discussion happens early. We do say that the medications that you’re on and that we would prescribe, knowing that you’re going to get pregnant, can be used throughout pregnancy and during breastfeeding. There’s often a comment of, “Really? I thought I couldn’t be on these medications during pregnancy.” And so that’s another good discussion to have—about the safety of these medications and the risk of congenital malformations.
We clear up that story and tell them they can’t use methotrexate, thalidomide, or other therapies that have been linked to malformations. The bigger complex discussion happens when we talk about the newer therapies like tofacitinib, because we don’t have much data. We have scant reports of women in the trial getting pregnant. Once they get pregnant they have to leave the trial. The good news is that so far the data on that exposure during the first trimester have not resulted in an increased rate of malformation as they saw in the animal study. So that’s really a focus during the first trimester.
The second trimester is when I’m emphasizing control of inflammation. That baby needs to grow quite significantly, and we do not want a preterm delivery. The baby is between 20 and 30 weeks of gestation. We really want to focus on inflammation control. I’m actually sort of more obsessed with inflammation control in the second trimester. They understand it completely. We’re both on the same page when we have that discussion about extreme preterm delivery and the rate of intrauterine and growth retardation. So we want the baby to grow. That’s important.
And then the third trimester comes. The good news is that a lot of women will feel really good during pregnancy. There is a hormonal influence. And as you get further along into pregnancy, progesterone becomes a predominant hormone, and it tends to have a nice effect on how our female patients feel during pregnancy. The third trimester, again, is a bit more up to negotiation. We see babies grow nicely. They’re past the 30-week range. We’re up to 34 weeks. A lot of women want to know, “Can I stop my medication?”
I think the biggest controversy is, do we or do we not continue biologics beyond 24 weeks? The story has ping-ponged all over the place. There was a distinguishing discussion between Europe and North America. A lot of us who were doing research in this area said that you could continue it until about 30 to 32 weeks and give them their last infusion. If the drug is given every 8 weeks, you could sort of plan that you would give it at 32 weeks—it made sense in terms of numbers—and then again after delivery.
Well, is that really necessary? Do we really understand what we’re doing? We started to explore that a little more, and it ended up being that if you gave the last infliximab infusion before week 30, there was a low rate of placental transfer and the baby had the lowest measurement of cord blood. So that’s what people were focused on—diminishing the amount of infliximab that the baby had in the cord blood.
We know that this drug does cross during the third trimester, exponentially—sort of late into the 20-week range and then up from there. That’s when we first started to find out about this, and this was based on infliximab. We know that adalimumab and ustekinumab also cross the placenta. It’s a similar molecule to vedolizumab. They cross. The one biologic or TNF [tumor necrosis factor] that has not been shown to cross the placenta is certolizumab. Certolizumab, because it’s pegylated and doesn’t have that Fc receptor that binds to the placenta for the transfer, does not cross. A study called the CRIB study showed very low rates of placental transfer, as measured in the cord blood.
The question is, does it matter? Is the baby at risk? If these drugs are measurable in the cord blood, is the baby at risk of infection or immune suppression? So far, we have not seen that. What we do to prevent that is tell mothers that the baby should not and cannot get live vaccines during the first 6 months of life. Just like for a patient who is on one of these drugs, we don’t give live vaccines. If the baby does indeed have measurable cord blood levels, then the baby is exposed to the TNF and can have any of these biologic strategies, except for certolizumab. They can get a live vaccine in the first 6 months of life.
So we do distinguish certolizumab from the other TNFs and other biologics. What’s interesting is that there is only 1 vaccine that is live in the first 6 months of life. That’s the rotavirus vaccine, which is an oral vaccine. So we counsel on that. We ask that the babies do not get that vaccine. The good news is that the vaccines for chickenpox, measles, mumps, and rubella are not given until 1 year of life. The babies are on schedule. At 12 months, they can get all of the nonactive vaccines on schedule. So we’re really only talking about the rotavirus vaccine. The other good news is that there are reports that in babies who unintentionally received the rotavirus vaccine, even if exposed, were OK. So I think we’re just being very cautious.