Dr Cynthia Seow on IBD Medications During Pregnancy

Dr Seow discusses work of her group on the PIANO Consensus in reviewing the safety of medications for IBD during preconception, pregnancy, postpartum, breastfeeding, and over the longer term to assess affects on the children.

Cynthia Seow MD, MSc, is professor at the Cumming School of Medicine at the University of Calgary, Calgary, Alberta, Canada, conducting clinical research in gastroenterology.

TRANSCRIPT:

Hello, my name is Cynthia Seow from the University of Calgary and I had the pleasure of leading the IBD medications during pregnancy section of the global consensus for the management of pregnancy and inflammatory bowel disease.

As you would know, medications in pregnancy is a really controversial area. People are worried about using medications during pregnancy and this fear is sometimes also extended to the physicians. But it is really important to remember that the evolving guidelines emphasize the importance of controlling disease activity for both maternal and fetal health. And this underpins all the statements for the use of medications in pregnancy in the setting of IBD.

However, we know that there are concerns because IBD medications have limited safety data for mother and child, and we'll go into the reasons for this shortly. Very importantly, if a woman is on medications, these should be continued during the pregnancy and we certainly know that specific to biologics or monoclonal antibodies during pregnancy, that de-escalating therapy or stopping this before the third trimester leads to adverse outcomes, including more disease flares.

So why has there been controversy over the use of medications in pregnancy? Well, clearly, number 1, pregnant women are not included in IBD clinical trials. Secondly, unmeasured confounding is innate to uncontrolled studies and of course in the setting of pregnancy these studies are uncontrolled. Very importantly, existing disease activity impacts the decision to continue or discontinue therapy. And this decision is not random. There is a reason why these women have been placed on the therapy in the first place. Perhaps reassuringly, there are low event rates for adverse events. However, this does make it more difficult to study. Again, there are small cohort sizes in the setting of IBD medications in pregnancy, especially with the novel therapies; there is just not as much data for safety in this setting.

Very importantly, congenital malformations occur in 5% to 8% of all births. Therefore, medications cannot be blamed as a sole cause for congenital anomalies. And importantly, the active disease is considered a teratogen, even perhaps more so than any medication. And lastly, preterm birth contributes to about 10% of all births, and this in itself predisposes to neonatal infection. And we know that uncontrolled disease activity is a lead cause of preterm birth.

So with this in mind, we need to think about the placental physiology and the transfer of medications from mother to baby. As you can see here with the placental physiology in the middle, that the drug gets into the maternal blood, it can cross through the syncytiotrophoblasts, across the cytotrophoblasts, and then can bathe their fetal endothelial cells and get into the fetal blood. When you look at monoclonal antibodies, importantly, there is minimal of any transfer during the first trimester. And in particular, there is no transfer of monoclonal antibodies between 3 and 8 weeks gestation, which is the critical time for organogenesis.

However, there is steady transfer in the second and third trimesters with 80% of drug transfer occurring in the third trimester. And this is how the monoclonal antibodies can be transferred into the fetal circulation and it does take some time for the drug to be cleared from the fetal circulation. However, when you compare this with small molecules, there is steady transfer throughout the period of gestation, but similarly, because it enters into the blood readily, it is also cleared readily after birth.

With this in mind, we had a number of GRADE statements looking at the impact of IBD medications during pregnancy. And in particular we looked at the impact on safety, specifically congenital malformations as well as infection risk.

GRADE statement 12: For women with IBD who are pregnant or attempting conception, we recommend continuing maintenance with 5-amino salicylate therapy. The level of evidence was low, but the recommendation was strong.

GRADE statement 13: In women with IBD who are pregnant or attempting conception, we suggest continuing maintenance sulfasalazine therapy. But importantly, because sulfasalazine impacts on folate absorption and metabolism, these women should be on 2 grams of folic acid supplementation. Overall, the use of this drug level of evidence very low in pregnancy and recommendation is conditional; not that much data.

GRADE statement 14: In women with IBD who are pregnant, we suggest use of corticosteroid therapy when clinically necessary with appropriate monitoring. The level of evidence is low, the recommendation is conditional. Beyond patient and physician's concerns about the risk of congenital anomalies or infection, it is really important to note that if a patient has acute disease, that corticosteroids can be used as an effective induction agent—again, underpinning the message that we should get disease under control. But even more importantly, we should remember that corticosteroids are only an induction agent. They are not a useful maintenance agent. And contingency plan should be made straight away about bridging these patients onto appropriate, safe, or low-risk maintenance therapy for the management of IBD during the pregnancy.

With regards to appropriate monitoring, we should be looking out for metabolic complications in the mother, including gestational diabetes and hypertension.

GRADE statement 15: In women with IBD, we recommend discontinuing maintenance methotrexate therapy prior to conception. This is a known teratogen, therefore the recommendation is strong even though the level of evidence is very low and constitutes mainly case reports and case series.

GRADE statement 16: In women with IBD who are pregnant or attempting conception, we suggest continuing maintenance thiopurine therapy as data does not demonstrate an increased risk of congenital malformations or infant infections. Level of evidence is very low. Recommendation is conditional, and we'll talk about some of the caveats of the data in subsequent slides.

These GRADE statements pertain to the use of monoclonal antibodies during pregnancy.

In women with IBD who are pregnant or attempting conception, we recommend continuing a maintenance antitumor necrosis factor therapy throughout pregnancy. The level of evidence is low and the recommendation is strong as there is a whole body of data demonstrating that these therapies are effective and of low risk. And again, stopping these therapies in the pregnancy leads to adverse outcomes, namely preterm birth, which is a major risk factor for infant infection.

GRADE statement 18: In women with IBD who are pregnant or attempting conception, we suggest continuing maintenance combination therapy with an antitumor necrosis factor antibody and thiopurine therapy throughout pregnancy. Remember as we discussed in the beginning that the decision to treat a pregnant woman with IBD is not a random event. And there are patients where it was decided that they should be on combination therapy based on disease phenotype. So keep this in mind.

But certainly for patients who are on combination therapy, if there is a decision to put the patient onto monotherapy, it is considered lower risk to withdraw the thiopurine, then withdraw the antitumor necrosis factor antibody.

GRADE statements 19 and 20 pertain to suggesting continuing maintenance vedolizumab and ustekinumab therapy throughout pregnancy with the level of evidence for both being low and the recommendation being conditional. These are newer biologic therapies than the anti-TNF agents, but are also considered to be low risk during pregnancy—and a reminder that there is no transplacental transfer during the critical period of organogenesis and therefore this does not contribute to an increased risk of congenital malformations and there is no evidence to suggest an increased risk of infection.

This was followed by a number of consensus statements, really based on global expert opinion where there was less data available.

Women with IBD who are pregnant and with active disease should start or optimize the same appropriate therapies as in nonpregnant patients with the exception of thiopurines, where there is a risk of idiosyncratic adverse events; methotrexate, which we've already discussed, is teratogenic; and then the oral small molecules, the Janus kinase inhibitors, and the sphingosine 1 receptor modulators, which cross readily across the placenta and are not considered a preferred therapy during pregnancy.

13: In women with IBD who continue during thiopurines during pregnancy precautions should be taken for intrahepatic cholestasis by measurement of liver enzymes, metabolite levels, and consideration of split dosing.

14: Women with IBD or pregnant have infections, fistula, or pouchitis that require antibiotics may take an appropriate course of a low-risk antibiotic knowing that the risk of infection or sepsis is of greater risk to the mom and the infant than taking therapies.

Consensus statement 15: Women with IBD may initiate or continue calcineurin inhibitors, which include cyclosporine and tacrolimus during pregnancy with careful monitoring if there are no viable alternate treatment options available. But in many jurisdictions, there are safer options for acute severe ulcerative colitis, including the antitumor necrosis factor agents.

Statement 16: Women with IBD who are pregnant or attempting conception should continue biosimilars to existing biologics as there is no significant difference in effectiveness or safety.

And finally, consensus statement 17: Women with IBD who are pregnant or attempting conception should continue existing anti-interleukin 23 therapy throughout pregnancy. This includes mirikizumab, risankizumab, and guselkumab.

Very importantly, when you look at the oral small molecules in pregnancy, it is the consensus that women with IBD should discontinue the following agents: ozanimod, etrasimod, tofacitinib, upadacitinib, and filgotinib prior to conception unless there is no effective alternative therapy to maintain maternal health. You will note that there are different cessation recommendations here. These are based on half-life. However, we should take a bigger view of this, and if a patient is to stop an oral small molecule, please remember that it's important to segue them, transition them to a more appropriate therapy and establish remission on the new therapy before attempting conception.

With regard to thiopurines, a short note to say that there was shunting through the 6-MMP pathway in pregnancy, which increases the risk of intrahepatic cholestasis in pregnancy and this was an FDA announcement and practical considerations include splitting the dosing, allopurinol cotherapy use of thioguanines, or as we mentioned earlier, biologic monotherapy.

In summary, when you're looking at IBD medications from preconception through pregnancy, remember that the use of aminosalicylates, thiopurines, and corticosteroids are considered effective therapies with corticosteroids only being an effective induction and not maintenance therapy, and there is low risk with using these in the appropriate setting. However, methotrexate is considered a teratogen and should be stopped 1 to 3 months prior to conception to allow the conjugates to be cleared from the system.

With regards to the advanced therapies, the monoclonal antibodies, antitumor necrosis factor, anti-integrins, anti-IL 12/23s and anti-IL 23s are considered to be of low risk and very effective therapies during preconception, first trimester, second trimester, and third trimester for maintenance of remission in women with inflammatory bowel disease. Regarding the Janus kinase inhibitors, these should be avoided unless there is no other viable option for maternal health and should be considered on a case-by-case basis.

Thank you again for watching the effect of IBD medications in pregnancy. Thank you.