Immunomodulatory drugs in pregnancy and lactation

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I'm Dr David Liew, your host for this episode, and today I'll be speaking to Kathy Paizis who's an obstetric medicine physician and nephrologist at the Mercy Hospital for Women in Melbourne. And it just so happens that I have the pleasure of working with her regularly at the Austin Hospital with my work as a rheumatologist. She's written an article in the June 2019 edition of Australian Prescriber on how to approach the sticky subject of immunomodulatory drugs in pregnancy and lactation. Kathy, welcome to the program.

Thanks, David.

So overall, the management of autoimmune disease in pregnancy requires a balance of a number of things. There's changing physiology, there's hormonal changes, there's immunomodulatory changes, all of which occur at different times of pregnancy. And that's not even to mention all of the medications that get involved. So let's drill down on this. Talk me through what happens to patients with autoimmune disease before, during and after pregnancy.

So, often we might refer some women for pre-pregnancy counselling before pregnancy. And that's very useful because I think sometimes you can allay some fears that people have about pregnancy, and also I suppose talk about the medications and planning for medications and what's safe and what's not safe.

Because I can imagine that most patients have some idea. There are some medications that they may have been told not to get pregnant on. There are some medications they know are affecting them systemically, and they're probably a little bit worried and concerned at that point. There's probably a lot of fear in the mind of patients in that situation.

That's correct, and I think the natural thing to do is when you're worried about sort of some medications is to stop them. And obviously, for some women that's the wrong thing to do. So I think having the opportunity to talk and discuss and present the evidence and the recommendations is helpful.

So let's talk a bit through that balance. Why is it not clearly a good thing for women to stop their medications before pregnancy?

I mean, I think it's always a team approach. So obviously, we're meeting them for the first time. They've got usually a rheumatologist that knows them for a long period of time. So I think obviously we need to work together, and then if someone has known someone for many years and is comfortable for them to come off their medications, and I'm normally comfortable, or maybe I'll sort of communicate with them and make sure that that's all okay. I think the worry is that by coming off some medications, a disease that is quiescent and well controlled becomes uncontrolled. So that poses, I suppose, a few problems, the first one being having uncontrolled disease in pregnancy and trying to get it under control, which usually means using steroids or prednisolone at higher doses, which we can do if we need to, but obviously if we can avoid that, then that's better for the women.

Decreased risk of gestational diabetes, decrease in the risk of infections and possibly early delivery, and also the fact that any inflammatory disease does increase the risk of pregnancy complications such as pre-eclampsia and small babies, intrauterine growth retardation, and the necessity of sometimes needing to deliver early because of those conditions. So increased inflammation during pregnancy is associated with worse pregnancy outcomes for the baby. And I think obviously some medications are less riskier than others. For some medications we can reassure women that the risks are low.

Perhaps we can just talk a little bit about how we've come to that knowledge, because that's something which is, I can imagine for you, is something that you have to explain quite a lot. How have we come to know that some medications are more safe, less safe? How the advice might vary, might be specific to certain circumstances. How have we accumulated this knowledge?

Yeah, so I suppose a lot of knowledge comes through just case studies and increasing number of women using them in pregnancy with data to suggest that they are safe. Also, studies looking at the presence of medications in cord blood, or not all medications will pass over to the baby. I just wanted to alert people to the Clinicians Health Channel. And under the MIMS button, there's the pregnancy and breastfeeding button, which is the Royal Women's Hospital site, for medications in pregnancy and breastfeeding. And that's an excellent site for people who are not particularly sure, that's updated regularly, and it gives a much more balanced assessment of medications in pregnancy and also breastfeeding as well as references.

Perhaps we can just run through a few commonly used medications and get a sense as to the kind of considerations that someone like yourself takes into mind. What about steroids during pregnancy? When should we be worried about this? When should we not be worried?

So I think most people that come along on steroids are always worried about cleft palate. So usually I reassure them and often their treating doctors that the data for cleft palate was in one sort of small study. We have a much larger group of women who have had steroids during pregnancy, and that association with cleft palate doesn't seem to have come through. So we always talk about sort of having the lowest dose of steroid to control disease. And I think from some recent data, trying to keep the dose less than 10 mg because of the high risk of gestational diabetes and then the risks associated with that. Also higher risk of infections and also higher risk of possibly early delivery.

So regarding the choice of steroid, prednisolone is metabolised by the placenta, whereas some of the other steroid preparations are less well metabolised. So high doses tend to reach the baby. So our choice would be prednisolone in pregnancy at the lowest dose possible. So also talk about if we need to use higher doses, well we just use them, get disease under control, and then try and bring the dose down after that.

I mean, that sounds like a very sensible approach. Maybe we can quickly run through a few of the commonly used drugs. What about methotrexate?

So we normally avoid methotrexate in pregnancy. So the main education, I suppose, pre-pregnancy is just making sure that they have adequate contraception. They understand the problems with methotrexate with regards to the increased risk of miscarriages and possibly increased risk of malformations, that it's a teratogenic medication and that when they're changing over from methotrexate to something else that the disease is well controlled before attempting pregnancy.

I guess leflunomide is probably a similar type of situation, really, isn't it? Where we were a little bit more concerned before, still wouldn't recommend it at all during pregnancy. Mycophenolate's another one that we're trying to avoid during pregnancy, isn't it?

Yeah. So mycophenolate, I suppose, we definitely know that it does cause higher risk of miscarriages. There's a specific pattern of congenital malformations that are associated with mycophenolate, and that's both sort of in the rheumatological and also we see that in the transplant population as well.

I guess that's why it's so important that there's pre-pregnancy counselling with someone with expertise and a knowledge in the area like yourself.

Yeah, we talk through all those scenarios I suppose, and what would happen with a flare and what the possibilities are and yeah, and also talking about breastfeeding, and for some women they might have to go back on their medications soon after delivery or what the choices are for women with breastfeeding as well. I think that's also an important factor of the pre-pregnancy counselling that I didn't mention before.

So speaking of medications, which are used both in the transplant and the rheumatological sphere, azathioprine and sulfasalazine. Tell me a little bit about those.

Yeah, azathioprine, we're very, I suppose, comfortable with, because we have information, going back with renal transplants from the 1960s, and it hasn't been shown to cause increased risk of congenital malformations, and it really allows us to manage renal transplants, lupus and lupus nephritis, and also some of the inflammatory bowel diseases during pregnancy. Now we've got the use of measuring TPMT so we can see what metabolisers people are and we can avoid the side effects where someone is a slow metaboliser and accumulates azathioprine metabolites.

So I think we're all fairly comfortable now with the use of azathioprine in pregnancy, and the data is very reassuring. And the only other thing is that it does have a small anti-folate sort of effect. And we do normally put people on a higher dose of folic acid when they're on azathioprine. Also I suppose with azathioprine, I think probably 10 years ago it was recommended that women don't breastfeed, but again, because of reassuring data, we would recommend that it's okay to breastfeed on azathioprine.

I guess hydroxychloroquine and sulfasalazine probably both fall in that category as well?

Yeah, so hydroxychloroquine, especially in women with lupus nephritis and lupus in general, we know they do much better in pregnancy with decreased risk of relapses on Plaquenil. There's also some interesting, other than its immunosuppressant effects, I suppose, is the other metabolic effects that Plaquenil seems to be sort of becoming much more popular. And I think in the pregnancy literature has been sort of studied for its antithrombotic and possibly effects on decreasing the risk of pre-eclampsia and also placental insufficiency because of those metabolic effects that it has in women with antiphospholipid syndrome in women that are positive.

So there's plenty of positives for hydroxychloroquine during pregnancy. So I think you need a good reason why women would stop their normal hydroxychloroquine before pregnancy. Because I often see women who had their hydroxychloroquine stopped at the beginning of pregnancy, and often I might restart it if there are sort of reasons to continue it.

Now just to real quickly run through calcineurin inhibitors, I guess we're starting to get slightly more into the more specialised and what'd you think of those during pregnancy?

Yeah, calcineurin inhibitors, again, we have a lot of information from our transplant cohorts in pregnancy, and these appear to be safe in pregnancy and also breastfeeding. They do, I suppose as you say, it's only for a specialised group of women, but I think in women with lupus nephritis who might have a relapse in pregnancy, it's provided another arm, I suppose, to try and get remission and maybe allowing you to bring down the steroid doses much faster than you would otherwise.

Absolutely. So just in summary, what are your key take-home messages to our frontline GP colleagues and to dispensing pharmacists who are dealing with these on an everyday basis?

I suppose, first of all, I think women on teratogenic medications should be on adequate forms of contraception, I suppose the best ones being Implanon and the Mirena. I think if people are unsure, you can consult the pregnancy and breastfeeding site, the Royal Women's Hospital. You can always ring the Women's or the Mercy or Monash and speak to the pharmacy department there. And they'll also give you some information or any of the obstetric physicians operating, any of those hospitals are happy also to speak to people.

So I think if people are unsure, rather than stopping medications, we're happy to be called or just make sure before stopping a medication that it is harmful in pregnancy. Also it's beneficial for women to come to pre-pregnancy counselling because we can all have a plan. We might start folate sort of early prior to pregnancy. We might consider anticoagulation in women that are high risk of getting pre-eclampsia. We may suggest putting them on aspirin once they get pregnant.

So I think it's nice to have that plan. It just makes it easier when we see the women when they're pregnant about you know, where we're going and what we're doing. I think also good to discuss breastfeeding so women have some idea of what's going to happen postpartum and because a lot of these diseases might flare and how we're going to manage it, how they're going to be followed up, and what to expect, I suppose. So I think it's all part of that package.

Kathy, that's been a tour de force. Thank you very much for sharing all your knowledge today and look forward to seeing you around the traps.

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The views of the guests or the host of this program are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm David Liew, and thanks for joining us once again on the Australian Prescriber Podcast.