Stephen A. Paget, MD: My name is Dr. Stephen Paget. I'm the Chief of Rheumatology at Hospital for Special Surgery. It's a pleasure today to introduce to you Dr. Lisa Sammaritano, Associate Professor of Medicine at the Weill Medical College at Cornell University. Lisa has had a particular interest, over the past few years, in the area of pregnancy, specifically related to musculoskeletal and autoimmune disorders. And today we are going to address some of the issues that physicians and patients have to consider in the presence of such problems.
Lisa, if you could give me some idea about the things that patients and physicians need to think about when a patient becomes pregnant, specifically related to either their autoimmune disorder or musculoskeletal problem.
Lisa Sammaritano, MD: The first thing is thinking about it before the patient becomes pregnant. For patients with any underlying illnesses, but especially in autoimmune disease, you really need to plan ahead of time. A lot of medications can have effects during pregnancy and some, in fact, need to be discontinued up to three months before becoming pregnant. That is one issue.
The next issue I think is trying to assess the risk of pregnancy for a given patient. The nature of the diagnosis, how active the disease is, and other factors help a physician to guide a patient in terms of deciding how risky a pregnancy is. They need to decide whether now is an appropriate time or would it perhaps be better to wait and try it at a later time when the disease is not quite so active.
Stephen A. Paget, MD: What is the difference between a woman who is pregnant and a woman who is not pregnant with regard to the hormonal system, with regard to their immunology? Why is it important? Is it that different a state?
Lisa Sammaritano, MD: It is. It's tremendously different in terms of immunology. When pregnant, women have a very big change in their immune system -- and although it is still not completely understood -- overall the effect is that of immunosuppression. There are some infections, for example, that pregnant woman will get or be susceptible to that, when not pregnant, they were able to fight off. That is felt to be because of the need to tolerate the fetus, since the fetus genetically is somewhat different from the mother. Because of that, there is an increased susceptibility to certain infections, and medications may have a different effect. You need to think about the effect of the immune change on the underlying disease and vice-versa.
Other changes are important as well, and they relate more to organ systems. The kidney, for example, in pregnancy has to filter up to 50% more blood than it does otherwise. For women with lupus who have underlying kidney problems, it is important to evaluate ahead of time whether or not their kidneys are up to that, because it is a stress on the kidney. Again we come back to the idea that it is important to check things ahead of time, to measure kidney function ahead of time.
On the issue of hormones, they obviously change dramatically during pregnancy, and we are not quite sure how these affect autoimmune diseases. Clinically, we know that in rheumatoid arthritis, for example, pregnancy tends to induce a remission in many patients. On the other hand, in lupus, although there is a lot of controversy about it, many people do believe that, especially in the later part of pregnancy, there is an increased risk of a lupus flare, and that has been related at least in part to changes in levels of estrogen. Estrogen can actually be pro-inflammatory. The sex hormones have their own effects on the immune system.
Stephen A. Paget, MD: It would be helpful now that you have given that basic information to go over various types of problems that some of our patients and physicians are dealing with and then try to see whether there is some specificity to the way in which you have to address that person's illness during the pregnancy state. Let's begin with rheumatoid arthritis. Rheumatoid arthritis is an inflammatory disorder. It gives joint inflammation in the upper and lower extremities. What happens during pregnancy, and what facts have to be taken into account during pregnancy?
Lisa Sammaritano, MD: During pregnancy, for patients with rheumatoid arthritis, it is often a wonderful time for a patient because she is often able to discontinue medications. About 75% of patients with rheumatoid arthritis will have at least a partial remission in their disease activity during the pregnancy itself. So the issues for pregnancy tend not to depend so much on the activity of the arthritis, but on the structural changes that may have occurred already because of arthritis. For example, if someone has instability in their cervical spine, the issues are regarding anesthesia at the time of delivery, total joint replacements, and things of that nature.
In general, within six to eight weeks after delivery, a woman with rheumatoid arthritis will have a recurrence of the pre-pregnancy disease activity, and that is important to realize too. Patients are often so happy that their disease is quiet that it can be difficult sometimes to help them understand that really one should start on medication again right after delivery to try to prevent that kind of a rebound effect.
Stephen A. Paget, MD: Are there any medications a patient with rheumatoid arthritis can take during the pregnancy?
Lisa Sammaritano, MD: Sure there are, and when talking about medicine and pregnancy, I guess overall the idea is looking at it as a spectrum. There are medications that have been around for a long time, such as corticosteroids, where we observed patients for many, many years and feel that low to moderate doses, especially, are fine during pregnancy. They have their own set of side effects in terms of internal problems, but in terms of fetal development and fetal problems, they tend not to affect the fetus. So, when possible, we rely on low-dose steroids during pregnancy for women with rheumatoid arthritis, unlike pre-pregnancy or postpregnancy.
There are other medications. The common medication used for rheumatoid arthritis, methotrexate, merits special attention, because that is actually contraindicated totally during pregnancy. It causes craniofacial and limb deformity in developing fetuses, and so that needs to be stopped three months before one becomes pregnant. It is important for patients to realize that ahead of time, and it is actually something that I address with patients when I start them on a remittive drug. You know, since a lot of these woman are young, of child-bearing age, it is important to address this even when making a decision about what medication might be best to start with.
Stephen A. Paget, MD: So, in general, in most patients with rheumatoid arthritis you try to stop all of the medications except the steroids?
Lisa Sammaritano, MD: I do. Anti-inflammatories are not as well studied during pregnancy as is aspirin, which has been around for a long time. They are probably okay to take during pregnancy up until the last couple of months; at that point you need to worry about affects on the fetus in terms of ductus arteriosis and premature closure that can cause pulmonary hypertension in the fetus. And they can also prolong labor. Before that, a lot of patients will take anti-inflammatories if needed; probably ibuprofen is considered the safest one. Personally, I have found that for the degree of response, 5 mg of prednisone tends to give a better response in many patients, probably with less potential for side effects.
Stephen A. Paget, MD: What about some of our newer medications, the anti-TNF medications such as etanercept and inflixamab? Is there is enough information to demonstrate safety or lack of?
Lisa Sammaritano, MD: No, there is not enough information to demonstrate either of those. I think that, in general, one would hope that just by virtue of remission occurring that it would be possible to discontinue that medication. It is difficult to note, because it is so new. And it's not that a controlled study will ever be done on these medications during pregnancy. I think the FDA has actually classified Enbrel as Category B in pregnancy, which means actually that there is no data that says it's a bad thing, no data in animals, for example, that show a lot of deformity or other problems. I try to stop it. If the patient has very severe disease, though, I think you have to weigh the potential risks versus the benefit and make that decision.
Stephen A. Paget, MD: What about in the post-partum state, when the woman is nursing -- and obviously some women nurse for a shorter period of time and others longer -- relative to transferring antibodies and protection. What do you usually recommend there as far as the reinstitution of medicines?
Lisa Sammaritano, MD: Well, again, it depends on the patient and on the medication. Steroids are considered -- again low-dose is optimal -- safe for women who are breast-feeding. Anti-inflammatories are in the middle, and we usually recommend ibuprofen and try to time the breast feeding about four hours after taking the medication to minimize the amount of ibuprofen in the breast milk. Other medications are considered relatively safe, for example, heparin in patients who need to be on that for some weeks post-partum. Interestingly, for patients who have problems with blood clotting during pregnancy who don't take warfarin (Coumadin) during the pregnancy, Coumadin is actually considered okay for women who are breast-feeding because it really doesn't go into the breast milk to any significant degree. So you have to decide how great the risk of increased disease activity is, how great a desire the patient has to breast feed, and then try to balance things between that.
Generally hydroxychloroquine and gold salts, people don't like to have their patients breast feeding on those medications, but if the patient insists sometimes you try to work out a compromise.
Stephen A. Paget, MD: If we could move to systemic lupus erythematosus for the last part of this, what are the problems that a patient with lupus can have and how much can they be anticipated before, during and after the pregnancy?
Lisa Sammaritano, MD: Well, unlike rheumatoid arthritis, the concern with lupus is that the disease activity will worsen significantly during pregnancy, especially during later pregnancy, and, as you know, years ago women with lupus were told not to become pregnant. If they did become pregnant, they were advised to terminate the pregnancies for medical reasons. I think that with more information, better medication and obstetrical care, that has changed. The most important thing to consider and evaluate in deciding whether or not now is a good time for a pregnancy in a woman with lupus is to look at the few things that have been clearly shown to have an impact on outcome of pregnancy, in terms of the fetus, pregnancy outcome itself, and maternal problems or morbidity.
The first is activity of disease, and it has been shown time and time again that patients with inactive disease at the time of conception overall do better. They have a much lesser chance of having a flare during a pregnancy if things are quiet when they start. Those studies suggest that disease should be inactive for six months prior to conception.
The next important point to consider in terms of assessing risk for pregnancy for a particular woman is what her renal function is. We had talked about what a stress pregnancy puts on the kidneys, and if a woman with lupus has renal insufficiency, it is important to assess her kidney function ahead of time. Based on that, one can give some estimate of how likely it is that kidney problems can become an issue during pregnancy. For some women with very limited kidney function, pregnancy really is contraindicated since it may worsen to the extent that they would require dialysis.
There are a couple of other very important factors that impact more on the pregnancy outcome and the newborn itself. One is anticardiolipin or antiphospholipid antibodies. These antibodies, present in about a third of patients with lupus, have a tremendous effect in terms of risk for miscarriage or fetal loss during the pregnancy. Years ago, it was felt that much of the adverse outcome in pregnancy really was due to the presence of these antibodies. And these antibodies can predispose the patient to blood clot formation or fetal loss, presumably because of blood clot formation in the placenta, although there clearly have to be other mechanisms that are acting earlier.
Identification of the antibody ahead of time is really critical, because there are several great studies that have been done recently that show that if a woman has suffered fetal losses from this antibody, treatment with medication -- aspirin and heparin -- through the pregnancy can improve viability and survival from 25% to 75%. So it is incredibly important to identify, and there are patients who are referred to rheumatologists from their obstetricians because there are patients who only have this antibody and it's a sort of limited autoimmune disease. They don't have underlying lupus, but they are identified because of their obstetrical history, and they benefit greatly from this kind of therapy.
I guess the last thing to mention, in terms of lupus for a pregnancy, is that there are other antibodies present in lupus -- anti-Ro and anti-La -- that can increase the risk for an inflammatory, although usually short-lived disorder, in the baby, called neonatal lupus. This can cause rash, change in blood counts or liver function, and, in very severe cases, can affect the conduction system of the heart so that the baby's heart rate can be affected. Again, that severe manifestation is very rare, and it only has happened in women who have this particular antibody. So, testing for it ahead of time and knowing ahead of time allows us to be more vigilant during the pregnancy.
Stephen A. Paget, MD: If you make a decision in concert with the patient, the woman who has lupus and who wants to become pregnant and their significant other, to go ahead with pregnancy, and there is some activity of the lupus, can they take medications safely in order to try to dampen the inflammatory response and improve the outcome?
Lisa Sammaritano, MD: Sure, for lupus, particularly, so many patients are on some dosage of steroid for active disease and, in general, will continue that. Some practitioners have felt that when a patient with lupus becomes pregnant, you should actually start corticosteroid just in case they develop a flare. We don't do that here. If a patient is on a dose of steroid, it doesn't seem to be the best time to try tapering it and, in general, we'll continue at a low dose during the course of the pregnancy.
I already mentioned methotrexate as inadvisable. Cyclophosphamide is also not medication that one can take during pregnancy unless perhaps towards the very end. It really is contraindicated. Azathioprine (Imuran) can be taken safely during pregnancy, and it is probably the only immunosuppressive that we feel comfortable allowing a woman to continue with, because there really are no reports of fetal anomalies based on that. If possible, that would be a medication in addition to steroid that one could consider during pregnancy.
Hydroxychloroquine (Plaquenil) has been quite controversial as to whether or not it's something that could be taken during pregnancy, and I think most recent evidence suggests that it probably is safe to continue if the patient really requires it for control, especially of there is severe discoid or other lupus rash. There is even some evidence that it may be beneficial in pregnancy in terms of decreasing risk of flare occurring during the pregnancy itself, but that is preliminary and from small studies.
Stephen A. Paget, MD: If anticoagulants are needed, you would more often use heparin than Coumadin during the pregnancy?
Lisa Sammaritano, MD: I only use heparin. Coumadin can cause an embryopathy. It's well recognized, and, in general, that occurs when it is given during the first trimester. In some countries outside the United States, it is used, and they will use it during a later period in pregnancy when it is felt not to have a potential to do that. In the U.S., standard practice is not to use it during pregnancy, and so we switch patients who are on Coumadin to heparin during the pregnancy or if they have the risk factor or cardiolipin antibody, we then will put them on heparin along with aspirin. Heparin has its own set of side effects, especially over the long-term - risk of osteoporosis in a woman who is already at risk for that because of the pregnancy. But fortunately the heparin molecule itself, even the low molecular rate, heparin, is too large to pass through the placenta; so it really doesn't represent a risk to the fetus. That's one great benefit of using it.
Stephen A. Paget, MD: Finally, do you find that it is best to have a multidisciplinary team, especially in high risk patients with lupus, in order to follow the patient through and bring them through safely?
Lisa Sammaritano, MD: Definitely. I think that who is a part of that team depends on the patient and their particular problems, but at the very least, it has to involve the rheumatologist and, for most patients, a high-risk obstetrician. In a patient with fairly uncomplicated lupus, I don't know that that is necessary, but certainly high-risk obstetricians have more experience with this. If someone has underlying renal disease, it is very important to have her nephrologist involved. The risk of preeclampsia is increased in patients with renal disease, whether or not they have underlying lupus, and so it is important to start off with baseline levels of protein, 24-hour urine protein.
Dr. Sammaritano was interviewed by Dr. Stephen A. Paget, Physician-in-Chief, Hospital for Special Surgery