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Maureen A. McMahon, MD, MS: Hello. I am Dr Maureen McMahon. Welcome to the Medscape InDiscussion podcast series on systemic lupus erythematosus (SLE). Today, we’ll discuss reproductive health and SLE with our guest, Dr Lisa Sammaritano. Dr Sammaritano is a professor of clinical medicine at Weill Cornell Medical College and an attending rheumatologist at Hospital for Special Surgery in New York City. Thank you for joining us today.
Lisa R. Sammaritano, MD: Thank you for inviting me.
McMahon: What I didn’t mention in the introduction is that you’re the lead author on the American College of Rheumatology (ACR) guidelines for reproductive health in patients with rheumatic diseases, which I have found incredibly helpful in my practice. I’m excited to talk to you today about this.
Many of our patients with SLE are in their childbearing years and their reproductive years, and so this can be a particularly important topic to them. I know in a busy clinic visit where you’re worried about their nephritis or other things are going on, we don’t always address it with our patients. I’m wondering what you usually do about talking to patients about issues related to reproductive health, and how you usually bring up the topic.
Sammaritano: I agree with you. It is an incredibly important issue. Not only are many of our patients within that reproductive window, but most of our patients are women, so it applies to many of our patients. I usually bring it up in an initial visit. I mention that this is an important part of their health in general, and that disease activity and certain medications can have an important impact on any pregnancy outcome. It’s important that people be aware of that at the start, when they’re not necessarily thinking about pregnancy. I usually say, this may not be applicable right now, but it’s important that you know about it. And then we just go over things very briefly.
One thing that has been suggested is the use of one key question, which is a published tool, asking, “Would you like to be pregnant within the next year?” That’s easy because it’s very quick, and when physicians or clinicians remember to incorporate that, it is very effective in terms of helping to focus the patient’s thoughts. If they do not want to be pregnant or are not sure, that then can lead to a quick discussion about contraception.
In recent years, we have been focusing — we, meaning rheumatologists in general — on trying to document the forms of contraception used and counseling given. I think there have been many efforts at many centers across the country to try to identify which patients are and are not using contraception to counsel them regarding that.
That’s one way that this discussion can go. The other way is if patients say, yes, now is the time that I am thinking of becoming pregnant. Then we can at least do some preliminary counseling and give them our general guidance. For women with lupus who are considering pregnancy, it’s important that their disease be well-controlled, whether in remission or at a low level of disease activity, for around 6 months before conception. And they should be stable on pregnancy-compatible medications. I know that’s a mouthful, but that is the big point from the reproductive health guidelines. Activity of disease is incredibly important in terms of outcomes for pregnancy, not just for the health of the mother but also for the outcome of the pregnancy itself.
I try to emphasize that to women — I think often women are willing to sacrifice their health if they think that they will have a successful pregnancy, because it is such an important thing for so many of us. It is important; it is about your health, and that is important. But also, if you want to have a healthy baby, it’s important for that, too.
McMahon: It is so important to bring it up with patients early on, because I think that once we bring it up, then even if it’s not a conversation they want to have right now, it’s a conversation that can recur over time and planning can happen.
Sammaritano: One other benefit of not just the ACR reproductive health guideline, but all the other publications and guidelines — European Alliance of Associations for Rheumatology (EULAR) just published a medication and pregnancy guideline this year — is that now all rheumatologists, not just those who focus or specialize in this, have easy access to data that they can relate to their patients, because it is not possible for every woman with lupus thinking of having a pregnancy to go see somebody who just specializes in that.
We all see patients with lupus. We all are going to have to counsel them about pregnancy, contraception, and other reproductive issues. I think having ready access to guidance for that is important.
McMahon: I think so too, and even for those of us who see a lot of these patients, I think it’s helpful to have that official guidance as well.
In terms of contraception, how do you usually approach that for your lupus patients?
Sammaritano: It is similar to the discussion about pregnancy planning and closely linked. If we counsel someone to avoid pregnancy because their disease is active or because they’re taking a teratogenic medication, that’s not enough. We need to help guide them because not all contraceptives are as effective or as safe as we would like them to be for our patients. I tell them that different forms of contraception that may or may not be best for you.
The general recommendation that we have made in the guideline is so-called LARC (long-acting, reversible contraception) is recommended for all of our patients with rheumatic disease, not just with lupus — regardless of whether their disease is active or quiet, regardless of whether they have antiphospholipid antibodies (APLs) or not, regardless of whether they are on an immunosuppressive, regardless of whether they are nulliparous (ie, have not had children). The LARC contraceptives are highly effective. That means the chance of pregnancy is less than 1 per 100 patient-years. The LARC contraceptives are intrauterine devices (IUDs) and the subdermal progesterone implant. We know less about the implant than we do about the IUDs, and so in our guideline, we recommended the IUD over the implant just for that reason.
There are so little data on the use of any contraceptive method in patients with lupus and/or antiphospholipid syndrome (APS). We have to extrapolate somewhat from the general literature. There’s a fair amount of literature on the use of certain contraceptives, specifically progestin-only contraceptives, in patients who have other prothrombotic conditions.
We have looked at that literature in formulating our recommendations for our APL-positive patients. First and foremost, we recommend the use of an IUD, and I usually recommend the progesterone-containing IUD because I think it has a lot of advantages. One advantage is that it can decrease menstrual cramps and menstrual bleeding. That can be a big benefit for women on warfarin for APS, because their menses otherwise can be quite heavy and lead to anemia. The progesterone is local in its actions, so there are minimal systemic side effects. There are varying formulations. There are smaller ones with less progesterone that can be used in adolescents or teenagers.
There are a lot of options for that. There are studies that show that these progesterones do not lead to an increased risk for thrombosis, unlike the estrogen-containing ones.
For lupus patients, regardless of their activity or APLs, we recommend an IUD. But some people don’t want an IUD, and that is understandable. If a patient doesn’t want an IUD, they shouldn’t have one, we then need to figure out another option for them.
Then what we do for our patients with lupus who do not have APLs is look at their level of disease activity. If it is quiet, meaning either in remission or low-level disease activity, they absolutely can consider use of an estrogen/progesterone contraceptive. Usually, that’s the pill. We avoid that in patients with moderate or active disease because the studies that confirmed no extra risk of flare, including the OC-SELENA study, excluded those patients. We can’t say that for sure it’s a bad thing. We can only say we have concerns because it hasn’t been studied, and the whole reason for the OC-SELENA study was a long-held belief that estrogen would cause flares. We’re very careful in that way.
For our patients who have active disease or who have APLs, we recommend they avoid estrogen. If they are not comfortable with an IUD or an implant, they can use a progesterone-only pill. It is effective, moderately effective. The risk for pregnancy is something like 1 in 20 patient-years instead of 1 in 100. But it’s effective, especially with consistent use.
The last thing I’ll say is that some people aren’t comfortable with any of these things. I have had patients who feel that way. They’ll say, I don’t want any hormones in my body. I don’t want anything foreign in my body. Then we tell them to do the next best thing — use the least effective birth control, but maybe use two forms.
Condoms are the least effective, but they’re a whole lot more effective than no contraception. Other low-effectiveness forms of contraception can be incorporated. You can use it with spermicide; you can use it with the rhythm or natural family planning method. So, just timing things.
One final note is that we also emphasize emergency contraception. That is the morning-after pill. It is safe for all our patients with lupus, whether they have active disease or APLs. I try to make a point of mentioning that to my patients because I don’t want them to have to rush to reach out to me, in an urgent way, when it becomes an acute issue. It is just a progesterone, and it is fine for all our patients to take. It’s available over the counter. They should be aware of that if they feel they want that or need that.
McMahon: When you think about having a pregnancy that is planned, what are some of the considerations when a patient comes in and says, okay, now I’m ready? What are some of your considerations, both with timing and what kind of testing you do? What other considerations do you keep in mind?
Sammaritano: For our patients with lupus, they must have a quiet or a low level of disease activity. I go over that with them. It’s interesting because when we wrote these guidelines, we described it as “quiet disease,” and patients say, what does that mean? It’s a good question. For example, they might say, If I have a little bit of a malar rash, and I always have that, can I never get pregnant? Or, If I have stiffness and a little joint pain when I wake up in the morning, does that mean my disease is active, and I can’t get pregnant? The answer to that is no — a low level of disease seems to be fine. And actually, several publications came out after our guideline was published that looked at low levels of disease activity, specifically one of which said outcomes are the same whether you enter pregnancy in remission or whether you enter pregnancy with a low level of disease activity.
We usually say [patients should have] around 6 months of things being stable. Does that mean they have to be off medications? Well, it means they have to be stable on pregnancy-safe medications, which is one of our next important concerns. For lupus patients, the most common issue is going to be mycophenolate because we use it so much, and it’s so effective. In that case, we transition them to azathioprine as our first-line substitution. And importantly, we need to check and make sure that they do well on it, that their disease doesn’t flare, and that they tolerate it, that they don’t have side effects over those first few months.
I usually give them about four months of azathioprine before saying, okay, I believe that this is working for you. It’s okay now to start trying.
There are many other teratogenic medications to look at. Certainly, for patients with APLs, if they’re on warfarin, they will be changed over to usually low-molecular-weight heparin. Whether that is done while they are trying or when they first have a positive pregnancy test is often up to the rheumatologist and the maternal-fetal medicine doctor. If it’s anticipated that it may take them a long time. They may want to continue with the warfarin and then make a quick change.
We look at other things, although it isn’t common, thankfully, for women to have such severe damage from their lupus that it precludes pregnancy. There are going to be some women who are unfortunately in that position. For example, someone who has a creatinine clearance in the 30s because of prior lupus nephritis. It doesn’t matter if the lupus nephritis is now long quiet — they still shouldn’t attempt a pregnancy because of the risk to them. The risk of going into complete renal failure is quite high. And there is a risk of losing that pregnancy because of inadequate renal response. The normal response during pregnancy by the kidneys is to increase the glomerular filtration rate by 50%. If someone has, for example, pulmonary hypertension, we know that’s a big risk factor for maternal morbidity and mortality in pregnancy.
For those few patients, we counsel them to avoid pregnancy.
There are other options. Certainly, those patients may be able to undergo in vitro fertilization (IVF), and if financial, social, and other circumstances permit, including their preference, they may be able to use a gestational surrogate to have a biological child.
Finally, as you mentioned, there are antibodies that we check. We check APLs if we don’t already know about them, and there’s no need to keep checking them during pregnancy because it’s unlikely that they’ll change. If someone has positive APLs and no history of obstetric or thrombotic complications, we just keep that in our awareness and we follow them carefully. We recommend that our lupus and APL-positive patients take low-dose aspirin during pregnancy to help prevent preeclampsia because of general population data saying that for those people who have some risk factors, it lowers the risk for preeclampsia.
Then for those who have a history of obstetric manifestations, we will recommend aspirin along with prophylactic low-molecular-weight heparin, obviously thrombotic complications, they’ll get the therapeutic dose.
Finally, I’ll just touch on the other important antibody: anti- SSA/Ro. We recommend checking that in all our lupus patients because we anticipate that about one third will be positive. It is important to know that, because at the very least, we can do some monitoring. If the patient is not already on hydroxychloroquine and assuming they can take it, that there are no allergies or contraindications, we recommend they take that. Really, for every lupus patient, but specifically for those with anti-Ro antibodies, because of data suggesting that it may decrease the risk of developing heart block.
There are controversies about monitoring in this area. The important thing to know about that is that the Society for Maternal-Fetal Medicine pulled back from recommending fetal echocardiograms during pregnancy, citing the lack of evidence of efficacy of treatment for first- or second-degree heart block in preventing third-degree and the potential negative side effects of administering dexamethasone during pregnancy. Data suggest that there can be long-term implications for neurodevelopmental issues in the offspring. However, most rheumatologists who are experts in this area and pediatric cardiologists are still sticking with both the monitoring as well as consideration of dexamethasone therapy, certainly if second-degree heart block is identified. The nice thing is that there is a study in progress — the STOP BLOQ study — being conducted by many investigators, with the principal investigators being Dr Buyon and Dr Cuneo, that is looking at home monitoring of the PR interval in women with high-titer anti-Ro antibodies.
The advantage here is we’ve long known that when this happens, it can happen really quickly. A week between fetal echoes or three weeks between fetal echoes, it may be too late. They have women testing themselves at home three times a day during the most important period, where we think this happens — 18 to 26 weeks — and then that is confirmed by a pediatric cardiologist.
If abnormalities are found and they are whisked off to have a formal fetal echo. If second-degree heart block is confirmed, they are given immediate treatment with dexamethasone and intravenous immunoglobulin.
What we know from preliminary results from that study, and what can impact our counseling for patients now, is that it takes, for the most part, a high titer of Ro antibody to give you this great risk. In the commercial assays, where less than 1 is negative and the scale goes up to greater than 8, that means that greater than 8 is likely to be the higher risk category. I think it is helpful for patients to know that if they have a value of 1.5, that is very unlikely to put them at risk. The other thing we know is that this monitoring can identify heart block risk. They have shown that it correlates, it performs well, so it does present a promising alternative for the future.
McMahon: That’s great and great to know about the STOP BLOQ study as well, because I’m sure there are a lot of patients who’d be interested in participating in that.
I wanted to touch on considerations for our patients who are interested in undergoing assisted reproductive procedures, because I think that’s coming up more and more frequently in our population.
Sammaritano: It’s a wonderful option for our patients. Briefly, the considerations are the same as the considerations for pregnancy because that’s the intended result. So, having quiet disease going into it, appropriate use of low-molecular-weight heparin if patients are APL positive or have APS, and I would say for those who are going through with IVF with plans to transfer an embryo and embark on pregnancy, they have to be on the appropriate pregnancy-safe medications. Patients do have options today that they didn’t have 20 years ago. Even a patient who doesn’t have a partner whose sperm she wants to use to fertilize her eggs can now freeze her eggs safely and effectively. That wasn’t possible in years past. It used to be that they could only freeze embryos.
I do have patients who are on mycophenolate who know that they need the mycophenolate, they can’t stop it. Or we don’t want to take a chance with changing right now because perhaps they’re in the midst of treatment for their lupus nephritis, and we want them to have the most effective therapy, but they’re 38 years old and they want to be pregnant. A great option is for those patients to undergo ovarian stimulation and then freeze either embryos or eggs for use in a few years, when it’s safe for them. The procedure itself is much safer now than it was in years past.
I always discuss with the reproductive endocrine doctor to minimize estrogen peaks as much as possible. But overall, we think that for most of our patients, this is a very feasible way to either attain pregnancy if there have been fertility issues, or perhaps to prolong or protect their fertility.
McMahon: And then finally, to round out the spectrum of issues for our patients, how do you counsel patients on hormone replacement therapy?
Sammaritano: As you know, hormone replacement therapy (HRT) has had so many highs and lows over the past 50 years. When the Women’s Health Initiative study came out in the early 2000s, it essentially stopped being given because of the concerns for breast cancer and cardiovascular disease. But then subsequent analyses of that data and further controlled studies showed us that it wasn’t so simple. It depends on the person and their risk factors and where they are in their reproductive lifespan. Those studies were giving hormones to women specifically to see if it helped cardiovascular health because of earlier studies that raised that possibility.
The women who were getting the hormones in that study were 60, 70 years old. The mean age, I think, was around 70. Now we know from further reanalysis and further studies that there seems to be a window of time where it is not harmful and perhaps even beneficial for cardiovascular health. That is for women who are immediately post-menopausal, within 5-10 years of menopause, less than age 60, and who do not have significant risk factors for breast cancer or cardiovascular disease. That’s all the general population information. So that, of course, we adapt to our patients. I will tell my patients that right now, this is recommended only for women who have severe vasomotor symptoms and their function is limited by hot flashes.
In addition, we have to think about specifics due to lupus. If a patient has very active disease, we would say no to HRT. The other SELENA study did find a small increased risk for mild-to-moderate flare in lupus patients who took HRT. So that is a discussion for APL-positive patients who obviously should not be taking estrogen. That is hard for people who have severe hot flashes or other vasomotor symptoms.
If a person is thinking about taking this because of genitourinary symptoms, vaginal atrophy, or frequent urinary tract infections, we think that intravaginal estrogen helps, which has predominantly local effects and is very effective for those symptoms. That is okay for APL-positive patients. There is a recently FDA-approved centrally acting drug [fezolinetant] that works well for hot flashes, which is not a hormone; it has the risk for liver function test abnormalities, and so it’s not something that you want to give everybody who’s had one hot flash. But for someone who really is debilitated, I think it’s a wonderful option for our APL-positive patients. That, I think, was just approved last year, in 2024.
McMahon: I think it’s great that even our APL-positive patients do have these other options for when they have debilitating symptoms.
I want to thank you so much, Dr Sammaritano. I’ve enjoyed our discussion today and I think it’ll be helpful for all of us who are dealing with patients who are in this age range and have issues.
Thank you for joining us. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on systemic lupus erythematosus. This is Dr Maureen McMahon, for the Medscape InDiscussion podcast.
Resources
2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases
EULAR Recommendations for Use of Antirheumatic Drugs in Reproduction, Pregnancy, and Lactation: 2024 Update
Contraception in Patients With Rheumatic Disease
Combined Oral Contraceptives in Women With Systemic Lupus Erythematosus
Pregnancy Outcomes Between Pregnant Systemic Lupus Erythematosus Patients With Clinical Remission and Those With Low Disease Activity: A Comparative Study
Prevention of Preeclampsia With Aspirin
Adverse Effects of Prenatal Dexamethasone Exposure on Fetal Development
Prospective Evaluation of High Titer Autoantibodies and Fetal Home Monitoring in the Detection of Atrioventricular Block Among Anti-SSA/Ro Pregnancies
The Effect of Combined Estrogen and Progesterone Hormone Replacement Therapy on Disease Activity in Systemic Lupus Erythematosus: A Randomized Trial
Fezolinetant Prescribing Information
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