Autoimmune and Inflammatory Medical Problems During Conception and Pregnancy
General autoimmunity
The European Alliance of Associations for Rheumatology (EULAR) declared for the first time that all tumor necrosis factor (TNF) inhibitors as safe throughout pregnancy and lactation.1 And this obviously also means that TNF inhibitors can be used in women receiving fertility treatments. The statement, moreover, summarized the current status of “allowed” antirheumatic drugs in general. This means that, in addition to TNFs, synthetic disease-modifying antirheumatic drugs (DMARDs) compatible with pregnancy include antimalarials, azathioprine, colchicine, cyclosporine, sulfasalazine, and tacrolimus. Regarding nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, a more restrictive approach to their use during pregnancy is recommended (which we are not certain makes sense).
According to Medscape Medical News, the new recommendations reflect the increasing recognition of the toxicity of chronic, higher-dose glucocorticoids, including during pregnancy:2 Synthetic DMARDS (csDMARDS), including azathioprine or mercaptopurine, chloroquine, colchicine, cyclosporine, hydroxychloroquine, sulfasalazine, and tacrolimus, are all compatible with pregnancy.
The teratogenic medications methotrexate, mycophenolate, and cyclophosphamide should be stopped prior to conception. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be considered during pregnancy to control disease activity, but they should be used intermittently and stopped after 28 weeks gestation. NSAIDs with a shorter half-life, like ibuprofen, are preferred. If a patient is having difficulty conceiving, discontinuing NSAIDs should be considered. Corticosteroids should be tapered to a 5mg daily dose or lower or stopped entirely, if possible. For more details, we recommend Reference #1.
References
Rüegg, et al. Ann Rheum Dis 2025; 84(6):P910-926
Hicks L. Medscape Medical News May 7, 2025; https://www.medscape.com/viewarticle/eular-task-force-expands-pregnancy-safe-drug-options-2025a1000b1a
The antiphospholipid antibody syndrome (APS) in pregnancy
But to document the flimsiness of many rheumatology studies on which these new recommendation are based on, here is another recently published related paper in the same medical journal which recently reported that TNF inhibitors in a human study “improved pregnancy outcomes” in women with the so-called antiphospholipid syndrome (APS).1 And before we go into further detail, we have to acknowledge a longstanding bias when it comes to reports on the APS, not the least because of the many changes in defining this alleged syndrome over the decades since the syndrome was first described in principle being defined by excessive thrombotic risk and increased miscarriage risk.2
In this recent multicenter study involving perinatologists as well as rheumatologists with decades-long interest (and many publications) in the APS, certolizumab pegol was used in women with APS and positive lupus anticoagulant, and were administered during gestational weeks 8 through 28, in addition to standard treatment (which, of course, varied). The primary adverse obstetrical outcome for the study was a composite of fetal death ≥10 weeks’ gestation or preeclampsia with severe features or placental insufficiency requiring delivery <34 weeks’ gestation. As already noted in the commentary on the preceding paper, we do not like composite outcomes, and here, new ones—we like even less alternative outcomes.
But our dislike of this study design even increased further based on the power analysis underlying the study, which was determined to require 45 patients, demonstrating any of the composite adverse pregnancy outcome(s) at 20% prevalence (95% CL, 9.6%-34.6%) with certolizumab versus (note !!!!) a historical control rate of 40% (in other words, this was not a prospectively randomized study but kind of a case control study, with all the limitations and potential biases of such a study). Moreover, practically speaking, especially considering the composite outcome, one has to wonder how clinically significant a 20% vs 40% rate in 45 patients (9 vs 18 patients) really is.
And then not 45 but 51 patients were enrolled (one wonders why and when the decision was made?), of which 9 (17.6%) had so-called primary adverse pregnancy outcomes; and 6 patients were excluded because of pregnancy loss <10 weeks or because of presumed genetic pregnancy loss.
Miraculously, that brought the real number of study subjects also back to the original 45, but emphasizes yet another bias in too many published studies on the subject of miscarriages: a diagnosis of an aneuploid karyotype in the products of conception does not automatically mean that the aneuploidy was causal. For example, trisomies 13, 15, 18, and 21 are known to survive. Finding one of these karyotypes in products of conception of a miscarriage does not mean that the aneuploidy was the cause of the miscarriage.
Moreover, all of these machinations, of course, changed the prevalence of primary adverse pregnancy outcome from 17.6% to 20.0%), thereby (and what a miracle, - barely) meeting the originally defined criteria of significant difference between (new after treatment) 20% and (historical) 40% primary adverse outcome(s). Unsurprisingly, the authors concluded that “certolizumab appears effective in preventing placenta-mediated adverse outcomes in high-risk patients with APS.”
Our conclusion, in contrast, is that even considering the unfortunately poor quality of increasing numbers of papers in even respected medical journals, it, indeed, is rare to see a study where patient selection appears as obviously manipulated as in this paper! What makes things, however, even worse is that this paper was not the product of a “paper mill” somewhere in Asia but includes as authors some of the most respected “experts” regarding the APS in pregnancy from both perinatal and rheumatology medical specialties.
For those interested in more reliable information on APS, we recommend a recently published review article.2
References
Branch, et al. Ann Rheum Dis 2025;84(6):1011-1022
Murvai, et al. BMC Pregnancy & Childbirth 2025;25:337
Hydroxychloroquine (Plaquenil®)affects preeclampsia risk
This drug—originally discovered as an antimalarial—was later found to have excellent general anti-inflammatory effects and has become a mainstay of rheumatology treatments, especially for systemic lupus erythematosus (SLE). Now, a Swedish study claimed that the drug in SLE patients also lowers preeclampsia risk.1
The study involved a total 959, 404 (42%) nulliparous pregnancies, of which 232 (57%) were unexposed and 172 (43%) were hydroxychloroquine-exposed; 555 (58%) were parous pregnancies, with 333 (60%) unexposed and 222 (40%) exposed.
Preeclampsia was recorded in 19 (11%) of 172 hydroxychloroquine-exposed pregnancies and 30 (13%) of 232 unexposed pregnancies. Summarizing their findings, the authors concluded that in women with SLE, hydroxychloroquine exposure in early pregnancy was associated with a lower preeclampsia risk, while any association with preterm delivery remained unclear.
Though a decline in preeclampsia risk with Plaquenil treatment makes logical sense, one would expect, in parallel, also a decline in premature deliveries, which is a constant finding in practically all autoimmune diseases.2 As some of the preeclampsia-related data analysis is also not very clear in this paper, we, frankly, would not put too much credibility behind this publication.
References
Nguyen, et al. Lancet Rheumtol 2025; S2665-9913(25)00076-1.doi: 10.1016/S2665-9913(25)00076-1. Online ahead of print.
Gleicher N. Clin Rev Allergy Immunol 2010;39(3):194-206
Familial Mediterranean Fever (FMF)
Surprisingly, even many physicians are not aware that FMF is a monogenic autoinflammatory disease. It, indeed, is the most common monogenic autoinflammatory disease and—as the name indicates—is most prevalent around the Mediterranean Sea and in Middle Eastern countries. Therefore, it should not surprise that the EULAR recently also published recommendations regarding treatment resistance and fertility concerns with FMF.1
Without going into too much detail (for that, we recommend Reference #1), first-line medication for FMF during conception period, pregnancy, and breastfeeding is still colchicine. The literature review—again unsurprisingly—discovered a trend toward preterm birth, which, as noted above, is characteristic of autoimmune diseases.2 Effects of colchicine on semen analyses require further investigation.
References
Ozen, et al. Ann Rheum Dis. 2035;84:899-909
Gleicher N. Clin Rev Allergy Immunol 2010;39(3):194-206