Confidence in the Use of Immunomodulatory Medications During Pregnancy: How Can Patient and Clinician Experience Be Improved?

In 2019, an excellent editorial by Dr. Megan Clowse was published in The Journal of Rheumatology, claiming that it was time to modify treatment to enable more women with rheumatoid arthritis (RA) to have successful pregnancies.¹ This fervent call arose from published evidence showing that women with RA often compromise in family planning decisions that often result in smaller-than-expected families. A similar pattern was seen in inflammatory bowel disease (IBD), where a systematic review found a 17-44% lower birth rate in nonoperated women with Crohn disease compared with controls.² Among the contributing factors, concerns regarding the safety of medications during pregnancy have emerged as a strong determinant. In the same period, Drs. Eric Mao and Uma Mahadevan wrote a powerful editorial to advocate for the use of tumor necrosis factor inhibitors (TNFi) throughout pregnancy in patients with IBD, as it was demonstrated that stopping therapy midpregnancy led to a higher rate of disease flares in the mother, increasing the risk of adverse pregnancy outcomes (eg, preterm birth, small for gestational age, stillbirth), as compared to continued therapy.³

Both editorials promoted a shift in paradigm toward embracing the use of immunomodulatory medications, including biologic agents, during pregnancy, whenever the benefit-risk assessment for both the mother and the child is favorable. Has this change happened over time? The article by Flatman et al, published in this issue of The Journal,⁴ provides an overview of the real-world experience in the use of TNFi during pregnancy in women with immune-mediated conditions, using MarketScan commercial claims data during the period 2011-2021. The study showed a progressive increase in the proportion of pregnancies with TNFi use throughout all trimesters, rising from 55% to 73%.

Such a trend may be explained mainly by 2 factors: (1) the increasing awareness that the discontinuation of TNFi at the beginning of pregnancy leads to a higher risk of maternal disease flares during pregnancy, hence, an increased risk of adverse pregnancy outcomes^3,5; and (2) the growing body of evidence regarding the safety of TNFi use during pregnancy, supported by systematic literature reviews and endorsed by clinical guidance issued and regularly updated by international and national scientific societies.^6-11

Evolving clinical recommendations now support broader TNFi use in pregnancy, underpinned by data showing no increased risk of infant infections and normal developmental milestones after exposure in utero. This approach also allows treat-to-target care to be maintained throughout pregnancy^10,12,13 (Figure). This implies the unique opportunity to taper and discontinue corticosteroids. At present, the unfavorable benefit-risk assessment of prolonged use of corticosteroids, even at moderate to low doses, is well established in the management of immune-mediated inflammatory diseases. The shift toward unwanted effects of corticosteroids is even more enhanced during pregnancy, as such medication may independently increase the risk of maternal metabolic alterations, such as hypertension and hyperglycemia, and the risk of fetal adverse outcomes, especially preterm birth.^12,14 Severe maternal and neonatal infections were also demonstrated to be driven by the use of corticosteroids rather than that by TNFi during pregnancy.¹⁵ Further, it has also been demonstrated that infants exposed to corticosteroids in IBD pregnancy are at increased risk of infections during the first year of life.^16,17 Interestingly, the work by Flatman et al⁴ showed that corticosteroid use during pregnancy and the postpartum period was less frequent in pregnancies exposed to TNFi throughout gestation as compared to those exposed in the first and/or second trimester only. This finding suggests that clinicians implemented guidance into their practice and took the use of TNFi during pregnancy as an opportunity to minimize the use of corticosteroids.

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Figure.

Schematic illustration of the implications of treatment patterns during pregnancy in immune-mediated inflammatory diseases. Maternal active disease during pregnancy and the use of corticosteroids for prolonged time to control inflammation are both risk factors for adverse pregnancy outcomes. By applying a treat-to-target strategy that included the use of TNFi during pregnancy, it has been possible to break this chain of events. TNFi can rapidly induce disease remission and allow the tapering and discontinuation of corticosteroids. The benefit-risk assessment of this approach is supposed to be favorable in most patients; however, individualized risk stratification is warranted. TNFi: tumor necrosis factor inhibitor.

As a whole, the change in treatment patterns during pregnancy in women with immune-mediated inflammatory diseases appears as a meaningful step forward in the optimization of care. However, let us reflect on the journey that established the confidence in the use of TNFi during pregnancy. It took more than 15 years of postmarketing use of TNFi to build such confidence, meaning that clinicians and patients were meanwhile faced with decision making in an uncharted field. The most striking example of this knowledge gap is the different approach taken across specialities.¹⁸ Specifically, gastroenterologists were well aware that IBD would get worse during pregnancy, so they were trailblazers in using TNFi and other biologic agents throughout pregnancy, whereas rheumatologists leveraged the possibility that inflammatory arthritis could remain quiescent in the majority of pregnant patients and they stopped TNFi at the beginning of pregnancy. It took several years to collect the evidence that the discontinuation of TNFi was a risk factor for maternal disease flares and related adverse pregnancy outcomes.⁵

Overall, women living with chronic inflammatory conditions and their children have been affected by the lack of data on the use during pregnancy of immunomodulatory medications. Until now, decisions have largely been individualized, with caution focused on protecting the fetus and opportunity centered on controlling maternal inflammation. Caution was also fostered by the information about the use in pregnancy that can be found in the Summary of Product Characteristics (SmPC) of most biologic agents. The SmPC often reports the recommendation not to use a medication during pregnancy because of insufficient data. This is the result of the systematic exclusion of pregnant patients from clinical trials, an approach that is currently challenged, as pregnant women should not be protected from research, but through research.¹⁹ Regulatory bodies have been working on methods and strategies to generate evidence on the use of medicines during pregnancy in the preapproval phase,^20,21 including the early engagement with pharmaceutical companies during drug development.²² Including pregnant patients in premarketing clinical trials has the goal of understanding the benefit-risk assessment antenatally. Eligibility would include pregnant patients who have a clear unmet medical need and are likely to benefit from an investigational drug. Both investigators and pregnant women should not be apprehensive about running or participating in such trials because the safety plan is carefully constructed, involving risk mitigation and enhanced monitoring.

Excluding pregnant participants from clinical trials indeed creates an illusion of caution, as risks do not disappear; they instead shift to the postmarketing clinical setting, where they expand. Clinicians and patients are faced with a knowledge gap that may lead to the discontinuation of treatment during pregnancy, which can be a suboptimal decision in patients with chronic inflammatory conditions as it may cause a disease flare. In addition, conflicting information between clinical guidance documents and the SmPCs can disrupt the patient-doctor relationship by means of confusion and tension in decision making.²³

The study of the patterns of use of TNFi during pregnancy by Flatman et al⁴ has shown that confidence can be significantly boosted over a decade thanks to data generation. To anticipate such evidence generation from the postauthorization setting to the clinical studies phase is going to be the next big step to improve the journey of clinicians and patients. Notably, academic journals are increasingly providing a platform for clinicians and researchers to voice nuanced perspectives, demonstrating a commitment to sharper academic discourse and advocacy in reproductive health management.²⁴ The pervasive fear of legal liability has been clearly addressed by prioritizing the right of pregnant women to experience the same benefits as other people whose treatments have undergone clinical trials.²⁵ In conclusion, the scientific, regulatory, and legal frameworks are in place. What remains is for stakeholders to align and collaborate so that pregnant women can make truly informed decisions for themselves and their babies.

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