Antirheumatic biologics in pregnant patients: a call for studies to address the knowledge gap

KEYWORDS:

• Pregnancy
• biologic drug
• prospective study
• immune response
• fathers exposed to biologics

The introduction of biological agents targeting cytokines and cells that are key players in autoimmune inflammation revolutionized the treatment of several autoimmune diseases [1]. Their effectiveness resulted in a greater proportion of patients achieving low disease activity and less organ damage making it possible to lead a more normal life including sexuality and procreation. Through the last two decades, the number of biologic agents has increased steadily, biosimilars of several innovator biologics have been introduced, and the array of indications for treatment has been expanded. In the following, the experience of biologicals regarding pregnancy is discussed, gaps in our present knowledge on their effect on reproduction are emphasized, and studies to generate new data are suggested.

1. Lack of pregnancy data for non-TNF inhibitor biologics

Recent consensus papers have surveyed the literature on biologics in pregnancy between the year 2000 at the start of their clinical use and up to 2015 [2,3]. Until now, pregnancy experience is largest for TNFα inhibitors (TNFi) [4], but is limited for biologics targeting other cytokines or immunocompetent cells [5]: Rituximab (monoclonal antibody to CD20 causing CD20 + B-cell depletion), Abatacept (inhibits T-cell activation by blocking interactions between antigen-presenting cells and T cells via binding to CD80/CD86 on antigen-presenting cells), Tocilizumab (monoclonal antibody directed against interleukin-6 receptors blocking downstream signaling) and Secukinumab (monoclonal antibody that selectively binds to and neutralizes IL-17A), Anakinra (recombinant interleukin-1 receptor antagonist), and Ustekinumab (human monoclonal antibody that binds to and interferes with IL-12 and IL-23 actions). The first gap of knowledge that should be closed concerns inhibitors of IL-1, IL-6, IL-17, IL-12/23, the T-cell inhibitor abatacept, and the B-cell inhibitors rituximab (RTX) and belimumab. Since randomized studies of medication exposure in pregnant women would not get ethical approval, the challenge is to get sufficient data on pregnancy exposures and appropriate controls. Due to the rarity of the diseases for which these biologics are used and the restricted indications, registry-based studies are best fitted to get results. Data acquired through Medical Birth registries that systematically collect data on pregnancy outcomes and can be linked to prescription databases and/or patient registries allow the collection of large samples and comparison to nonexposed pregnancies. As assessment of disease activity often is lacking in administrative registries, clinic-based registries that collect clinical and laboratory data in a prospective manner give more precise information. However, they are time-consuming and should preferentially include a national or international collaboration between multiple centers to allow for faster collection of relevant data.

2. Can prenatal exposure to biologics impair the immune response in children?

Administration of biologics during pregnancy that are IgG1 antibodies or possess the Fc-receptor could weaken the immune response in exposed neonates and interfere with their immune defense and vaccination responses. IgG is actively transported by binding to fetal Fc-receptors in the placenta [3]. Studies of mother–child pairs investigating concentrations of several biologics in maternal serum and cord serum found differences in cord serum levels related to the structure of a given biologic [6]. Complete monoclonal antibodies when given in the second or third trimester show equal or higher serum levels in the child at birth, whereas fusion proteins are present in low levels and Fab fragments are negligible or not detectable [4].

Few studies have investigated effects of different biologics on the child’s immune system. Severe B-cell depletion has been observed in children exposed to RTX in utero, but with a quick recovery of B cell numbers within 3–6 month of life and normal vaccination responses [7]. In one prospective study, 7 children exposed in utero had detectable levels of TNFi until 6 months of life; they presented a more immature B- and T-helper cell phenotype that normalized within 12 months of age with normal immunoglobulin production and normal vaccine responses [8].

Data from pregnancies in women with inflammatory bowel disease (IBD) showed no increase of serious infections in the first year of life in children who had been exposed to infliximab or adalimumab in the third trimester [9]. For other non-TNFi biologics data on the risk of serious infection during the first year of life are anecdotal or completely lacking [4].

The report of a fatal disseminated BCGitis in a child born to a mother with IBD who had received infliximab shortly before delivery [10] resulted in the recommendation not to give life vaccines during the first 6 months of life to children exposed to TNFi prenatally. However, other studies found no adverse effects of BCG or Rota virus vaccination [8,11]. It is not clarified whether the recommendation to delay live vaccines also applies for first trimester and early second trimester exposure. A study from the Pregnancy in IBD And Neonatal Outcomes registry (PIANO) investigated whether prenatal exposure to biologics also could weaken the response to inactivated vaccines [12]. The vaccination response between infants born to mothers exposed to biologic therapy (infliximab, adalimumab, certolizumab pegol, golimumab, natalizumab, vedolizumab, or ustekinumab, either as a single agent or in combination with an immunomodulator, at any time between conception and delivery) and infants born to mothers treated with other immunomodulators was compared. No significant difference in proportions of infants with protective antibody titers against hepatitis B or protective antibody titers to tetanus toxoid born to mothers exposed to biologics versus unexposed mothers was found [12].

Long-term safety data in regard to immune responses of prenatally exposed children are absent for IL-1, IL-6, IL-17, IL-12/23, and abatacept. Prospective, controlled studies should be a priority in children exposed to B-cell inhibitors as they impair both numbers and function of B cells [13].

3. Pregnancies fathered by men exposed to biologics

Birth outcomes in children fathered by men treated with biologics before conception have been studied for TNFi [14], for other biologics data are anecdotal and of weak quality [2]. Studies based on national registries that allow linkage of National Patient registries and National Prescription registries with Medical Birth registries would be feasible for collecting preconception biologic exposure of men on a large scale [14].

4. Conclusion

The priority of future research should be prospective, controlled studies of pregnancy exposure to biologics with a focus on non-TNFi biologics where data up to date are limited. The research includes follow-up studies of children prenatally exposed to any biologic, also TNFi, with a focus on immune response to infection and to vaccination. A third area of research to be initiated is the effect of biologics on the health of children who have been fathered by men treated with biologics. All three research issues should preferentially be based on long-term registries that include a sufficient number of patients and controls or are collaborations between centers that collect prospective exposure data. The follow-up studies of children require linkage with maternal data and child registries that collect data over years and decades. The latter could unravel also the risk for malignancies and autoimmunity in exposed children. Closing the gaps of knowledge in this area will assist clinicians in counseling and managing patients of both genders wishing for children.

Declaration of interest

M Østensen received speaker fees from Abbvie, Novartis, Roche, UCB. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This article was not funded.