Original articleExposition to anti-TNF drugs during pregnancy: Outcome of 15 cases and review of the literature
Introduction
Most of Crohn's disease (CD), spondyloarthropathies (SpA), and many rheumatoid arthritis (RA) occur during the reproductive years of women. This holds true also for juvenile idiopathic arthritis (JIA). Fertility can be impaired, either by disease activity (one explanation in animal models is having excess amounts of TNF-alpha [1]), or by drugs such as NSAIDs [2]. Some nulliparous women with CD, SpA, JIA or RA, become convinced that they will never be fertile, and so decide to discard their contraception [3]. Therefore, it is nearly inevitable that a growing number of unplanned pregnancies will occur in women treated by TNF blockers, especially since those treatments could reduce infertility [4]. Reproductive immunologists have even predicted the use of TNF blockers like etanercept to treat infertility, which has prompted warnings about the safety of this procedure [1]. Accordingly, rheumatologists should inform their patients that TNF blockers might unexpectedly reverse infertility states. Physicians must also advise women wishing to conceive not to use TNF blockers during pregnancy until extensive reports have clearly demonstrated their safety for the mother and the offspring and that there is no risk of adverse effects on the further development of children [5], [6], [7]. As IgG subclasses cross the placenta as early as the late first trimester, this should raise concern about the safety of these drugs beyond this period (although total foetal IgG levels remain low until the late second or early third trimester) [8]. Significant infliximab levels were detected in one offspring whose mother's refractory Crohn's disease had been treated throughout pregnancy by five infusions of 10 mg/kg of infliximab [9].
Nevertheless, published data so far does not clearly demonstrate that TNF blockers significantly increase the risk of trouble for foetuses and babies [3], [4], [5], [6], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39]. In animal models, no malformation was induced after exposure to high doses of TNF blockers during pregnancies (up to 60–100 times the peak dose was administered to rabbits and rats [27], [40], [41], [42]). Accordingly, anti-TNF drugs are still classified by the FDA as “pregnancy risk category B”, as human studies are still insufficient to guarantee their safety for the foetus although no adverse effects have been observed in animal pregnancies [4].
Although Carter et al. recently reported on a possible risk of minor forms of VACTERL association [43], elective termination of pregnancy in a woman becoming inadvertently pregnant, while being treated with TNF blockers, should not be requisite. In this respect, it is striking to notice that only a small number of women becoming pregnant while under TNF blockers asked for elective termination (n = 16) [5], [14], [20], [23], [24], [35]. This is in accordance with the observation that the desire for maternity is high in those patients, often aged 30 and over.
To provide further information on this important topic, we report on 15 pregnancies occurring in French women being treated with anti-TNF drugs during conception (15/15), first (15/15), second (3/15), or third trimester (2/15), including 12 pregnancies with live births, and review the current literature.
Section snippets
Methods
French rheumatologists connecting to the web-site of the CRI (Club Rhumatismes et Inflammation: http://www.cri-net.com) were asked in 2006 to download and fill in a structured questionnaire for every case of pregnancy which had occurred in women who were still being treated by a TNF blocker at the time of conception or during their pregnancy, regardless of the year of introduction of the drug, and outcome of the pregnancy (i.e. favourable or not). The questionnaire is provided in Appendix A.
Results
Data about the 15 patients and pregnancies are gathered in Table 1.
The 15 patients were suffering from SpA (n = 8), RA (n = 4), JIA (associated with celiac disease in one case) (n = 2), or psoriatic arthritis (n = 1). Three were treated with infliximab: two at 3 mg/kg for RA and JIA with celiac disease, and one at 5 mg/kg for SpA. One RA patient and one SpA patient were treated with adalimumab (40 mg every other week). The remaining 10 patients were treated with etanercept: two for RA, one for JIA, one
Discussion
The design of this study (the questionnaire can be downloaded from the French CRI site: http://www.cri-net.com) is subject to selection bias (possible reporting of the more favourable cases), although to the best of our knowledge, foetal malformations in women exposed to anti-TNF during their pregnancy have not yet been reported to French health agencies. Moreover, a control group was not included. As the number of full-term pregnancies (n = 12) is small, no conclusion can be drawn regarding the
Conflict of interest statement
Frédéric Lioté received research grants from ABBOTT and WYETH.
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2020, Pharmacological ResearchCitation Excerpt :Defining optimal strategies for the use of bDMARDs in pregnancy is paramount for the management of patients with autoimmune diseases [19]. Preclinical evidence [93–95] and consistent, though scattered, data from humans [29,35,94,96–98] suggest that the majority of bDMARDs, especially anti-TNFs, are well-tolerated during pregnancy and do not harm newborns during the perinatal period [99]. Animal models, however, are not suitable to study the complexity and duration of human development, and clinical data from studies encompassing longer follow-up times of newborns exposed to bDMARDs during pregnancy are needed.