Letter to editor: comment on ‘The need for contraception in patients taking prescription drugs: a review of FDA warning labels, duration of effects, and mechanisms of action’ by Zhang et al.

We read with interest the paper by Zhang et al. published online in Expert Opinion on Drug Safety [1] and appreciated the authors’ attempt to provide a comprehensive overview of the contraception warnings regarding the use of FDA-approved drugs while offering insights for the potential areas of further research. However, we would like to point out some inaccurate information, which might be seriously misleading for the management of pharmacotherapy in reproductive-age women.

Some drugs of choice in pregnancy, based substantial scientific evidence collected in the last decades, are unfortunately not clearly distinguished from severely teratogenic drugs such as thalidomide, various cytostatics, and retinoids.

Triptans are e.g. not considered teratogenic, based on animal studies and on a considerable number of cases of pregnancy exposure in humans, but comparatively safe, with sumatriptan being the drug of choice in pregnancy for migraine-treatment if paracetamol is not effective [2]. Although triptans were shown to be associated with an increased rate of spontaneous abortions in a meta-analysis, it is not yet proven whether this finding is a drug effect or caused by relevant risk factors coming along with the maternal disease [3].

Lamotrigine has also been presented as a drug which is associated with fetal harm in Table 1 [1]. However, the safety data regarding the use of lamotrigine among pregnant women strongly oppose this argument. Lamotrigine and levetiracetam have been reported to be associated with the lowest prevalence of major congenital malformations among the antiepileptic exposure groups (n = 4195, 2.31% [95% CI, 1.87–2.78%] for lamotrigine and n = 817,1.77% [95% CI, 0.98–2.79%] for levetiracetam) [4]. The earlier findings regarding a possible association of lamotrigine with a dose-dependent risk of major congenital malformations, particularly oral clefts, was not consistent and not proven (discussed elsewhere [5]). Erythropoietin is mentioned as an agent which may lead to pool fetal growth [1]. The source of this finding is exclusively the animal studies. This proposed adverse fetal effect has never been proven in human studies, and it is even uncertain that erythropoietin crosses the human placenta in meaningful quantities [6,7]. On the other hand, successful use of erythropoietin in pregnant women has repeatedly been reported [8,9].

We would like to highlight that the recommendation of contraception during or after the use of a medication is mostly rooting from ‘legal’ concerns, often based on the theoretical potential of harm and is not always an indicator of scientifically proven harm. Therefore, an inadvertent pregnancy-exposure to a drug, for which contraception is recommended, should not necessarily imply a significant teratogenic risk until such a risk is suggested by a careful individual risk assessment, based on the established teratological principles and the relevant scientific data available [10].

By uncritically lumping together proven teratogens and medications considered to be quite safe in pregnancy, the authors have provided a quite undifferentiated basis for a potential scientific discussion. Therefore, their appreciable attempt to assist clinicians and patients in their rational decision-making about drug use during reproductive age or in pregnancy, is indeed partly misguiding, potentially causing unnecessary concerns among patients in need of pharmacotherapy in pregnancy, and among their treating physicians.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.