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Reply to the Letter to the Editor by Kessler Y et al. regarding the manuscript “Safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation: Analysis of the WHO pharmacovigilance database.”

We thank Kessler Y, Ning X and Cohen JM for their Letter to the Editor (1) and agree that non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin, by crossing the placenta, could cause foetal adverse outcomes through the inhibition of the prostaglandin synthesis pathway (2). Nephrotoxic effects of NSAIDs and aspirin depend on the time of drug exposure during gestation (2). Most malformations occur prior to the eighth week after conception because of an abnormal developmental process (3). Renal aplasia, which was reported in association with fremanezumab in one safety report included in our study (4), indicates that kidneys undergo no primary growth or development, and differs from renal agenesis whereby kidneys are absent because the first steps of development do not occur (5). Current literature suggests that the risk of birth defects from NSAIDs and aspirin use in the first trimester cannot be excluded but appears low based on conflicting findings affected by the inherent limitations of observational studies and small sample sizes (6,7). NSAIDs and aspirin use during the second and third trimesters of gestation may cause foetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment (8). Consistently, in 2020, the Food and Drug Administration (FDA) issued a warning recommending avoiding NSAIDs and aspirin in pregnancy at 20 weeks or later because of the potential reduction of amniotic fluid (9). In addition to functional adverse effects, NSAIDs and aspirin use during the second and third trimesters may affect renal structure itself (8). Nephrogenesis, which begins from the fifth gestational week, is usually complete by 36 weeks (8), thus structural changes such as abnormal glomeruli and tubules, ischemic injury, cortical necrosis, reduced number of nephrons and loss of differentiation between proximal and distal tubules, may occur as result of the inhibition of prostaglandin release (7,8). Moreover, inhibition of prostaglandin synthesis by NSAIDs or high-dose aspirin therapy in the third trimester has the potential for causing premature closure of the ductus arteriosus (10). Due to the scant clinical richness of VigiBase on the timing of drug exposure during pregnancy, we could not ascertain the gestational trimester when exposure to either fremanezumab (the suspected drug in the safety report to which the authors of the Letter to the Editor referred) and the antimigraine preparation acetylsalicylic acid/caffeine/paracetamol (recorded as concomitant drug) occurred. Starting from the available information on the reported adverse event with renal aplasia, based on the herein resumed state-of-the-art concerning the safety of NSAIDs and aspirin use in pregnancy, we hypothesized that foetal exposure to fremanezumab likely occurred during the first trimester. Therefore, we discussed that the reported concomitant drugs, including the acetylsalicylic acid/caffeine/paracetamol preparation, have not been associated so far with an increased risk of major birth defects when used in the first trimester. Nevertheless, we still treated the concomitant drugs reported in this safety report along with fremanezumab as potential confounders (see Table 3 from Noseda R et al.).