To the Editor Preterm birth increases risk of neurodevelopmental delays.1 High-risk pregnancies for preeclampsia development are at increased risk of preterm birth, the rate of which is dependent on the definitions and screening criteria.2 Voutetakis et al3 raise concern of a potential long-term effect of aspirin given to prevent preterm preeclampsia in high-risk pregnancies owing to disruption of cyclooxygenase (COX) 2 and prostaglandin-E2 (PGE2) signaling, potentially affecting prenatal and postnatal brain development with subsequent neurodevelopmental impairments. There are some considerations for this argument. Several prior studies have shown that prophylactic use of low-dose aspirin (LDA) during pregnancy has no negative association with perinatal morbidity and mortality.2 Aspirin, particularly at low dose, is less effective at inhibiting COX2, an inducible enzyme, as opposed to COX1, a constitutive enzyme.2 The few studies in murine models that investigated the COX2/PGE2 pathway in brain and neurodevelopment only considered COX2-deficient knock-in rodents, ie, selective inhibition of COX2 as opposed to a dose-response effect of aspirin, an effect that might also be tissue dependent. In assessment of 5-year neurodevelopmental outcomes of children born preterm (22-32 weeks of gestation) using the Etude Epidemiologique des Petites Ages Gestationnels cohort study, prenatal LDA was not associated with adverse neonatal or long-term outcomes.4 The data also suggest LDA may even reduce neurobehavioral difficulties. This observation was based on findings by Harding et al,4 who reported preterm infants (<32 weeks of gestation) carrying the COX2–765 C allele had a slightly worse cognitive outcome at 2 to 5 years, presumably owing to production of lower levels of COX2. The negative adverse neurodevelopmental outcomes of prenatal LDA treatment in offspring are consistent with findings from several investigations demonstrating a marked increase in autism and attention-deficit/hyperactivity disorder in the early 1980s, with the substitution of acetaminophen for aspirin from birth to early childhood.5 Maternal use of acetaminophen during pregnancy has also been associated with hyperactivity and emotional symptoms at age 7 years,5 which has not been reported with LDA treatment during pregnancy.4
Mirzakhani H, McElrath TF, Weiss ST. Vital Considerations for Aspirin in Prevention of Preeclampsia, a Multifaceted Pregnancy Disorder. JAMA Pediatr. Published online November 04, 2019. doi:https://doi.org/10.1001/jamapediatrics.2019.4018
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