Vital Considerations for Aspirin in Prevention of Preeclampsia, a Multifaceted Pregnancy Disorder

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