In infants born extremely preterm, aspirin or NSAID use during pregnancy are associated with increased risk of quadriparetic cerebral palsy
- Correspondence to: Dr Peter H Gray
Newborn Services, Mater Mothers’ Hospital, Raymond Tce, South Brisbane, Queensland 4101, Australia;
Commentary on: Tyler CP, Paneth N, Allred EN, et al. ELGAN Study Investigators. Brain damage in preterm newborns and maternal medication: the ELGAN study. Am J Obstet Gynecol 2012;207:192.e1–9.
Implications for practice and research
Maternal aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of cerebral palsy in extremely preterm infants.
It would seem, however, that aspirin given to women at high-risk for pre-eclampsia may be beneficial.
Exposure to NSAIDs should be considered with caution until further information is available.
The issue of taking medications during pregnancy and the risks involved has been the topic of many reviews. Aspirin is a NSAID that is prescribed to prevent recurrent abortion and to reduce the risk of pre-eclampsia. From animal studies it has been suggested that NSAIDs when taken during pregnancy have the potential to result in perinatal brain injury.1
Data were extracted from the Extremely Low Gestational Age Newborns (ELGAN) study of infants born <28 weeks gestation and in 14 institutions in the USA. Demographic and pregnancy variables were obtained from the medical records and by mothers’ reports of exposure to aspirin, NSAIDs, paracetamol (acetaminophen) and antibiotics during pregnancy. The infants had routine cranial ultrasound scans during the neonatal period, with ventriculomegaly and echolucent lesions as markers of cerebral white matter damage being recorded. At 2 years corrected for prematurity, the diagnosis of cerebral palsy (CP) was made following a standardised neurological examination. The infants were classified according to CP subtypes. A total of 877 children had complete information and were included for analysis.
Overall, 5.6% of the women in the study took aspirin and 7.2% took another NSAID. Paracetamol was used by 50.4% of the women with antibiotic usage at 25.9%. Ultrasound scanning indicated that 10% of the infants had ventriculomegaly, with 6.7% having echolucent lesions. On follow-up, 11.4% of the infants had CP: 6% quadriparesis; 3.5% diparesis and 1.8% hemiparesis. After adjusting for potential confounding variables, none of the four drugs were associated with an increased risk of cerebral white matter injury or hemiparetic CP. Children were at increased risk of quadriparetic CP if exposed to aspirin (OR 3.0, 95% CI 1.3 to 6.9) and if exposed to other NSAIDs (OR 2.4, 95% CI 1.04 to 5.8). Diparetic CP was only increased in children whose mothers had taken an NISAID without medical care provider approval.
Tyler and colleagues showed that the risk of quadriparetic and diparetic CP was increased when mothers had taken aspirin and other NSAIDs during pregnancy. The information was obtained from a large cohort of infants born extremely preterm. The overall incidence of CP was comparable to other studies, but the proportion of children with quadriparesis (53%) was appreciably greater than that reported by others,2 ,3 which may have influenced the overall results. The authors suggested the use of NSAIDs may be a marker for perinatal inflammation which resulted in damage to the fetal brain and that the drugs may not be directly in the causal pathway. There is evidence that antenatal steroids are associated with a reduction in the incidence of CP, possibly due to an effect on immunomodulation.2 Information and analysis of data on the use of antenatal steroids in the present study would have been beneficial. The dosage and the duration of the maternal medication was not analysed in the present study.
Aspirin exposure was associated with an increased risk of CP, with information on the use of aspirin during the first trimester lacking. However, a recent review of aspirin administration to prevent adverse pregnancy outcomes concluded that based on the results of randomised clinical trials, low-dose aspirin started between 8 and 16 weeks’ gestation appeared to be safe for the fetus.4 The information provided in the current study should not change those recommendations. Exposure to NSAIDs was also associated with CP, but not ultrasound markers of cerebral white matter injury. Previous studies have suggested that antenatal indomethacin is associated with an increased risk of periventricular leukomalacia, but not CP. Antonucci et al5 recommend that NSAIDs should only be given in pregnancy when the maternal benefits outweigh the fetal risks. With the results of the current study, it would seem that maternal exposure to NSAIDs should be considered with caution until further information is available.