Antenatal steroids – boon or bane?

Retrospective observational study highlights the need of further study in to determinte the long term impact og Antenal steroids.

Antenatal corticosteroids (ACS) is recommended as treatment for preterm birth as it prevents respiratory distress syndrome (RDS), neonatal death, intraventricular hemorrhage (IVH).¹ Cochrane review reported that ACS decreases significantly the probability of developmental delay in childhood and recent meta-analysis also indicated that neurodevelopmental outcomes among preterm children² are favorable who have received ACS. Recently regarding the usage of ACS before 34 weeks’ gestation who were not born preterm have raised concerns and also in those who received between 34-36 weeks’ gestation pertaining to cognitive impairment and neuropsychiatric disorders among children.³ A meta-analysis demonstrated that decreased head circumference and increased risk of low birthweight⁴ was seen with repeated exposure of ACS.

Researchers at Nagoya University Graduate School of Medicine have found smaller volumes of bilateral amygdale and caudate nuclei which are important for emotion processing and motor control, respectively in neonates that were exposed with ACS. The exact mechanism causing decreased segmental volumes have not been fully understood but multiple etiologies have been considered for the same like excess exogenous glucocorticoids at critical developmental time windows⁵ leading to dysregulation of the maternal and fetal hypothalamic-pituitary- adrenal axis, various neuropathological changes and dysfunction of a variety of complex functions with programming influence on the nervous system, especially the meso-cortico-limbic system.

Use of inhaled glucocorticoids by adults demonstrated smaller amygdala volume in them than controls seen in a prospective population-based cohort study done in UK. Liverani et al. also proved that to predict the behavioral outcomes like emotions at 5 years of age,⁶ amygdala volume at term-equivalent age is one of the crucial factors.

It was observed that only in infants born at or after 28 weeks’ gestation the association between ACS and smaller volumes of the bilateral amygdalae and caudate nuclei was seen and possible mechanism causing the different effect of ACS based on gestational age are:

1. Expression of glucocorticoid receptors in the fetal brain varies significantly across different regions and undergoes dynamic changes throughout pregnancy.
2. The brain development process is complex that shows distinct characteristics unique to each trimester.
3. Extremely preterm (<28 weeks gestation) status and associated severe neonatal complications may affect the subsequent brain volume masking the ACS effect.
   
   

This study does not state that ACS is harmful but further research regarding its long-term impact in term of behavioral disorders and neuropsychiatric disorders needs to be explored. ACS therapy is very important for survival of preterm infants but in countries where use of ACS is well established optimization is required.⁷ The risk-benefit ratio needs to be assessed before administration of ACS and prophylactic use of it should be avoided.

References:

1. McGoldrick E, Stewart F, Parker R, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2020;12(2):CD004454.
   
   
2. Ninan K, Liyanage SK, Murphy KE, Asztalos EV, McDonald SD. Evaluation of long- term outcomes associated with preterm exposure to antenatal corticosteroids: a systematic review and meta-analysis. JAMA Pediatr 2022;176(6):e220483
   
   
3. Asztalos EV, Murphy KE, Matthews SG. A growing dilemma: antenatal corticosteroids and long-term consequences. Am J Perinatol 2022;39(6):592–600.
   
   
4. CrowtherCA,MiddletonPF,VoyseyM,AskieL,ZhangS,MartlowTK,etal.Effects of repeat prenatal corticosteroids given to women at risk of preterm birth: An individual participant data meta-analysis. PLoS Med 2019;16(4):e1002771.
   
   
5. VanderMerweJL,SaccoA,ToelenJ,DeprestJ.Long-termneuropathologicaland/ or neurobehavioral effects of antenatal corticosteroid therapy in animal models: a systematic review. Pediatr Res 2020;87(7):1157–70.
   
   
6. LiveraniMC,LoukasS,GuiL,PittetMP,PereiraM,TruttmannAC,etal.Behavioral outcome of very preterm children at 5 years of age: prognostic utility of brain tissue volumes at term-equivalent-age, perinatal, and environmental factors. Brain Behav 2023;13(2):e2818.
   
   
7. Kazuya Fuma et al, Impact of antenatal corticosteroids on subcortical volumes in preterm infants at term-equivalent age: A retrospective observational study, European Journal of Obstetrics & Gynecology and Reproductive Biology (2024). DOI: 10.1016/j.ejogrb.2024.08.034