Progesterone as a Neuroprotective Agent in Neonatal Hypoxic-Ischaemic Encephalopathy: A Systematic Review

Abstract

Hypoxic-ischaemic encephalopathy (HIE) in the newborn baby is a major contributor to neonatal mortality and morbidity across the world. Therapeutic hypothermia (HT) is the current standard treatment for moderate to severe HIE, but not all babies benefit. Potential neuroprotective actions of PROG include anti-apoptotic, anti-inflammatory and anti-oxidative effects and reduction of energy depletion, tissue/cellular oedema and excitotoxicity. In pre-clinical studies of neonatal HIE, progesterone (PROG) has neuroprotective properties, but has not been the subject of systematic review. Here our objective was to evaluate the evidence base for PROG as a potential therapeutic agent in HIE. The PICO framework was used to define the following inclusion criteria; Population: human neonates with HIE/Animal models of HIE, Intervention: PROG +/- other agents, Comparison: V.S. control, Outcome: pathological, neurobehavioural and mechanistic outcome measures. Medline, EMBASE and CINHAL were then searched between August to October 2018 using pre-defined medical subject heading and key words. Study inclusion, data extraction and risk of bias (ROB) analysis using the SYRCLE ROB tool were carried out by two authors. 14 studies were included in the review. They typically displayed a high ROB. This systematic review suggests that PROG had positive effects on neuropathology and reduced neurobehavioural deficits post-hypoxic-ischaemic (HI) injury. However, there was sex dimorphism in the effects of PROG. In addition, there are limitations and biases in these studies and there remains a need for well-designed large pre-clinical studies with greater methodological quality to further inform the efficacy, safety, dose, timing and frequency of PROG administration. With such data, large animal studies could be planned combining PROG administration with and without HT.