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 (TH) is the current standard treatment for moderate to severe HIE, but not all babies benefit. Potential neuroprotective actions of progesterone (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, 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 keywords. 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 reduced neuropathology and reduced neurobehavioural deficits post-hypoxic-ischaemic (HI) insult in 8 and 3 studies, respectively. 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 TH.

Keywords: Brain injury; Hypoxia-ischemia; Hypoxic-ischemic encephalopathy; Neonatal brain injury; Neuroprotection; Perinatal brain injury; Progesterone.

Fig. 1

Search strategy outline.

Fig. 2

Risk of bias analysis. Bias assessed as per the SYRCLE tool for all 14 studies included.

Fig. 3

Schematic diagram (adapted from Hassell et al. [75], Nair et al. [8] and Douglas-Escobar and Weiss [4]), illustrating the different pathological phases of cerebral injury after onset of hypoxia-ischaemia. Progesterone may be useful as an adjuvant to therapeutic cooling by exerting neuroprotective effects during the primary (acute) phase, latent phase and secondary phase of the disease process of HIE. Most animal studies adopted pre-insult administration of PROG due to convenience of such study design. We appreciate the difficulty in pre-emptive administration of PROG to at risk foetuses but propose that PROG may be useful when given both before and after HI injury. The proposed mechanisms of neuroprotection by PROG are listed in no particular chronological order relative to the pathological phases of HIE. CO, cardiac output, HI, hypoxia-ischaemia, EAAs, excitatory amino acids, NO, nitric oxide, OFRs, oxygen free radicals.