Differences in the development of the male and female brain are an evolving area of investigation. We are beginning to understand the underpinnings of male and female advantages due to differences in brain development as well as the consequences following hypoxic-ischemic brain injury in the newborn. The two main factors that appear to affect outcomes are gestation age at the time of injury and sex of the subject. This review starts with a summary of differences in the anatomy and physiology of the developing male and female brain. This is followed by a review of the major factors responsible for the observed differences in the face of normal development and hypoxic injury. The last section reviews the response of male and female subjects to various neuroprotective strategies that are currently being used and where there is a need for additional information for more precise therapy based on the sex of the infant.

Neonatal hypoxia ischemia (HI; reduced oxygen and/or blood flow to the brain) can cause various degrees of tissue damage, as well as subsequent cognitive/behavioral deficits such as motor, learning/memory, and auditory impairments. These outcomes frequently result from cardiovascular and/or respiratory events observed in premature infants. Data suggests that there is a sex difference in HI outcome, with males being more adversely affected relative to comparably injured females. Brain/body temperature may play a role in modulating the severity of an HI insult, with hypothermia during an insult yielding more favorable anatomical and behavioral outcomes. The current study utilized a postnatal day (P) 7 rodent model of HI injury to assess the effect of temperature modulation during injury in each sex. We hypothesized that female P7 rats would benefit more from lowered body temperatures as compared to male P7 rats. We assessed all subjects on rota-rod, auditory discrimination, and spatial/non-spatial maze tasks. Our results revealed a significant benefit of temperature reduction in HI females as measured by most of the employed behavioral tasks. However, HI males benefitted from temperature reduction as measured on auditory and non-spatial tasks. Our data suggest that temperature reduction protects both sexes from the deleterious effects of HI injury, but task and sex specific patterns of relative efficacy are seen.

Preterm infants are often treated with caffeine as a respiratory stimulant. However, follow-up data shows caffeine may also have neuroprotective potential. There are several theories as to how caffeine might protect the brain, but none have been proven. This study looked at caffeine effects on microglial activation in rodent brains post hypoxic ischemic (HI) injury. Rat pups underwent either sham or HI surgery on P6, followed by treatment with either caffeine or saline. Forty-eight hours post-injury, brains were collected and underwent paraffin embedding and sectioning followed by immunofluorescence staining. Ionized calcium binding adaptor molecule 1 (Iba-1) was used to label microglia, and 4′,6-diamindino-2-phenylindole (DAPI) was used to label DNA. Cell size measurements of microglia were obtained to gauge microglia activation, and chromatin condensation (DAPI optical density) was used as an index of neuronal cell death. Results suggest that caffeine does offer protective effects, based on significantly increased levels of cell death in HI-saline animals not seen in caffeine-treated HI males and females. However, the mechanism of action may be different. Male HI animals showed marginally reduced microglial activation following caffeine treatment, whereas females did not. Results indicate that though caffeine may act protectively in both sexes by reducing cell death, the benefits may be mediated by different mechanisms.

Infants born prematurely have an increased risk of experiencing brain injury, specifically injury caused by Hypoxia Ischemia (HI). There is no approved treatment for preterm infants, in contrast to term infants that experience Hypoxic Ischemic Encephalopathy (HIE) and can be treated with hypothermia. Given this increased risk and lack of approved treatment, it is imperative to explore and model potential treatments in animal models of preterm injury. Hypothermia is one potential treatment, though cooling to current clinical standards has been found to be detrimental for preterm infants. However, mild hypothermia may prove useful. Caffeine is another treatment that is already used in preterm infants to treat apnea of prematurity, and has shown neuroprotective effects. Both of these treatments show sex differences in behavioral outcomes and neuroprotective effects, which are critical to explore when working to translate from animal to human. The effects and research history of hypothermia, caffeine and how sex affects these treatment outcomes will be explored further in this review article.

Magnesium sulfate (MagSul) is used clinically to prevent eclamptic seizures during pregnancy and as a tocolytic for preterm labor. More recently, it has been implicated as offering neural protection in utero for at-risk infants. However, evidence is mixed. Some studies found that MagSul reduced the incidence of cerebral palsy (CP) but did not improve other measures of neurologic function. Others did not find any improvement in outcomes. Inconsistencies in the literature may reflect the fact that sex effects are largely ignored, despite evidence that MagSul shows sex effects in animal models of neonatal brain injury. The current study used retrospective infant data to assess differences in developmental outcomes as a function of sex and MagSul treatment. We found that on 18-month neurodevelopmental cognitive and language measures, preterm males treated with MagSul (n = 209) had significantly worse scores than their untreated counterparts (n = 135; p < 0.05). Female preterm infants treated with MagSul (n = 220), on the other hand, showed a cognitive benefit relative to untreated females (n = 123; p < 0.05). No significant effects of MagSul were seen among females on language (p > 0.05). These results have tremendous implications for risk–benefit considerations in the ongoing use of MagSul and may explain why benefits have been hard to identify in clinical trials when sex is not considered.

Background/Objectives: Determine the appropriate duration for multichannel sleep studies in former preterm infants with cardio-respiratory events beyond term equivalent age. Hypothesis: A sleep study of 10 h will provide equivalent information compared to a 20-h study to detect significant cardio-respiratory abnormalities in this population. Methods: Single-center retrospective study of 50 infants with 20-h sleep study. Studies were evaluated for periodic breathing, obstructive, central, mixed apnea, desaturations, and bradycardia. Each study was partitioned into two 10-h epochs, compared to one another and the 20-h study. Results: Differences were detected at the level of individual sleep studies when each epoch was compared to each other and a total 20-h study. 10-h study missed 17–31% of breathing abnormalities detected over 20 h adjusted for study time. Group analysis showed no statistical difference in the number and duration of events between epochs. Conclusions: A 20-h sleep study improves the detection of breathing abnormalities missed with a 10-h study.