Each year approximately four million neonates become seriously deprived of oxygen (O₂) during birth (1). There are numerous obstetric complications that can lead to an asphyxic birth. These can be loosely defined as peripartum in nature, such as placental abruption, vasa praevia (a condition where fetal blood vessels cross the external orifice of the uterus and often rupture), or a hypoxic–ischemic event at birth (2, 3). This latter category includes uterine rupture, shoulder dystocia, cord prolapse, maternal cardiopulmonary arrest, and a difficult or prolonged delivery (4). This transient but potentially catastrophic deprivation of oxygen in the intrapartum period is thought to be directly responsible for 691,000 deaths and 1.02 million stillbirths each year, making it the fifth most common cause of childhood deaths under 5 years (5–7). For those infants that do survive, the multi-organ damage that can ensue means the risk of developing severe life-long morbidities is high. Intrapartum asphyxia results in a burden of 42 million disability years (DALYs). To put this figure in context, this is twice the DALYs imposed by diabetes (8). Although it is a global issue, recent evaluations of the incidence of intrapartum asphyxia in high income countries, where adequate obstetric care is available during the peripartum period, have incidences ranging from 4.3 to 8.5% of term live births (9). This is in stark contrast to an incidence of around 23% in developing countries where women’s health care remains under-resourced and many women delivery at home, without professional assistance (10).

The unpredictable nature of the many obstetric complications that contribute to intrapartum asphyxia, in addition to the multi-organ damage associated with intrapartum oxygen deprivation (11), presents a unique set of challenges to clinical and research professionals in their endeavor to implement effective treatments for intrapartum asphyxia. Despite the burden of intrapartum-related neonatal deaths and morbidities, research investment into intrapartum asphyxia and associated morbidities remains low, potentially due to it being a condition that is most prevalent in low resource settings. When reviewing the research investment into neonatal deaths it is clear that this is an area hampered by the “10/90 gap,” meaning only 10% of research expenditure is directed toward 90% of the world’s global burden of disease (12). This should be of concern to the medical community, as the Millennium Development Goal to reduce the under-five mortality by two-thirds by 2015 was not achieved (7), and neonatal death is an increasing contributor to this category of childhood survival (13).

One cannot assume there will be a dramatic shift in research investment strategies. Hence, there is a clear need to consolidate our knowledge of the overall pathophysiology of intrapartum asphyxia; evaluate our current approaches to studying intrapartum asphyxia; and develop targeted treatments, keeping in mind the limits on application of highly sophisticated medical interventions in low resource settings. In the following review, we discuss the effects of intrapartum asphyxia on the cerebral, cardiovascular, cardiorespiratory, and musculoskeletal systems, including current treatment/management strategies and their limitations. We then provide an update on the preclinical models available for research into intrapartum hypoxia and assess treatments considered in the pipeline for clinical translation.

Characterization of brain injury following intrapartum asphyxia has been the focus of many basic science and clinical investigations. However, in a clinical retrospective study, Hankins et al. (14) observed that for 70% of cases, low oxygen was not the direct cause of hypoxic–ischemic encephalopathy (HIE), but rather HIE was a condition that developed secondary to renal, hepatic, and cardiac dysfunction following birth asphyxia (14). While the brain is the obvious target of interventions to allay progressive damage arising from hypoxia, oxidative stress, and inflammation at birth, the need to protect other vital organs such as the heart, kidneys, lungs, and diaphragm has received much less attention. This is made pertinent by the fact that hypothermia has not been shown to offer protection to the many other organ systems affected by birth asphyxia (15, 16), and also from the plausible possibility that HIE arises secondarily to poor cardiorespiratory function in the minutes and hours after an asphyxic birth. These types of studies highlight the true nature of the global oxygen deprivation associated with birth asphyxia and the need to investigate all consequential injury.

The body is composed of almost 40% skeletal muscle, and this tissue is not only essential for locomotion, but also plays an important role in the metabolism of proteins and amino acids for various organ systems (93). Hypoxia in adult skeletal muscle increases production of ROS, which increases the degradation of myofibrillar structural proteins (93). Exposure to hypobaric hypoxia in adults reduces maximal force production and muscle endurance as assessed by static handgrip contractions (95). Acute hypoxia increases oxidative stress and reduces mitochondrial function in mouse skeletal muscle (96), and structurally, hypoxia causes severe muscle atrophy (97). Hypobaric hypoxia results in a significant reduction in muscle mass and muscle fiber cross-sectional area (CSA) (97).

Given the obvious susceptibility of the skeletal muscle to hypoxic damage, the possibility that deficits in skeletal muscle function could be contributing to the functional motor deficits observed in survivors of intrapartum asphyxia with CP should not be overlooked. As discussed previously, CP is the most common deleterious morbidity associated with birth asphyxia. It is a condition characterized by hypotonia in the neonate (98), and children with CP often suffer from a range of neuromuscular disabilities including deficits in motor coordination, gait abnormalities and, in severe cases, upper and lower limb spasticity (99–101), and reductions of muscle endurance and peak power of the arms and legs, even in children with mild CP (102). A small study reported significant reductions in lower limb mass in children with CP (103); however, investigations into the structural changes in these muscles are lacking.

A large body of work has been dedicated to the development of treatments for the muscular symptoms of CP; for example, the use of botulinum toxin A injection to treat limb muscle spasticity, which has been shown to improve movement for children with lower limb spasticity (104–106). While the body of opinion would be that most of the muscle disability arises secondarily from damage to central pathways governing motor activity, the direct effects of mild to moderate intrapartum asphyxia on the axial muscles obviously require further consideration.

A major issue faced by researchers and clinicians focusing their efforts on understanding the effects of birth asphyxia is the availability of an appropriate research model. Conventional altricial laboratory rodents such as mice and rats are commonly used to study the biochemical and pathological changes within the gray and white matter regions of the brain following intrapartum asphyxia. However, use of these species poses significant limitations due to the immaturity of their offspring at the time of birth. Therefore, any findings regarding tissue damage or alterations in normal organ development following a hypoxic episode at birth must be interpreted with caution. These would not be considered as appropriate models to study damage to peripheral organs such as the kidney after intrapartum asphyxia.

Large precocial models are much more useful in this regard as their advanced stage of development at the time of birth closely mimics the human physiological response to intrapartum asphyxia [see review in Ref. (107)]. Indeed, understanding perinatal brain injury following a hypoxic–ischemic insult was highly advanced by classic studies by Meyer et al. in the non-human primate in the 1970s (108). There is a particular ethical dilemma in the use of non-human primates, and the cost of experimentation in these species means the study of all neurological disorders in non-human primates is not always appropriate; however, they continue to be used of gain insight into the neurological outcomes of intrapartum asphyxia (109). There has also been extensive work conducted investigating the effect of birth asphyxia on the brain using both sheep and pigs. In sheep, we and others have developed and characterized a clinically relevant model of HIE in the near-term lamb (110–112), and Miller and colleagues use this model to investigate potential rescue therapies using melatonin and stem cells (113–116). Another group has used the newborn piglet to investigate the neurological effects of intrapartum asphyxia (117, 118), the effects of cooling (119) and to explore potential early biomarkers of neuronal injury (120). However, these animals are expensive, difficult to house and long-term studies, looking at the life course effect of HIE require many years.

The need for an appropriate small animal model to investigate the systemic effects of an asphyxial birth and the testing of potential interventions is met to some extent by using the spiny mouse (Acomys cahirinis). This is a precocial rodent native to the deserts of Africa and Middle East, where after a relatively long gestation (39 days) the neonate has completed organogenesis of major organ systems (121–124), and are fully furred, mobile and have open eyes.

Unlike other rodents, the brain of the spiny mouse is relatively well myelinated at birth (125), and the brain growth spurt in this species occurs in the days just prior to birth; this is later in gestation than the guinea pig, monkey, and sheep, but earlier than the rat and rabbit, and prior to birth as in the human. In addition, this species has a hormone profile similar to the human, with the adrenal gland producing cortisol as its major circulating glucocorticoid instead of corticosterone as seen in most rodents. The fetal spiny mouse adrenal gland is also able to synthesis the steroid dehydroepiandrosterone, making the spiny mouse perhaps one of few rodents to have a fetal-placental unit where the fetal adrenal–hepatic–placental axis plays an important role in fetal brain development during gestation, as it does in higher primates, including humans (124, 126). Finally, one of the unique intrauterine developmental aspects of the spiny mouse is the completion of nephrogenesis (the formation of the filtering units in the kidney) before birth in this species (121). This makes the study of renal hemodynamics in the early neonatal period, and the study of insults on the kidney at birth in the spiny mouse particularly relevant to the human situation.

A model of near-term intrapartum asphyxia has been produced in the spiny mouse and is characterized by global acidemia, hypoxemia, and increased plasma lactate (127). In this model, it was noted that animals that did not survive the insult (~40%) exhibited abnormal gasping behavior and were unable to establish breathing. It was therefore proposed that the respiratory muscles may be involved in this failure, and the status of the diaphragm was assessed (127). This study revealed significant structural and functional deficits in the diaphragm 24 h after birth (127). This was characterized by muscle fiber atrophy, with a 20% decrease in CSA of all three major muscle fiber types and a 27% reduction in calcium (Ca²⁺)-activated force (127) as assessed in skinned single muscle fibers. There was an increase in the expression of two pro-atrophic genes—Atrogin-1 and MuRF-1. It is therefore reasonable to assume that these deficits may be contributing to respiratory failure in these animals and thus the high mortality rate observed in this model. Since those initial studies, the spiny mouse model of intrapartum asphyxia has been used to describe molecular, structural, and functional alternations in the neonatal brain and diaphragm, kidney, gonads, and skeletal musculature, and assess the therapeutic potential of the antioxidant melatonin and intracellular energy buffer creatine (127–135).

These preclinical studies have contributed significantly to our knowledge of the longer-term impact of intrapartum asphyxia. Some of the key findings to date include neurological injury being associated with mitochondrial derangement in the cortical subplate, thalamus, and piriform cortex (133) and significant behavioral deficits in tests that assess movement and motor coordination (132). Furthermore, when the same animals were placed in an open field on postnatal day 1, and their movement was recorded, asphyxia pups traveled less distance, spent more time immobile, and made significantly fewer jumps (132). These observations suggested that these animals may have significant deficits in neuro-motor activity.

These observations were further characterized with studies aimed at directly investigating the potential effects of intrapartum asphyxia on the skeletal muscle. At 24 h of age, as was observed in the diaphragm, all three muscle fiber types showed significantly reduced size. This deficit persisted until at least 1 month of age in males, along with a significant reduction in the proportion of type I fibers and a corresponding increase in type IIb/d fibers (135). Additionally, the neonatal gastrocnemius muscle was functionally assessed ex vivo and, akin to the diaphragm, exhibited reduced fatigue resistance in male offspring (128, 135). It is apparent that the skeletal muscle is indeed significantly affected in the immediate neonatal period following asphyxia at birth, and these deficits are persisting into at least early adulthood in our model. Therefore, it is not unreasonable to assume that the same may be the case for human infants who survive birth asphyxia.

Finally, the first rodent model of neonatal AKI secondary to intrapartum asphyxia has been developed in the spiny mouse. Neonatal AKI was confirmed by a twofold increase in mRNA expression of Ngal, an early marker of kidney injury, and plasma and urinary electrolyte imbalances 24 h after insult (128). Assessment of kidney structure following intrapartum asphyxia also showed significant levels of damage and immaturity, across the renal cortex, medulla, and renal papillae. At 1 month of age, male intrapartum asphyxia offspring had a permanent loss of nephrons. Compensatory hypertrophy of remaining nephrons was apparent in this cohort, but despite this, at 3 months of age (young adult), GFR in male asphyxia offspring was significantly lower than controls (136). It is of interest that cardiac structure and function in spiny mouse neonates was unaltered by intrapartum asphyxia. Clinically, while cardiovascular dysfunction is observed in some survivors of intrapartum asphyxia, the effects on the heart are heterogenous. Therefore, the absence of an effect in surviving spiny mouse pups after asphyxia is perhaps not surprising.

When it comes to managing the risk of a hypoxic event at birth, the main issue faced by clinicians is the unpredictable nature of intrapartum asphyxia. Most often, it is not until the woman is in labor that obstetricians become fully aware that the fetus is at risk, and by this stage there is little they can do other than to deliver the baby as quickly as possible. Furthermore, apart from hypothermia, which as previously discussed has limited success, there are no other effective treatments for preventing the two waves of energy failure that ensues following an asphyxic birth.

A number of antenatally applied treatments that aim to prevent intrapartum hypoxic brain damage have been proposed and include the use of ascorbic acid, tetrahydrobiopterin, phenobarbital, N-acetylcysteine (NAC), xenon, and argon. However, these have either provided disappointing results (ascorbic acid and xenon), require specialized ventilatory equipment (xenon and argon), revealed unfavorable safety profiles (NAC), or, while showing promise (e.g., allopurinol, melatonin, and argon), currently lack full clinical evaluation, including their capacity to target hypoxic injury in organs other than the brain. Pharmacokinetically, all of these agents have a short duration of action and cannot be expected to provide a benefit lasting through birth into neonatal life unless their administration continues throughout the entire ante-, intra-, and postpartum periods.

The gold standard would be a safe treatment that could be administered maternally before birth to provide protection in the event of a hypoxic episode during labor. Such a treatment should be cheap and easily administered so that it could be made available in the areas where the incidence of birth asphyxia is highest. It must also have the capacity to minimize the initial energy failure that occurs at the time of the insult, as well as having potent antioxidant capabilities to reduce the oxidative stress that ensues in the period immediately after birth. This would reduce or prevent the second wave of energy failure and oxidative stress and prevent the multi-organ injury that results. It will also need to be benign should intrapartum hypoxia not arise.

Elsewhere, we have proposed that antenatally administered creatine can provide the fetus and neonate with an additional pool of anaerobic energy during severe hypoxia, and it is a treatment that will provide protection not only to the brain but also to the other major organs that often damaged by “oxygen starvation” at birth (137). Creatine, as phosphocreatine, provides a phosphate group for the anaerobic regeneration of ATP from ADP (138). This system is crucial in maintaining intracellular energy homeostasis, serving as both a spatial and temporal energy buffer in cells with high and fluctuating energy demands such as striated muscle and neurons of the central nervous system (139). In addition to this role, it is also known to have other important properties. The conversion of creatine to phosphocreatine utilizes a proton, reducing intracellular acidity and thus maintaining acid–base balance (140). It has also been reported to have antioxidant properties in studies investigating the effect of hypoxia on the skeletal muscle (140, 141) and brain (133). These studies hypothesized that increasing total intracellular creatine before birth (creatine + phosphocreatine) would protect the fetus from the damaging effects of birth asphyxia by providing an additional, anaerobic source of ATP when oxidative phosphorylation fails due to the hypoxic insult. The antioxidant properties of creatine could also act to reduce the oxidative stress associated with the global hypoxia–ischemia that ensues. Using our spiny mouse model of birth asphyxia, we have shown that supplementing the maternal diet with 5% creatine monohydrate for a period of 19 days before delivery, caused significant creatine loading in the fetal brain, heart, kidney, liver, and diaphragm muscle (127, 131). These studies also reported a significant reduction in neonatal mortality rate after birth asphyxia (127, 131) and was protective for the brain (133), diaphragm (127), kidney (128, 136), and axial skeletal muscles (134, 135).

Despite these interesting and promising results, to date there have been no clinical studies investigating the potential for creatine to prevent birth asphyxia-induced injury. However, this was the subject of a recent review in which the limited amount of data available was highlighted (142). A full Cochrane has also been published (142); however, due to the lack of data for human pregnancy, this brought to light the need for clinical translation of this potentially life-saving treatment. If antenatally administered creatine proves to be effective and safe, it would be a cheap and readily available prophylactic treatment that could be recommended to all pregnant woman as a safeguard in the event of intrapartum hypoxia and neonatal asphyxia, thus reducing the high mortality, morbidity, and financial burden associated with this common and devastating event, in much the same way that folate supplementation has prevented neural tube defects. In the 1960s, Smithells and Hibbard discovered that women who gave birth to children with serious birth defects, notably neural tube defects, had evidence of impaired folate status. Some 30 years later, randomized controlled trials showed that they were right, and folate supplementation was effective at protecting against neural tube defects (143). In addition to our extensive evidence from animal studies that support a benefit for the fetus of increasing tissue creatine content above normal levels, we have recently shown that women who deliver small babies have lower urine creatine concentrations (144), suggesting that inadequate creatine availability may impact fetal growth. We are currently testing this hypothesis in a large prospective cohort of low risk pregnant women.

Reducing the under-five mortality rate by two-thirds by 2015 was a Millennium Development Goal that unfortunately was not achieved (7). While advancements in obstetric monitoring and therapies such as hypothermia have helped reduce the rate of intrapartum-related brain damage and death significantly in the last decade, more needs to be done to address problems associated with the more extensive (multi-organ) compromises that may affect these infants. This has significant economical and emotional burdens that have not been adequately addressed and is of particular relevance for developing countries where medical resources may be limited. Severe hypoxia at birth is essentially a cardiorespiratory problem, and while brain damage has received the most attention, the global nature of the hypoxic–ischemic insult and myriad of biochemical disruptions that follow cause significant injury to many organ systems, as outlined in this review. Year 2016 marks the beginning of new global Sustainable Development Goals, with the aim to have the “Under-5” mortality rate below 25 per 1,000 live births by 2030 (145). As we embark on this new period it is important that we engage in preclinical and clinical studies designed to directly address the multi-faceted outcomes of intrapartum asphyxia. Careful consideration to appropriate animal models is required to ensure that the limited resources invested in this research provide the maximum, and most relevant, outcomes that further our understanding of injury to all the major organ systems in the neonates. The development of adjuncts to hypothermia and new therapies should be carefully considered for their applicability in the developing world if we are to truly combat the global burden of intrapartum asphyxia. Furthermore, experimentally, we are duty-bound to provide evidence for the effectiveness of new therapies beyond the neonatal period, i.e., into infancy, childhood, and the adult stages of life.

All authors contributed to writing and drafting this review.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.