Perinatal Asphyxia—oxygen deficit at delivery—can lead to severe hypoxic ischaemic organ damage in newborns followed by a fatal outcome or severe life-long pathologies. The severe insults often cause neurodegenerative diseases, mental retardation and epilepsies. The mild insults lead to so-called “minimal brain-damage disorders” such as attention deficits and hyperactivity, but can also be associated with the development of schizophrenia and life-long functional psychotic syndromes. Asphyxia followed by re-oxygenation can potentially lead to development of several neurodegenerative pathologies, diabetes type 2 and cancer. The task of individual prediction, targeted prevention and personalised treatments before a manifestation of the life-long chronic pathologies usually developed by newborns with asphyxic deficits, should be given the extraordinary priority in neonatology and paediatrics. Socio-economical impacts of educational measures and advanced strategies in development of robust diagnostic approaches targeted at effected molecular pathways, biomarker-candidates and potential drug-targets for tailored treatments are reviewed in the paper.
Keywords: Paediatrics, CNS injury, Neurodegeneration, Diabetes, Cancer, Personalised medicineAsphyxia—insufficient oxygen supply—can lead to severe hypoxic ischaemic organ damage in newborns followed by a fatal outcome or severe life-long pathologies. Although birth asphyxia is not always distinguishable as the cause of perinatal and postnatal death, its pronounced impact for the mortality in newborns is well-documented, representing profound deficits in current healthcare systems worldwide. Secondary to birth asphyxia, a postnatal manifestation of hypoxic-ischaemic encephalopathy (HIE) is frequently observed being associated with either mild or severe organ damage in asphyxiated newborns, both leading to the development of chronic pathologies. The severe insults often cause neurodegenerative diseases, mental retardation and epilepsies. The mild insults lead to so-called “minimal brain-damage disorders” such as attention deficits and hyperactivity, but can also be associated with the development of schizophrenia and life-long functional psychotic syndromes. In some particular cases it is difficult to discriminate between mild and severe asphyxia: advanced methodology to improved diagnosis of birth asphyxia and prediction of individual short- and long-term outcomes obligatory needs to be developed. The task of individual prediction (Fig. 1 ), targeted prevention and personalised treatments before a manifestation of life-long chronic pathologies usually developed by asphyxiated newborns, should be given the extraordinary priority in paediatrics.
Newborn with asphyxic deficits. For timely protection against severe outcomes, a predictive diagnostics should be performed to detect individual pathology predisposition followed by targeted preventive measures and creation of personalised treatment algorithms. Data taken from [1]
According to the statistical data collected in years 2000–2002 by the Global Burden of Disease Study, worldwide 56 million deaths occur every year, from that 10.5 million, i.e. 20% represent children aged below 5 years. In this group, the leading cause of death is perinatal complications [2]. Current statistical data considering epidemiology of prenatal, perinatal and postnatal pathologies are worldwide have not been systematically analysed; sometimes these data are even controversial as provided for single countries. Here we overview the most systematic studies as published to the issue. One the most reliable issue-related studies performed in the USA has demonstrated the perinatal morbidity comprising 60% of the child death cases giving a general idea of the biggest impact of perinatal complications in childhood [3] and reflecting extensive issue-related problems in corresponding healthcare system as well as massive deficits in knowledge about and/or practical application of targeted prevention and effective treatment of neonatal, perinatal and postnatal pathologies.
Particularly alarming statistical data are currently delivered by developing countries with large populations. Currently one-third part of all neonatal deaths registered worldwide occurs in India [4, 5]. The most frequent prenatal, perinatal and neonatal complications leading to death are summarised in Fig. 2 for Tamil Nadu—one of the Indian regions.
Frequent complications leading to neonatal deaths with the highest contributions by birth asphyxia as monitored Tamil Nadu, India. Data taken from [1, 6]
It is obvious that the number of deaths during the first week of life comprises the highest overall mortality in newborns. Consequently, in Tamil Nadu, 81.5% of deaths were monitored during the first week of life, compared to more than 4-times (18.5%) and 10-times (8.2%) lower mortality during the second week and after the sixth month of life, respectively [6].
Further studies performed in South Africa have demonstrated clear area-dependent preferences in distribution of neonatal death rates (Fig. 3 ). There is an obvious inverse relationship between a decreased density of healthcare units and an increased mortality in newborns.
Prevalence of neonatal mortality represented in percentages with respect to a delivery area as monitored in South Africa [7]
Intensity of medical care has great impacts on neonatal death rates even in countries, where a healthcare is generally well established. Hence, despite of the overall low mortality of newborns in Canada, an increased risk of stillbirth and neonatal death during weekends is well documented indicating significant fluctuations in the intensity, i.e. quality of healthcare, the level of which, therefore, depends of the day of a week [8].
Currently a categorisation of perinatal complications is still not well classified. Worldwide there are three actively used diagnostic systems, namely Nordic-Baltic, Aberdeen and Wigglesworth one [9]. Among perinatal complications, 40% of all cases are defined as “unknown”, when diagnosed according to the parameters of the Aberdeen classification system alone. The Wigglesworth system provides satisfactory diagnosis for less then 60% of cases. Although in average 85% of the cases can be reliably diagnosed by a combination of all three diagnostic systems, still 15% of the cases remain undiagnosed [9]. Therefore, we conclude the absolute necessity to optimise currently used diagnostic systems by utilising innovative non-invasive technologies and creating reliable approaches capable to provide information for follow-up personalised treatments.
Among different countries, a prevalence of birth asphyxia varies dramatically depending on corresponding geographic localisation and socio-economical level of development (Fig. 4 ).
The prevalence of birth asphyxia as documented by a series of population studies: a corresponding number of cases has been calculated per 1,000 life births. Data taken from [10–21]
The data are well in agreement with the above given conclusions about a direct influence of the healthcare quality on delivery outcomes.
Hypoxic ischaemic organ damage can occur at antepartum—prenatal asphyxia, at intrapartum—perinatal (birth) asphyxia, or after delivery as postpartum asphyxia. Acute maternal infections, pre-maturity of a newborn and multiple births are the most frequent natural risk factors leading to hypoxic conditions in a fetus or newborn [8]. However, specifically perinatal asphyxia (PA) occurring at the parturition process of delivery is the leading cause of the overall mortality due to hypoxic-ischaemic damage to newborns. Consequently, the quality of a medical care at birth is crucial for the overall newborn mortality and long-term outcomes. The impact of a density of healthcare units is even more pronounced in prevalence of PA-related mortality (Fig. 5 ) compared to this of general mortality in newborns (Fig. 3 ).
Significant regional preferences in PA-related mortality depending on the density of healthcare units (maximal and minimal density in metropolitan and rural area, respectively) as documented for South Africa. Data taken from [1, 7]
Current limited perinatal and postnatal diagnostics cause long-term consequences in a society, which can include a spectrum of negative aspects. From a social and ethical point of view, innovative technologies for an early/predictive diagnostics and individualised treatment should be applied in all routine medical services. From an economic point of view, emphasis should be put into the costs effectiveness to promote advanced healthcare with appropriate budgets for targeted prevention applied before pathologies manifest.
What are the potential measures that can be applied already now? One example of the high impact of educational measures to improve the healthcare system is given in Figs. 6 and and7 7 .
Ratio of newborns with asphyxic deficits born to uneducated versus educated mothers. Data taken from [22]
Influence of maternal and paternal professional activity on prevalence of birth asphyxia in sub-grouped families as monitored in Nepal [16, 23]
The prevalence of birth asphyxia registered for children born to educated mothers is several times lower compared with those born to uneducated/illiterate mothers. It is evident that strong restrictions in the amount of education lead to dramatic deficits and costs that are essentially then felt in other branches of the system, including a consequently chaotic healthcare in the society. When the whole spectrum of asphyxia-related pathologies is considered such as type 2 diabetes, neurodegenerative diseases and cancer, the consequent costs increase dramatically for treatment of manifesting pathologies. Therefore, new guidelines are essential to regulate the field in favour of educational measures, personalised treatment approaches before manifesting pathologies, particular emphases on primary prevention, innovative reimbursement programmes introduced by policy-makers [22].
Depending on the grade of oxygen deficiency that a newborn suffered at delivery and individual reactions developed under asphyxic event, the corresponding perinatal asphyxia is graduated either as mild or severe one. The latter is the most frequent cause of perinatal and neonatal death as well as of severe injury of central nervous system (CNS) and damage to other organs resulting in hypoxic-ischaemic encephalopathy, nephropathy, and cardiomyopathy as the most usual long-term outcomes. The APGAR score is named by the author, Dr. Virginia Apgar, who has developed the system in the middle of 20th century [24]. Since that time, it is still the worldwide practised grading of the severity of perinatal asphyxia, as summarised in Fig. 8 .
A brief description of the APGAR system for the severity grading of perinatal asphyxia (PA) in newborns: PA severity ranges between 0 and 10, whereby 10 (healthy) corresponds to the best score 2 for all five parameters evaluated; *acrocyanosis occurs due to altered parameters of blood flow resulting in a gradually changing skin colour. Data taken from [1, 24]
The Apgar score uses five criteria: Appearance, Pulse, Grimace, Activity, and Respiration, shortly APGAR. Ranging from zero to ten, the scores below 3 are considered as critically low for cases of the highest emergency, 4 to 6—as fairly low, and the scores equal to or above 7 correspond to generally normal states of the newborn’s health. In regions with a traditionally high neonatal mortality, the Apgar score is frequently calculated as less than seven. Hence, in Saudi Arabia, the Apgar scores below 7 were registered for 22% of newborns; 7.6% of them represented cases of neonatal morbidity [19]. In Tanzania, Apgar scores below 7 for registered for 79% of the neonatal deaths [21]. These are clear indications for perinatal asphyxia as the major cause of neonatal morbidity.
The APGAR grading of a severity of perinatal asphyxia is relevant for the most probable short-term outcomes, such as generalised survival potential and an immediate risk of severe damage to CNS after asphyxic event. However, this diagnostic system has not been designed for prognostic purposes, evaluation of long-term risks and individual outcomes. Adequate diagnostic systems are currently missing and obligatory must be created to predict and prognose long-term risks and individual outcomes for asphyxiated newborns. In particular, a reliable diagnostic and prognostic system should be further created for newborns suffered from mild asphyxia graded as fairly to slightly low APGAR scores. Long-term affects of mild asphyxia are completely underestimated, due to less dramatic short-term outcome compared to severe asphyxia. Although mild insults do not cause perinatal death, the most frequent long-term outcomes include functional psychotic syndromes, attention deficit disorder, hyperactivity, epilepsies, schizophrenia and plenty of other chronic/life-long pathologies, which are assumed to be potentially caused by a sub-optimal delivery. The reaction towards mild insults is highly individual and should be subjected to extensive pre/clinical studies, in order to promote optimal protective measures and possibly full recovery.
The overall concept foresees advanced strategies as summarised in Fig. 9 . An optimal set-up of stakeholders and a high quality of the performance of single operating steps (sub-projects) guarantee for a discovery and qualification of innovative diagnostic approaches and valid drug targets to be successfully implemented in clinical practice. The crucial step in the overall experimental scheme is a well-established animal model to simulate clinical conditions. In the case of perinatal asphyxia, these are robust experimental conditions for totally-reproducible birth asphyxia and reliable (neuro)physiological tests characterising the specific features of the pathology. The animal model that has been created to simulate the perinatal asphyxia with characteristic asphyxia-related long-term outcomes in humans is described below. Optimal experimental conditions and general regulations including ethical aspects for a successful bio-preservation and bio-banking will be separately discussed in current and follow-up journal-issues.
Advanced strategies in the development of a robust diagnostic platform and novel drug targets with high potential for their clinical implementation
A reliable animal model of perinatal asphyxia has been established by M. Herrera-Marschitz et al. [25]. This model provides highly reproducible results and is well-acknowledged worldwide. The most important steps are illustrated in Fig. 10 .
The sequence of steps resulting in a set-up of clinically relevant perinatal asphyxia conditions and well reproducible asphyxiated newborn rats [25]. The uterus horns containing foetuses are placed in a water-bath at 37°C for 20 min to simulate severe birth asphyxia. Without re-oxygenation, the asphyxiated pups die after 22 min. By using this model, mild insults can be observed by 5–10 min simulation of perinatal asphyxia followed by immediate re-oxygenation
Pregnant Wistar rats at the last day of gestation are neck-dislocated and quickly hysterectomised. The uterus horns containing fetuses are placed in a water-bath at 37°C for time-periods ranging 0–20 min, in order to simulate the in vivo mild (below 10 min) and severe (above 15 min) birth asphyxia. Following asphyxiation, the uterus horns are rapidly opened, and the pups are removed and stimulated for breathing (re-oxygenation period). In vivo and in vitro neurophysiological evaluations are performed in order to characterise the severity grade of asphyxia and brain injury [26]. The long-term CNS effects of the simulated asphyxia are examined by behavioural evaluations. Ex vivo and in vitro analyses characterise the consequent damage to several organ, pathology-specific alterations in (sub)cellular structures and condition specific molecular patterns.
Adult rats subjected to perinatal asphyxia as described above, are tested for long-term modifications in non-spatial and spatial memory, and in motor tasks. They display impaired novel object recognition in accordance with the rodent model used to assess non-spatial working memory deficits [27, 28]. In contrast, the Y maze or Barnes, maze tests validated for spatial memory deficits, do not demonstrate any effects by the asphyxiation episodes, at delivery [28–30]. An evident impairment in motor coordination is monitored by rotarod performance; however, no significant difference in intensity of non-finalised motor behaviour and time-course of gross motor activity can be observed between the asphyxiated and control rats [28]. Taken together, the experimental rates exposed to the birth asphyxia, evidently, demonstrate altered fine movement functions, reflecting deficits in motor coordination and balance, whereas the locomotion and general motor activity remained non-affected. The cognitive and motor deficits observed in rats indicate the deleterious effects of birth asphyxia similar to those observed in human newborns suffered from perinatal asphyxia. The above described experimental model allows for monitoring of the deficits in cognitive performance, specific asphyxia-induced changes in motoric and stress-mediated behaviour [31, 32].
The principles underlie the “gene hunting”-technology of “subtractive hybridisation”, applied to profile differentially expressed gene-transcripts, has been described in several publications [33–35].
This strategy has been chosen to identify functional groups of genes, differentially regulated in the brain under the severe birth asphyxia versus normoxia [36–38]. The transcription profiling revealed the following functional groups of genes affected by the asphyxia [36]:
synthesis of signalling molecules (such as nitric-oxide) and heat-shock proteins nuclear and DNA-binding factors transcription and translation regulation energy metabolism membrane transport ion-handling several metabolic pathways (e.g. nucleic acid, lipid metabolism) redox-control and free-radical production proto-oncogenes.These functional groups comprise the genes, the transcriptional rates of which are significantly altered in brain of asphyxiated rats. Concomitantly, the same functional groups have been reported as resulting from research projects dedicated to the translational alterations identified by differential protein profiling [39]. These extensive alterations in the central molecular pathways can be potentially implicated in the development of potential asphyxia-related chronic complications, such as several sorts of degenerative processes in organs and onset of pre/cancerous lesions in the affected organs as summarised in Fig. 11 .
Metabolic particularities, impairments and individual outcomes by perinatal asphyxia. Abbreviations: mtDNA = mitochondrial DNA; chrDNA = chromosomal DNA; ATP = adenosine three-phosphate; PPPM = predictive, preventive and personalised medicine
Asphyxia is characterised by hypoxia (mild or severe oxygen deficiency) and the pH-values reduced below 7. Depending on the grade of oxygen deficits (see previous subchapters in the manuscript) perinatal asphyxia causes either severe brain injury or subtle perturbations affecting further development of the central nervous system (CNS) [40–42]. Under global hypoxia, “up-stream” CNS damage is followed by ischaemic lesions in kidney [43] and heart [44]. Global hypoxia impairs the general availability of oxygen [45, 46], affecting the electron transport pathways [47], increasing calcium influx and triggering fragmentation of both chrDNA and mtDNA [48]. The consequently triggered cascade of biochemical events creates a significant imbalance in central oxygen-dependent molecular pathways. Even more damaging is the reversion to normal oxygen levels during the post-asphyxic re-oxygenation associated with an extensive production of highly reactive oxygen species. Respectively, suppression and over-activation of the affected molecular pathways occur during both periods: hypoxia and re-oxygenation [36, 38]. Established chronic deficits underlie severe pathologies developed as individual long-term outcomes of perinatal asphyxia. Among them is the synthesis of compounds critical for postnatal CNS-development, nerve growth and “synaptogenesis” which are impaired by and depend on the asphyxia severity and damaging effects by the post-asphyxic re-oxygenation [26, 49–54]. Metabolic particularities of the asphyxia/re-oxygenation pathology are summarised in Fig. 11 . Hypoxic-ischaemic encephalopathy [55–57], CNS damage [58, 59], epilepsy [60, 61], nephropathy [43], cardiomyopathy [62, 63], vascular pathologies [64], senescence [32, 65], diabetes mellitus [66, 67], cancer [68], neurodegenerative diseases [58], morbidity and mortality [69] and tissue remodelling [70] all belong to individual short- and long-term outcomes of birth asphyxia. Specialised issue of The EPMA Journal, further treat the major related topics, namely “PPPM in Diabetes”, “PPPM in Neurodegenerative Diseases”, “PPPM in Cancer”, “PPPM in Cardiovascular Diseases”, “PPPM in Body Culture and Sport Medicine”, “Healthcare Overview”, where the articles overview the innovative technologies of predictive diagnostics, targeted prevention measures and desirable personalisation of medical care [71–80].
Blood tests is a highly attractive approach for performing non-invasive examinations to accurately diagnose a severity grade of birth asphyxia and to predict/prognose individual predispositions to or a progression of secondary complications in asphyxia affected newborns. Furthermore, the discovered blood-brain barrier permeability in hypoxic-ischaemic encephalopathy well explains potential correlations in pathology specific molecular profiles between brain and blood, justifying the high prognostic value of non-invasive blood examinations [81].
In newborn term infants with intra-partum signs of foetal distress, the blood-plasma levels of lactate-dehydrogenase are considered as a good predictor of hypoxic-ischaemic encephalopathy during the first 12 h after birth. This result is of clinical interest offering a potential inexpensive and safe prognostic marker in newborn infants with perinatal asphyxia [82].
The oxidative stress markers as measured in blood, are well recognised as the good predictors of poor outcomes in newborns with asphyxic deficits [83].
Acute kidney injury is a common consequence of perinatal asphyxia, occurring in up to 56% of these infants. Therefore, the pathology specific biomarkers are of great clinical value being currently under extensive consideration by researchers [84].
S100B is considered as one of the most potent blood-markers, significantly increased in blood serum 24 h after severe birth asphyxia insult in newborns [85–89].
Our recent studies demonstrated highly increased S100B expression rates, specifically, in the mesencephalon of the experimental rats, even 1 month after severe birth asphyxia. Potentially the brain tissue of the mesencephalon area overproducing S100B can be also the source of the increased S100B levels in the blood-serum, due to the blood-brain-barrier breakdown that is characteristic for hypoxic-ischalmic encephalopathy. However, the proteins of S100-family cannot be considered as asphyxia specific biomarkers, since significantly increased expression levels of them have been detected in blood of several patient cohorts, who suffer from different types of pathologies—neurodegenerative and vascular disorders [90–92], cardiomyopathy [93], several cancer types [94, 95].
The diagnostic approaches, which utilise pathology-specific biomarkers, are more promising in predicting an individual predisposition to pathologies, monitoring a disease progression and serving as the selective targets for tailored therapeutic measures. Here we provide some examples for potential biomarker-candidates discovered in our recent studies. Hence, a significant elevation of TAU-protein transcriptional rates has been demonstrated in the blood of experimental rats with expression peaks specific for the brain-regions in certain time-frame: 48-h—in mesencephalon and hypothalamus and 1-week—in telencephalon, as monitored after the severe asphyxic insult (see Fig. 12 ).
Transcription levels of the TAU-protein as measured in experimental rats exposed to birth asphyxia versus control animals (normoxia). The transcriptome-profies are specific for the brain-regions – Mesencephalon, Hypothalamus and Telencephalon. The brain-region/time specific peaks correlate with the appearance of TAU-transcripts in full blood of all asphyxiated animals tested. Data taken from [96]
Moreover, there is an evident correlation between the expression peaks in individual brain-regions and appearance of the TAU-transcripts in blood of asphyxiated pups. The up-regulation of the TAU-levels is characteristic for Alzheimer’s disease and has been implicated in the pathology-specific molecular mechanisms [97].
Further, the measurements of the HER-2 transcripts in brain and full blood revealed sufficient differences between the groups of asphyxiated and normoxic animals as demonstrated in Fig. 13 .
Transcription levels of the HER-2 protein as measured in experimental rats exposed to birth asphyxia versus control animals (normoxia). The transcriptome-profies are specific for the brain-regions – Mesencephalon, Hypothalamus and Telencephalon. The brain-region specific up-regulation (1 month after asphyxia) and down-regulation (48 h) correlates well with the respective appearance/disappearance of HER-transcripts in full blood asphyxiated animals. Data taken from [96]
According to the above given results, both TAU-protein and HER-2 can be considered as biomarker-candidates for further validating tests in clinical studies.
Re-oxygenation of newborns with asphyxic deficits triggers a cascade of compensatory biochemical events to restore function, which may be accompanied by improper homeostasis and oxidative stress. In the clinical scenario, no specific treatments have yet been established to protect asphyxic newborns against hypoxic/re-oxygenation stress. In the clinical setting, after resuscitation of an infant with birth asphyxia, the emphasis is on supportive therapy. Several interventions have been proposed to attenuate secondary neuronal injuries elicited by asphyxia, including hypothermia. Hypothermia has been pointed out to be an effective intervention against the secondary neuronal injury, elicited by the birth asphyxia [98]. Applied immediately after birth asphyxia, hypothermia generally lowers metabolic rates, and diminishes the glutamate levels in brain [98–100]. Although promising, the clinical efficacy of hypothermia has not been fully demonstrated. It is evident that new approaches are warranted.
In the context of neuroprotection, several sentinel proteins have been described to protect the integrity of the genome (e.g. PARP-1, XRCC1, DNA ligase IIIα, DNA polymerase β, ERCC2, DNA-dependent protein kinases). They act by eliciting metabolic cascades leading to (i) activation of cell survival and neurotrophic pathways; (ii) early and delayed programmed cell death, and (iii) promotion of cell proliferation, differentiation, neuritogenesis and synaptogenesis. It is proposed that sentinel proteins can be used as markers for characterising long-term effects of perinatal asphyxia, and as targets for novel therapeutic development and innovative strategies for neonatal care [101].
Nicotinic acid and nicotinamide have been proposed to protect against oxidative stress [102, 103], ischaemic injury [104] and inflammation [105] by replacing the depletion of the NADH/NAD + -pair produced by PARP-1, which is over-activated under severe hypoxic conditions [106]. Therapeutic application of nicotinamide has been reported to prevent several of the changes induced by perinatal asphyxia on monoamines, even if the treatment is delayed for 24 h, suggesting a clinically relevant therapeutic window [107]. Therefore, this approach is currently considered as the therapeutic strategy against the long-term deleterious consequences of birth asphyxia as well as for several pathophysiologic conditions such as myocardial reperfusion injury, stroke, neurotrauma, arthritis, multiple sclerosis and severe complications secondary to Diabetes mellitus [105].
The application of low concentrations of NO-inhibitors is beneficial against extensive ischaemic lesions in brain [108]. Pre- and post-hypoxic treatment with NMDA-receptor antagonists appears to reduce cerebral tissue injury [109, 110]. Calcium-channel blockers have also been demonstrated to have beneficial effects [109] by reducing post-asphyxic lesions in brain.
Pretreatment with barbiturates may improve survival and reduce the severity of brain injury [109]. It reduces cerebral metabolism [111] and decreases oxygen consumption [112]. By lowering the oxygen consumption, it prevents free-radical destruction of the cell membranes [113]. The barbiturate pretreatment reduces the intra- and extra-cellular accumulation of water and, in this way, prevents convulsions [114].
Postnatal treatments with free-radical scavengers such as dimethylthiourea, xanthine-oxidase, and allopurind-inhibitor improve clinical outcomes after perinatal asphyxic insults [115, 116].
The Authors—Olga Golubnitschaja and Mario Herrera-Marschitz—have been granted for the bilateral collaboration by The German Agency for Academic Exchange (DAAD); the international project numbered D/06/33975 (2006–2010) was dedicated to “Perinatal Asphyxia”. The authors thank to DAAD for the support. Also, the authors would like to thank M.Sc. Viktoriya Peeva for the literature search to the topic performed in 2008–2009.
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