Perinatal asphyxia

Abstract

Introduction

In resource-rich countries, the incidence of severe perinatal asphyxia (causing death or severe neurological impairment) is about 1/1000 live births. In resource-poor countries, perinatal asphyxia is probably much more common. Data from hospital-based studies in such settings suggest an incidence of 5–10/1000 live births.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions in term or near-term newborns with perinatal asphyxia? We searched: Medline, Embase, The Cochrane Library and other important databases up to June 2006 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 25 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: anticonvulsants (prophylactic), antioxidants, calcium channel blockers, corticosteroids, fluid restriction, head and/or whole body hypothermia, hyperbaric oxygen treatment, hyperventilation, inotrope support, magnesium sulphate, mannitol, opiate antagonists, and resuscitation (in air versus higher concentrations of oxygen).

Key Points

Estimates of the incidence of perinatal asphyxia vary. In resource-rich countries, severe perinatal asphyxia (causing death or severe neurological impairment) is 1/1000 live births; in resource-poor countries, studies suggest an incidence of 5–10/1000 live births.

Limited evidence from three small, weak RCTs suggests that mortality may be lower in infants treated with antioxidants compared with placebo.

There is limited evidence that hypothermia reduces mortality and neurodevelopmental disability in infants with perinatal asphyxia.

Limited evidence from one small RCT suggests that a magnesium sulphate/dopamine combination may be more effective than no treatment in reducing a combined outcome of mortality, abnormal scans, and failure to feed.

Small RCTs with flawed methods suggest that anticonvulsants are of no benefit in reducing mortality or improving neurodevelopmental outcomes in term infants with perinatal asphyxia.

Resuscitation in air lowered mortality in infants with perinatal asphyxia compared with resuscitation in 100% oxygen. However, current clinical practice is to use 100% oxygen.

Limited evidence from a systematic review that reported problems with publication bias in the RCTs it identified suggests that hyperbaric oxygen treatment lowers rates of mortality and adverse neurological outcomes in infants with perinatal asphyxia and hypoxic–ischaemic encephalopathy. This treatment, although widely used in China, is not standard practice in other countries.

We don't know whether calcium channel blockers, corticosteroids, fluid restriction, hyperventilation, inotrope support, mannitol, or opiate antagonists are helpful in infants with perinatal asphyxia.

About this condition

Definition

The clinical diagnosis of perinatal asphyxia is based on several criteria, the two main ones being evidence of cardiorespiratory and neurological depression (defined as an Apgar score remaining less than 7 at 5 minutes after birth) and evidence of acute hypoxic compromise with acidaemia (defined as an arterial blood pH of less than 7 or base excess greater than 12 mmol/L). In many settings, especially resource-poor countries, it may be impossible to assess fetal or neonatal acidaemia. In the immediate postpartum period when resuscitation is being undertaken, it may not be possible to determine whether the neurological and cardiorespiratory depression is secondary to hypoxia–ischaemia, or to another condition such as feto-maternal infection, or metabolic disease. Consequently, resuscitation and early management will often be of suspected rather than confirmed perinatal asphyxia. This review deals with perinatal asphyxia in term and near-term newborns.

Incidence/ Prevalence

Estimates of the incidence of perinatal asphyxia vary depending on the definitions used. In resource-rich countries, the incidence of severe perinatal asphyxia (causing death or severe neurological impairment) is about 1/1000 live births. In resource-poor countries, perinatal asphyxia is probably much more common. Data from hospital-based studies in such settings suggest an incidence of 5–10/1000 live births. However, this probably represents an underestimate of the true community incidence of perinatal asphyxia in resource-poor countries.

Aetiology/ Risk factors

Perinatal asphyxia may occur in utero, during labour and delivery, or in the immediate postnatal period. There are numerous causes, including placental abruption, cord compression, transplacental anaesthetic or narcotic administration, intrauterine pneumonia, severe meconium aspiration, congenital cardiac or pulmonary anomalies, and birth trauma. Postnatal asphyxia can be caused by an obstructed airway, maternal opiates — which can cause respiratory depression — or congenital sepsis.

Prognosis

Worldwide, perinatal asphyxia is a major cause of death and of acquired brain damage in newborn infants. The prognosis depends on the severity of the asphyxia. Only a minority of infants with severe encephalopathy after perinatal asphyxia survive without handicap. However, there are limited population-based data on long-term outcomes after perinatal asphyxia, such as cerebral palsy, developmental delay, visual and hearing impairment, and learning and behavioural problems. After an asphyxial event, there may be an opportunity to intervene to minimise brain damage. The first phase of brain damage — early cell death — results from primary exhaustion of the cellular energy stores. Early cell death can occur within minutes. Immediate resuscitation to restore oxygen supply and blood circulation aims to limit the extent of this damage. A secondary phase of neuronal injury may occur several hours after the initial insult. The mechanisms believed to be important in this process include oxygen free radical production, intracellular calcium entry, and apoptosis. Treatments during the postresuscitation phase aim to block these processes, thereby limiting secondary cell damage and minimising the extent of any brain damage.

Aims of intervention

To minimise mortality, and brain and other organ damage, with minimal adverse effects.

Outcomes

Mortality: treatment failure measured by rates of death before hospital discharge. Neurological impairment: includes incidence of neurodevelopmental disability assessed at greater than 12 months of age using a validated tool, and severity of hypoxic–ischaemic encephalopathy assessed using a validated tool.

Methods

Clinical Evidence search and appraisal March 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to March 2007, Embase 1980 to March 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 1. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and the National Institute of Health and Clinical Excellence (NICE). Abstracts of studies retrieved from the initial search were assessed independently by two information specialists. Predetermined criteria were used to identify relevant studies. Study design criteria for inclusion in this review were: systematic reviews, RCTs, and quasi-randomised studies. Open trials were included because blinding was not possible for all interventions; however, those assessing neurological deficit were blind to treatment group. Small trials (fewer than 20 people) and trials with less than 80% follow-up were included. There was no minimum length of follow-up. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Perinatal asphyxia.

Important outcomes	Mortality, Neurological impairment
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of interventions in term or near-term newborns with perinatal asphyxia?
3 (114)	Mortality	Allopurinol versus placebo or no drug treatment	4	–1	0	–1	0	Low	Quality point deducted for sparse data. Directness point deducted for composite outcome in one RCT
1 (60)	Neurological impairment	Allopurinol versus placebo or no drug treatment	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (63)	Mortality	Miltiorrhizae versus citicoline (cytidine diphosphate choline)	4	–3	0	–1	0	Very low	Quality points deducted for sparse data, and for allocation, blinding, and randomisation flaws. Directness point deducted for composite outcome
4 (559)	Mortality	Head, and whole-body, hypothermia versus normothermia	4	0	0	–1	0	Moderate	Directness point deducted for the use of composite outcome in three RCTs
2 (231)	Neurological impairment	Head, and whole-body, hypothermia versus normothermia	4	0	0	0	0	High
7 (675)	Mortality	Hyperbaric oxygen treatment	4	–3	0	0	0	Very low	Quality points deducted for poor follow-up, and for allocation, blinding, and randomisation flaws
7 (649)	Neurological impairment	Hyperbaric oxygen treatment	4	–3	0	0	0	Very low	Quality points deducted for poor follow-up, and for allocation, blinding, and randomisation flaws
1 (33)	Mortality	Magnesium sulphate plus inotrope support versus no drug treatment	4	–1	0	–1	0	Low	Quality point deducted for sparse data. Directness point deducted for composite outcome
1 (25)	Mortality	Mannitol versus no drug treatment	4	–2	0	0	0	Low	Quality points deducted for sparse data and wide confidence intervals
5 (1737)	Mortality	Resuscitation in air versus pure oxygen	4	–3	0	0	0	Very low	Quality points deducted for poor follow-up, and for allocation, blinding, and randomisation flaws
4 (155)	Mortality	Prophylactic anticonvulsants versus no drug treatment	4	–3	0	0	0	Very low	Quality points deducted for sparse data, allocation and blinding flaws, and lack of placebo control
2 (155)	Neurological impairment	Prophylactic anticonvulsants versus no drug treatment	4	–3	0	0	0	Very low	Quality points deducted for sparse data; methodological, allocation, and blinding flaws; and lack of placebo control

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Apgar score

Quantitative score, usually measured at 1, 5, and 10 minutes after birth. The infant's heart rate, respiratory effort, muscle tone, response to stimulation (usually pharyngeal suctioning), and colour are assessed. For each of these five components, assessors award a maximum of 2 points for normal, 1 point for poor, and 0 points for bad. An Apgar score of less than 7 indicates moderate neuro/cardiorespiratory depression, and a score of less than 3 indicates severe depression. The Apgar score is less reliable in premature infants, in whom it directly correlates with gestation.

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

Hypoxic–ischaemic encephalopathy (neonatal encephalopathy)

An abnormal neurobehavioural state in newborn infants, which is described clinically by stages. Stage 1 (mild): hyperalertness, hyper-reflexia, dilated pupils, tachycardia, and absence of seizures. Stage 2 (moderate): lethargy, hyper-reflexia, contraction of the pupils, bradycardia, seizures, hypotonia with weak suck, and Moro reflex. Stage 3 (severe): stupor, flaccidity, seizures, small pupils that react poorly to light, decreased stretch reflexes, hypothermia, and absent Moro reflex.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate vision loss

Loss of three or more lines of distance vision measured on a special eye chart, corresponding to a doubling of the visual angle.

Near term

Greater than 34 completed weeks' gestation and less than 37 weeks' gestation. (i.e. 35 and 36 weeks' gestation)

Neurodevelopmental disability

Defined as any one or combination of the following: non-ambulant cerebral palsy, developmental delay, auditory and visual impairment.

Term

Greater than 36 completed weeks' gestation.

Very low-quality evidence

Any estimate of effect is very uncertain.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.