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BIRTH ASPHYXIA
SCENARIO ............................................................................................................................................1 LEARNING OBJECTIVES .................................................................................................................2 TERMS ...................................................................................................................................................3 1. INTRODUCTION .............................................................................................................................3 2. CIRCULATION OF THE NEWBORN ..........................................................................................3 2.1 CARDIOVASCULAR SYSTEM .......................................................................................................3 2.2 RESPIRATORY SYSTEM ...............................................................................................................4 3. PROBLEMS DURING LABOUR....................................................................................................5 3.1 FETAL DISTRESS ..........................................................................................................................5 3.2 CARDIOTOCOGRAPHY AND FETAL PH ....................................................................................5 3.3 PASSAGE OF MECONIUM ...........................................................................................................6 3.4 INSTRUMENTAL DELIVERY ........................................................................................................6 4. PERINATAL ASPHYXIA ................................................................................................................7 4.1 DIAGNOSIS ...................................................................................................................................7 5. HYPOXIC-ISCHAEMIC ENCEPHALOPATHY .........................................................................8 5.1 SEVERITY ......................................................................................................................................8 5.2 PATHOPHYSIOLOGY ...................................................................................................................9 5.3 TREATMENT .................................................................................................................................9 5.3.1 RESUSCITATION ...................................................................................................................9 5.3.2 ANTI-CONVULSANTS ..........................................................................................................10 5.3.3 HYPOTHERMIA ...................................................................................................................10 5.4 PROGNOSIS ................................................................................................................................10 5.5 WITHDRAWAL OF LIFE SUPPORT ...........................................................................................11 6. CONCLUSION ................................................................................................................................11 7. REFERENCES ................................................................................................................................11

SCENARIO
A male baby is delivered at term using Ventouse. There had been Type 2 decelerations on the fetal heart rate tracing during the labour, and the baby was born covered in meconium. He did not breathe but had a heart rate of 50 beats per minute. The baby was resuscitated from birth and the neonatal team was called to continue resuscitation. At 5-minutes of age the baby was still blue and only had a heart rate of 60 per minute; by 10minutes of age the heart rate was 120 and the baby started to have occasional gasps. Apgar scores at 1, 5, and 10 minutes were 1, 1 and 3. He was attached to a ventilator and transferred to the neonatal intensive care unit.

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An EEG was performed and the staff instituted a treatment to cool the baby to a core temperature of 34C using a cooling blanket. Regular respirations were established and he was extubated at 12-hours. However, he remained very jittery with a high-pitched cry and the nurses reported that he felt very floppy. On the second day he was noticed to have tonic-clonic convulsions and apnoeic attacks. Blood glucose at the time was 3mmol/L. He required ventilation again but the tonicclonic convulsions continued despite large doses of phenobarbitone. An MRI scan showed areas of infarction in both cerebral hemispheres, with an abnormal signal in the basal ganglia and the internal capsule, indicating a poor prognosis. The neonatologist arranged to talk to the parents about the prognosis and to discuss continuation of life support with them.

LEARNING OBJECTIVES
1. Terms i. ii. iii. Phenobarbitone Type II decelerations Ventouse

2. Fetal circulation and changes at birth 3. Problems during labour i. ii. iii. i. ii. i. ii. Abnormal CTG Significance of meconium in labour Instrumental delivery Causes of asphyxia Diagnosis of asphyxia and the Apgar score Treatment Prognosis

4. Asphyxia

5. Hypoxic-Ischaemic Encephalopathy

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TERMS
Phenobarbitone - (also see text) this is a barbiturate used to prevent tonic-clonic seizures. It is a first-line treatment for neonatal seizures, despite accumulating evidence that seems to indicate it is often ineffective or even harmful (Boylan et al., 2002). Type II decelerations - see text Ventouse - see text

1. INTRODUCTION
Birth asphyxia accounts for 23% of worldwide neonatal death (Lawn et al., 2005). Its associated neurological syndrome, hypoxic-ischaemic encephalopathy, can result in death and significant disability. This paper considers the case of a male baby, delivered at term, with birth asphyxia.

2. CIRCULATION OF THE NEWBORN 2.1 CARDIOVASCULAR SYSTEM

During gestation, the fetus receives its nutrients from the placenta via the umbilical vein. The oxygenated blood from the umbilical vein passes into the liver and the ductus venosus, which passes into the inferior vena cava. The orientation of the inferior vena cava means that on entering the right atrium, the blood passes through the foramen ovale into the left atrium. From here it can pass into the left ventricle to be pumped to the upper limbs, the coronary and cerebral arteries. Blood from the superior vena cava mainly passes into the right ventricle, where a small portion (~12%) is pumped to the lungs, whilst the rest passes through a fetal vessel connecting the pulmonary artery to the aorta, the ductus arteriosus. In the fetus, the blood pressure in the right side of the heart is greater than the left side; the reverse is true in the adult. This is due to the high pulmonary vascular resistance in the fetus. With its first breath, the neonates circulation changes dramatically (fig. 1). There is a significant decrease in the pulmonary vascular resistance as a rise in oxygen levels relieves hypoxic vasoconstriction, causing the blood vessels to dilate. This, along with an increase in the systemic resistance, means that the pressure gradient across the heart is reversed. This

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reversal causes the closure of the foramen ovale and the constriction of the ductus arteriosus (Naish et al., 2009).

Figure 1. The fetal and the newborn circulation. A) Fetal circulation before birth. B) After birth (Naish et al., 2009).

2.2 RESPIRATORY SYSTEM

Before birth, the fetal lungs are filled with fluid. This fluid must be cleared before the lungs can provide adequate gas exchange. This fluid is partly removed mechanically, as the thorax

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is squeezed through the birth canal, whilst the remainder is reabsorbed by the lung circulation and lymphatic vessels. Another prerequisite for gas exchange is a reduction in the surface tension in the lung. This relies on an amphiphilic substance known as surfactant. Molecules of surfactant align along the air-fluid interface, reducing the surface tension sufficiently so that it can be overcome by inspiration pressure, allowing air into the alveoli.

3. PROBLEMS DURING LABOUR 3.1 FETAL DISTRESS

The term fetal distress has varying connotations; perhaps it is more correct to refer to a fetus as being at risk. Parturition is a stressful event for the fetus, though one which is it is designed to cope with; fetal distress therefore refers to stress over and above that experienced in normal labour (Rennie, 2012).

3.2 CARDIOTOCOGRAPHY AND FETAL pH

Continuous monitoring of the fetal heartbeat during labour can take place through the use of a cardiotocograph (CTG). This can measure changes in the fetal heart rate whilst simultaneously recording uterine contractions. Three common abnormalities seen on a CTG are: 1. Type I decelerations (early) - slowing of the fetal heart is coincident with the uterine contractions and usually occur when there is compression of the fetal head, resulting in vagal stimulation. These are not associated with hypoxia. 2. Type II decelerations (late) - here the slowing of the fetal heart does not resume to baseline until the contraction has finished. This indicates impaired blood flow through the placenta and is associated with fetal hypoxia. 3. Variable decelerations - here there are short-lived irregular dips in the starting at the contraction and of variable duration. This is probably due to compression of the umbilical cord. The baby in this scenario had type II (or late) decelerations. This indicates uteroplacental insufficiency and would explain his resulting hypoxia (Levene et al., 2000).

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In conjunction with the CTG, a fetal scalp pH measurement may be helpful. This involves obtaining blood transvaginally, making a shallow cut and obtaining the blood via capillary action. A low pH (< 7.20) indicates acidosis and is associated with hypoxia (Levene et al., 2000).

3.3 PASSAGE OF MECONIUM

Meconium can be passed from the bowel during fetal hypoxia. The meconium can then be aspirated, preventing the normal physiological changes that take place in the respiratory system and circulation at birth. The passage of meconium occurs in 10-20 % of pregnancies and is often seen as a marker of fetal distress. However, only 0.4% of those subsequently develop cerebral palsy (Nelson and Ellenberg, 1984).

3.4 INSTRUMENTAL DELIVERY

Instrumental delivery may be indicated in cases where there is fetal distress or there is a fail in progression of the second stage of labour. The criteria for instrumental delivery, whether by forceps or ventouse, can be remembered by the acronym FORCEPS (Table 1). F O R C E P Fully dilated cervix Occipito-anterior position (occipito-posterior position possible with ventouse) Ruptured membranes Cephalic presentation Engaged presenting part: i.e. the babys head positioned at or below ischial spines with no head palpable abdominally Pain relief: analgesia must be satisfactory for the procedure. Minimum of perineal nerve block for ventouse or low-forceps; epidural or pudendal nerve block for midforceps. S Sphincter: bladder must be empty

Table 1. Criteria for instrumental delivery. Adapted from (Pitkin et al., 2003). Ventouse, or vacuum extraction, uses suction to assist delivery. A suction cup is placed on the fetal head in the midline, overlying or just anterior to the posterior fontanelle. Although

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there is a trend to choose vacuum extraction over forceps to assist delivery, ventouse is associated with a higher failure rate (Yeomans, 2010). However, maternal complications (episiotomy, cervical tearing, and perineal laceration) are reduced with the use of vacuum extraction compared to forceps. Vacuum extraction has a similar rate of fetal morbidity compared to forceps, but with a higher incidence of specific complications including cephalhaematoma, retinal haemorrhages and subgaleal haematomas (Schaal et al., 2008). The appropriate method to assist delivery should therefore depend on the circumstances and the experience of the obstetrician.

4. PERINATAL ASPHYXIA
Perinatal asphyxia, or birth asphyxia, occurs when the fetus is deprived of adequate supply of oxygen. This may occur in utero, during labour, delivery or shortly after birth. There are numerous causes (Table 2), most commonly placental abruption, clotting of placental arteries and infection (Locatelli et al., 2008). Perinatal Placental cord abruption Cord compression Transplacental anaesthetic or narcotic Intrauterine pneumonia Severe meconium aspiration Congenital cardiac or pulmonary abnormalities Birth trauma Post natal Obstructed airway Maternal opiates (via respiratory depression) Congenital sepsis Table 2. Possible causes of birth asphyxia. Adapted from (McGuire, 2007).

4.1 DIAGNOSIS
The Apgar score, first described in 1953 by Virginia Apgar, remains a reliable and reproducible indicator of birth asphyxia (Table 3). This scoring system is typically performed at 1, 5, 10 minutes following birth. An Apgar score of 3 or less has become a widely used

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criterion for identifying asphyxia; using this definition, the incidence of asphyxia is considered to be 3-9 per 1000 births (Nelson and Ellenberg, 1984).
Sign Heart rate Respiratory effort Muscle tone Reflex irritability Colour 0 Absent or < 60/min Absent Limp No response Pale, overall cyanosis 1 < 100/min Weak cry Some flexion Some motion Centrally pink, blue periphery 2 > 100/min Strong cry Good flexion Cry Pink

Table 3. Apgar score (Levene et al., 2000). Despite its wide use, a very low Apgar score can be misleading. Many infants with an Apgar score of zero can be resuscitated without any long-term neurological problems. Therefore the criteria for asphyxia that has a high possibility of causing harm must be somewhat stricter. The diagnosis and definition of perinatal asphyxia depends upon a number of characteristics: an Apgar score less than 3 at > 5 min; neonatal neurological sequelae; and evidence of acute hypoxic compromise with acidaemia (arterial cord pH < 7 or base excess greater than 12 mmol/L) (McGuire, 2007).

5. HYPOXIC-ISCHAEMIC ENCEPHALOPATHY
Asphyxia results in simultaneous hypoxia and ischaemia. Although perinatal asphyxia is very much a multi-system disorder, its effect on the brain is most important in terms of the outcome. The resulting neurological syndrome is referred to as hypoxic-ischaemic encephalopathy (HIE). This is a variable constellation of symptoms and signs including alterations in consciousness, abnormal tone, convulsions/seizures and inability to maintain steady respiration (Mupanemunda and Watkinson, 1999).

5.1 SEVERITY
The severity of the syndrome can be assigned to one of three grades (Table 4). The severity of the HIE can be used as a prognostic indicator. The neonate in this case would be grade III; unfortunately this has a very poor prognosis, with a ~75% mortality rate. Should the baby survive, it is very likely to have severe mental impairment (Sarnat and Sarnat, 1976).
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Stage 1 Consciousness Seizures Hyperalert None

Stage 2 Lethargic Common: focal or multifocal

Stage 3 Stuporose Uncommon: excluding decerebration Flaccid Hours to weeks Periodic pattern with isopotential phases, later totally isopotential

Muscle tone Duration EEG

Normal < 24 hours Normal

Mild hypotonia 2 14 days Variable changes: seizures < 1-1.5 Hz spike and wave

Table 4. Sarnat and Sarnat classification of HIE. A scheme for assessing the clinical severity of hypoxic-ischaemic encephalopathy (Sarnat and Sarnat, 1976).

5.2 PATHOPHYSIOLOGY
The clinical signs of hypoxic-ischaemic encephalopathy indicate that it is not a single event but rather a cascade of molecular events set in motion by the initial insult. The severity of the iscaemia influences the mechanism of cell death (Bonfoco, 1995). Severe ischaemia results in necrosis whilst milder ischaemia causes apoptosis. Oxidative stress and excitotoxicity from excess glutamate results in inflammation, causing further injury (Ferriero, 2004). HIE results in a characteristic pattern on MRI imaging. Typically the basal ganglia is most affected, with little injury to the white matter. However, there may be a transient increase in the T2-weighted MRI signal in the internal capsule, as occurred in this case (Rutherford et al., 2006). This characteristic pattern of damage to the basal ganglia and surrounding cells may be due to increased expression of nitric oxide synthase at these sites, causing greater oxidative stress and excitotoxicity (Fatemi et al., 2009).

5.3 TREATMENT
5.3.1 RESUSCITATION The immediate aim of resuscitation is to establish effective oxygenation and ventilation. In this case of asphyxia, first it must be ensured the airways are clear of meconium. The baby would then be intubated and given positive pressure ventilation. Circulatory support may also

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be necessary, consisting of external cardiac massage and adrenaline (Mupanemunda and Watkinson, 1999). It is also very important to avoid hypoglycaemia, as this would exacerbate any brain damage. The neonate in this case has a blood glucose level of 3 mmol/L. This is within the normal range for a newborn (> 2 mmol/L in the first 24 hours). 5.3.2 ANTI-CONVULSANTS Seizures are common with hypoxic-ischaemic encephalopathy, although they may not be readily clinically observable (Kossoff, 2011). These seizures are often treated with anticonvulsants such as phenobarbitone or phenytoin. Currently, there is little evidence in the literature to support the use of anticonvulsants in neonatal seizures (Boylan et al., 2002; Booth, 2004). 5.3.3 HYPOTHERMIA Experimentally it has been shown that mild hypothermia (a reduction in body temperature of 3-5 C) reduces cerebral injury and can improve neurological function following asphyxia (Azzopardi et al., 2000). The results in clinical trials have reported more mixed results. Cooling, although it may not significantly reduce death or severe disability from perinatal asphyxia, does seem to improve neurologic outcomes in survivors (Azzopardi et al., 2009). Although the exact mechanism remains unclear, the neuroprotective effects of mild hypothermia may be a due to an inhibitory effect on a variety of harmful cellular processes that are induced by HIE. It seems to influence multiple pathways, reducing cerebral metabolism, inhibiting apoptotic signalling pathways and reducing immune system activation (Fatemi et al., 2009).

5.4 PROGNOSIS
In mild HIE, complete recovery is expected. Infants with moderate HIE that have a normal feeding and neurological assessment at 7 days also have an excellent prognosis. In severe HIE, survivors are likely to have neurodevelopmental difficulties, especially cerebral palsy. In addition to cerebral palsy, microcephaly, hydrocephaly, epilepsy, deafness, cortical blindness or mental retardation can all occur as a result of HIE (Lissauer, 2007).

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5.5 WITHDRAWAL OF LIFE SUPPORT

With severe hypoxic-ischaemic encephalopathy, the risk of death and serious disability is very high. Therefore, the withdrawal of life support is an option. Although brain death cannot be diagnosed in neonates, irreversible brain injury can be evaluated, usually by electroencephalogram (EEG) or Doppler assessment of the cerebral arteries.

6. CONCLUSION
Birth asphyxia remains an important cause of death and severe brain damage. Its prevention is a priority in modern obstetrics. Future treatment is likely to focus on neuroprotection. Given the many pathways by which the ischaemic brain damage takes place, the treatment is likely to be multi-modal, preventing excitotoxicity through the use of glutatmate antagonists, using antioxidants to reduce oxidative stress and continuing the current, promising treatment of hypothermia. Word Count: 1992

7. REFERENCES
AZZOPARDI, D., BROCKLEHURST, P., EDWARDS, D., HALLIDAY, H., LEVENE, M., THORESEN, M., WHITELAW, A. & GROUP, T. S. 2008. The TOBY Study. Whole body hypothermia for the treatment of perinatal asphyxial encephalopathy: a randomised controlled trial. BMC Pediatr, 8, 17. AZZOPARDI, D., ROBERTSON, N. J., COWAN, F. M., RUTHERFORD, M. A., RAMPLING, M. & EDWARDS, A. D. 2000. Pilot study of treatment with whole body hypothermia for neonatal encephalopathy. Pediatrics, 106, 684-94. AZZOPARDI, D. V., STROHM, B., EDWARDS, A. D., DYET, L., HALLIDAY, H. L., JUSZCZAK, E., KAPELLOU, O., LEVENE, M., MARLOW, N., PORTER, E., THORESEN, M., WHITELAW, A., BROCKLEHURST, P. & GROUP, T. S. 2009. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med, 361, 134958. BONFOCO, E., KRAINC, D., ANKARCRONA, M., NICOTERA, P. & LIPTON, S. A. 1995. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense

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insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci U S A, 92, 7162-6. BOOTH, D. & EVANS, D. J. 2004. Anticonvulsants for neonates with seizures. Cochrane database of systematic reviews (Online), CD004218-CD004218. BOYLAN, G. B., RENNIE, J. M., PRESSLER, R. M., WILSON, G., MORTON, M. & BINNIE, C. D. 2002. Phenobarbitone, neonatal seizures, and video-EEG. Arch Dis Child Fetal Neonatal Ed, 86, F165-70. FATEMI, A., WILSON, M. A. & JOHNSTON, M. V. 2009. Hypoxic-ischemic encephalopathy in the term infant. Clin Perinatol, 36, 835-58, vii. FERRIERO, D. M. 2004. Neonatal brain injury. N Engl J Med, 351, 1985-95. KOSSOFF, E. 2011. Neonatal seizures due to hypoxic-ischemic encephalopathy: should we care? Epilepsy Curr, 11, 147-8. LAWN, J., COUSENS, S., ZUPAN, J. & STEERING, L. N. S. 2005. Neonatal survival 1 - 4 million neonatal deaths: When? where? why? Lancet, 365, 891-900. LEVENE, M. I., TUDEHOPE, D. I. & THEARLE, J. 2000. Essentials of Neonatal Medicine, Blackwell Science. LISSAUER, T. & CLAYDEN, G. 2007. Illustrated Textbook of Paediatrics, Elsevier. p. 141 LOCATELLI, A., INCERTI, M., GHIDINI, A., GRECO, M., VILLA, E. & PATERLINI, G. 2008. Factors associated with umbilical artery acidemia in term infants with low Apgar scores at 5 min. Eur J Obstet Gynecol Reprod Biol, 139, 146-50. MCGUIRE, Q. 2007. Perinatal Asphyxia. Available: http://clinicalevidence.bmj.com/x/mce/file/2007-11-0320.pdf. Last accessed 21st Feb 2013. MUPANEMUNDA, R. H. & WATKINSON, M. 1999. Key topics in neonatology, BIOS Scientific Publishers, 128-134. NAISH, J., REVEST, P. & SYNDERCOMBE COURT, D. 2009. Medical Sciences, Saunders, 637-642. NELSON, K. B. & ELLENBERG, J. H. 1984. Obstetric complications as risk factors for cerebral palsy or seizure disorders. JAMA, 251, 1843-8. PITKIN, J., PEATTIE, A. B. & MAGOWAN, B. A. 2003. Obstetrics and gynaecology: An illustrated colour text, Churchill Livingstone, 58-60. RENNIE, J. M. 2012. Rennie and Roberston's textbook of neonatology, Churchill Livingstone, 121-122.

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RUTHERFORD, M., SRINIVASAN, L., DYET, L., WARD, P., ALLSOP, J., COUNSELL, S. & COWAN, F. 2006. Magnetic resonance imaging in perinatal brain injury: clinical presentation, lesions and outcome. Pediatr Radiol, 36, 582-92. SARNAT, H. B. & SARNAT, M. S. 1976. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol, 33, 696-705. SCHAAL, J. P., EQUY, V. & HOFFMAN, P. 2008. Comparison vacuum extractor versus forceps. Journal De Gynecologie Obstetrique Et Biologie De La Reproduction, 37, S231S243. YEOMANS, E. R. 2010. Operative Vaginal Delivery. Obstetrics and Gynecology, 115, 645653.

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