28 Neonatal Implications of Intrapartum Fetal Hypoxia

 28

Neonatal Implications of Intrapartum

Fetal Hypoxia

◈

Justin Richards

Handbook of CTG Interpretation: From Patterns to Physiology, ed. Edwin Chandraharan.

Published by Cambridge University Press. © Cambridge University Press 2017.

Introduction

Intermittent fetal hypoxia is an integral part of normal childbirth, and the healthy fetus is

extremely well adapted to withstand this unharmed. As the uterine muscle contracts

during the process of labour, the blood supply to the placenta is reduced, and oxygen and

nutrient delivery to the fetus is reduced. Between uterine contractions, the uterine muscle

relaxes and oxygen and nutrient supply is restored. Studies in animals have shown that

intermittent, regular and complete interruption of fetal blood supply is well tolerated if

these interruptions are shorter in duration and the fetus is given adequate time to

recover. This is borne out by what we observe in clinical practice.

When Does Fetal Hypoxia Pose a Risk for the

Fetus?

Despite very effective fetal adaptations to cope with acute oxygen and nutrient

deprivation during labour, neonatal brain injury resulting from inadequateMechanisms of Hypoxic Brain Injury

oxygen in the perinatal period (perinatal hypoxic-ischaemic encephalopathy

[HIE]) is estimated to account for 23 per cent of neonatal deaths worldwide1 and

9–10 per cent of neonatal deaths in the United Kingdom.2

In babies that survive, a significant number will develop long-term neurological

sequelae ranging from mild behavioural disorders to significant cognitive

impairment and/or cerebral palsy.

Fetal asphyxia occurs when inadequate oxygen supply leads to anaerobic

respiration and subsequent metabolic acidosis and hyperlactaemia. A mild

degree of asphyxia occurs in all normal deliveries with no adverse sequelae;

however, the chances of significant injury increase as metabolic acidosis

becomes more profound.

Studies demonstrate that an umbilical cord blood pH <7.0 is associated with an

increased risk of brain injury, although even at these levels the majority of

babies will recover without long-term effects.

There are other factors which may reduce the ability of the fetus to cope with

hypoxia during delivery. Placental dysfunction is known to be associated with an

increased risk of HIE, and chorioamnionitis is more common in the placental

histology of babies with HIE, suggesting that inflammation may also be a

contributory factor. In babies that develop HIE, having clinical signs of sepsis

increases the risk of brain injury.3,4

Asphyxia that is severe enough to lead to significant neonatal encephalopathy

usually also leads to damage to multiple organ systems in the fetus and newborn.

Renal and hepatic impairment are common, but usually recover with time.

Cardiac dysfunction may lead to hypotension requiring inotropic support and

respiratory involvement to pulmonary hypertension and respiratory failure.In normal cellular energy metabolism in the fetal and neonatal brain, glucose is

transported into the cell and, through gluconeogenesis and the Krebs cycle, leads to a

reduction of NAD to NADH. NADH is used to transport electrons into the respiratory

chain which in turn drive oxidative phosphorylation through the reduction of oxygen.

The end products are high-energy phosphate compounds (mainly ATP) used to power the

cell (Figure 28.1). As part of this process, small quantities of oxygen-free radicals are

formed, but in normally functioning cells, these are scavenged through antioxidant

mechanisms.

Figure 28.1 Normal cellular energy metabolism demonstrating pathways of ATP

production from glucose and oxygen.

The mechanisms of brain injury following hypoxic insult are complex and involve

two stages.

1. Interruption of oxygen and nutrient supply to the fetal brain leads to primary

energy failure within minutes. There is a rapid depletion of intracellular ATP stores

and ultimately cellular necrosis is caused by a failure of sodium potassium pump if

oxygen supply is not restored.

2. Reperfusion following resuscitation leads to a rapid restoration of oxidative

phosphorylation. Initially ATP levels return almost to normal; however, a period of

secondary energy failure follows, when cellular energy supplies fall again. This is

caused by a cascade of cytotoxic reactions within the cell triggered by the

processes of reoxygenation.3. During primary energy failure, electrons accumulate in the mitochondria. When

oxygen levels are restored, these electrons combine with oxygen to produce highly

reactive free radicals that overwhelm the normal cellular antioxidant mechanisms

and lead to the production of highly toxic reactive oxygen compounds that damage

the intracellular structures.

4. Ultimately these cytotoxic reactions trigger programmed cell death (apoptosis).

Current evidence suggests that excessive oxygen levels may exacerbate this

process – this is the reason that air is now recommended for resuscitation of the

newborn in the first instance.

Clinical Features of Hypoxic-Ischaemic

Encephalopathy

Table 28.1 Clinical grading system for HIE9

Clinical assessment of a baby following HIE is essential to guide treatment and

determine prognosis. In 1976, Sarnat and Sarnat published a staging system for

assessment of HIE that classified babies according to examination as stage 1

(mild), 2 (moderate) or 3 (severe).5 This allowed clinicians to predict the likely

outcome of babies with HIE, and a modified version forms the basis of standard

assessment to this day (Table 28.1).

After a severe hypoxic insult, brain activity is initially suppressed during

primary energy failure, and clinically the baby is profoundly hypotonic. Reduced

brain activity and hypotonia persist through a latent phase often lasting several

hours, until the process of secondary energy failure begins.

During this time, monitoring of brain activity using a cerebral function monitor

(CFM) shows reduced cortical activity. Following the latent phase, there is a

release of excitatory neurotransmitters within the brain associated with the baby

developing seizure activity. In severe HIE and neonatal encephalopathy, seizures

often persist for up to 5–7 days, reaching a maximal peak at 1–2 days.6Grade 1 Grade 2 Grade 3

Irritability

hyperalert

Lethargic Comatose

Mild hypotonia Marked abnormalities of

tone

Severe hypotonia

No seizures Seizures Prolonged seizures

Poor sucking Requires tube feeding Failure to maintain spontaneous

respiration

Management of HIE

The mainstay of treatment for HIE is supportive, with respiratory support,

seizure control and implementation of nasogastric tube feeds often required, as

well as managing disruption to other organ systems.

Following the results of recent studies of therapeutic hypothermia,7 this is now a

standard of care for babies with moderate or severe HIE (Sarnat stages 2 or 3)

in healthcare environments that are able to provide safe intensive care.8

The CFM may be used to help make a more objective, early assessment of

encephalopathy when deciding which babies are likely to benefit from

therapeutic hypothermia. Hypothermia is moderate, with the aim to reduce core

temperature to between 33°C and 34°C for 72 hours, followed by gradual

rewarming.

MRI scanning 3–7 days after the hypoxic event and EEG/CFM add valuable

information to clinical assessment when determining prognosis and are routinely

performed in most centres offering therapeutic hypothermia.

Regular discussions of the condition of the baby and likely outcome with parents

are essential throughout the stay in intensive care. In severely affected infants

with stage 3 HIE that remain comatose, it is usually appropriate to discussOutcomes

Table 28.2 Comparison of outcomes for moderate vs severe HIE in the Cochrane metaanalysis of cooling for HIE7

Severity of HIE Outcome Treatment group

Therapeutic

hypothermia

Standard care

(normothermia)

Moderate(Sarnat

stage 2)

Death 33/244 (13%) 53/232 (23%)

Death or major disability 89/243 (37%) 123/229 (54%)

Major disability in

survivors assessed

56/211 (27%) 70/179 (39%)

Severe(Sarnat

stage 3)

Death 75/143 (52%) 96/142 (68%)

Death or major disability 100/143 (70%) 120/140 (86%)

Major disability in

survivors assessed

26/68 (37%)* 24/47 (51%)*

palliative care with the parents, particularly if CFM/EEG and/or MRI scan show

evidence of severe injury with poor prognosis.

Outcomes for babies with stage 1 HIE are good, with death or disability rates <1

per cent.

In both moderate and severe encephalopathy (Sarnat stages 2 and 3), rates of

death or disability in a recent Cochrane meta-analysis7 were lower in babies

receiving therapeutic hypothermia (Table 28.2).

Disability includes cerebral palsy and developmental delay as well as hearing

and visual disturbances. Overall risk of death or disability in severe HIE

remains high despite modern intensive care and therapeutic hypothermia, with

only 30 per cent of babies surviving without major disability.7* These results were not statistically significant in the subgroup analysis.

References

1. Newborn death and illness. WHO. Available from:

www.who.int/pmnch/media/press_materials/fs/fs_newborndealth_illness/en/

2. Perinatal mortality 2009. CMACE. Available from: http://hqip.org.uk/assets/NCAPOPLibrary/CMACE-Reports/35.-March-2011-Perinatal-Mortality-2009.pdf

3. Jenster M, Bonifacio SL, Ruel T, Rogers EE, Tam EW, Partridge JC, et al. Maternal or

neonatal infection: association with neonatal encephalopathy outcomes. Pediatr Res

2014;76(1):93–9.

4. Wu YW, Colford JM. Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis.

JAMA 2000;284(11):1417–24.

5. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and

electroencephalographic study. Arch Neurol 1976;33(10):696–705.

6. Wyatt J. Applied physiology: brain metabolism following perinatal asphyxia. Curr

Paediatr 2002;12(3):227–31.

7. Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for

newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev

2013;1:CD003311.

8. IPG347. Therapeutic hypothermia with intracorporeal temperature monitoring for hypoxic

perinatal brain injury. NICE. 2010. Available from: www.nice.org.uk/guidance/ipg347

9. Levene ML, Kornberg J, Williams TH. The incidence and severity of post-asphyxial

encephalopathy in full-term infants. Early Hum Dev 1985;11(1):21–6.