Are we (mis)guided by current guidelines on intrapartum fetal heart rate monitoring? Case for a more physiological approach to interpretation

Authors


Abstract

Original interpretations of fetal heart rate (FHR) patterns equated FHR decelerations with ‘fetal distress’, requiring expeditious delivery. This simplistic interpretation is still implied in our clinical guidelines despite 40 years of increasing understanding of the behaviour and regulation of the fetal cardiovascular system during labour. The physiological basis of FHR responses and adaptations to oxygen deprivation is de-emphasised, whilst generations of obstetricians and midwives are trained to focus on, and classify, the morphological appearances of decelerations into descriptive categories, with no attempt to understand how the fetus defends itself and compensates for intrapartum hypoxic ischaemic insults, or the patterns that suggest progressive loss of compensation. Consequently, there is a lack of confidence, marked variation in FHR interpretation, defensive practices, unnecessary operative interventions, and a failure to recognise abnormal FHR patterns, resulting in adverse outcomes and expensive litigation.

Introduction

Intrapartum electronic fetal heart rate (FHR) monitoring is widely practiced in the UK, the USA and in many other developed countries.[1, 2] It is associated with reduced early onset neonatal seizures,[3] and is credited with the near elimination of unexpected intrapartum fetal mortality;[4] however, its use is associated with the increased costly and not infrequently harmful operative delivery of nonacidotic babies.[5, 6] This results, at least in part, from the training of obstetricians and midwives to focus on the morphological appearances of FHR decelerations and their descriptive labels, rather than understanding how the fetus defends itself and compensates for intrapartum hypoxic ischaemic insults. This approach has persisted, in spite of 40 years of increasing basic science and clinical knowledge of the behaviour and regulation of the fetal cardiovascular system during labour. Admittedly, standardised and simplified clinical guidelines are essential for good-quality clinical care and patient safety;[7, 8] however, current guidelines on intrapartum FHR interpretation may be contributing to the operative delivery of nonacidotic infants because of their focus on reference values for baseline FHR, variability, and classification of FHR decelerations into label categories without articulating the relationships between these parameters, and their collective link with fetal wellbeing, in a way that is intuitive to a thinking clinician. Many clinicians apply them in isolation and intervene for fetal compromise on the basis of isolated FHR tachycardia, reduced variability, lack of acceleration, or uncomplicated variable decelerations.

In addition, these guidelines do not provide the clinician with an unambiguous and comprehensive algorithm for intrapartum FHR interpretation, with recommendations for management, and until such an algorithm is developed there can be no consistent response to FHR patterns. Furthermore, they are silent on scenarios associated with fetal damage, such as fever, chorioamnionitis, fetal systemic inflammatory response syndrome (FSIRS) and its noxious synergistic interaction with hypoxia, fetal strokes, lack of fetal cycling behaviour, maternal disease, and the recognition of maternal heart rate (MHR) monitoring, to name a few. Other pieces of ‘quasi-guidance’ have emerged in recent years to plug the gaps in the guidelines. For example, many maternity units in the UK require their staff to apply the mnemonic ‘DR C BRaVADO’ to the interpretation of the cardiotocograph (CTG, a graphical presentation of the FHR and uterine contractions), where ‘DR’ stands for define risk, C stands for contraction frequency in 10 minutes, BRa stands for baseline rate, V stands for variability, A stands for accelerations, D stands for decelerations, and ‘O’ stands for overall classification. The user is compelled to document their assessment of the CTG features by ticking relevant boxes, but no reference is made to the evolution or progression of the FHR, the success or failure of fetal compensation, or the potential fetal consequences. Some clinicians regard this ‘tick box’ exercise as the object of FHR interpretation. The current UK National Institute for Health and Care Excellence (NICE) guidance recommends FHR evaluation and documentation every hour, and by a ‘fresh pair of eyes’ every 2–4 hours. The evidence for this approach is at best slim, and in the author's opinion it makes no difference how many times the CTG is reviewed and by however many ‘pairs of eyes’ if they are all ‘programmed’ to provide morphological description of FHR decelerations. This exercise provides just a snapshot of the FHR patterns without an understanding of their evolution, and cannot possibly permit an accurate assessment of the fetal condition or a thoughtful analysis of the urgency or optimum route of delivery. Each fetus should be used as its own control and greater attention paid to changes in its FHR characteristics over time.

In 2008 the report of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), American College of Obstetricians and Gynecologists, and the Society for Maternal–Fetal Medicine multidisciplinary expert workshop on electronic FHR monitoring recommended a three-tier system for FHR classification: category 1, normal FHR pattern predictive of normal acid base status at the time of observation; category II, intermediate FHR pattern not classified as category I or III, but not predictive of abnormal acid base status; and category III, abnormal FHR pattern associated with abnormal acid base at the time of observation.[9] The three-tier NICHD categories are similar to the UK NICE classification of ‘normal’ ‘suspicious’, and ‘pathological’, but unlike the NICE guidance it avoided the trap of assigning equivalent value to all CTG features in defining the intermediate category.[10] Compared with categories I and III, however, category II is massively heterogeneous and disproportionately large, including ≥80% of intrapartum FHR patterns.[11, 12] More importantly, category II may be interpreted as a cohort of static FHR patterns with no expectation on the user to: (1) reference the evolution from an antecedent normal or even a category-III pattern; or (2) prospectively predict the likely FHR trajectory. The inclusion of ‘early decelerations’ amongst the features of a normal category-I pattern is open to the erroneous interpretation that FHR decelerations synchronous with uterine contractions are benign. Amongst a panel of experts, the inter-observer reliability of the three-tier system of interpretation was found to be moderate only, and poor for the category-III pattern.[13] Parer et al.[14] have proposed the subdivision of category II patterns to create a minimum of a five-tier system, including a colour-coded example,[15] which they suggest would facilitate research in this arena. An international collaborative revision of the 30-year-old FHR guidelines from the International Federation of Gynecology and Obstetrics (FIGO) is underway, and one hopes that a more meaningful and intuitive approach to FHR interpretation will emerge.

As the FHR is sensitive to hypoxaemia (reduced systemic pO2) and hypoxia (reduced oxygen in the tissues), but lacks specificity for the development of acidosis (increased acid H+ within the tissues), the clinically important end point of hypoxia, FHR monitoring even with secondary tests would result in an increase in the operative delivery of nonacidotic babies. More than 40 years ago, Beard et al.[16] showed that most CTG abnormalities were not associated with fetal acidosis, suggesting that our definition of a ‘pathological’ CTG and its relationship with fetal asphyxia must be flawed. On the other hand, if intrapartum CTG interpretation was based on tracking the evolution of fetal defensive and compensatory responses to hypoxic ischaemic insults, then it should be possible, at least theoretically, to discriminate from a pool of ‘pathological’ CTGs those fetuses at genuine risk of acidosis and acidaemia (increased H+ in the bloodstream) or impaired neonatal adaptation from the subset that are not. In this commentary the author will describe the characteristics of the FHR and current guidance for their interpretation, the physiological basis for fetal compensation for types, degrees, and durations of hypoxic ischaemic insults, and the patterns that suggest progressive failure of compensation, and propose an algorithm for intrapartum FHR interpretation based on what is known about intrapartum fetal adaptation to hypoxic ischaemic insults. The author recently drew from these principles to describe and explain the CTG patterns associated with fetal injury.[17]

The normal CTG and its significance

A normal CTG should have a stable baseline FHR of 110–160 bpm without significant decelerations, normal variability of 5–25 bpm, and, crucially, periods of reduced FHR variability, which alternate with periods of increased variability with or without accelerations: so-called cycling behaviour. Fetal cycling activity is a key behavioural state of the normal term or near-term fetus. It suggests neurological integrity and the absence of significant acidaemia or acidosis.[18, 19] Cycling may be absent in hypoxia, chorioamnionitis, fetal infection, severe meconium aspiration syndrome, exposure to drugs, including oxytocin, recreational substances, opiates, major neurological or chromosomal abnormalities, intracranial haemorrhage or other forms of brain damage, and in fetuses <28–32 weeks of gestation. A quantitatively normal FHR variability that does not exhibit alternating periods of reduced variability is not normal. Intriguingly, the significance of this key fetal behaviour is ignored by some regulatory guidelines on intrapartum FHR monitoring.

A normal CTG symbolises fetal wellbeing,[20] normoxia,[21] normal acid base status,[22, 23] absence of asphyxia,[22, 23] and a low probability of developing intrapartum fetal asphyxia,[24] barring obstetric catastrophes. It also suggests that the fetal neurological and cardiovascular systems are intact, and able to react and defend the fetus against intrapartum insults. In contrast, the fetus with an abnormal CTG is at risk of adverse outcome and long-term neurological deficits,[24-27] and if exposed to asphyxiating intrapartum insults may display maladaptive responses instead of the predictable sequence of compensatory responses.

FHR decelerations

The FHR deceleration induced by cord compression is a chemoreceptor-mediated parasympathetic reflex, in contrast to the late decelerations caused by myocardial depression. It is widely believed that the purpose of these responses is to reduce myocardial workload and oxygen demand.[28] The appearance of FHR decelerations in response to uterine contractions suggest that the fetus is either hypoxaemic as a result of reduced transplacental oxygen transfer, in which case the decelerations are usually delayed in onset relative to the contractions, uniform, and slow in downward and upward trajectories (late decelerations), or that blood flow through the umbilical cord is interrupted, in which case the decelerations are immediate and sharp. Therefore, in my opinion terminologies like ‘unprovoked decelerations’ should be abandoned. There cannot be such a concept simply because we have not observed or recorded the stimulus for the FHR deceleration.

Over 80% of the intrapartum FHR decelerations are variable decelerations, yet it is the very CTG abnormality for which there is the least agreement between observers.[29] They are characterised by a sharp fall in FHR from the baseline to the nadir in ≤30 seconds, and may vary in depth, shape, duration, and temporal relationship with uterine contractions. Over the years the emphasis has been placed on morphological classification, which tells us nothing about fetal wellbeing and the consequences of intermittent cord compression/occlusion, nor does it help us to predict the FHR behaviour subsequently. Emphasis should instead be placed on the fetal response and compensation to the decelerations. ‘Early decelerations’, as originally described by Hon and Quilligan, and subsequently as ‘type-1 dips’ by Caldeyro-Barcia (gentle downward and upward slopes with the nadir synchronous with the contractions) are rare in labour. Because ‘early decelerations’ are not associated with fetal acidosis, many clinicians conclude that all decelerations that are synchronous with contractions are ‘early’ and are therefore benign!

The original morphological descriptions of FHR decelerations were derived under controlled animal experimental conditions based on their presumed mechanisms, which are not representative of human labour. For example, if head and cord compressions gave rise to ‘early’ and ‘variable’ decelerations, respectively, what type of hybrid decelerations would be observed if both fetal head and cord were compressed simultaneously, or better still if there was reduced transplacental oxygen transfer in the same labour? Therefore, the current obsession with the classification of the FHR decelerations into categories is unhelpful in assessing the fetal state. The important point is that the fetus is, or is not, compensating and defending itself adequately, and this will be evident in the evolving FHR patterns in a healthy fetus with a previously normal CTG.

Baseline FHR variability

The origin of the FHR variability is complex and its mathematical evaluation is beyond the scope of this commentary. In practice, it is observed as irregular fluctuations in the amplitude and frequency of the baseline FHR on a CTG trace, and is quantified as the amplitude of peak-to-trough in beats per minute. In order to exhibit a normal FHR variability the fetus requires an intact cerebral cortex, midbrain, vagus nerve, and cardiac conductive tissues. Even in the presence of decelerations or bradycardia a fetus that exhibits a normal baseline FHR variability has a very low risk of acidaemia, immediate death, or asphyxial brain injury.[30-32] In contrast, absent or reduced FHR variability was associated with significant newborn acidaemia in term and preterm infants.[32-34] In a recent systematic review minimal or undetectable FHR variability was the most consistent predictor of newborn acidaemia.[30] In contrast, increased FHR variation was observed in association with severe acidosis and hypotension in a hypoxia ischaemia model using term-equivalent fetal sheep.[35] In clinical practice these increased FHR variations associated with severe acidosis are often abrupt, erratic, high amplitude, and lack the natural wavelike characteristic of normal FHR variability. Strictly speaking they should not be classified as saltatory patterns as this implies exaggerated but normal wavelike variability. The clinical significance and interpretation of FHR variability has been reviewed and summarised as follows.[17]

  1. If the FHR variability is normal there is a limited role for fetal acid base analysis.[36, 37]
  2. Unless fetal asphyxia can be reliably excluded, intermittent or sustained reductions in FHR variability may signal the onset of decompensation in the presence of intrapartum FHR decelerations.
  3. A fetus with a previously normal FHR variability will not switch to reduced or absent variability during labour without the input of asphyxial FHR decelerations.
  4. It is not possible to distinguish between asphyxial and non-asphyxial causes of reduced FHR variability without determining the fetal acid base status if the FHR variability is absent at the very outset of the monitoring.

Fetal cardiovascular and metabolic response to intrapartum hypoxia

As the constant supply of oxygen is essential for cellular energy production and integrity, the fetal cardiovascular system, like its adult counterpart, is programmed to rapidly detect and redress any form of oxygen deprivation. The main aim of this program is to centralise the circulation and maintain perfusion of the essential organs, the brain, the myocardium, and the adrenals at the expense of the non-essential organs, such as the fetal lungs, skin, muscles, liver, kidneys, and the gastrointestinal tract.[38, 39] This response is qualitatively similar but may differ quantitatively across the spectrum of insults, and is also finely tuned to match the severity of the insult and the tolerance of the host. If the hypoxic insult is slow and persistent the fetus has ample time to make metabolic adjustments and exhibit different FHR patterns.[38, 39] In the absence of metabolic acidaemia fetal sheep at least can sustain these protective cardiovascular adaptations virtually indefinitely,[40-42] but they begin to fail with the development of acidaemia, with substantial falls in fetal and cerebral oxygen consumption at pH <7.0.

The pathological consequences of acidaemia include loss of vascular tone, myocardial cell injury/depression, resulting in hypotension and ischaemic brain injury; however, another layer of protection operates within the brain in which the regional redistribution of flow shunts blood away from the cortex to the deep nuclei and brainstem structures.[39] In contrast, during acute and total profound asphyxia (e.g. massive abruption, total cord occlusion, or uterine rupture) fetal pO2 falls precipitously within minutes. Unlike the slow and persistent insult this insult paradigm produces a rapid and generalised vasospasm mediated by the chemoreceptors, which is quickly followed by hypoxic decompensation, profound systemic hypotension, and brain infarction, and the regional brain redistribution of blood is unsuccessful in protecting the deep nuclei.[43, 44]

In this issue of BJOG, Chandraharan reviewed the tenuous evidence for the use of fetal scalp pH.[45] True, the non essential fetal tissues may develop acidosis during the hypoxia-driven centralisation of the circulation, and scalp pH may not reflect successful fetal cardiovascular compensation; however, it is also true that acidaemia leads to a loss of vascular tone and hypotensive brain damage. As vasoparalysis results in fetal injury regardless of the pH value, it follows that successful maintenance of the fetal mean arterial pressure (MAP) during hypoxia is more important than the pH in ensuring good outcome. Therefore, if the technology existed fetal MAP would be the ideal parameter to monitor instead of surrogates like pH or lactate level. Fetal scalp pH estimation and the CTG may have developed independently of each other, but they are not independent variables in practice. The decision to determine fetal pH depends on CTG interpretation; therefore, poor CTG interpretation reduces the value of FBS. As CTG interpretation has so far been based on features that did not necessarily predict acidaemia, it is reasonable to suggest that previous studies of the role of pH included fetuses that were not at genuine risk of acidaemia, hence the observed poor correlation between pH and adverse outcomes.

To my mind, the real questions are: (1) what levels and/or duration of fetal acidaemia (peripheral or otherwise) are associated with vasoparalysis/fetal hypotension; and (2) what CTG features, if any, predicted these pH levels? The precise answers to these questions are currently unknown and are likely to be host dependent and probably modulated by factors other than hypoxia and acidaemia. Available data suggest that there is no single pH value at which damage will occur in all fetuses;[46] however, for any individual fetus, the FHR variability will be reliably depressed before the pH drops to levels sufficient to induce neurological injury.[47, 48]

The role of infection and the inflammatory response

Fetal SIRS is associated with fetal hypotension, neonatal encephalopathy, meconium aspiration syndrome, multi-organ dysfunction,[49-51] and cerebral palsy,[52] but we know very little about the FHR changes induced by inflammation either alone or in combination with hypoxia. Furthermore, only 10–15% of cases of chorioamnionitis/FSIRS exhibit maternal signs.[53] Although FHR tachycardia, reduced variability, or lack of cycling may be observed, these are inconsistent findings. Current electronic FHR monitoring technology is not designed to detect FSIRS. In one study, tachycardic fetuses with infection had an increased risk of encephalopathy and cerebral palsy, but had no acidaemia or bradycardia,[54] suggesting that infection may exert neurological injury directly or via a non-hypoxia pathway. Further still, fetal inflammation and hypoxia appear to act synergistically to increase the risk of encephalopathy and cerebral palsy exponentially.[50, 55] Inflammation probably sensitises the fetal brain to hypoxic damage by lowering the threshold at which hypoxia triggers neuronal apoptosis.[56] Clinicians should exercise caution with uterotonic agents and traumatic deliveries in these cases.

Intrapartum FHR interpretation—a step-wise physiologic approach

Step 1—the normal and the abnormal initial CTG

If the CTG is normal the fetus is very likely to be neurologically intact, normoxic, without acidaemia or acidosis, at low risk of intrapartum asphyxia, and is able to react and defend itself against intrapartum hypoxia. Surveillance may continue depending on the situation or the woman may be monitored by intermittent auscultation. If the initial baseline FHR in a term fetus is ≥160 bpm with decelerations and reduced variability, particularly in association with meconium-stained amniotic fluid in early labour, the clinician should consider fetoplacental infection, meconium aspiration syndrome, chronic hypoxia, antecedent brain injury, maternal systemic disease, drugs, or chromosomal abnormality (Figure 1). Senior staff involvement should be sought early, with consideration given to delivery by caesarean section. The outcome may still be unfavourable because of the underlying disorder, but the additional challenge of labour and potential exacerbation of the pre-existing insult will be avoided. Fetal scalp sampling for pH is often impractical in early labour, and is an insensitive tool for the assessment of fetal wellbeing in the presence of FSIRS, fetal stroke, or compensated hypoxic insult. Meconium is strongly associated with histological chorioamnionitis, and in one study the RR of fetal infection was ≥50-fold if FHR tachycardia was associated with meconium in early labour.[57]

Figure 1.

Proposed clinical algorithm for intrapartum FHR interpretation based on fetal defensive and compensatory responses to hypoxic ischaemic stimuli. Firstly, a starting normal FHR pattern is essential to establish fetal wellbeing and the capability to react and defend itself. Then, using each fetus as its own control, the behaviour of the FHR is tracked/monitored as it adjusts and adapts to intrapartum insults over time. The emphasis is on the sequence and temporal relationships between the FHR features that characterise adequate/appropriate adaptation and those that suggest progressive failure of compensation.

Step 2—recognition of the compensated and the decompensating fetus

An intact fetus with a previously normal CTG will exhibit predictable patterns of FHR responses if exposed to hypoxic ischaemic insults during labour, namely: slowly evolving hypoxia; subacute hypoxia; and acute hypoxia.

Slowly evolving hypoxia

Starting from a normal CTG, the first abnormality to emerge in response to intermittent episodes of oxygen deprivation (e.g. cord compression) or hypoxaemia (e.g. excessive oxytocin infusion) is the appearance of FHR decelerations. The second is a progressive increase in baseline FHR if the stressor is persistent and threatening. The third is reduced variability, which is a marker of decompensation.[22-25] The important point is the order and temporal relationship between these FHR abnormalities. Recovery follows the same order, and can only be confirmed when the decelerations have disappeared and the baseline FHR and variability have normalised. The duration of time that an individual fetus can spend at its maximum FHR without damage is variable and host dependent. Fleischer et al.[58] showed that 50% of term well-grown fetuses in spontaneous labour with clear liquor and ‘reactive’ CTG will develop acidosis in 115 minutes with late decelerations, 145 minutes with variable deceleration, and 185 minutes with flat and non-variable trace, but these times will not apply to fetuses with reduced reserve, such as in the case of intrauterine growth restriction (IUGR) or infection, where acidosis may develop earlier and more rapidly. The following conclusions may be drawn from the above discussion.

  1. If uterine contractions do not provoke FHR decelerations in a previously normal CTG, the fetus is unlikely to be hypoxaemic, hypoxic, acidaemic, or experiencing cord compression.
  2. In the presence of persistent FHR decelerations a progressive rise in the FHR suggests additional cardiovascular adaptation and fetal ‘stress’, but any rise in the FHR without antecedent decelerations is not attributable to an evolving intrapartum hypoxia.
  3. During labour, reduced FHR variability that was not preceded by decelerations and a progressive rise or acute fall in FHR from a previously normal CTG is not associated with an evolving hypoxia. As the fetal myocardium fails the FHR may fall slowly towards a terminal bradycardia. This should not be mistaken for recovery.
  4. The amplitude and duration of the decelerations depends on the intensity of the stressor. Others may profoundly disagree, but in my opinion it is irrelevant whether these decelerations are morphologically ‘early’ or ‘late’ and, provided the baseline FHR and variability are maintained, the fetus is well compensated (Figure 1).

Subacute hypoxia

This pattern is characterised by complicated variable decelerations with amplitude ≥60 bpm, duration ≥90 seconds, and a recovery phase at the baseline lasting <60 seconds. This very brief interdeceleration interval is likely to have two consequences: (1) it is insufficient to rid the fetus of its carbon dioxide burden accumulated during the decelerations, leading rapidly to respiratory and subsequently metabolic acidosis; (2) the fetus is unable to raise its baseline FHR and therefore its cardiac output. Provided the FHR variability is normal and the interdeceleration interval ≥60 seconds the fetus is compensated; however, subacute hypoxia is associated with a rapid decline in pH of 0.01 every 2–4 minutes.[18] Early recognition and remedial action is essential, as there may be insufficient time for further assessment, e.g. to obtain, analyse, and react to a fetal scalp sample result.

Acute hypoxia (prolonged FHR deceleration and bradycardia)

The majority of acute onset intrapartum FHR decelerations, in which the baseline FHR stabilises around 80–100 bpm, with normal variability, are associated with non-asphyxial vagal events,[59-61] and usually arise from normal or near normal FHR patterns. In the absence of cord prolapse or occlusion, major abruption, uterine rupture, maternal collapse, or infusion of a bolus of oxytocin, 90% of these episodes will recover or show signs of recovery by 6 minutes, and 95% will recover by 9 minutes.[18] They can be managed expectantly. The mother should be turned to her left side and rehydrated if she is hypotensive. If, however, the FHR falls <80 bpm, with a loss of baseline variability, immediate delivery should be considered, especially if the antecedent CTG was abnormal as loss of variability signals fetal decompensation and injury. Although some of these patterns do recover, many do not. Against this background the NICE guidance on prolonged decelerations defined as baseline FHR < 100 bpm (abnormal) and 100–109 bpm (suspicious) for <3 or 3–10 minutes is open to misinterpretation. Many of these cases are transferred urgently to the theatre, during which time the FHR recovers but operative delivery is undertaken anyway to comply with the guideline and fear of recurrence if the delivery was deferred.

Conclusion

The continuing focus on the morphological appearances of FHR decelerations by current guidelines and training modules denies the clinician an understanding of how the fetus defends itself, compensates for intrapartum hypoxic ischaemic insults, and the ability to recognise the patterns that suggest loss of compensation. This may be adding to the increased operative delivery of nonacidotic babies. An intact fetus with a normal CTG will exhibit a predictable set and sequence of FHR responses if exposed to hypoxic ischaemic insults during labour. In the presence of an abnormal CTG using the trends in fetal defensive/compensatory responses for interpretation allows the clinician to discriminate between the fetus at risk of acidosis from one that is not at risk.

I make no claim for the superior clinical utility of the proposed algorithm without a significant shift in our attitude to intrapartum FHR interpretation, the content of current training modules, and prospective field evaluation; however, its basis on available data on the behaviour and regulation of the fetal cardiovascular system during labour is undeniable. The author has successfully used and taught others to use the algorithm to monitor fetuses in labour and to fine-tune the application of existing guidelines in his institution and also in training courses for the last 12 years.

Disclosure of interests

AU runs courses on intrapartum CTG and fetal ECG analysis at St George's Hospital in London, and in other UK hospitals and overseas. He uses fetal ECG monitoring in his practice. He accepts instructions from and advises claimants' and defendants' lawyers on matters related to fetal monitoring, and is also involved in the revision of the FIGO guidelines on FHR monitoring.

Contribution to authorship

Sole author.

Details of ethics approval

Not applicable.

Funding

None.

Acknowledgements

None.

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