CORRESPONDENCE

 

Commentary on the published position statement regarding the pathogenesis of fetal basal ganglia-thalamic hypoxic-ischaemic injury

 

 

To the Editor: Bhorat et al^[1] have published a 'position statement' regarding the provenance of basal ganglia and thalamic (BGT) injury following perinatal hypoxia-ischaemia. The authors buttress their position statement designed for litigation defence, with literature that unfortunately does not support their premise.

 

Rennie and Rosenbloom^[2]

Bhorat et al.^[1] begin by citing Rennie and Rosenbloom's^[2] 2011 article in which they examined the question of how long obstetric intervention could be deferred before fetal neurological injury occurred.

Bhorat et al.^[1] cite this article in support of their notion that a gradual onset of hypoxia may damage only the watershed areas of the brain without affecting the central deep nuclei. Rennie and Rosenbloom, however, never examined whether gradual onset of prolonged hypoxia in labour could lead to BGT injury. All their cases reflected either sentinel events or persistent fetal bradycardia. Irrespective, Bhorat et al.^[1] wish to infer that the two patterns are immiscible, with prolonged hypoxia causing watershed injuries, and all BGT patterns are linked to acute and profound hypoxic events.

 

Shankaran et al.^[3] and Sie et al.^[4]

Bhorat et al.^[1] go on to describe 'a strong association between BGT pattern injury and sudden-onset hypoxic-ischaemic events', which they refer to as perinatal sentinel events (PSEs). Citing articles from Shankaran et al.^[3] and Sie et al.^[4] they append to the definition of sentinel event what they call 'concealed events' such as (occult) cord compression.

The definitions offered by Shankaran et al. and Sie et al. were unique to their specific research and are not generally accepted nor consistent with the definition promulgated by the American College of Obstetricians and Gynecologists (ACOG)/American Academy of Pediatrics (AAP)^[5] (whose definitions in this regard Bhorat et al.^[1] singularly fail to cite). Irrespective of this, Shankaran et al.^[3] found no significant difference between the number of BGT injuries in their designated PSE group compared with the study subjects who lacked such criteria.

Whereas there is no disputing the association between BGT pattern injury and sentinel events (as defined by ACOG/ AAP^'51), there is no basis for making such statements as 'a large proportion of BGT injuries follow PSEs that are not clinically obvious', and 'there is no reason to believe that brain injury pathogenesis differs between clinically obvious PSEs and those of uncertain origin.' Continuing this syllogistic cascade, Bhorat et al.^'11 provide the exculpatory assertion that 'typically, PSEs are not foreseeable ...', asserting that the injury could not be averted by obstetric intervention because it was sudden, severe and profound. However, both published evidence^[6] and clinical experience, including articles cited by the author, fail to support this position. For example: instances of cord prolapse, uterine rupture and prolonged bradycardia may be foreseeable and manageable, to the point that adverse perinatal outcomes may be avoided.

 

Pasternak and Gorey,^[7] Okumura et al.^[8]

Bhorat et al.^[1] cite Pasternak and Gorey.^[7] This article examined eleven instances of infants delivered following the onset of persistent bradycardia. Four cases were associated with uterine rupture; two cases were related to cord problems (cord thrombus, cord rupture), and five had bradycardia of unknown origin without further description of the obstetric events preceding delivery. Magnetic resonance imaging (MRI) scans were performed in eight cases. In one, the MRI was normal (case 8). Of the rest, MRI revealed BGT involvement with relative sparing of the cerebral cortex. None of the cases had specific perirolandic cortex (PRC) involvement. Case 2 had parasagittal cortex ('watershed') involvement; case 9 left frontal cortex, and case 11, 'parasagittal cortex'. The heterogeneity of the findings aside, there is no description or suspicion of any preceding 'concealed' SE.

Bhorat et al.^[1] then cite two cases of bradycardia leading to BGT injury for which there were no 'apparent causes', as reported by Okumura et al.^[8] This narrative cannot justify the inference that there must have been some 'occult' SE leading to the described outcome. In addition, neither Okumura nor Pasternak and Gorey's work contradicts the more recent work of Baxter,^[9] showing the importance of the duration of persistent terminal bradycardia and BGT (and white matter) injury. Again, there is no mention of any occult injury.

It is unknown (but unlikely) that every fetal bradycardia is the consequence of some sudden but unknowable 'sentinel' event. More common than the sudden unpredictable bradycardia related to placental abruption, a prolapsed cord, ruptured uterus, uterine tetany or compulsive maternal pushing is the predictable, discoverable appearance of prolonged bradycardia following a prolonged series of decelerations or associated with excessive uterine activity, and unrestrained pushing.

Citing Pasternak,^[7] whose publication never addressed that question, Bhorat et al.^[1] double down on their previous assertions, stating that 'the BGT pattern is rarely seen in the absence of an (overt) PSE'.

 

Murray et al.^[10]

In further support of their approach, Bhorat et al.^'11 cite Murray et al.^[10] relating to the benefits of this argument in the 'successful defendant viewpoint in South African courts in the late 2010s'. The gist of this argument is that BGT injury is always associated with sudden sentinel events (SEs) or SEs of 'unknown origin', rendering obstetric intervention ineffective because of the suddenness and severity of the insult.

The article by Murray et al.^[10] examined 35 babies with hypoxic-ischaemic encephalopathy (HIE). SEs were found in 11.5% of affected infants. It describes the affected infants' cardiotocographic (CTG) patterns, noting that the time from evident abnormality to delivery was 22 minutes in the case of SEs (underscoring the difficulty of successful intervention). In contrast, the interval from abnormality to delivery was 145 minutes in the other cases (illustrating the period during which intervention may have made a meaningful difference to the outcome).

This research did not address specific neuroradiological patterns and is consistent with other evidence, including the work of Martinez-Biarge et al.^[11] and Smith et al^[12]

Further, the publication of Murray et al.,^[10] therefore, does not support the notion propagated by Bhorat et al^[1] that sudden known and unknown SEs cause BGT injury in the majority of cases, nor the idea that such injury is unavoidable.

 

The ACOG/AAP consensus statement^[5] and Volpe et al.^[13]

Bhorat et al.^[1] concede that expert witnesses for plaintiffs offer an alternative view on the pathogenesis of BGT injury consistent with the ACOG/AAP consensus statement as well as the writings of Volpe et al.,^[13] an internationally recognised authority in the field of paediatric neurology.

Bhorat et al.^[1] suggest that ACOG has been imprecise in their use of the terms 'prolonged' and 'partial' hypoxia when describing the pathogenesis of cerebral-deep nuclear neuronal injury because it contradicted 'terminology introduced in our first paragraph'. However, the ACOG/AAP position terminology also appears in a multidisciplinary article on 'Neuroimaging in the term newborn with neonatal encephalopathy' published under the auspices of the Neonatal Brain Society.^[14] In this article, the associated risk factors for 'central/BGT (also known as 'cerebrocortical-deep nuclear)' brain injury were 'sentinel events; severe partial asphyxia with prolonged duration or combination of partial and near-total asphyxia'.

Bhorat et al.^[1] disagree.

 

Smith et al.^[12]

Bhorat et al.^[1] take issue with a publication by Smith et al.,^[12] who also offered evidence in support of prolonged hypoxia as a cause for BGT injury in the absence of any identifiable PSE.

Bhorat et al.^[1] and Buchmann and Bhorat^[15] refer to 'criticism' of the article, citing their own objections (rebutted in a published response by Smith et al.^[16]). The comments by Bhorat et al. are the only published criticism of Smith et al.^[16] In this respect they seem to stand alone in the international community.

 

Baxter^[9]

Bhorat et al.^[1] cite Baxter,^[9] who analysed the perinatal outcome in pregnancies complicated by known prolonged and persistent fetal bradycardia to determine how long a known insult must be present before injury ensued.

The data establish an increasing likelihood of BGT injury with an expanding duration of insult defined as a persistent fetal bradycardia 'with or without sentinel events'. In this article, 25% of infants were affected when bradycardia lasted >11 minutes, whereas 85% were affected by a duration of >20 minutes.

In their discussion, Bhorat et al.^[1] focus on a comment made by Baxter that perirolandic injury may not require a more chronic partial type of insult (contrary to that suggested by Volpe et al.^[13] and others^[5,14]) and may be compatible with a more rapidly developing hypoxic insult. With this commentary, Bhorat et al.^[1] presumably suggest that ACOG/AAP,^[5] Volpe et al.^[13] and Wisnowski et al^[14] have been mistaken in the notion that PRC injury is indicative of a more insidious prolonged, partial hypoxia. While this may (or may not) be true, Bhorat et al.^[1] are citing a comment, out of context, about an aspect of hypoxic-ischaemic injury that went unaddressed in the data-analysis provided by Baxter. Not only is this discussion peripheral to the focus of the publication, but it also obfuscates a more pertinent observation, namely that Baxter only addressed one kind of event leading to BGT injury rather than an examination of all BGT injuries in the context of all known preceding risk factors.

 

Nakao et al.^[17]

The subsequent publication addressed in the 'position statement' is the work of Nakao et al.^[17] This article discussed the issue of cerebral palsy (as distinct from neonatal encephalopathy (NE)). The aim was to investigate the association between the timing of a hypoxic-ischaemic insult and brain injury in infants with cerebral palsy (CP). The research was based upon fetal heart rate (FHR) patterns, grouped as prenatal and intrapartum patterns, compared with neuropathology defined as either a BGT pattern (indicated in their assumptions as due to acute profound hypoxia) or watershed injury, which arose from prolonged hypoxia.

It should be self-evident that no assumptions can be made when data are unavailable for analysis or interrogation. In that regard, the publication is confusing. Of 1 593 subjects considered by Nakao et al.,^[17] the majority were excluded from analysis. Those excluded from the analysis were infants who died within 6 months of birth, infants deemed to have less than severe CP and those whose records were missing. The remaining cases were a mixture of preterm and term births, of whom three-quarters had a BGT pattern and one-quarter a purely watershed injury.

The authors interpreted persistently abnormal CTG tracings beginning before the onset of labour as indicative of a hypoxic insult causing BGT injury. However, many of these study subjects suffered abruptio placentae before the onset of labour. This occurrence is a recognised SE leading to adverse outcomes independently of whether or not it occurred during labour.

In interpreting their data, the authors subsequently indicated that intrapartum CTG patterns that change from reactive tracings to ones with prolonged decelerations should indicate 'acute' stress. In contrast, patterns changing from a reactive tracing to a Hon pattern (recurrent decelerations in FHR, high baseline FHR and decreased variability followed by low baseline FHR) were considered indicative of 'subacute' stress. There was no evidentiary basis presented for these assertions.

Nakao et al.^[17] concluded that BGT lesions were more prevalent in situations of acute stress than in subacute stress, but that BGT lesions with cortical involvement followed a gradual, partial insult. The data to support these various contentions are not evident from the published material. However, the conclusions reached make it clear that some BGT injury may follow prolonged partial hypoxia. The authors state: 'Furthermore, severe BGT lesions were more prevalent in acute and total insult, and cortical involvement accompanying BGT damage was characterised by a gradual and partial insult'. Personal communication (between Smith and Nakao, 31 August 2023) has revealed that 'abnormal cortical highlighting was observed mostly in the perirolandic cortex within the BGT group of severe CP cases, often accompanied by the abnormal signs around the interhemispheric fissure and/or insular cortex'.

The issue of the pathogenesis and patterns of cortical damage associated with BGT injury due to hypoxic ischaemia is a developing field, as was recently highlighted by the article of Misser et al.^[18] They described a spectrum of BGT and PRC involvement, including extension of the cortical injury beyond the PRC. The damage may be very subtle or limited to the sensorimotor strip (PRC) with little or no widening of the central sulcus (mild subtype). Moderate PRC injury showed paracentral lobule and sensorimotor cortex injury, resulting in some widening of the interhemispheric fissure. In the third subtype, severe PRC injury subtype, there is extension of the injury to the margins of the paracentral lobule and the lateral edges of the central sulcus, with involvement of the subcortical white matter. The fourth subtype is the newly described 'massive paramedian injury' (MPI) type characterised by broad widening of the interhemispheric fissure secondary to near-complete destruction of the paracentral lobule, with resultant diamond-shaped excavation of the central core of the cerebrum, including part of the centrum ovale. This injury extends towards the superior frontal gyrus (anteriorly) and variably towards the superior parietal lobule (posteriorly). The authors concluded that the combination of perirolandic, basal ganglia, thalamic and other high metabolic substrate injuries shown in their MPI group closely approximates the study findings reported in experimental animals.

The obstetric correlates of 11 of the patients were analysed by Misser et al.,^[18] but obstetricians were not included. The data derived from 'comprehensive clinical details from the base hospitals' were used to infer that the MPI group corresponded in vivo with prolongation of the second stage of labour (a feature identified in all patients with MPI), and consequent severe, sustained hypoxic-ischaemic insult to the susceptible fetus. Common to all their 11 cases were significant intrapartum factors, including prolongation of labour, particularly the second stage, often with impaction of the fetus in the birth canal for prolonged periods leading to fetal compromise, augmentation of labour by oxytocin (27%), and failed operative vaginal delivery (27%).

Despite the limited clinical analysis provided, their cases illustrate that parasagittal central type hypoxic-ischaemic brain injury can sometimes be identified in more severe sustained hypoxia ischaemia, and is consistent with the observations of Nakao et al^[17]

Overall, the Nakao publication is open to criticism due to the retrospective analysis accompanied by numerous exclusions, as well as failure to consider acknowledged obstetric precedents of hypoxic injury (which include failure of monitoring and iatrogenic factors, including the use of oxytocin). Failure to consider all cases and failure to account for all known risk factors precludes adequate logistic regression as a means of determining independently associated risk factors for neurological injury.

Selecting from a large medicolegal database, Elsingergy et al.^[19] studied the distribution frequency of individual deep nuclei injury in children with CP demonstrating isolated BGT, v. those with a BGT-watershed (WS) pattern of hypoxic-ischaemic injury. Of 762 MRI reports, 435 (57%) had isolated BGT involvement. Bhorat et al.^[1] would like us to believe that these 435 children all either had SEs or had severe but undetectable events that happened so quickly and quietly ('silently') that the hospital staff involved were not able to act in a reasonable time to affect the outcome. Is this a realistic probability?

The concluding paragraph of Bhorat et al.^[1] refers to the need for 'holistic' and 'unbiased' review of information aimed at 'fair resolution without waste of time and resources'. These comments are patronising and emotive in the sense that the terms 'bias', 'fair' and 'waste' suggest that adherents of any view other than those espoused by Bhorat et a/. cause unfair biased practice ending in wasteful expenditure.

The onus is on Bhorat et al.^[1] to prove the theory they present - it is not good enough to get together as a group and just decide what is convenient.

The article by Nakao et al.^[17] has been used by Bhorat et al.^[1] in an uncritical manner to suggest that fetal priming related to intrauterine infection, fetal growth restriction and cord abnormalities renders the fetus susceptible to injury from 'relatively mild hypoxic-ischaemic insult'. At best, such a view is disingenuous. While there may be some truth in the assertions made, the priming factors were never examined in any detail by Nakao et al., and the notion of 'mild' hypoxia is inchoate, existing only in considerations peculiar to the reasoning of Bhorat et al.^[1]

In summary: Bhorat et al.^[1] lump together and reject all the expert opinions provided by ACOG/AAP,^[5] Wisnowski et al.^[14] on behalf of the Neonatal Brain Society, as well as Volpe et al.^[13] and Kinney and Volpe^[20] whose views do not coincide with their own.

 

The 'Position Statement'

Bhorat et al.^[1] use their 'summary of the current state of knowledge' to promulgate their position statement, which they assert should be used by obstetricians engaged as defence experts in CP litigation cases. In suggesting this, they display remarkable certainty about the validity of their own views. This attitude starkly contrasts with any philosophical enquiry (including medical science), which disavows finality of thought.

The position statement links BGT pattern of injury to SEs. These events are sudden and 'typically unforeseen and unpreventable'. The article maintains an unsustainable bias mitigated only by the subsequent statement that 'concealed' sentinel events (a linguistic contradiction) may be detectable using continuous CTG monitoring. This suggestion would, however, seem to validate the data presented by Smith et al.,^[12] even in the authors' estimation.

Bhorat et al.^[1] also state that a PSE may occur before labour and result in BGT injury. This assumption is valid when talking of abruptio placentae or a ruptured uterus. However, there is currently no evidence that other 'priming' factors are associated with the antepartum pathogenesis of BGT injury. Volpe et al.,^[21] reviewing recent evidence linking placental vascular mal-perfusion of the fetus (FVM) to the risk of neonatal HIE, conclude that 'the finding that FVM is associated with neonatal encephalopathy and particularly HIE raises the question of whether detection of FVM in utero could lead to institution of preventative measures prior to labour'. While predisposition to injury may be present, the occurrence of injury is currently considered to require both the predisposition as well as a 'second-hit' exposure to hypoxic stress as a result of labour itself.

The notion that 'priming' causes susceptibility to hypoxic injury is uncontested. Placental insufficiency causing fetal growth restriction ending in birth-related asphyxia is a long-accepted epidemiological association. However, the notion that 'relatively mild hypoxia' may cause injury (while possibly true) is currently a notion without factual basis. In the context of labour, there is no evidence of undefined 'mild' hypoxia leading to sudden or undetectable (and therefore unpreventable) injury.

Bhorat et al.^[1] concede that BGT injury may follow gradual-onset FHR rate pattern deterioration over >1 hour. However, they indicate that this is 'uncommon'. Bhorat et al.^[1] have no evidence to substantiate this, as no systematic, population-based study of the provenance of BGT injury exists. None of the data reviewed here and in the Bhorat article provide this. Hence the notion that BGT injury due to gradual deterioration in the FHR is uncommon is not only unsupported, but flies in the face of inferential data that are available.

Bhorat et al.^[1] use the Baxter^[9] data to infer that the prevention of BGT injury would require intervention within 10 minutes. Again, this is highly disingenuous, implying that all BGT injuries are the same and caused by the same mechanism (namely persistent fetal bradycardia). They state that such rapid intervention cannot be attained in South Africa. While this may be true, it needs to be pointed out that baseline fetal bradycardia is just one known risk factor giving rise to BGT injury. More significantly, the emergency management of suspected fetal distress encompasses not only operative delivery but also fetal resuscitation in utero. It is incorrect to infer that nothing can be achieved through intervention, even if the goal of rapid caesarean delivery may not be attainable.

Bhorat et al.^[1] reiterate that BGT injury patterns, with or without cortical involvement, are both equally associated with PSEs. This view is inconsistent with the cited literature and promotes an idiosyncratic definition of PSE, leading to the incongruous (oxymoronic) notion of unknown SEs. The accepted definition of SEs has been set out in the ACOG/AAP^[5] consensus statement on NE, and it is clear that not all instances of BGT injury are associated with SEs, much less unpreventable.

 

Conclusion

Bhorat et al.^[1] have provided a self-styled 'position statement' on BGT injury. In doing so, they have uncritically referenced literature and inappropriately used it as the inferential basis for their views, which are unashamedly offered to preferentially assist in the defence of allegations of medical negligence, to which cause they have allied themselves. Its acceptance would also confound the fair adjudication of medicolegal matters. This position is unconscionable and is not helpful to society at large, nor does it assist in better understanding the preventable risks associated with BGT injuries or reducing its incidence in the future.

The onus is on Bhorat et al.^[1] to marshal more compelling support for their idiosyncratic theory, and more equipoise. Expert witnesses in CP matters should examine all clinical case evidence, as well as critically evaluate available medical literature to provide unbiased, evidence-based opinions.

J Anthony

Retired associate professor and Head of Unit: Maternal and Fetal Medicine, Groote Schuur Hospital

J Smith

Emeritus Professor of Neonatology, Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa js7@sun.ac.za

L Murray

Private Practice in Obstetrics and Gynecology, Cape Town, South Africa

G F Kirsten

Emeritus Professor of Neonatology, Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa

G Gericke

Extraordinary Professor in Human Genetics, Faculty of Health Sciences, University of Pretoria, South Africa

Y Kara

Paediatrician, Umhlanga Hospital and St Augustines Hospital, Durban, South Africa

V Davies

Paediatrician and neonatologist, visiting associate professor, Department of Paediatrics and Child Health, University of the Witwatersrand, Johannesburg, South Africa

D Pearce

Paediatric neurology consultant, University of the Witwatersrand, Donald Gordon Medical Centre Johannesburg, South Africa

R van Toorn

Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa

M M Lippert

Certified paediatric neurology, private practice in Paediatric Neurology, Unitas Hospital, Pretoria, South Africa

J W Lotz

Emeritus Professor of Radiology, Division of Radiodiagnosis, Stellenbosch University, Cape Town, South Africa

S Andronikou

Pediatric neuroradiologist and paediatric radiologist at the Children's Hospital of Philadelphia, USA; professor of radiology at the Perelman School of Medicine, University of Pennsylvania, USA

B Alheit

Cape Town, South Africa

L van Wyk

Neonatologist, Department of Paediatrics and Child Health Child Health, Stellenbosch University, Cape Town, South Africa

AS Ebrahim

Obstetrician and gynaecologist, St Augustine's Hospital, Durban, South Africa

B S Schifrin

Formerly professor of obstetrics and gynecology (maternal-fetal medicine), Keck School of Medicine, University of Southern California, Los Angeles, California, USA

Author contributions. JA, JS, LM, JWL, SA, BSS, YK, VD: conceptualisation, analysis and interpretation of published data, and manuscript writing and editing; MML, DP, RVT, BSS, AE, BA, GG, GFK, LVW: critical review and editing of manuscript. All authors approved the final version.

 

References

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19. Elsingergy MM, Worede F, Venkatakrishna S, Andronikou S. Deep nuclei injury distribution in isolated 'basal ganglia-thalamus' (BGT) versus combined 'BGT and watershed' patterns of hypoxic-ischaemic injury (HII) in children with cerebral palsy. Clin Radiol 2022;77(11):825-832. https://doi:10.1016/j.crad.2022.04.019        [ Links ]

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