Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT04054453 |
| Other study ID # |
NIHR200144 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 1, 2020 |
| Est. completion date |
October 30, 2024 |
Study information
| Verified date |
August 2023 |
| Source |
Thayyil, Sudhin |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The aim of the study is to examine if a pragmatic, evidenced based and generalisable
intrapartum care bundle involving birth companions and empowering mothers will reduce birth
injury-related epilepsy at 18 months of age in India.
The care bundle will have four key elements (interventions): (1) birth companion providing
constant 1:1 care during labour and early perinatal period; (2) fetal surveillance during
active labour by a nurse or midwife using a graphic display Doppler; (3) labour management by
an electronic partogram with an 'alert' and 'nag' feature based on the current WHO
guidelines; (4) brain oriented early newborn care with resuscitation where indicated.
The care bundle will be evaluated using a prospective interrupted time series design,
recruiting 80,000 women delivering in one of the three participating centres in south India,
over two years. Accurate baseline data will be collected during the first year and the
optimised care bundle will be introduced during the second year. All full term newborn
infants admitted to the neonatal unit with perinatal brain injury during both periods, will
have detailed assessments including video electroencephalography, and magnetic resonance
imaging, and will be followed up until 18 months of age.
Primary outcome is the number of infants with epilepsy (categorised per current ILAE
guidelines) at 18 months of age expressed as per 1000 term livebirths. The investigators will
use a segmented logistic regression to divide the time series into pre- and post-intervention
segments, with the intervention date as the intersection between segments. The difference in
the two segments will be quantified using the level (step change) and slope (trend change).
The total duration of the study is four years including 24 months of recruitment and 18
months of follow-up.
Description:
Epilepsy is a condition where individuals are prone to recurrent epileptic seizures; which
means a change in the electrical activity of the brain resulting in a change in behaviour or
movement. Epilepsy is a symptom of the condition of which there are many different causes,
including brain injury occurring around the time of birth.
Worldwide approximately 50-70 million people have epilepsy, and 4.6 million develop epilepsy
each year. The incidence of epilepsy in low and middle-income countries (LMICs) (1.3 per 1000
people) is 2 to 3 times higher than that in high-income countries (0.49 per 1000 people). The
Prevention Task Force of the International League Against Epilepsy [1] estimated that
perinatal brain insults accounted for the largest attributable fraction of paediatric and
adult epilepsy in LMICs with median (95% confidence intervals) estimated fractions of 17.4%
(14.7 to 18.9) and 11.4% (7.8 to 15.4). The contribution (population attributable risk) of
perinatal brain insults towards preventable epilepsy is 3 times higher than that of central
nervous system infections with parasites, virus and bacteria (5.3%), and traumatic brain
injury (6.6%). The task force concluded that health programmes to improve prenatal and
intrapartum care in LMIC may prevent a substantial proportion of epilepsy in LMICs[1].
12 million people were estimated to be living with epilepsy in India in 2015, accounting for
1/6th of the global epilepsy burden [2]. The annual economic burden of epilepsy to the Indian
economy was estimated to be £1.3 billion ($1.74 USD) with a cost of £260 ($344 USD) per
patient per year in 2001[3], based on the burden of 5 million people with epilepsy in India
at that time. Hence the current costs, based on 12 million people with epilepsy in 2015 [2],
may be much higher. Approximately 500,000 new epilepsy cases occur in India every year[3], of
which 87,000 (17.4%) are likely to be related to a birth related brain injury. The vast
majority of these cases will have additional neurodisabilities including cerebral palsy,
deafness and blindness. Hence, the social and economic burden of epilepsy related to
perinatal brain injury is likely to be much higher than isolated epilepsy.
Hypothesis. Epilepsy from perinatal brain injury can be reduced by the use of a pragmatic,
evidenced based and generalisable intrapartum care bundle that involves birth companions,
intelligent fetal heart rate monitoring, an e-partogram and brain oriented neonatal
resuscitation, in Indian public sector hospitals.
5. Aims and objectives
Primary aim
1. To examine if epilepsy caused by birth related brain injury in Indian public sector
hospitals can be prevented by pragmatic care bundle for improving the intra-partum care.
Secondary aims
1. To examine if the intra-partum care bundle reduces the incidence of neonatal
encephalopathy.
2. To examine if the intra-partum care bundle reduces the incidence of neonatal seizures.
3. To examine if the intra-partum care bundle reduces caesarean rates.
4. To examine the acceptability of the care bundle by families and frontline labour room
staff.
5. To examine the cost-benefits of the intrapartum care bundle
6. Methods The study will be conducted over a four-year period. Baseline data will be
collected during year 1, and the care bundle will be introduced during year 2. The
primary outcome will be assessed at 18 months of age.
Element I: Constant birth companion providing 1:1 care during labour and early perinatal
period
Following necessary training, the companion will contribute towards maternal empowerment
through support described below during the entire first and second stage:
(i) Hydration/nutrition: provide drinking water and light refreshments to women as
desired, during labour.
(ii) Mobilisation/massage/reassurance: encourage and assist women to be mobile during
labour, massage back and body as required, and provide constant reassurance.
(iii) Prompt healthcare staff to perform regular observations as described under fetal
surveillance.
(iv) Prompt staff to adhere to WHO's infection and control guidelines and hand hygiene.
(v) Encouragement during 2nd stage: support women to push at appropriate times. (vi)
Assist in immediate skin to skin care after delivery and early breast feeding.
Element 2: Fetal surveillance during active labour by a nurse or midwife (i) Clinical
assessment of the woman with appropriate risk categorisation (ii) Intelligent
auscultation on admission using graphic display Doppler, and subsequent fetal heart
recording every 30-45 minutes in 1st stage, and every 5-10 minutes in 2nd stage, and
after each contraction.
(iii) Escalation to medical staff when appropriate
Element 3. Labour management by an electronic medical record with an 'alert' and 'nag'
feature (e-partogram) (i) Prompt, regular observation of maternal, and fetal wellbeing
and progress of labour with the 'alert feature' and 'nag' feature of the software on a
Tablet computer.
(ii) Rationalise induction and augmentation i.e. artificial rupture of membranes and use
of oxytocin only with infusion pumps.
Element 4. Brain oriented early newborn care with resuscitation where indicated (i)
Early skin to skin care after birth, promoting early feeding (ii) Newborn resuscitation
(NLS) by nurses/midwives and doctors as indicated (iii) Prevention of hyperthermia in
babies with suspected brain injury
Although, the primary focus of the care bundle is prevention, rather than treatment of
perinatal brain injury, inadequate resuscitation and hyperthermia can worsen the brain
injury, and hence may increase the risk of epilepsy. All recruiting centres in the study
currently have good neonatal resuscitation facilities managed by neonatal doctors, and
this will be maintained in both phases of the study. In most cases, the inadvertent
hyperthermia can be prevented by not using radiant warmers, or by securely attaching the
servo control temperature probes over the abdomen when such warmers are used. This
element of the care bundle will be further modified based on the baseline data on the
exact incidence of neonatal meningitis and isolated symptomatic hypoglycaemia with
occipital brain injury in these settings.
Assessment of Neonatal brain injury The following data will be collected on all babies
admitted to the neonatal unit or presenting with brain injury (e.g. seizures,
encephalopathy, meningitis, intracranial bleeds) before 72 hours of age, following
informed parental consent.
1. Clinical examination including accurate staging of neonatal encephalopathy using
the NICHD Neonatal Research Network modified Sarnat staging. The NICHD examination
will be performed between 1 to 6 hours age and repeated at 24 hours and 72 hours of
age. The babies will be classified as having mild, moderate or severe hypoxic
ischemic encephalopathy based on the neurological examination between 1 to 6 hours
of birth, if in addition these babies have evidence of intra partum hypoxia as
defined by - an acute perinatal event (e.g. cord prolapse, cord rupture, uterine
rupture, maternal trauma, haemorrhage, or acute cardiorespiratory arrest) and
either a 10-minute Apgar score of 5 or less at 5 minutes or assisted ventilation
initiated at birth and continued for at least 5 minutes. In cases where a blood gas
is available, a pH of 7.0 or less or a base deficit of 16 mmol/L or more in a
sample of umbilical cord blood or any blood during the first hour after birth will
be used an evidence of an acute intrapartum event [27].
2. Infection screening including automated blood cultures and cerebrospinal fluid
examination in all babies with suspected early onset (age <72 hours) sepsis. Part
of this blood will be collected and stored for transcriptomic analysis of infection
and encephalopathy.
3. Twelve lead video EEG and amplitude integrated EEG for at least 4 hours using a
dedicated research EEG monitor in all babies with encephalopathy or suspected
seizures. Approximately 2 to 3 EEG will be performed daily at each centre. The EEG
will be uploaded on to a secure cloud-based server for central reporting, while the
aEEG will be reported locally in real time for clinical decision making.
Many neonatal seizures manifest with subtle clinical signs or may remain entirely
subclinical despite the presence of clear electrographic seizure activity on
EEG[28]. The investigators will classify neonatal seizures as per the levels of
diagnostic certainty proposed by the recent Brighton Collaboration Neonatal
Seizures Working Group led by Dr Ronit Pressler[29]. A neonatal seizure will be
defined as a transient electrographic change in the brain due to an abnormal,
excessive or synchronous neuronal activity either with the occurrence of clinical
signs (electro-clinical) or without them (electrographic-only).
Level 1 (Definite seizures) - Seizures confirmed on conventional EEG with
(electro-clinical seizure) or without (electro-graphic only) clinical
manifestations.
Level 2a (Probable seizures) - Seizures confirmed on aEEG with (electro-clinical
seizure) or without clinical manifestations (electro-graphic only) Level 2b
(Probable seizures) - Clinically assessed focal clonic or focal tonic seizure
directly witnessed or reviewed on video by experienced medical personnel when EEG
or aEEG was not available.
Level 3: (Possible seizure) - Clinical events suggestive of epileptic seizures
other than focal clonic or focal tonic seizures, directly witnessed or reviewed on
video by experienced medical personnel Level 4: (Not seizure) - Reported seizure
event (as previously defined) but insufficient evidence to meet the case definition
Level 5: (Not seizure) - Reported seizure event (as previously defined), documented
or witnessed by experienced medical personnel and evaluated by simultaneous
conventional EEG or aEEG and determined NOT to be a case of neonatal seizure.
The investigators will use an optimised neonatal EEG with predefined positions for
easy application of the electrodes by research nurses. These leads will provide
both a 12 montage EEG and aEEG, which will be uploaded on the cloud server for
reporting (Figure 1B and C).
4. 3 Tesla magnetic resonance imaging, diffusion tensor imaging and single voxel
thalamic proton spectroscopy using the HELIX trial sequences. Approximately 3 to 4
neonatal MR scans per week will be performed at each centre, during year 1 and 2.
In addition, repeat MR scans will be performed at around 18 months of age in all
children with epilepsy. Thus, approximately 3 to 5 repeat MRI scans per month will
be performed during years 3 and 4, at each centre. The anonymised MR data will be
uploaded on to a central server at Imperial College. The conventional MR images
will be reported locally in real time, while DTI and MRS will be analysed centrally
at Imperial College London following the study completion.
Neurodevelopmental follow up and Epilepsy
1. All babies admitted to the neonatal unit with a birth related brain injury within
72 hours of birth will be followed up until 18 months. This will include all babies
with HIE, seizures, proven early onset neonatal meningitis, symptomatic
hypoglycaemia associated with brain injury, or any other birth related injury on
the MRI scan (e.g. intracranial bleed, arterial stroke) associated with increased
risk of epilepsy. The same criteria for follow up will be strictly followed during
both phases of the study to avoid a selection bias in the follow up.
2. The research nurses will provide information and training (including video
demonstration of seizures) to parents on recognising seizures at home and will
advise on the subsequent actions to be taken. A 24/7 mobile phone contact number
will be provided to the parents for reporting any seizures. In addition, the
research nurses will maintain a monthly telephone/WhatsApp message contact with the
parents after discharge for a clinical update. If seizures are present, information
on the seizure type, exact age at onset of seizures, frequency and medication use
will be collected. The research nurses will also encourage parents to video record
the seizure episodes on mobile phones, whenever possible.
3. A dedicated monthly multi-disciplinary research clinic will be established at each
of the three recruiting centres at Chennai, Bangalore and Calicut. The clinic will
be jointly conducted by a neonatologist, paediatric neurologist, speech and
language therapist and physiotherapist, and care pathway will be provided to each
infant based on a detailed neurological assessment including Prechtl's at 3 months.
Depending on these babies will have 3 to 7 further clinic appointment until 18
months of age. The speech and language and the physiotherapy teams at the
recruiting sites will be trained and supervised by the study occupational therapy
consultant.
4. Any infant developing seizure will be asked to attend the next monthly
multidisciplinary research clinic for further evaluation (please see more details
under the evaluation phase). It is very likely and expected that the acute
management of the seizure would be at the nearest health care facility, either in a
private or public sector, rather than the recruiting centre. These data will be
captured by the research nurses. The clinical data will be entered into the study
database using an electronic case report form. The diagnosis of epilepsy will be
based on the standard ILAE criteria of two or more unprovoked seizures 24 hours
apart beyond the neonatal period[62]. A repeat video EEG may be performed any time
in selected cases, if clinically required or if there is any diagnostic
uncertainty.
5. At 18 months of age, all children with brain injury (with or without epilepsy) will
have a detailed neurological examination for cerebral palsy, hearing and vision
assessment and a Bayley Scales of Infant developmental examination (Version III).
The children with epilepsy may have a repeat MRI scan under light oral sedation,
full montage sleep and awake video EEG if clinically appropriate. All
neurodevelopmental assessments will be performed by a Bayley III certified
neurodevelopmental paediatrician or occupational/physiotherapist.
