Intelligence and Neurodevelopmental Outcome After Prenatal Exposure to Labour Epidural Analgesia: a Sibling Matched Clinical Ambidirectional Cohort Study
Conditions: Pregnancy, Epidural Analgesia, Obstetric
Sponsor: Universitaire Ziekenhuizen KU Leuven

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PROTOCOL FOR A COHORT STUDY 
Intelligence and neurodevelopmental outcome after 
prenatal exposure to labour epidural analgesia: a 
sibling matched clinical ambidirectional cohort study 
 
 
Version number: v2  –  Date 1/11/2024 
 
Internal ref. nbr:  S69530 
Sponsor 
University Hospitals Leuven (UZ Leuven) 
Herestraat 49, B-3000 Leuven 
 
Coordinating Investigator 
Professor Dr. Sarah Devroe 
 
 
 
 

UZ/KU Leuven 
 
 
Protocol: Labour epidural analgesia-IQ 
Internal Ref.: S69530 
 
 
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LIST OF PARTICIPATING SITES 
List Of Participating Sites 
Principal Investigator 
UZ Leuven, Herestraat 49, 3000 Leuven, Belgium 
Prof. Dr. Sarah Devroe 
 
Confidentiality Statement 
The information in this document is strictly confidential and is available for review to 
Investigators, potential Investigators and appropriate Ethics Committees, Institutional 
Review Boards or Competent Authorities. No disclosure should take place without written 
authorization from the Sponsor 
 
 

UZ/KU Leuven 
 
 
Protocol: Labour epidural analgesia-IQ 
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SIGNATURES 
Title: Intelligence and neurodevelopmental outcome after prenatal exposure to labour epidural 
analgesia: a sibling matched clinical ambidirectional cohort study 
Protocol: Labour epidural analgesia-IQ 
The undersigned confirm that the above referenced protocol has been acknowledged and accepted, 
they agree to conduct the Study in compliance with the approved protocol, and will adhere to: the 
ICH guidelines, the most recent version of the Declaration of Helsinki, the EU General Data 
Protection Regulation 2016/679 (GDPR), relevant Belgian laws implementing the GDPR, the Belgian 
Law of August 22nd 2002 on patient rights, and any other regulatory requirements and Standard 
Operating Procedures (SOPs), as applicable. 
The undersigned agree not to disclose the confidential information contained in this document for any 
purpose other than the evaluation or conduct of the Study, without prior written consent of the 
Sponsor. 
 
Coordinating Investigator 
 
Name & Title 
Signature 
Date 
Prof. Dr. Sarah Devroe 
 
1/11/2024 
 
 
Principal Investigator (University Hospitals Leuven, Leuven, Belgium)  
 
Name & Title 
Signature 
Date 
Prof. Dr. Sarah Devroe 
 
1/11/2024 
 
 
Co-investigators 
 
Name & Title 
Signature 
Date 
Dr. Tom Bleeser  
 
 
 
 
 
1/11/2024 
 
 
Prof. Dr. Steffen Rex 
 
 
 
 
 
 
 
 
1/11/2024 
 
 
Prof. Dr. Jurgen Lemiere 
 
 
 
 
 
 
 
1/11/2024 
 
 
Prof. Dr. Jaan Toelen 
 
 
 
 
 
 
 
 
1/11/2024 
 
 
 

UZ/KU Leuven 
 
 
Protocol: Labour epidural analgesia-IQ 
Internal Ref.: S69530 
 
 
Version: v2, 1/11/2024 
 
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TABLE OF CONTENTS 
LIST OF PARTICIPATING SITES ................................................................................................................. 2 
SIGNATURES ........................................................................................................................................... 3 
TABLE OF CONTENTS .............................................................................................................................. 4 
FUNDING AND SUPPORT ........................................................................................................................ 6 
ROLES AND RESPONSIBILITIES ................................................................................................................ 6 
STUDY SYNOPSIS .................................................................................................................................... 7 
1. 
Background and Rationale ....................................................................................................... 9 
1.1 Labour pain and management ............................................................................................. 9 
1.2 Neurodevelopmental effects of labour epidural analgesia .......................................... 10 
2. 
Study Objectives and Design ................................................................................................. 11 
2.1 
Study objectives ............................................................................................................... 11 
2.2 
Primary Endpoints ........................................................................................................... 11 
2.3 
Secondary Endpoints ....................................................................................................... 11 
2.4 
Study Design ..................................................................................................................... 12 
2.5 
Expected duration of the study .................................................................................... 12 
2.6 
Translational research .................................................................................................... 12 
3. 
Study Population / Eligibility Criteria ................................................................................. 13 
3.1 
Inclusion criteria............................................................................................................... 13 
3.2 
Exclusion criteria ............................................................................................................. 13 
4. 
Assessment of Efficacy .................................................................................................................. 14 
5. 
Assessment of Safety .................................................................................................................... 14 
5.1 
Specification, timing and recording of safety parameters ..................................... 14 
5.2 
Treatment stopping rules .............................................................................................. 14 
6. Identification of study participants, contact with study participants and intelligence testing .......... 14 
7. 
Statistics and Data Analysis .......................................................................................................... 16 
8. 
Data handling ............................................................................................................................ 18 
8.1 
General data handling information .............................................................................. 18 
8.2 
Study specific data handling information ................................................................... 19 
9. 
Ethical and Regulatory Considerations ............................................................................... 21 
9.1 
Ethics Committee (EC) review & reports ................................................................. 21 
9.2 
Protocol / GCP compliance ........................................................................................... 21 

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9.3 
Data protection and participant confidentiality ....................................................... 21 
10. 
Research Registration, Dissemination of Results and Publication Policy ............... 21 
11. 
Insurance/Indemnity ............................................................................................................ 22 
12. 
References ............................................................................................................................. 23 
 
 
 

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FUNDING AND SUPPORT 
Funder 
Type of Financial or Non-Financial Support 
ESRA (European Society for 
Regional Anaesthesia) 
Grant of €10 000 to finance the intelligence tests and 
questionnaires 
 
 
 
 
 
 
ROLES AND RESPONSIBILITIES 
The Principal Investigator (PI) is responsible for the conduct of the Study at his/her Participating Site, 
and for protecting the rights, safety and well-being of Study participants. As such the PI must ensure 
adequate supervision of the Study conduct at the Participating Site. If any tasks are delegated, the PI 
will maintain a log of appropriately qualified persons to whom he/she has delegated specified Study-
related duties. The PI will ensure that adequate training is provided and documented for all Study 
staff, prior to conducting assigned Study-related activities. Even when certain activities are delegated, 
the PI will ultimately remain responsible for the conduct of the Study at his/her Participating Site. 
It is the Coordinating Investigator's (CI’s) responsibility to supervise the general conduct (e.g. Study 
progress, communication, protocol training and support of the participating sites, annual reporting 
to the Ethics Committee (EC), end of Study notification(s) and results reporting…) of the Study. 
The CI fulfils both Investigator and Sponsor responsibilities, as outlined in International Conference 
on Harmonisation – Good Clinical Practice (ICH-GCP) E6(R2) and applicable regulations. 
PI and CI shall each be referred to as «Investigator(s)». 
 
 
 

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STUDY SYNOPSIS 
 
Title of clinical Study 
(«Study») 
Intelligence and neurodevelopmental outcome after prenatal 
exposure to labour epidural analgesia: a sibling matched clinical 
ambidirectional cohort study 
Protocol Short Title 
Acronym 
Labour epidural analgesia-IQ 
Sponsor name 
University Hospitals of Leuven (UZ Leuven) 
Coordinating Investigator 
Prof Dr. Sarah Devroe 
           Contact Address CI Herestraat 49, 3000 Leuven, Belgium 
           Contact Email CI 
sarah.devroe@uzleuven.be 
           Contact Phone CI 
016/34.42.70 
Public database nbr 
NA 
Principal Investigator 
Prof Dr. Sarah Devroe 
Medical condition or 
disease under investigation 
Prenatal exposure to labour epidural analgesia 
Study rationale 
In Belgium, labour epidural analgesia (LEA) has been used for 
decades in the vast majority of vaginal deliveries (up to 83% of 
deliveries). Labour epidural analgesia is the most effective and safest 
way to allow pregnant women a nearly pain-free labour- and birth 
experience. Recent data showed that the use of LEA was associated 
with a reduced risk for severe maternal morbidity, neonatal 
resuscitation and with a reduced risk for low Apgar scores. 
However, prenatal exposure to labour epidural analgesia has been 
associated by several study groups with an increased risk for autism 
spectrum disorder (ASD) in the children, but these studies suffer 
from several important limitations which may have induced 
significant bias (e.g., not correcting for unmeasured confounders). 
Associations with other neurodevelopmental disorders (e.g., 
Attention Deficit Hyperactivity Disorder (ADHD), oppositional 
defiant disorder (ODD) and conduct disorder (CD)) and cognitive 
functioning have not been investigated yet. There is hence an urgent 
need for a study allowing definitive conclusions by overcoming the 
limitations of the previous studies. We will perform the first sibling-
matched clinical cohort study using a prospective investigator-
assessment of multiple domains of cognitive functions. We 
hypothesize that prenatal exposure to LEA will neither be 
associated with reduced intelligence nor with more 
neurodevelopmental disorders. Validating our hypothesis holds the 
potential to grant women the assurance to confidently receive the 
most efficacious method for labour analgesia, free from 

UZ/KU Leuven 
 
 
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apprehension that it might have adverse implications for their 
children's neurodevelopment. 
Primary objective 
To compare the intelligence of children prenatally exposed to labour 
epidural analgesia with that of sibling matched unexposed children. 
Secondary objective(s) 
To compare parentally reported traits of ASD, ADHD, ODD and 
CD of children prenatally exposed to labour epidural analgesia with 
that of sibling matched unexposed children. 
Endpoints 
-Primary endpoint: Wechsler full scale intelligence quotient 
-Secondary endpoints: multiple indexes assessed by the Wechsler 
intelligence scale: verbal comprehension index, visual spatial index, 
working memory index, fluid reasoning index and processing speed 
index. Total scores and subscores of the parental questionnaires 
“social 
responsiveness 
scale” 
(SRS) 
and 
“vragenlijst 
voor 
gedragsproblemen bij kinderen 6-16” (VvGK6-16) are additional 
secondary endpoints. 
Sample size 
At least 64 prenatally exposed children and 64 prenatally unexposed 
children 
Summary of eligibility 
criteria 
Dutch speaking sibling pairs discordant for prenatal exposure to 
labour epidural analgesia will be included. Children born from 1st 
January 2014 until 1st November 2019 will be included. Children 
prenatally exposed to maternal surgery, foetal 
surgery/interventions, chemotherapy, radiotherapy, radiology and 
oncologic pathology will be excluded. Children with a diagnosis of 
severe disability of genetic origin (e.g., Fragil X, Down 
syndrome,…), history of head trauma, major congenital birth 
defects, children born at a gestational age < 37 weeks or > 42 
weeks, or with a birth weight < 2.5 kg will be excluded. Children 
exposed to general anaesthesia after birth, twins/triplets/multiple 
births will be excluded. Elective and intrapartum caesarean sections 
will be excluded. 
Maximum duration a 
research subject remains in 
the study 
Study will be conducted in 2024-2027. The end of the study for 
each individual participant is determined by the date at which the 
neuropsychological testing is planned. Neuropsychological testing 
usually takes no longer than 2 hours. 
Participating research sites 
UZ Leuven, Herestraat 49, 3000 Leuven, Belgium 
Third parties 
NA 
 
 
 
 

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1. Background and Rationale   
In the European Union, nearly 4,100,000 children were born alive in 20211. It can be estimated that 
during the delivery of more than 3,300,000 children, the mother received labour epidural 
analgesia (LEA) to manage labour pain2-4. This occurs during critical phases of foetal brain 
development5. Exposure of the developing brain to LEA has been associated by several study groups 
with autism spectrum disorder (ASD)6-11. To the best of our knowledge, currently, there is no data 
available on the potential association between LEA and other neurodevelopmental disorders, 
including attention-deficit/hyperactivity disorder (ADHD)12, oppositional defiant disorder (ODD) en 
conduct disorder (CD). One of the most consistent findings is that neurodevelopmental disorders 
are characterized by lower and/or discrepant intelligence profiles16, 17 (e.g., 30-70% of children 
with ASD have an intellectual disability)18-23. In general, these neurodevelopmental disorders affect 
10% of the children worldwide and lead to impairments in various aspects of functioning, such as 
cognition, communication, social interaction, and motor skills24. While these deficits become 
frequently symptomatic in early childhood, they affect individuals throughout their entire 
lifespan24, 25, can lead to a range of adverse outcomes, including difficulties in academic and 
career development, severe mental disorders, and even premature death26, 27. 
Neurodevelopmental disorders place a significant economic burden on individuals, families, 
and societies by increasing healthcare costs, educational costs, expenses for caregivers and social 
services, legal costs, and necessitating long-term care and mental care25. Families caring for a child 
with a neurodevelopmental disorder face higher financial costs and have reduced working hours 
with higher rates of poverty as a consequence25. In the European Union, the societal economic 
burden of ASD can be estimated to be as high as €140,000 billion28, 29 and for ADHD, it can be 
estimated as €21,000 million30, 31. Therefore, gaining knowledge on the aetiology, pathophysiology 
and possible prevention strategies of neurodevelopmental disorders is a public health priority25. 
There is an urgent need to further investigate LEA as a potential risk factor for long-
term neurodevelopmental consequences. We hypothesize that prenatal exposure to LEA will 
neither be associated with reduced intelligence nor with more neurodevelopmental disorders. 
Validating our hypothesis holds the potential to grant women the assurance to confidently receive 
the most efficacious method for labour analgesia, free from apprehension that it might have adverse 
implications for their children's neurodevelopment. 
 
1.1 Labour pain and management 
Labour pain is very severe pain caused by uterine contractions and perineal tissue damage, leading to 
intense maternal emotional distress and – if untreated – to a high risk of postpartum depression32, 33. 
Additionally, the maternal stress response to pain results in maternal hyperventilation, release of 
catecholamines and other vasoactive mediators, causing decreased uterine blood flow with foetal 
distress and neonatal asphyxia as potential consequences32, 33. LEA is currently the gold 
standard in the management of labour pain33, 34. LEA can be medically indicated, e.g., a high risk for 
caesarean section. In several European countries and the United States of America, up to 83% of 
pregnant women receive LEA for delivery2-4, 32, 33. In other countries (e.g., the UK), LEA is 
much less implemented35, 36. Patient satisfaction is higher for LEA when compared with other 
approaches, and LEA is considered safe during delivery for both the mother and the foetus33, 34, 37, 38. 

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Recent data even showed that the use of LEA was associated with a reduced risk for severe 
maternal morbidity36, neonatal resuscitation and with a reduced risk for low Apgar scores39. 
However, the investigation of long-term consequences of the use of LEA has been started only 
recently. 
 
1.2 Neurodevelopmental effects of labour epidural analgesia 
Observational studies 
In 2020, a first retrospective clinical cohort study showed an association between LEA and 
ASD [hazard ratio (HR) 1.37, 95% confidence-interval (CI): 1.23-1.53]6. Additionally, a clear dose-
response relationship was reported, raising a safety concern for public health6. Thereafter, 
other retrospective observational studies corroborated this finding7-11, even when taking several 
confounders into account (e.g., maternal age at delivery, parental education and income, birth 
weight, prematurity, pregnancy complications etc.). In contrast, other retrospective observational 
studies failed to confirm an association between LEA and ASD40-43, especially when using a sibling 
matched design8, 10, 40-42. Likewise, the only prospective observational study (using caregiver 
questionnaires) performed so far failed to prove this association44. 
 
Systematic reviews and meta-analyses 
Recent systematic reviews found a significantly increased risk for ASD when confounders were not 
taken into account [HR 1.3, CI: 1.25-1.3545 and HR 1.24, 95% CI: 1.14-1.3432]. When potential 
confounders were considered, the effect was smaller but still statistically significant [HR 1.13, 95% 
CI: 1.03-1.2545 and HR 1.11, 95% CI: 1.06-1.1632]. When only studies using a sibling-matched design 
were analysed, one meta-analysis concluded that there was no significant association [HR 1.07, 95% 
CI: 0.99-1.16]45, whereas another meta-analysis demonstrated a significant association in sibling-
matched designs [HR 1.10, 95% CI: 1.02-1.18], with however no dose-response effect32. It was 
concluded that the statistically significant association between LEA and ASD may be 
explained by unmeasured confounders (e.g., genetic factors)45. 
While nearly all studies focused on the association between LEA and ASD, other 
neurodevelopmental outcomes have been reported only in a limited number of studies. There was 
no evidence for an association between LEA and learning disorders46, ADHD8, 10, intellectual 
developmental disorder8 and epilepsy8. A single retrospective cohort study observed that LEA was 
even associated with a reduced risk for developmental concerns (gross and fine motor function, 
communication and social functioning39, while another study observed an increased risk47. 
Apart from being contradictory, the available studies suffer from several important limitations 
which may have induced significant bias. First, it is obvious that retrospective studies without 
sibling matching cannot correct for unmeasured/unmeasurable confounders such as genetic 
factors, which could contribute to the predisposition for ASD45. Second, with the exception of one 
study44, all studies assessed the outcomes retrospectively, using already existing population-
based datasets and administrative records (e.g., health insurance databases, which were obviously 

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not specifically designed to investigate this subject). Third, there are no studies prospectively 
assessing investigator-assessed outcomes allowing an objective neurocognitive testing. 
Fourth, in several studies8, 39, 41, both vaginal deliveries and caesarean sections were included. 
Fifth, the majority of studies focussed on ASD and did not assess other cognitive 
functions. Last, the neurophysiological mechanism by which LEA could cause 
neurodevelopmental disorders remains entirely elusive.  
LEA has been used for decades in the vast majority of vaginal deliveries (up to 83%2-4, 32, 33). 
LEA is the most effective and safest way to allow pregnant women a nearly pain-free labour- and 
birth experience33, 34, 37, 38.  A detrimental effect on neurodevelopmental outcomes would be a 
massive public health issue, unsettle parents and caregivers, and put birthing persons at risk for pain 
and untoward maternal and neonatal outcomes. There is hence an urgent need for a study 
allowing definitive conclusions by overcoming the majority of the above-mentioned 
limitations. We will perform the first sibling-matched clinical cohort study using a 
prospective investigator-assessment of multiple domains of cognitive functions. 
 
2. Study Objectives and Design 
2.1 Study objectives 
The primary objective of this clinical ambidirectional cohort study is to compare the intelligence 
of children prenatally exposed to LEA with those of sibling-matched unexposed 
children. In line with a recent systematic review investigating associations with ASD, and by 
appropriately taking confounders into account, we hypothesize that prenatal exposure to LEA will 
neither be associated with reduced intelligence nor with more neurodevelopmental disorders (ASS, 
ADHD)45. Validating our hypothesis holds the potential to grant women the assurance to confidently 
receive the most efficacious method for labour analgesia, free from apprehension that it might have 
adverse implications for their children's neurodevelopment. 
The secondary objective is to compare parentally reported traits of ASD, ADHD, ODD and CD 
between exposed and unexposed children. 
 
2.2 Primary Endpoints 
Primary outcome will be the Wechsler full-scale intelligence quotient which will be assessed using the 
Wechsler Intelligence Scale for Children (WISC).  
 
2.3 Secondary Endpoints 
Secondary outcomes will include the multiple indices assessed by the Wechsler intelligence scale: 
verbal comprehension, working memory, visual spatial, fluid reasoning, processing speed. 
 

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The absolute risk reduction for a clinically relevantly decreased intelligence quotient, defined as an 
IQ<85, will be calculated. 
The total scores and subscores of the parental reported questionnaires “social responsiveness scale” 
(SRS) and “vragenlijst voor gedragsproblemen bij kinderen 6-16” (VvGK6-16) will be additional 
secondary outcomes. For the SRS questionnaire, the total score reflects the severity of parental 
reported social deficits in the autism spectrum. Additionally, five subscale scores will be analyzed: 
social awareness, social cognition, social communication, social motivation, and restricted interests 
and repetitive behavior. The VvGK6-16 is the Dutch versions of the “Disruptive Behavior Disorders 
Rating Scale” (DBDRS) and have four domains that will be analyzed: inattention, hyperactivity and 
impulsivity (ADHD), oppositional defiant disorder (ODD) and conduct disorder (CD). 
 
2.4 Study Design 
Ambidirectional cohort study with retrospective assessment of the exposure to prenatal labour 
analgesia and prospective assessment of the Wechsler intelligence quotient of the children and two 
parental questionnaires (SRS and VvGK6-16). Confounding bias will be reduced by using sibling 
matching and by adjusting for confounders in mixed-effects regression models. 
 
2.5 Expected duration of the study 
In the table below, the research timeline can be found.  
 
2024 
2025 
2026 
2027 
2028 
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 
 
 
 
 
 
 
 
 
 
 
 
Identification of cohort 
 
Contacting participants to schedule neuropsychological testing 
 
Neuropsychological testing 
 
Data analysis, writing article and publication 
 
The end of the study for each individual participant is determined by the date at which the 
neuropsychological testing is planned. Neuropsychological testing usually takes no longer than 2 
hours. 
 
2.6 Translational research 
NA 
 

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3. Study Population / Eligibility Criteria 
3.1 Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
Sibling pairs discordant for prenatal exposure to LEA will be included: 
Exposed children 
Unexposed children 
• 
Children prenatally exposed to labour 
epidural analgesia  
• 
Sibling of an exposed child 
• 
Prenatally not exposed to labour 
epidural analgesia 
• 
Children born from 1st January 2014 until 1st November 2019 
(In our centre, a new technique of LEA has been introduced in 2014 and 
thereafter, clinical practice has remained largely unchanged. Neurocognitive 
testing will start on 1st November 2025 and completion is anticipated for 31st 
December 2027. During this period, these children will have an age of 6-14 years. 
The Wechsler Intelligence Scale for Children is validated for children with this 
age.) 
• 
Parental informed consent  
 
3.2 Exclusion criteria 
Participants eligible for this study must not meet any of the following criteria: 
Exposed children 
Unexposed children 
• 
Children whose mothers underwent maternal surgery or foetal surgery/interventions 
during the same pregnancy. 
• 
Children exposed to general anaesthesia after birth 
• 
Children prenatally exposed to chemotherapy, radiotherapy, radiology, oncologic 
pathology 
• 
Children born at a gestational age < 37 weeks or > 42 weeks, or with a birth weight < 2.5 
kg  
• 
Twins, triplets, multiple births 
• 
No Dutch-speaking children 
• 
Diagnosis of severe disability of genetic origin (e.g., Fragil X, Down syndrome,…), history 
of head trauma, major congenital birth defects 
• 
Elective caesarean section and intrapartum caesarean section (the number of caesarean 
sections will be reported and compared between both groups) 

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• 
Foetus died before start of delivery 
 
4. Assessment of Efficacy 
See section “2. Objectives and Design”. 
5. 
Assessment of Safety 
5.1 
Specification, timing and recording of safety parameters 
The sponsor will assess whether any relevant safety information that becomes available during the 
study should be reported ad hoc to the EC. 
 
5.2 
Treatment stopping rules 
NA 
 
6. Identification of study participants, contact with study 
participants and intelligence testing 
6.1 Identification of study participants 
In the period 2014-2024, approximately 14 000 parturients received LEA in our centre. Eligible 
sibling pairs discordant for prenatal exposure to LEA will be identified retrospectively in this period 
using the birth lists and hospital file system of our centre. For mothers having more than two eligible 
children with discordant prenatal LEA exposure (e.g., one exposed child and five unexposed 
children; two exposed children and four unexposed children), a computer random number 
generator will be used to select one exposed child and one unexposed child (i.e., sibling pairs) in 
these mothers. This will be done because a 1/1 ratio of exposed/unexposed children results in the 
sample size calculation in the lowest total number of children that should be included in this study. 
This 1/1 ratio with optimal statistical power will be used, as performance of the intelligence tests is 
time consuming: it is desirable for the participants and to limit financial resources. 
 
6.2 Contact with study participants 
After identification, we will send an invitation to the parents and their children by mail or e-mail with 
information on this study and our contact details. One week after receiving this invitation, we will 
start to contact the parents by telephone to ask for their willingness to participate, to send them the 
informed consent and to schedule the assessment of the Wechsler intelligence test. If the parents 
prefer to have more time before making a decision, we will send an e-mail with a link to an online 
planning tool to schedule the Wechsler intelligence test or to contact us again in case they decided 
not to participate. Depending on the results of this contact, the following actions will be undertaken: 

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• 
The parents agree to participate and an intelligence test is scheduled 
No further contact is needed.  
 
• 
The parents will contact us again to inform us on their decision  
In case we do not receive a decision after one month, we will contact the parents 
again by telephone. When the parents are still interested in participating in the study, 
we will ask to schedule an intelligence test by telephone or resend the link for the 
online planning tool. We will continue this cycle of checking the responses after one 
month and contacting the parents again until they mention that they do not want to 
participate anymore. This method of continuing contact with the parents is important 
because practical problems can be a crucial reason for non-response, even for highly 
motivated parents. 
 
• 
No telephone number can be found in the hospital file system. 
First, the child's patient file will be checked for a telephone number, followed by the 
mother, brothers or sisters' file. 
 
• 
Parents do not pick up the phone or a voicemail is heard. 
In both cases, we will continue to call the parents until we succeed in talking directly 
to them. No message will be left in voicemails. Study information will be sent by e-
mail or mail if telephone calls remain unanswered. 
 
• 
When the parents indicate that they are not interested in participation in the study at any stage of 
the phone calls, we will not contact them again anymore. 
To allow estimating selection bias by passive non-response analysis, the active or 
passive reason for refusal of participation will be asked and one of the following 
categories will be registered: 
 
▪ 
No time 
▪ 
Too demanding 
▪ 
No interest in study 
▪ 
Health problem 
▪ 
Negative experience with delivery 
▪ 
Specific reason, i.e.  … 
 
6.3 Intelligence testing 
The intelligence test will be performed by trained investigators. First, the investigators will follow the 
theoretic course on the assessment of intelligence testings to obtain a Pearson® certificate. 
Thereafter, the investigators will practice the assessment of the intelligence testing on volunteering 
children of friends and family under supervision and with feedback of Jurgen Lemiere, a pediatric 
neuropsychologist at UZ Leuven with extensive experience of intelligence testing. Only after achieving 
proficiency of the intelligence test assessment, they will start with the assessments for the study. 

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The intelligence test will be performed in UZ Leuven or can also be performed at home if it is not 
possible to come to the hospital.  
First, the parents and the children will be given detailed written and oral information and will then be 
asked to sign the informed consent. 
Thereafter, the intelligence testing will be performed while the parent(s) wait in a different room. 
During this time, the parent will be asked to complete the parental questionnaires. 
Multiple investigators will assess the Wechsler intelligence quotient. Each of these investigators will 
always assess both siblings of each sibling pair. 
After the test, child and the parent will receive a €25 voucher. This voucher is intended to cover 
travel expenses and to compensate for the time and effort invested in participating. Additionally, 
parents will be asked if they wish to be informed about the IQ score. This score, along with an 
explanation of how it compares to the general population, will be sent via mail after completion of the 
study. It will be emphasized that individual results and differences between the siblings should be 
interpreted with caution. Individual results can be affected by many factors, e.g., the efforts, 
concentration and motivation at the moment of testing. Furthermore, individual differences between 
siblings probably do not only represent the effects of labour epidural analgesia, but are also affected 
by many other factors. The study results will be discussed as well. The phrasing and communication 
of results will be done individually and will be conducted in collaboration with Jurgen Lemiere, a 
pediatric neuropsychologist at UZ Leuven. Our telephone number will be mentioned in the e-mail and 
the parents can call us personally in case of questions or concerns. These concerns will be discussed 
with Jurgen Lemiere and follow-up will be provided if desired. 
 
Withdrawal of participation 
In case one sibling or its parents decide to withdraw his/her participation to the study, the results of 
the other sibling will still be included in the study. 
7. Statistics and Data Analysis 
Analysis 
A non-inferior sibling matched study design will be used. The inferiority margin represents the largest 
difference acceptable to show non-inferiority. The inferiority margin will be set at half of the standard 
deviation of the normative score for each instrument in a normal population, which is shown in the 
table below. The difference of the outcome in the unexposed group minus the outcome in the exposed 
group will be investigated. The null hypothesis states that this difference is greater than or equal to 
the inferiority margin, i.e., LEA is inferior to no LEA. The alternative hypothesis states that this 
difference is smaller than the inferiority margin, i.e., LEA is non-inferior to no LEA. Non-inferiority is 
defined as the upper limit of the 95% confidence interval for the difference of the outcomes between 
exposed and unexposed children being lower than the inferiority margin. 

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Standard deviation in a normal 
population 
Inferiority margin 
Wechsler intelligence test 
15 
7.5 
Social 
responsiveness 
scale 
(SRS) 
10 
5 
Vragenlijst 
voor 
gedragsproblemen bij kinderen 
6-16 (VvGK6-16) 
3 
1.5 
A sibling matched study design is used to take unmeasured (e.g., genetic) confounders into account.  
It will be compared whether following measured confounders are different between exposed and 
unexposed children: gender of the child, birth weight, gestational age at delivery, exposure of the 
mother during pregnancy to smoking, alcohol, illegal drugs, paritus history, pregnancy diabetes, 
pregnancy induced hypertension, pre-eclampsia, eclampsia, premature rupture of membranes, 
antepartum 
hemorrhage6-11, 
39-42, 
47.  
The analyses of the primary and secondary outcomes will be adjusted for these measured confounders 
with statistically significant differences (p < 0.05) between both groups. 
The primary and secondary outcomes will be analysed in mixed-effects regression models with a 
random intercept to take the clustering of the siblings into account. The primary/secondary outcome 
will be the dependent variable; the group (exposed/unexposed) and the measured confounders 
(previous paragraph) will be the independent variables. The Wechsler full scale intelligence quotient 
scores, primary indexes of the Wechsler intelligence scale, and the total scores and subscores of SRS 
and VvGK6-16 will be analyzed using linear mixed regression models.  The absolute risk reduction for 
IQ-scores <85 (the definition of a clinically relevantly decreased intelligence) will be analysed by using 
Poisson mixed regression models with the identity link51. 
A dose-response effect will be investigated by adding the duration of prenatal exposure to LEA as an 
independent variable to the regression model. 
The results of the adjusted matched analysis will be compared with an unmatched analysis without 
taking confounders into account (two sample t-test). 
The characteristics of the study participants (see section 8.2) will be compared between both groups.   
The potential selection bias caused by non-response rate will be assessed by comparing all known 
demographic variables (see section 8.2) between the subjects with response with these of the subjects 
without response, by wave analysis and passive non-response analysis 52, 53. 
A significance level of 0.05 two-sided will be used. Strong claims will be made only for the primary 
outcome in the primary analysis (i.e., primary objective). Secondary outcomes will be analyzed without 
correction for multiple testing.   
SAS software (SAS System for Windows version 9.4, SAS Institute Inc, USA) will be used.  

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In case of missing data, first an attempt will be done to complete these data by reviewing the hospital 
files, contacting the parents again etc. Therefore, and because this is a prospective study in which the 
investigators will collect all data, we expect a low number of missing data, especially for the 
confounders and study characteristics. Participants/sibling pairs with missing data for the 
intelligence/neurodevelopmental outcomes will be included in the analyses and the number of missing 
data will be reported for each outcome.  
 
Sample size 
For the primary outcome, assessment of the Wechsler intelligence quotient in 64 sibling 
pairs will allow to show non-inferiority of LEA in comparison with no LEA, with the 
inferiority margin being 7.5 [being half the standard deviation and half the difference between the 
average IQ (100) and the clinical cut-off value for a decreased IQ (85)]12, 17, 54-56.  For this sample size 
calculation, a one-sided alpha of 0.025 and 80% power is used, it is expected that there will be no 
difference between the population average of exposed and unexposed children, and it is assumed 
that the standard deviation of the primary outcome will be comparable to that of a normative 
population of children (i.e., 15)12, 17, 54-56. While 64 sibling pairs are sufficient to show non-inferiority, 
all children agreeing to participate in the entire cohort will be included in the study to further 
increase the power of the study. Additionally, this sample size calculation assumes the worst-case 
scenario of absence of correlation between the intelligence quotient of siblings. As observing a 
certain correlation within these pairs would be likely, this would also further increase the power of 
the study. 
 
8. Data handling  
8.1 General data handling information 
Data collection, handling and processing for the purpose of this Study will be performed in compliance with 
applicable regulations, guidelines for clinical studies and internal procedures.  It remains the responsibility 
of the Investigator to check that all data relating to the Study, as specified in the Study protocol, are entered 
into the electronic Case Report Form ((e)CRF) in accordance with the instructions provided and that the 
forms are filled out accurately, completely and in a timely manner. 
(e)CRFs are provided by the Sponsor for each participant. The Study data will be transcribed from the 
source records into an (e)CRF by Study Staff.  
The (e)CRFs shall under no circumstances capture personal data such as but not limited to the 
participant or their relative(s) name, home address, contact details, full date of birth medical record 
number (e.g. UZ Leuven EAD number), social security number etc.  
 
When the researchers (co-investigators) enter the data in RedCap, a record ID is generated, which is a 
unique pseudonymized code that is associated with a specific trial participant. In RedCap, no identifiers 
will be entered. On a secured departmental server, an Excel file will be stored, containing the identifiers 
required to contact the participants. 
 

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8.2 Study specific data handling information 
Redcap will be used to capture study related data. 
The following data will be collected in the (e)CRF : 
 
Characteristics of study participants, recruitment information (These data are required to describe the 
characteristics of the study participants and to contact and recruit the participants. The data will be obtained 
from the medical files, unless specified otherwise below.) 
• 
e-mail address (only visible for researchers involved in sending e-mails, from medical file or 
phone calls) 
• 
Group (exposed/unexposed) 
• 
Age group (2,5-6/7-13) 
• 
Theoretical date of last menstruation 
• 
Age child 
• 
Age mother at delivery 
• 
Gender child (Required for adjustment for confounders) 
• 
Child deceased (yes/no) (Required to avoid contacting parents of deceased children for intelligence 
testing. Also required to construct the flowchart of the included and excluded participants in the 
study.) 
• 
Additional notes 
• 
Will participate/refuses to participate in study (Obtained in phone calls) 
• 
Reason for refusal (Obtained in phone calls) 
• 
Additional notes on answer during telephone call (Obtained in phone calls) 
• 
All data is complete (yes/no) 
• 
Exclusion of this patient (yes/no) 
 
Pregnancy (These data are required to adjust for confounders, as these factors could affect primary and 
secondary endpoints. These data will be obtained from the medical files.) 
• 
Partus history 
• 
exposure of the mother during pregnancy to smoking  
• 
exposure of the mother during pregnancy to alcohol 
• 
exposure of the mother during pregnancy to drugs 
• 
pregnancy diabetes 
• 
pregnancy induced hypertension 
• 
pre-eclampsia 
• 
eclampsia 
• 
premature rupture of membranes 
• 
antepartum hemorrhage 
• 
data complete (yes/no) 
 
Delivery (These data are required to describe the characteristics of the study participants. This is important 
as these factors could be a potential consequence of the exposure to LEA and could be a cause of impaired 
primary and secondary outcomes57, 58. These data will be obtained from the medical files.) 
• 
Gestational age at delivery (Required for adjustment for confounders) 
• 
Birth weight (Required for adjustment for confounders) 
• 
Mode of delivery (vaginal/caesarean section) 
• 
Emergency caesarean section (yes/no) 

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• 
Type of labour analgesia (CSE/epidural/none) 
• 
Duration of labour analgesia 
• 
Duration of delivery 
• 
Use of forceps or vacuum extraction 
• 
Fetal presentation (cephalic versus all other presentations) 
• 
Dystocia 
• 
Birth trauma 
• 
Umbilical cord compression 
• 
Labour induction 
• 
Neonatal resuscitation 
• 
Admission to the neonatal intensive care unit after delivery 
• 
Foetal pH at birth 
• 
Apgar score at birth 
 
Intelligence testing 
• 
date when intelligence testing was completed 
• 
neuraxial analgesia during delivery 
• 
Did your child receive anaesthesia? 
o Type of anaesthesia (general/local) 
• 
Remarks of parents 
• 
Results of Wechsler intelligence score testing 
o Full-scale intelligence quotient 
o Primary index scores 
▪ 
verbal comprehension index 
▪ 
 visual spatial index (WPPSI-IV and WISC-V) 
▪ 
working memory index 
▪ 
 fluid reasoning index (WPPSI-IV, WISC-V) 
▪ 
 processing speed index 
• 
Result of the SRS questionnaire 
o Total score 
o Subscores 
▪ 
social awareness 
▪ 
social cognition 
▪ 
social communication 
▪ 
social motivation 
▪ 
restricted interests and repetitive behavior 
• 
Result of the VvGK6-16 questionnaire 
o Inattention 
o hyperactivity and impulsivity 
o oppositional defiant disorder (ODD) 
o conduct disorder (CD) 
 
Immediately before the start of the data analysis, the RedCap database will be exported to SAS 
software (SAS 9.4, SAS Institute Inc., Cary, NC, USA) for the statistical analysis. 
 
 
8.3 Direct Data Access 

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The investigator(s) and the institution(s) will permit trial-related monitoring, audits, EC review, and 
regulatory inspections (where appropriate) by providing direct access to source data and other 
documents. 
 
9. Ethical and Regulatory Considerations 
9.1 Ethics Committee (EC) review & reports  
 
Before the start of the Study, this protocol and other related documents will be submitted for review to 
the EC for Study authorization. The Study shall not commence until such approvals have been obtained 
and until other relevant essential Study documents, such as duly signed contract agreements, evidence of 
adequate Study financing etc. are in place. 
9.2 Protocol / GCP compliance 
The Study must be performed in accordance with the protocol, current ICH and ICH-GCP guidelines, and 
applicable regulatory and country-specific requirements. ICH guidelines are an international ethical and 
scientific quality standard for designing, conducting, recording, and reporting studies that involve the 
participation of human participants. Compliance with this standard provides public assurance that the rights, 
safety, and well-being of Study participants are protected, consistent with the principles that originated in 
the most recent version of the Declaration of Helsinki, and that the Study data are credible, reliable and 
reproducible. 
9.3 Data protection and participant confidentiality 
The Study will be conducted in compliance with the requirements of the EU General Data Protection 
Regulation 2016/679 (GDPR), and the relevant Belgian laws implementing the GDPR including the Belgian 
Privacy Act of 30 July 2018 on the protection of privacy in relation to the processing of personal data. 
Any collection, processing and disclosure of personal data, such as participant health and medical 
information is subject to compliance with the aforementioned personal data protection laws (cfr. Data 
Processing Annex (DPA) in Appendix).  
Any personal data shall be treated as confidential at all times including during collection, handling and use 
or processing, and the personal data (including in any electronic format) shall be stored securely at all times 
and with all technical and organizational security measures that would be necessary for compliance with 
EU and national data protection legislation (whichever is more stringent). The Sponsor shall take 
appropriate measures to ensure the security of all personal data and guard against unauthorized access 
thereto or disclosure thereof or loss or destruction while in its custody. 
10. Research Registration, Dissemination of Results and 
Publication Policy 
The Declaration of Helsinki (latest version) and European and Belgian regulations require that every 
research Study involving human participants be registered in a publicly accessible database before 
recruitment of the first participant. The CI is responsible for registering the Study.  
In addition, the CI will fulfil their ethical obligation to disseminate and make the research results publicly 
available. As such the CI is accountable for the timeliness, completeness and accuracy of the reports. 
Researchers, authors, Sponsors, editors and publishers must adhere to accepted guidelines for ethical 
reporting. Negative and inconclusive, as well as positive results must be published or otherwise made 
publicly available. Sources of funding, institutional affiliations and conflicts of interest must be declared in 
publication.  

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Publications will be coordinated by the CI. Authorship to publications will be determined in accordance 
with the requirements published by the International Committee of Medical Journal Editors and in 
accordance with the requirements of the respective medical journal. 
 
11. Insurance/Indemnity 
In accordance with the Belgian Law relating to experiments on human persons dated May 7, 2004, 
Sponsor shall assume, even without fault, the responsibility of any damages incurred by a Study Patient 
and linked directly or indirectly to the participation to the Study, and shall provide compensation 
therefore through its insurance.” 
 
 

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12. References 
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46 Flick RP, Lee K, Hofer RE, et al. Neuraxial labor analgesia for vaginal delivery and its effects on 
childhood learning disabilities. Anesth Analg 2011; 112: 1424-31 
47 Shima M, Tokuda N, Hasunuma H, et al. Association of epidural analgesia during labor with 
neurodevelopment of children during the first three years: the Japan Environment and Children's 
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48 Walkden GJ, Pickering AE, Gill H. Assessing Long-term Neurodevelopmental Outcome Following 
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51 Curtis LH, Hammill BG, Eisenstein EL, Kramer JM, Anstrom KJ. Using inverse probability-weighted 
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52 Halbesleben JR, Whitman MV. Evaluating survey quality in health services research: a decision 
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53 Phillips AW, Reddy S, Durning SJ. Improving response rates and evaluating nonresponse bias in 
surveys: AMEE Guide No. 102. Med Teach 2016; 38: 217-28 
54 Gano D, Andersen SK, Glass HC, et al. Impaired cognitive performance in premature newborns 
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