Fetal Brain Care: Therapies for Brain Neurodevelopment in Fetal Growth Restriction
Phase: NA
Conditions: Fetal Growth Retardation, Intrauterine Growth Restriction
Sponsor: Institut d'Investigacions Biomèdiques August Pi i Sunyer

FetalBrainCare (December 2022) 
 
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FETAL BRAIN CARE 
Therapies for brain neurodevelopment in fetal 
growth restriction 
 
 
 
 
 
 
Chief investigators: Elisenda Eixarch, Míriam Illa, Eduard Gratacós 
Principal investigator: Elena Monterde 
 
 
 
 
Date: December 2022  
Setting: BCNatal | Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de 
Déu), Barcelona, Spain  
Research line: Fetal brain development and fetal therapy 
NCT: 05038462 

FetalBrainCare (December 2022) 
 
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ADMINISTRATIVE INFORMATION 
This document provides information about an understanding of the background, rationale, 
objectives, and procedures for entering participants into the study, study population, 
interventions, methods, statistical analyses, ethical considerations, and administration of the 
study. Every care has been taken in drafting this protocol, but corrections or amendments may 
be necessary. The study will be conducted in compliance with the approved protocol, the 
Declaration of Helsinki (2008), and the principles of Good Clinical Practice (GCP). 
 
Structures study summary 
Public title 
Fetal Brain Care 
Scientific title 
Fetal Brain Care: Therapies for brain neurodevelopment in fetal growth 
restriction (FGR) 
Contact for public queries 
FETALBRAINCARE@clinic.cat 
Contact for scientific queries 
Chief investigators:  Elisenda Eixarch, Míriam Illa, Eduard Gratacós 
Principal investigator: Elena Monterde 
 
BCNatal – Fetal Medicine Research Center (Hospital Clínic and Hospital 
Sant Joan de Déu), Barcelona, Spain 
Setting of recruitment 
BCNatal - Hospital Clínic and Hospital San Joan de Déu, Barcelona, Spain 
Hospital General de l’Hospitalet, Barcelona, Spain 
Hospital Germans Trias i Pujol, Barcelona, Spain 
Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 
Hospital del Mar, Barcelona, Spain 
Hospital Dexeus-Quirón, Barcelona, Spain 
Problem studies 
Neurodevelopment in FGR 
Participants  
Pregnant women with FGR 
Study type 
A multicenter, randomized, double-blind clinical trial 
Interventions 
Maternal administration of 1000 mg of Lactoferrin + 1000 mg of DHA every 
day orally or placebo 
Sample size 
304 participants: 152 for each arm of randomization (Lactoferrin + DHA, 
placebo) 
Inclusion and exclusion criteria  
Inclusion: 
Singleton pregnancies 
Non-malformed fetus 
Pregnancies with FGR 
24-32.6 weeks of gestation 
 
Exclusion: 
Chromosomal or structural abnormalities 
Critical Doppler 

FetalBrainCare (December 2022) 
 
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Maternal mental or psychiatric disorders 
Maternal allergy to cow’s milk protein 
Data of first enrolment  
January 2023 
Study aims  
To evaluate the impact of maternal supplementation with DHA and 
Lactoferrin on neurodevelopment in pregnancies with FGR, as assessed by 
fetal brain MRI and postnatal neurodevelopmental tests. 
To evaluate the impact of maternal supplementation with DHA and 
Lactoferrin on fetal growth assessed by prenatal ultrasound in FGR. 
To evaluate the impact of maternal supplementation with DHA and 
Lactoferrin on perinatal morbidity (neonatal acidosis, intraventricular 
hemorrhage III/IV, necrotizing enterocolitis, periventricular leukomalacia, 
sepsis, bronchopulmonary dysplasia) and mortality in FGR. 
 
Roles and responsibilities 
Name 
Affiliation 
Role 
Elisenda Eixarch (EE) 
BCNatal 
Co-Chief investigator, Coordinator of Fetal Neurology Unit, 
specialist in Obstetrics and Fetal Medicine.  
General coordination and supervision of the project and analysis, 
interpretation and dissemination of results. 
Míriam Illa (MI) 
BCNatal 
Co-Chief Investigator, Member of Fetal Neurology Unit, 
specialist in Obstetrics and Fetal Medicine.  
General coordination of the project, data collection 
supervision, neurosonography evaluation, supervision of fetal 
MRI acquisition and analysis, supervision of postnatal follow-
up, and analysis, interpretation and dissemination of results. 
Eduard Gratacós (EG) 
BCNatal 
Co-Chief investigator, Director of Department of Obstetrics, 
Gynecology and Neonatology of Hospital Clinic Barcelona, Director 
of BCNatal Center.  
General coordination and supervision of the project and analysis, 
interpretation and dissemination of results. 
Elena Monterde (EM) 
BCNatal 
Principal investigator, specialist in Obstetrics and Fetal Medicine 
at Hospital Clínic. 
Patient 
recruitment, 
data 
collection, 
neurosonography 
evaluation, MRI analysis, supervision of postnatal follow-up, 
and analysis, interpretation and dissemination of results. 
Francesc Figueras (FF) 
BCNatal 
Head of Maternal-Fetal Medicine Department at Hospital 
Clínic, specialist in Obstetrics and Fetal Medicine. 
Co-supervisor of patient recruitment at BCNatal, statistical 
support. 
Mª Dolores Gómez Roig 
(DG) 
BCNatal 
Head of Gynecology and Obstetrics Department at HSJD, 
specialist in Obstetrics and Fetal Medicine. 
Co-supervisor of patient recruitment at BCNatal, statistical 
support. 
Eva Meler (EMB) 
BCNatal 
Member of Intrauterine Growth Restriction Unit at Hospital 
Clínic, specialist in Obstetrics and Fetal Medicine.  
Co-supervision of fetal recruitment, clinical follow-up, and 
ultrasound evaluation. 
Anna Peguero (AP) 
BCNatal 
Member of Intrauterine Growth Restriction Unit at Hospital 
Clínic, specialist in Obstetrics and Fetal Medicine.  

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Co-supervision of fetal recruitment, clinical follow-up, and 
ultrasound evaluation. 
Edurne Mazarico (EMG) 
BCNatal 
Member of Intrauterine Growth Restriction Unit at Hospital 
Clínic HSDJ, specialist in Obstetrics and Fetal Medicine.  
Co-supervision of fetal recruitment, clinical follow-up, and 
ultrasound evaluation. 
Mónica Rebollo (MR) 
BCNatal 
Neuroradiologist at HSJD. 
Responsible of the acquisition, processing and analysis of fetal 
brain MR. 
Marta Gómez-Chiari (MG) 
BCNatal 
Neuroradiologist at HSJD. 
Responsible of the acquisition, processing and analysis of fetal 
brain MR. 
Carme Fons (CF) 
HSJD 
Head of Neurology Unit at HSJD, specialist in Paeditrician 
Neurology.  
Responsible of the neoantal follow-up and functional assessment. 
Susana Fernandez (SF) 
Hospital 
General 
Hospitalet 
Coordination and patient recruitment in Hospital General de 
l’Hospitalet, data collection, clinical follow-up, and ultrasound 
evaluation. 
Carmina Comas (CC) 
Hospital 
Can 
Ruti 
Coordination and patient recruitment in Hospital Germans 
Trias i Pujol, clinical follow-up, and ultrasound evaluation. 
Beatriz Lorente (BL) 
Hospital 
Can 
Ruti 
Patient recruitment in Hospital Germans Trias i Pujol, data 
collection, clinical follow-up, and ultrasound evaluation. 
Irene Ribera (IR) 
Hospital Sant 
Pau 
Coordination and patient recruitment in Hospital de la Santa 
Creu i Sant Pau, clinical follow-up, and ultrasound evaluation. 
Antonio Fernandez (AF) 
Hospital Sant 
Pau 
Patient recruitment in Hospital de la Santa Creu i Sant Pau, data 
collection, clinical follow-up, and ultrasound evaluation. 
Jose Luis Hernandez (JLH) 
Hospital 
del 
Mar 
Coordination and patient recruitment in Hospital del Mar, data 
collection, clinical follow-up, and ultrasound evaluation. 
Gerard Albagies (GA) 
Hospital 
Dexeus-Quirón 
Coordination and patient recruitment in Hospital Dexeus-
Quirón, data collection, clinical follow-up, and ultrasound 
evaluation. 
Erika Muñoz (EMZ) 
BCNatal 
Lab technician. 
Coordinator of sample collection and storage, sample analysis. 
Nuria 
Sebastian-Galles 
(NS) 
Univesitat 
Pompeu Fabra 
Barcelona 
Coordination of the neurodevelopmental assessment at 
Speech Acquisition and Perception Lab. 
Chiara Santolin (CS) 
Univesitat 
Pompeu Fabra 
Barcelona 
Performance of the neurodevelopmental assessment at 
Speech Acquisition and Perception Lab. 
 
ABBREVIATIONS 
AC 
Abdominal circumference 
ADHD 
Attention deficit hyperactivity disorders 
BPD 
Biparietal diameter 
CPR 
Cerebroplacental ratio 
DCS 
Diffuse correlations spectroscopy 
DHA 
Docosahexaenoic acid 

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DV 
Ductus venosus 
ECG 
Electroencephalography 
ET 
Ejection time 
FEW 
Fetal estimated weight 
FGR 
Fetal Growth Restriction 
FL 
Femur length 
GCP 
Good Clinical Practice 
HC 
Head circumference  
HSJD 
Hospital Sant Joan de Déu 
ICT 
Isovolumetric contraction time 
IRT 
Isovolumetric relaxation time 
MCA 
Middle cerebral artery 
MPI 
Myocardial performance index 
MRI 
Magnetic resonance imaging 
MRS 
Magnetic resonance spectroscopy 
NST 
Non-stress test 
PI 
Pulsatility index 
PIm 
Mean pulsatility index 
PSQI 
Pittsburg Sleep Quality Index 
PSS 
Perceived Stress Scle 
RCOG 
Royal College of Obstetrics and Gynecologists 
RCT 
Randomized Controlled Trial 
RF 
Radio frequency 
TAPSE 
Tricuspid Annular Plane Systolic Excursion 
UA 
Umbilical artery 
UtA 
Uterine artery 
WHO 
World Health Organization 
 
 
 
 

FetalBrainCare (December 2022) 
 
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INTRODUCTION 
Two-thirds of the neurodevelopmental disorders are estimated to be related with an insult 
occurring during the prenatal period and fetal growth restriction (FGR), that occurs in 7-10% of 
pregnancies, can account for up to one-quarter of cases of special educational needs. However, 
there is currently no treatment to prevent or ameliorate the effects of FGR on 
neurodevelopment. Promising experimental results have shown that maternal supplementation 
with Lactoferrin and docosahexaenoic acid (DHA) has strong neuroprotective effects in fetuses 
with FGR. However, no clinical trials have evaluated their effects in humans. We propose a 
randomized double-blind placebo-controlled trial to assess whether Lactoferrin and DHA can 
improve neurodevelopment in FGR fetuses and infants. 
 
Prenatal origin of altered neurodevelopment 
Neurodevelopmental disorders emerge early in life, and two-thirds are estimated to be related 
with an insult occurring during perinatal period. Fetal growth restriction (FGR) is a prevalent 
condition that affects 7-10% of all pregnancies in developed countries, being associated with 
short- and long-term neurodevelopmental problems, including motor and cognitive delay (1). 
For instance, a recent cohort study showed that one-quarter of schoolchildren with special 
educational needs due to sensory, motor and intellectual disabilities were related to FGR 
combined with prematurity (2). FGR is also associated with a higher risk of autism spectrum (3) 
and attention deficit hyperactivity disorders (ADHD) (4). Moreover, brain macro- and 
microstructural, 
as 
well 
as 
metabolic 
and 
connectivity 
alterations 
underlying 
neurodevelopmental dysfunctions have been characterized in subjects with FGR at different 
stages of development, starting in utero (5) and persisting postnatally during early infancy (6) 
and adolescence (7). Despite the prevalence and impact of this condition in developed societies, 
there are no effective prenatal therapies to either improve placental function, or to prevent its 
deleterious effects on neurodevelopment. 
 
Therapeutic strategies in perinatal period 
Several evidences suggest that early postnatal life interventions, such as breastfeeding, may 
improve neurodevelopmental outcomes in FGR (8). Furthermore, experimental data 
demonstrates that postnatal environmental enrichment can reverse FGR effects on brain 
function and structure, by improving memory, reducing anxiety, as well as refining the 
organization of brain connections and increasing dendritic spines (9). However, all these 
strategies are applied after birth, when the adverse effects of FGR on brain development have 
already been established. Prenatal life represents the optimal window of opportunity to reduce 
the long-term brain consequences of FGR. Brain development is a complex process that starts 
early in utero and is prolonged after birth, conferring a high sensitivity to any circumstance, 
either positive or negative. This period, which includes the prenatal period, is called "critical 
window of opportunity" and any strategy applied during this episode could have a more 
pronounced effect on brain function and structure, thus reverting more effectively the adverse 
consequences of prenatal insults, such as FGR (10).  
Prenatal therapy should be non-invasive, ensure placental crossing and have an impact on the 
pathophysiological mechanisms. Among the potential strategies aimed at protecting 
neurodevelopment under FGR, DHA and Lactoferrin emerge as good candidates. DHA is a fatty 
acid that is transferred across the placenta to reach fetal circulation and exerts a central role in 
the central nervous system development (11). Poor maternal DHA intake has been related with 
delayed brain and retinal development (12) and its administration after hypoxic-ischemic injury 

FetalBrainCare (December 2022) 
 
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improved long-term anxiety and memory in rats (13). On the other hand, Lactoferrin is found in 
human milk and crosses the blood brain barrier once it has been absorbed in the gastrointestinal 
tract. Lactoferrin modulates a wide range of neuronal processes and various mechanisms have 
been proposed to explain its neuroprotective effects (14). Animal studies strongly suggest that 
maternal Lactoferrin supplementation has a fetal brain protective role in placental insufficiency 
(15) and preterm hypoxic-ischemic injury (16). 
 
Evidence supporting the neuroprotective effect of DHA 
Previous studies have suggested a beneficial effect of DHA on brain function and structure. At 
experimental level, the administration of DHA in a hypoxic-ischemic rat model (13) was related 
with a long-term improvement in anxiety and memory. In addition, imaging studies in primate 
linked DHA administration with cortical improvement in aging and in neuropsychiatric diseases, 
including schizophrenia (17) and ADHD (18). Moreover, enhancing the nutrient supply with DHA 
to FGR infants born prematurely improved white matter maturation measured by DTI at term-
equivalent age (19). Administration of DHA has also demonstrated to improve dendritic spine 
density (20) and morphological alterations (20,21) in adulthood. The effect of maternal 
supplements containing DHA has also been evaluated in several clinical trials. A recent review 
summarizing the results of these studies concluded that there is contradictory evidence on the 
potential beneficial effect on neurodevelopment during childhood (22,23). Accordingly, whereas 
administration of the DHA did not improve neurodevelopment in general population, it might 
be beneficial in high-risk population. 
 
Evidence supporting the neuroprotective effect of Lactoferrin 
Although no clinical studies have evaluated the role of Lactoferrin on neurodevelopment, 
experimental research has proposed Lactoferrin for neuroprotection during early stages of life. 
Maternal administration of Lactoferrin in the perinatal period has been associated with brain 
metabolism restoration in both placental insufficiency (15) and preterm hypoxic-ischemic (16) 
rat models. Lactoferrin administration during breastfeeding in a preterm rat model also resulted 
in an amelioration of the microstructural brain damage detected by diffusion weighted imaging 
studies in specific brain areas, such as the striatum, corpus callosum and external capsule in the 
neonatal period (16)(24). Moreover, an increased rate of learning and long-term memory was 
observed with Lactoferrin supplementation in piglets (25). Additionally, both DHA and 
Lactoferrin have been demonstrated to have a neuroprotective role in several neurological 
disorders, including Parkinson's disease, schizophrenia and ADHD (18,26,27).  
Altogether, despite the existence of indirect evidence, direct proof of the protective effects of 
DHA or Lactoferrin administration prenatally in FGR remained elusive. 
 
Experimental data supporting the potential benefit of DHA and Lactoferrin in FGR 
The present proposal is the result of years of investigation on brain development in FGR 
conducted by our research group. An important contribution was the demonstration that FGR 
is strongly associated with altered neurodevelopment, even in its milder clinical forms. We have 
previously described how this effect was mediated by increased brain perfusion, and we 
introduced the use of fetal brain Doppler for the identification of high risk cases (28–32). In 
addition, the group pioneered the use of advanced MRI techniques to demonstrate macro- and 
microstructural, as well as metabolic, connectivity and functional brain changes not only in the 
postnatal stage (6,33–38), but also in prenatal life (5,39–43). These evidences of abnormal brain 

FetalBrainCare (December 2022) 
 
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development in FGR constituted the starting point to focus our strategy on preventing prenatal 
brain damage. 
In parallel with clinical studies, we developed and validated an animal model of FGR in pregnant 
rabbits that reproduces clinical features of FGR including high perinatal mortality, reduced birth 
weight, hemodynamic changes and structural/functional changes of the brain (30,44–49). Once 
the model was validated, we tested our hypothesis regarding prenatal administration of specific 
therapy to revert, partially or totally, the deleterious effects of FGR on the developing brain. We 
conducted a serial of experiments in our animal model of FGR, obtaining promising results with 
DHA and Lactoferrin. In our model, maternal administration of DHA or Lactoferrin during 
pregnancy was associated with neurodevelopmental improvement at the neonatal and at 70 
days of life (equivalent to adolescence in humans), at both structural and functional levels (49). 
At neonatal period, maternal administration of DHA and Lactoferrin improved neuronal 
arboritzation and reversed oligodendrocytes dysmaturation observed in FGR animals, especially 
after DHA administration. At long-term, period, maternal administration of DHA and Lactoferrin 
improved brain connectivity at macro- and micro- levels, by increasing global efficiency of 
structural brain networks and improving hippocampal perineuronal networks and dendritic 
spines. Functional improvements could also be observed by means of reduced anxiety and 
better memory and learning competences. This study provided for the first-time evidence that 
fetal neurodevelopment improved after maternal supplementation with DHA or Lactoferrin in 
FGR. 
 
National or international groups working in the same specific or related lines 
Regarding the impact of FGR in brain development, our research group pioneered in 
demonstrating its effects in both brain structure and function, being one of the most productive 
research groups in this field nowadays. Other groups working in the same field include the Child 
Development Disorders in the University of Geneva directed by Petra Huppi and the Center for 
the developing Brain in Kings College directed by David Edwards. They mainly focused on the 
development of imaging biomarkers based on MRI and are currently working in different 
strategies to prevent severe brain damage, particularly in preterm deliveries. 
In summary, the present research protocol aims at testing the positive results observed in animal 
models in a clinical study with pregnant women. If successful, this study will provide the first 
supporting evidence of an effective strategy to reduce the neurodevelopmental impact of FGR, 
moving a step forward that will open the door to therapies with the potential to improve the 
neurodevelopmental health of thousands of children yearly. Furthermore, this evidence could 
open new research pathways and the opportunity to apply similar strategies in other perinatal 
conditions associated with poor neurodevelopment, including toxic exposure, prematurity and 
cardiac defects. 
 

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STUDY AIMS 
Hypothesis 
Main hypothesis: 
1. A prenatal intervention based on maternal supplementation with DHA and Lactoferrin 
improves neurodevelopment in FGR.  
 
Secondary hypothesis:  
1. A prenatal intervention based on maternal supplementation with DHA and Lactoferrin in 
FGR improves fetal growth.  
2. A prenatal intervention based on maternal supplementation with DHA and Lactoferrin in 
FGR improves perinatal morbidity and mortality. 
 
Objectives 
Main objective: 
1. To evaluate the impact of maternal supplementation with DHA and Lactoferrin on 
neurodevelopment in pregnancies with FGR, as assessed by fetal brain MRI and postnatal 
neurodevelopmental tests. 
Secondary objectives:  
1. To evaluate the impact of maternal supplementation with DHA and Lactoferrin on fetal 
growth assessed by prenatal ultrasound in FGR.  
2. To evaluate the impact of maternal supplementation with DHA and Lactoferrin on perinatal 
morbidity (neonatal acidosis, intraventricular hemorrhage III/IV, necrotizing enterocolitis, 
periventricular leukomalacia, sepsis, bronchopulmonary dysplasia) and mortality in FGR. 
 
 
 

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METHODS 
Study design 
A multicenter, randomized, double-blind clinical trial on 304 pregnant women with FGR at 24-
32 weeks of gestational age randomized to: (1) Maternal administration of 1000 mg of 
Lactoferrin + 1000 mg of DHA every day orally or (2) placebo. 
The study design of the RCT adheres to standard criteria for randomized trials, and it is registered 
in the Clinical Trials Gov (https://clinicaltrials.gov/) with the following NCT: 05038462.  
 
Study population 
Singleton pregnancies being diagnosed of FGR from 24 to 32.6 weeks of gestation. FGR will be 
defined either by (1) an estimated fetal weight (EFW) below the 3rd centile or (2) EFW< 3th 
centile or umbilical artery >95th centile or uterine artery mean pulsatility index > 95th centile.  
After the recruitment, women will be randomized to two equally sized groups: 
1. Lactoferrin + DHA 
2. Placebo 
Personnel who manage the patients in the clinical setting and also the patients will be blinded 
for each group of randomization the patient is belonged to.  
 
Inclusion criteria: 
• 
Singleton pregnancies 
• 
Non-malformed fetus 
• 
Pregnancies with FGR 
• 
24-32.6 weeks of gestation 
 
Exclusion criteria: 
• 
Chromosomal or structural abnormalities diagnosed during pregnancy or in the 
neonatal period.  
• 
Critical Doppler study suggesting the need for delivery within the next 14 days at the 
time of diagnosis: reverse end-diastolic velocity in the umbilical artery or ductus venosus 
pulsatility >95th centile.  
• 
Maternal mental or psychiatric disorders. 
• 
Maternal allergy to cow's milk protein. 
 
Study setting 
The study will be coordinated by BCNatal, resulting from the integration of Hospital Clinic and 
Hospital Sant Joan de Déu in Barcelona (Spain), which is one of the most important university 
centers of maternal-fetal and neonatal medicine in Europe and a world-wide reference in this 
field. Both hospitals, with more than 7,000 deliveries per year, are university hospitals and 
tertiary referral institutions for high-risk pregnancies. They are part of BCNatal Fetal Medicine 
Research center, a research center in fetal and perinatal medicine, recognized as one of the 
world’s best research teams in the field that has as a main objective to demonstrate how 
prenatal life has an impact on childhood and adult life. The center counts with a multidisciplinary 

FetalBrainCare (December 2022) 
 
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team of more than 70 members including doctors, engineers, biologists, nurses, psychologists 
as well as an own management structure. 
Five external recruitment centers (Hospital Sant Pau, Hospital General Hospitalet, Hospital del 
Mar, Hospital Germans Trias i Pujol, Hospital Dexeus-Quirón), will take care of standard clinical 
follow-up, delivery and biological samples collection. 
Neurodevelopmental assessment will be carried out in collaboration with the Speech Acquisition 
and Perception Groups of the Universitat Pompeu Fabra Barcelona under the supervision of 
Nuria Sebatian-Galles.  
 
Sample size estimation 
A final total sample size of 304 cases of FGR has been estimated based on the main outcome 
measures of the study: improvement in 5 units in the treated group in comparison to non-
treated one with a SD of 13 units (as reported in Shavchev S, Ultrasound Obstet Gynecol 2013; 
42: 201–206) with a 80% of statistical power with a risk of type 1 error of 5%. We also have 
estimated a 30% loss to follow-up rate. 
 
Recruitment 
For the recruitment it is important to identify those patients at a higher risk to develop FGR. The 
criteria to identify those patients are based on the criteria established by the RCOG (50). We will 
also identify those patients with a FEW <p10 or PImAU >p95 on the second trimester ultrasound. 
Patients presenting any of these criteria, serial ultrasound assessments would be scheduled, at 
24, 28 and 32 weeks of gestation. We will provide those patients with an information sheet of 
our study in order to contact us in case they want to participate if FGR is diagnosed during 
pregnancy.  We will also identify the FGR in the specific unit of the different centers that 
participate in the current study.   
 
Enrolment visit 
Pregnancies with a diagnose of FGR between 24-32.6 weeks of gestation are considered eligible 
for this clinical trial and the same day of the first evaluation in the specific unit of each center 
they will be identified by one of the investigators involved in the recruitment. 
The visit serves to identify inclusion/exclusion criteria in a more comprehensive manner and to 
address all eligible patients about the purpose of the study and the voluntary nature of the 
participation. If the patient agrees to participate, she will be referred to BCNatal for the 
enrolment visit.   
This enrolment visit includes: 
1. A face-to-face interview in order to identify any exclusion criteria. If the candidate meets all 
the requirements, an informed consent form will be given to her to be signed after a detailed 
explanation of all study’s procedures. The informed consent comprised two parts, one for 
study participation (Appendix 1) and another for biochemical analyses and DNA collection 
for genetic analyses. 
2. Socio-demographic data, clinical history, anthropometric measures and blood samples for 
the assessment of basal maternal levels of DHA and Lactoferrin, angiogenic factors and 
cytokines will be taken. 
3. Several questionnaires will be given and explained to the patient for a self-report to be 
completed at home.  

FetalBrainCare (December 2022) 
 
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4. Randomization. 
5. Medication delivery. 
6. The patient will be informed about the contact email of the study in order to address specific 
questions or problems related to the study. 
7. Next appointments will be given to the patient. 
 
Randomization 
After obtaining the informed consent, the patient will be randomized in one of the two arms of 
this trial. Patient randomization will be done through a dedicated website for the study. 
Randomization sequences will be generated to assure balanced distribution within study arms 
(cluster randomitzation 12:12). The randomization list will be unknown to investigators and 
recruitment centers. Patients and clinicians will be blinded to the nature of study drug: 
supplements or placebo (double-blind).  
 
Intervention  
The idea behind the intervention is focused in maternal supplementation: the neuroprotective 
effects of maternal supplementation with Lactoferrin and DHA could prevent or ameliorate the 
effects of FGR on neurodevelopment. That intervention is based in robust scientific evidence as 
explain above.  
The intervention consists in the maternal administration of 1000 mg of Lactoferrin + 1000 mg of 
DHA every day orally. The intervention will start at the time of inclusion and will finish at 
delivery.  
Placebo with the same appearance, weight and taste will be also administrated daily until the 
end of pregnancy.    
 
Participant timeline 
Promotion of adherence 
Efforts to promote adherence begins at the earliest stages of the study. During the first visit at 
enrollment, participants are repeatedly provided with information about key features of the 
study. Specific actions will be planned in order to minimize loss to follow-up, which is one of the 
potential limitations of this study. During the prenatal period, such cases are expected to be few 
since diagnosis of FGR implies a close clinical monitoring by fetal ultrasound weekly. A personal 
work-note will be given to each participant in order to register the compliance of the 
intervention to ensure a high adherence. However, cases lost could increase after delivery. 
Aiming to reduce these cases, reminders will be sent by phone and email to patients. 
 
Assessment of compliance 
The compliance of the intervention is essential and people involved will reinforce this concept. 
For analysis purposes, the intervention will be considered complete if treatment with at least 
90% adherence is maintained at least for 4 completed weeks. Since the intervention is usually 
well tolerated and no major side effects have been described, we do not expect to stop or modify 
the intervention secondary to side-effects or harms. During the intervention period, clinicians 
will encourage and ask directly about compliance and the personal work-note will be revised in 
every weekly follow-up visit. At the end of participation in the study, participants will be asked 
to return the excess of medication in order to estimate the adherence. Finally, biomarkers for 

FetalBrainCare (December 2022) 
 
13
treatment compliance will be assessed in a random subgroup of 100 women by a dosage 
quantification of both Lactoferrin and DHA in maternal and cord blood samples. 
 
Desertion from the study 
Data from patients enrolled in the trial who wants to desert it for any reason will be registered.  
 
Measurements 
All participants will receive an intervention divided in several phases: 
1. Inclusion and randomization at 24-32.6 weeks of gestation: 
o Signature of informed consent form 
o Register of socio-demographic data 
o Randomization (randomization arms 12:12) 
2. Administration of treatment/placebo according to randomization group: 
o Maternal administration of 1000 mg of Lactoferrin + 1000 mg of DHA every day orally 
o Placebo with the same appearance, weight and taste will be also administrated daily 
3. Nutritional and lifestyle interviews and maternal blood sampling at inclusion: 
o Nutritional interview: adherence to the Mediterranean diet within a 17-items scale 
o Lifestyle interview: Perceived Stress Scale, Pittsburgh Sleep Quality Index and WHO-5 
Well-being Index 
o Maternal blood sampling in a random subgroup of 100 women: angiogenic factors, 
cytokines and DHA/Lactoferrin levels 
4. Prenatal follow-up: 
o Fetal growth and feto-placental Doppler every 7-14 days according to the standard 
clinical protocol 
o Neurosonography at the moment of enrolment and at 32 and 36 weeks of gestation 
o Fetal brain MRI at 34 weeks of gestation  
o Speech discrimination task at 36 weeks of gestation  
o Echocardiography following the standard clinical protocol at 32 weeks of gestation 
o Nutritional and lifestyle interviews at 36 weeks of gestation 
o Computerized non-stress test (NST) at inclusion, 28 and 36 weeks of gestation in those 
patients with Doppler alteration following the standard clinical protocol 
5. Collection of perinatal data at delivery 
6. Placental pathology 
7. Maternal blood sampling at delivery in a random subgroup of 100 women: angiogenic 
factors, cytokines and DHA/Lactoferrin levels 
8. Fetal cord blood sampling at delivery in a random subgroup of 100 neonates: 
DHA/Lactoferrin levels 
9. Postnatal follow-up: 
o Blood pressure and heart rate at 6 and 24-month of corrected postnatal age 
o IM thickness and head circumference at delivery, 6 and 24-month of corrected postnatal 
age 
o Neurodevelopmental assessment: 
▪ 
Speech discrimination task at 4-month of corrected postnatal age 
▪ 
Attention switching task at 12-month of corrected postnatal age 
▪ 
Vocabulary assessment at 18, 24 and 36-month of corrected postnatal age 
▪ 
Logical reasoning task at 19-month of corrected postnatal age  
▪ 
Bayley III test at 6 and 24-month of corrected postnatal age 
▪ 
Early Childhood Behavior Questionnaire for temperament at 24-month of corrected 
postnatal age 

FetalBrainCare (December 2022) 
 
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Maternal nutritional and lifestyle assessment 
At the moment of recruitment, participants will receive a pack containing one of each of the 
questionnaires below detailed. All questionnaires are self-reported.  
▪ 
Diet quality: the adherence to the Mediterranean diet within a 17-items scale will be 
registered for each.  
▪ 
Anxiety and stress: The Perceived Stress Scale (PSS) is one of the best currently available 
instruments to evaluate the presence of anxiety and stress during pregnancy (51,52). The 
WHO-5 Well-being Index will be also registered.  
▪ 
Sleep quality: The Pittsburgh Sleep Quality Index (PSQI) is based on eighteen self-reported 
questions about the person own sleep quality. The scale evaluates seven rated components, 
including, sleep subjective, quality, duration, disturbances, and latency, habitual sleep 
efficiency, use of sleeping medication, as well as daytime function. The score from each 
category is added to achieve a global score that range from 0 – 21. A cutoff score of 5 or 
above is indicative of a sleep disturbance. This scale has been recently validated in the 
obstetric population (53), in which an abnormal result was associated with an increased risk 
of preterm birth (54). 
 
At 36 weeks of gestation, participants will receive again the pack containing one of each of the 
nutritional and lifestyle questionnaires. 
 
Prenatal follow-up 
Fetal growth assessment  
Fetal biometry: includes evaluation of fetal growth using the Hadlock formula (55) based in a 
composite sonographic measurement of fetal head (biparietal diameter, BPD; head 
circumference, HC), abdominal circumference (AC) and femur length (FL). Fetal measurements 
will be performed following previously published techniques. 
 
Feto-placental Doppler assessment 
Umbilical artery (UA) pulsatility index (PI) will be performed from a free-floating cord loop. 
Normal UA will be considered as a PI below the 95th percentile (56).  
The middle cerebral artery (MCA) PI will be obtained in a transversal view of the fetal head, at 
the level of its origin from the circle of Willis (57–59). Three consecutive high-quality images 
with no artefacts will be recorded using previously reported parameters. Normal MCA will be 
considered as a PI over the 5th percentile.  
The cerebroplacental ratio (CPR) will be calculated as a ratio of MCA PI to UA PI (60–62). Normal 
CPR will be considered as a PI over the 5th percentile. The MCA PI and CPR values below the 5th 
percentile will be considered indicative of cerebral blood flow redistribution (60–62).  
The ductus venosus (DV) can be visualized either in a mid-sagittal longitudinal plane of the fetal 
trunk or in an oblique transverse plane through the upper abdomen. The sample volume will be 
positioned at its origin from de umbilical vein. The measurement has to be obtained in the 
absence of fetal breathing movements. Normal DV will be considered as a PI below the 95th 
percentile (63).  
To examine the uterine artery (UtA), the probe has to be placed on the lower quadrant of the 
abdomen, angled medially and using the color Doppler to identify the UtA at the apparent 
crossover with the external iliac artery. Measurement will be taken approximately 1cm distal to 

FetalBrainCare (December 2022) 
 
15
the crossover point. The PI of the left and right arteries will be measured and the mean PI will 
be calculated. Normal mean UtA will be considered as a PI below the 95th percentile (64).  
Prenatal Doppler ultrasound examinations will be performed in the absence of fetal movements. 
Pulse Doppler parameters will be performed automatically from three or more consecutive 
waveforms, with the angle of insonation as close to zero as possible.  
 
Fetal neurosonographic assessment  
Fetal neurosonography will be performed at enrolment and at 32 and 36 weeks of gestation by 
an expert examiner at BCNatal using a two-dimensional transabdominal and transvaginal 
approach. Neurosonography will follow guidelines from the International Society on Ultrasound 
in Obstetrics and Gynecology (65), as well as guidelines for fetal brain assessment (66). Cortical 
development evaluation will be performed according Pistorius et al. (67), allowing quantification 
of brain sulcation in normal fetuses by ultrasound.  
Fetal neurosonographic assessment will include the following parameters:  
1. Axial planes:  
• 
Transventricular plane: lateral ventricles width, parieto-occipital fissure depth and 
grading, central sulcus grading.  
• 
Transthalamic plane: cephalic circumference, Sylvian fissure depth and grading, superior 
temporal fissure grading.  
• 
Transcerebellar place: transverse cerebellar diameter, antero-posterior diameter of 
cisterna magna. 
2. Sagittal planes: 
• 
Midsagittal plane: corpus callosum (length, total area and regional areas(68)), craneo-
caudal diameter of vermis. 
• 
Parasagittal plane: central sulcus grading.  
3. Coronal planes: 
• 
Transcaudate plane: craneo-caudal diameter of the anterior horns, cingulate fissure 
depth and grading.  
• 
Transcerebellar plane: calcarine fissure depth and grading.  
 
Neurosonographic images will be analyzed offline by experts blinded to group randomization, 
including grading and measurement of sulcal and fissure depths, together with delineations of 
the corpus callosum to obtain the total and regional areas. 
 
Fetal Magnetic Resonance Imaging 
Fetal brain MRI will be performed at 34 weeks of gestation in a 3 Tesla scan at BCNatal-Hospital 
Clínic, using a body array radio-frequency (RF) coil. Several sequences for the evaluation of fetal 
brain (micro-) structures and metabolic profile by MRS will be acquired. First, single-shot fast 
spin-echo T2-weighted sequences (TR 2010 ms; TE, 137 ms; slice thickness 3.5mm; no inter-slice 
gap acquisition) will be acquired in the three orthogonal planes, oriented along the axis of the 
fetal brainstem, obtaining 4-loops of transverse, 2-loops of coronal and 2-loops of sagittal single 
shoot slices. MRS data will be acquired from the frontal lobe based on T2-w reference images 
and with Point Resolved Spectroscopy (PRESS) localization, as previously reported (43). The final 
MRI acquisition protocol will be adjusted so that it does not exceed 30-45 minutes. Fetal MRI 
data will be used to perform 2D measurements of cortical development (sulcal depth and 
grading) and 3D reconstruction of fetal brain following a methodology developed in our group 

FetalBrainCare (December 2022) 
 
16
to automatically measure total brain and grey and white matter volume, cortical folding 
parameters and cortical thickness. The MRS data obtained will be processed by linear fitting in 
the frequency domain (LC Model) based on metabolite basis-sets available and each metabolite 
will be quantified based on a reference water spectrum, as well as using metabolite ratios. 
 
Speech discrimination task 
We will implement a procedure that has been already defined (69) in order to investigate speech 
discrimination in fetuses with FGR at 36 weeks of gestation at the Hospital Clinic. A loudspeaker 
will be positioned at approximately 10cm from the mother’s abdomen, typically on top of a thick 
pillow placed on the mother’s lap. Loudspeaker will play the stimuli for the fetus at a standard 
intensity of 95dB (enough to pass the uterine wall). Intensity will be measured prior to testing. 
While sounds are played to fetus, mothers listened to a children story through noise-cancelling 
headphones connected to another device. Prior the stimuli, mother will do a 15-20-minute 
resting in order to help to minimize fetuses’ movements. Different stimuli will be presented to 
the fetus and we will monitor continuously fetuses’ heart rate with a fetal cardiotocograph, a 
standard tool to measure fetal well-being. We will analyze changes in fetuses’ heart rate in 
response to sound switch.   
 
Fetal echocardiography assessment 
Fetal cardiovascular remodeling will be assessed at 32 weeks of gestation by measuring the 
following parameters: 
• 
Heart area/thorax: cardiac area will be delineated in end-diastole from a 4-chamber 
view and divided by thoracic area in order to calculate cardio-thoracic ratio.  
• 
Right ventricular sphericity: will be calculated by dividing the end-diastolic base to apex 
ventricular length by the transverse ventricular diameter measured in 2D in an apical or 
basal 4-chamber view (70).  
• 
Septum thickness: will be measured from an apical or basal 4-chamber view at end-
diastole. 
• 
Pericardial effusion: we will evaluate the presence or not of pericardial effusion. It is 
considered physiological if <2mm and does not exceed the atrioventricular level.   
• 
TAPSE: will be calculated using M-more real time from an apical or basal 4-chamber 
view, measuring the maximum displacement of the valvular ring between end-systole 
and end-diastole (71). 
• 
Aortic diameter and velocity: measurement of the size of the Aortic artery at the level 
of the valve ring in systole. The assessment of the Aortic flow will be done by the 
applications of color Doppler and measurement of the peak systolic velocity (normal 
<120 cm/s).  
• 
Pulmonary diameter and velocity: measurement of the size of the Pulmonary artery at 
the level of the valve ring in systole. The assessment of the Pulmonary flow will be done 
by the applications of color Doppler and measurement of the peak systolic velocity 
(normal <120 cm/s). 
• 
Myocardial performance index (MPI): will be measured in a cross sectional view of the 
fetal thorax, in an apical projection and at the lever of the 4-chamber view of the heart 
(72). Briefly, the Doppler volume sample will be placed to include both the lateral wall 
of the ascending aorta and the mitral valve where the click corresponding to the opening 
and closing of the two valves can be clearly visualized. The isovolumetric contraction 
time (ICT), ejection time (ET) and isovolumetric relaxation time (IRT) will be calculated 

FetalBrainCare (December 2022) 
 
17
using the beginning of the mitral and aortic valves clicks as landmarks and the MPI will 
be calculated as follow: (ICT + IRT)/ET. 
• 
Aortic isthmus PI: will be measured either in a sagittal view of the fetal thorax with clear 
visualization of the aortic arch, placing the gate a few millimeters beyond the origin of 
the left subclavian artery; or in a cross sectional view of the fetal thorax, at the level of 
the three vessel and traquea view, placing the gate just at the converge of the aortic 
isthmus and the arterial duct (73–75).  
 
Computerized NST 
The non-stress test is an assessment tool used to evaluate fetal health through the use of electric 
fetal monitors that continuously record the fetal heart rate. Computerized NST provide more 
objective and accurate fetal information since does not depend on subjective visual inspection. 
This test will be done at inclusion, 28 and 36 weeks of gestation in those patients with Doppler 
alteration. Variables being assessed will include: 
• 
Signal loss 
• 
Basal heart rate 
• 
Accelerations >10 bpm 
• 
Accelerations >15 bpm 
• 
Total accelerations 
• 
Decelerations >20 missed beats 
• 
Short term variation 
• 
Sinusoidal pattern 
• 
Fetal movements 
 
Placenta pathology  
After delivery, placentas will be collected and formalin fixed. After 24-48h, basic histological 
assessment will be carried out at the pathology service at the Hospital Sant Joan de Deu and 
Hospital Clínic. Tissue sections will be formalin-fixed and paraffin-embedded, followed by 
hematoxilina-eosin staining. Experienced placental pathologist blinded to randomization group 
will evaluate all placentas to ascertain the presence of placental lesions. Variables beeing 
assessed will include:  
• 
Placental weight 
• 
Maternal vascular malfusion 
• 
Fetal vascular malfusion 
• 
Chronic villusitis of undetermined etiology 
• 
Chronic villusisis of probable infectious origin 
• 
Peri-villous fibrin deposits 
• 
Diffuse chronic intervillositis  
 
Maternal and fetal cord blood sample analysis 
At the recruitment and delivery, maternal and fetal cord blood will be collected and stored to 
evaluate adherence and response to DHA and Lactoferrin supplementation, by measuring 
biomarkers in maternal and fetal cord blood, including Lactoferrin and DHA levels. Angiogenic 
factors will be determined in maternal blood at the recruitment and delivery in order to relate 
the expected improvement to the pathophysiology of FGR. Also, at recruitment and delivery, 

FetalBrainCare (December 2022) 
 
18
cytokines (TNFa, IL-6, IL-8, IL-4, IL-10) will be measured in maternal blood to evaluate the anti-
inflammatory effect of the maternal supplementation.  
Maternal and fetal cord blood analysis will be performed in a random subgroup of 100 women 
and 100 neonates.  
10 mL of maternal blood will be drawn from an indwelling cannula in the brachial vein and kept 
in EDTA treated tubes. 10 mL of cord blood will be obtained from the umbilical vein after cord 
clamping at delivery and kept in EDTA treated tubes. In both cases, plasma, erythrocytes and 
buffy coat will be separated by centrifugation at 2500 rpm for 10 minutes at 4º C.  Erythrocytes 
will be used to analyze the red blood cell membrane fatty acid composition. Plasma will be 
stored immediately at -80ºC for further analysis when patient recruitment is completed.  
Red blood cell membrane fatty acid composition will be determined by chromatography. 
Lactoferrin levels, angiogenic factors and cytokines will be analyze using specific kits.  
 
Postnatal follow-up 
Cardiovascular assessment and IM thickness 
• 
Systolic and diastolic blood pressure will be obtained at 6 and 24 months of corrected 
age by a trained physician from the brachial artery using a validated ambulatory 
automated Omron 5 Series device, while the infant is resting. Blood pressure percentiles 
will be calculated according to published reference values (76). Heart frequency will be 
also registered. 
• 
At delivery and also at 6 and 24 months of corrected age, weight, height and head 
circumference will be measured at planned follow-up visits.  
 
Neurodevelopmental assessment 
• 
Bayley-III Scale of Infant and Toddler Development (77) will be performed at 6 and 24 
months of corrected postnatal age at the Hospital Clínic. This scale is an individually 
administered instrument that assesses infant development across five domains, 
including cognitive, language and motor competencies. Parent reported questionnaires 
are incorporated into the Bayley-III scale to assess social-emotional and adaptive 
behaviors. Psychologists performing the evaluation will be blinded to randomization 
group. 
• 
Speech discrimination task at 4-month of corrected postnatal age. The procedure will 
be based on a pilot study ran by the same research team lead by Nuria Sebastian-Galles 
at Universidad Pompeu Fabra. Infants will be presented with sequences of sounds that 
are consistent with their native language and sequences of sounds that are not 
consistent with native language. Such sounds will be short sentences or words, and will 
be paired with neutral visual stimuli in order to keep the infant entertained. The 
experiment will last maximum 10 minutes. To evaluate infants’ response to speech we 
will use three distinct measures: 
o Electroencephalography (ECG) 
o Pupillometry using an eye-tracker (non-invasive sensor that detect the pupil 
size) 
o Heart rate measured with Diffuse Correlations Spectroscopy (DCS). DCS sensors 
will be incorporated in the ECG cap. 
• 
Attention switching task at 4-month of corrected postnatal age. The aim of this task is 
to measure infants’ ability to flexible switch their attention from one object to another. 
The procedure will be developed based on previous studies (78). Infants will be seated 

FetalBrainCare (December 2022) 
 
19
in front of a computer screen equipped with an eye-tracker. On the screen there will be 
two boxes, then an attention getter will appear in between the two boxes to grasp 
infants’ attention. Next, an animated toy accompanied with sounds will appear in one 
of the boxes.  
• 
Vocabulary assessment at 18, 24 and 36-month of corrected postnatal age. We will 
assess vocabulary knowledge of infants. We will use and adaptation of the MacArthur-
Bates Questionnaire (79) that has been extensively used in the BabyLab (UPF) to assess 
vocabulary knowledge at different ages. The questionnaire will be filled by caregivers to 
gather important information about the children’s early language abilities such us 
vocabulary comprehension and production as well as gestures and grammar.  
• 
Logical reasoning task at 19-month of corrected postnatal age. The aim of this task is 
investigating reasoning in infants and the basic logical representations available at 19 
months. The procedure will be a logic reasoning task used in previous studies (80). Test 
will take from 4 to 10 minutes.  
• 
Early Childhood Behavior Questionnaire for temperament at 24-month of corrected 
postnatal age. We will assess temperament using the Early Childhood Behavior 
Questionnaire. Caregivers will be asked to rate the frequency of some children’s 
behavior in different situations during the previous 1 or 2 weeks, in a 7-point scale. The 
regular version of the questionnaire assesses 18 dimensions of temperament (activity 
level/energy, attentional focusing, attentional shifting, cuddliness, discomfort, fear, 
frustration, high-intensity pleasure, impulsivity, inhibitory control, low-intensity 
pleasure, motor activation, perceptual sensitivity, positive anticipation, sadness, 
shyness, sociability, soothability).  
 
The Bayley scale will be performed by the postnatal follow-up platform of BCNatal’s Fetal and 
Perinatal Medicine research group. All the other neurodevelopment assessment, as well as the 
speech discrimination task at 36 weeks of gestation, are optional and will be carried out in the 
Speech Acquisition and Perception Lab of the Universitat Pompeu Fabra Barcelona. Participants 
will be contacted by telephone in order to explain the expanded neurodevelopment assessment. 
A specific consent form will be signed in case patients decide to participate.  
 
Variables 
Socio-demographic data: birth date, both parents’ socioeconomic status and educational level, 
pregestational weight and height, ethnicity, smoking status, parity, relevant medical history, last 
menstrual period.   
Nutritional and lifestyle interviews: adherence to the Mediterranean diet, perceived stress 
scale, Pittsburgh sleep quality index, WHO-5 Well-being Index.  
Maternal blood sampling: DHA and Lactoferrin levels, angiogenic factors and cytokines. 
Prenatal follow up: estimated fetal weight and Doppler ultrasound measurements, neurological 
profile assessment (neurosonography and MRI), cardiovascular profile assessment and 
computerized NST assessment.  
Perinatal data: mode of delivery, induction of labor, emergency cesarean section, gender, 
weight and height, Apgar score at 1 and 5 minutes, arterial and venous cord birth pH, pregnancy 
complications, exposure to corticoids, perinatal death, maternal and fetal cord blood DHA and 
Lactoferrin levels, maternal levels of angiogenic factors and cytokines and placental pathology.  

FetalBrainCare (December 2022) 
 
20
Postnatal 
follow 
up: cardiovascular and 
neurodevelopmental 
profile 
assessment, 
anthropometrical assessment and breastfeeding assessment (type of neonatal feeding, duration 
of maternal breastfeeding, start of complementary diet, maternal supplements).   
 
 
 

FetalBrainCare (December 2022) 
 
21
DATA COLLECTION AND STATISTICAL ANALYSIS 
Main outcome variables 
1. Bayley III scale at 24 months of age 
Secondary outcomes 
1. Cortical development 
2. Fetal brain volume assessed by fetal MRI 
3. Corpus Callosum area assessed by Neurosonography 
4. Neonatal weight 
5. Perinatal morbidity and mortality 
6. Postnatal neurodevelopmental assessment 
7. Occurrence of adverse effects 
 
The primary analysis will be based on the intention-to-treat population. A secondary analysis 
will be performed according to effective treatment. Single and multiple models will be tested. 
Logistic regression for qualitative and linear regression for quantitative outcome 
(neurodevelopment test variables) will be done. We will consider a significant improvement in 
neurodevelopment secondary to the intervention if an improvement in at least 5 units in one of 
the variables being assessed in the Bayley III test is observed in comparison to the placebo group. 
Statistical analysis will be performed by the research team and supported by statistical services 
from Fundació Sant Joan de Déu. Differences in these principal variables between experimental 
groups (treated vs placebo groups) would be assessed by t de Student test for comparison of 
means between two independent samples. 
Potential confounding variables that might influence the outcome of our study have been 
evaluated carefully. The variables identified included: corticoids administration during 
pregnancy for lung maturation, gestational age at delivery, mode of delivery (spontaneous 
vaginal delivery, instrumented vaginal delivery or cesarean section), type of delivery (labor 
induction or spontaneous onset), fetal distress at delivery, duration of breastfeeding, gender, 
socioeconomics and marital status, abuse of toxic substances and additional intake of DHA or 
Lactoferrin from diet or from commercial medicines. Despite randomization is expected to 
counteract for these potential confounders, a preliminary statistical analysis will be performed 
to ensure both study groups have similar baseline characteristics. At the middle of the study 
period, a preliminary analysis of the data will be performed. The analysis will evaluate 
performance of Bayley III at the 6 months of age and structural changes at the neurosonography 
and MRI between groups. In order to keep the study masked and not stop the randomization 
process, an independent researcher will pseudonymize the already included patients. 
Researchers could identify from which experimental group the data comes, without knowing 
from which individual they come.  
 
 
 
 

FetalBrainCare (December 2022) 
 
22
POTENTIAL DIFFICULTIES AND LIMITATIONS 
Discontinuing or modifying interventions and adherence: Since the intervention is usually well 
tolerated and no major side effects have been described, we do not expect to stop or modify 
the intervention secondary to side-effects or harms. During the intervention period, clinicians 
will encourage and ask directly about compliance. Finally, biomarkers for treatment compliance 
will be assessed by a dosage quantification of both Lactoferrin and DHA in maternal and cord 
blood samples.  
Duration of intervention: Some included patients will deliver before finishing 4 weeks of 
treatment due to worsening of Doppler status. In this case, these patients will be excluded from 
the final analysis. In addition, in order to evaluate the effect of different durations of 
intervention, this variable will be assessed in a secondary analysis of the data.  
Prematurity: The potential effect of prematurity in neurodevelopment can produce a bias in the 
results obtained. In order to explore this effect, we will apply two strategies. First, as previously 
mentioned, we will adjust all the statistical analysis by gestational age at delivery. In a second 
step, we will perform a secondary analysis of the obtained results stratifying by the moment of 
delivery (= 32 weeks). 
Breastfeeding: As breastfeeding is one of the postnatal interventions showing demonstrated 
benefits in this population, we will promote breastfeeding in patients included in this study. We 
will collect data about breastfeeding rate and duration and all statistical analysis on 
neurodevelopmental tests will be adjusted by this information. In addition, a secondary analysis 
of the data will be performed stratifying by the duration and type (exclusive or mixt) of 
breastfeeding.  
Loss to follow-up: Specific actions will be planned in order to minimize loss to follow-up, which 
is one of the potential limitations of this study. During the prenatal period, such cases are 
expected to be few, since diagnosis of FGR implies a close clinical monitoring by fetal ultrasound 
weekly. However, cases lost could increase after delivery. Therefore, the sample size has been 
calculated estimating a loss to follow-up rate up to 30% at 6 months of follow-up. Aiming to 
reduce these cases, reminders will be sent by phone and email to patients 
 
ETHICAL ASPECTS 
The project has been approved by the Institutional Review Board for clinical research 
(HCB/2018/1131 and PIC-29-19). The patients will be thoroughly informed prior to enrolment, 
and written informed consent will be obtained. This project fully complies with the relevant 
national, European and international ethics-related rules and professional codes of conduct, 
including the declaration of Helsinki in its latest version and the GCP guidelines on good clinical 
practice in therapeutic trials (Directive 2001/20/EC). 
 
 
 
 

FetalBrainCare (December 2022) 
 
23
APPENDIX 1: study participation informed consent  
Study title: FetalBrainCare 
Principal investigator:  
Elisenda Eixarch Roca 
Specialist in Gynecology and Obstetrics. Doctor’s degree in Medicine and Surgery 
Senior specialist of the Institute of Gynecology, Obstetrics and Neonatology 
Coordinator of the Fetal Neurosonography Unit 
Department of Maternal-Fetal Medicine 
Hospital Clínic de Barcelona (93 227 54 00) 
 
Míriam Illa Armengol 
Especialista en Ginecología y Obstetricia. Doctor en medicina y cirugía 
Miembro de la Unidad de Neurosonografía Fetal 
Departamento de Medicina Materno-Fetal 
Hospital Sant Joan de Déu (93 253 21 00) 
 
Center: BCNatal (Hospital Clínic de Barcelona - Hospital Sant Joan de Déu) 
Promotor: IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer) 
 
INTRODUCTION 
 
We are writing to you to invite you to participate in the clinical trial (FetalBrainCare). This 
study is carried out jointly with other centers in Spain (Hospital Clínic de Barcelona, Hospital Sant 
Joan de Déu, Hospital Sant Pau, Hospital Can Ruti, Hospital del Mar y Hospital Dexeus-Quirón). 
It has been approved by the Clinical Research Ethics Committee of each center in accordance 
with current legislation (Law 14/2007 on biomedical research). It is our intention that you receive 
correct and sufficient information so that you can decide whether or not to participate in this study. 
For this reason, read this information sheet carefully and we will clarify any doubts that may arise. 
In addition, you can consult with the people you deem appropriate.  
 
VOLUNTARY PARTICIPATION 
 
You should know that your participation in this study is voluntary and that you can decide 
not to participate or change your decision and withdraw your consent at any time without altering 
your relationship with your doctor or causing any harm to your treatment.   
 

FetalBrainCare (December 2022) 
 
24
GENERAL DESCRIPTION OF THE STUDY 
 
We offer you the possibility of participating in this study because we have detected in the 
ultrasound of the third trimester of pregnancy that your baby has an intrauterine growth restriction 
(IUGR). IURG is a complication that appears during pregnancy and consists of a decrease in the 
growth of the baby, generally secondary to a malfunction of the placenta. The malfunction of the 
placenta means that the placenta does not get enough blood, which means that the baby receives 
less nutrients affecting both its growth and the correct development of the organs, with a more 
important effect on the brain and the heart.  
 
WHY ARE WE CONDUCTING THIS STUDY? 
 
Nowadays, there is no treatment that has been shown to cure the alteration of the 
placenta, as well as to protect the brain and the heart from the lack of nutrients. Increasing the 
maternal intake of certain nutrients with protective effects on the development of the brain and 
the heart could constitute a fundamental pillar for the prevention of complications in these babies. 
In this way, with this study we want to demonstrate that with a maternal supplementation with 
docohexaenoic acid (DHA) and lactoferrin with fetuses diagnosed with IUGR, we are able to 
improve brain and cardiac development.  
 
HOW DOES THE STUDY WORK? 
 
We need to include a total of 304 pregnant women with the finding of an IUGR in the fetus 
to evaluate whether the supplementation of maternal nutrition with DHA and lactoferrin protects 
neurological and cardiac development in these babies. If you agree to participate, it will be 
determined randomly if you fall into the group of patients which will receive the supplementation 
(1000mf of lactoferrin + 1000mf od DHA daily orally) or if you fall into the placebo group (similar 
presentation to that used in the treatment group, but without containing DHA or lactoferrin). You 
are just as likely to receive the supplementation as placebo. Neither you nor the medical 
personnel treating you will know if you are in the supplementation group or the placebo group. 
This is the only way to answer the question of whether this treatment is really helpful in patients 
like you.  
 
WHAT DO I HAVE TO DO IF I DECIDE TO PARTICIPATE IN THE STUDY? 
 
You will take the supplementation/placebo every day from the start of the study (24-32.6 
weeks) until the 37th week of pregnancy. At the beginning of the study, a maternal blood sample 
will be collected in addition to the usual clinical follow-up in a random subgroup of 100 women. 
This subgroup of patients will be randomly selected. Subsequently, you will follow the usual follow-
up proposed by your medical center (medical appointments, ultrasounds, blood and urine tests 

FetalBrainCare (December 2022) 
 
25
and blood pressure measurement). However, during the follow-up of the pregnancy, additional 
examinations will be carried out aimed at evaluating in a very specific way the neurological and 
cardiovascular development of the baby. For this propose, a neurosonography (ultrasound 
evaluation aimed at evaluating neurological development) and an echocardiography (ultrasound 
evaluation aimed at evaluating cardiac development) will be scheduled at Hospital Clínic or at 
Hospital Sant Joan de Déu at the time of inclusion in the study and during pregnancy monitoring. 
Additionally, an MRI will be performed to be able to asses neurological development very 
precisely at BCNatal around 34 weeks of gestation. In addition, both at the start of the study and 
at 36 weeks of gestation, you will be given questionnaires you should fill out in order to assess 
your lifestyle and stress level. You will be able to give birth in your center of origin. In the same 
subgroup of 100 patients, a sample of umbilical cord blood and maternal blood will be collected 
at the time of delivery. After delivery, medical data about you and your baby will be collected. In 
addition, the baby’s neurodevelopment will be closely monitored, both at the center of origin and 
at Hospital Clinic or Hospital Sant Joan de Déu. At 6 and 24 months of life, a neurodevelopmental 
assessment will be carried out by applying a functional test called the Bayley III test. The same 
day that this test is performed, the baby’s blood pressure will be determined. During the 
pregnancy and postnatal follow-up, you will be contacted by telephone by the Speech Acquisitions 
and Perception Group of the Universitat Pompeu Fabra in order to expand the 
neurodevelopmental assessment of the baby. A specific consent form will be signed in case you 
decide to expand this study.  
 
Apart from completing the study visits and activities, you must also notify any adverse 
event that happens to you or changes in the medication. Except in an emergency, you cannot 
modify the medication you are taking or take other medications or “medicinal plants” without first 
consulting with the study doctor.  
 
 
BENEFITS AND RISKS DERIVED FROM YOUR PARTICIPATION IN THE STUDY 
 
The main Benefit expected from this study is to objectify an improvement, especially in 
the brain development in babies who have suffered IUGR during fetal life. However, it is possible 
that any benefit will be obtained for your health or for your child for you participation in this study, 
either due to lack of efficacy of the supplements under study or due to taking placebo. If during 
the course of this study definitive data are obtained on the usefulness or otherwise of the 
treatment, you will be informed so that you can make the decision you deem appropriate about it.  
 
Both DHA and lactoferrin are considered dietary supplements according to the Spanish 
Agency for Medicines and Medical Devices (AEMPS). Both substances at the proposed doses 
have been shown to be safe without presenting adverse or undesirable effects. There is prior 
information in humans on the safety of DHA during pregnancy and lactation. In the case of 
lactoferrin, information on safety in pregnancy and lactation comes from animal studies. Even the 
administration of these substances at higher doses that those proposed in this study have been 

FetalBrainCare (December 2022) 
 
26
used for other problems without evidence of significant undesirable effects, although some 
patients and at very high doses have presented gastrointestinal discomfort (stomach or intestinal 
discomfort, diarrhea and constipation) and some episodes of skin rash. In this case, you can 
contact you doctor to assess these discomforts and whether or not to continue the treatment.  
 
In addition, no risk is expected from the tests performed during the study. Both obstetric 
ultrasound and Tesla MRI have proven to be safe and not harmful, which is why today they are 
routine tests in obstetric monitoring when indicated.  
 
 
INSURANCE 
 
If you suffer any damage from participating in the study, all means will be made available 
to remedy it. In addition, the promoter has contracted a Civil Liability Insurance according to 
current legislation that covers any eventuality, providing compensation in case of impairment of 
your heath or injuries that may occur in relation to your participation in the study, provided that 
these are not consequence of the disease itself.    
 
WHAT HAPPENS WITH THE INFORMATON WE COLLECT? 
The Hospital Clínic, with Tax Identification Code 0802070C, as responsible for the 
processing of you data, informs you that the treatment, communication and transfer of personal 
data of all participants will comply with the EU Regulation 2016/679 of the European Parliament 
and the Council of April 27th 2016 regarding the protection of natural persons with reference to 
the processing of personal data and the free circulation of data and to the Organic Law 3/2018 of 
December 5th on Protection of Personal Data and Guarantee of digital rights.  
Data collected for this study will be identified only by a code, so any information identifying 
the participants will be included. Only the study investigators and his collaborators with specific 
permission will be able to relate your data collected in the study with your medical history.  
Your identity will not be available to any other person except for a medical emergency or 
legal requirement. The health authorities, the Research Ethics Committee and personnel 
authorized by the study promoter will have access to your personal information, when necessary 
to verify data and study procedures, but always maintaining confidentiality in accordance with 
current legislation.  
Only coded data Will be transferred to third parties and other countries, which in no case 
will contain information that can directly identify the participant (such as name and surname, 
initials, address, social security number, etc.). In case this transfer occurs, it would be for the 
same purpose as described in the study and guaranteeing confidentiality.  

FetalBrainCare (December 2022) 
 
27
If a transfer of encrypted data is made outside the EU, either to entities related to the 
hospital center where you participate, to service providers or researchers who collaborate with 
your doctor, your data will be protected by safeguards such as contracts or other mechanisms 
established by the data protection authorities.  
In addition to the rights that the previous legislations already contemplated (access, 
modification, opposition and data cancellation, deletion in the new Regulation) you can now also 
limit the processing of data that are incorrect, request a copy or request that data to be transferred 
to a third party (portability). To exercise these rights, or if you want to know more about 
confidentiality. You should contact the main researcher of the study or the Data Protection 
Delegate or the Hospital Clínic de Barcelona through protecciodades@clinic.cat. You have also 
the right to contact the Data Protection Agency if you are not satisfied.  
Data already collected cannot be delete even if you leave the study to ensure the validity 
of the research and to comply with legal duties and drug authorization requirements. But no new 
data will be collected if you decide to stop participating.  
The researcher and the sponsor are obliged to keep the data collected for the study for 
at least 5 years after its completion. Subsequently, the personal information will only be kept by 
the center for the care or your health and by the sponsor for other scientific research purposes if 
the patient has given its consent to do so, and if this is permitted by law and applicable ethical 
requirements.  
 
ECONOMIC COMPENSATION 
 
You will not be charged for your participation in the study and for the study drugs. You 
will not receive any financial compensation for your participation in this study.  
 
WHAT WILL BE DONE WITH THE BLOOD SAMPLES?  
At the time of inclusion in the study, a maternal blood sample will be drawn in order to 
determine baseline levels of DHA and lactoferrin as well as angiogenic factors and certain 
cytokines. At the time of delivery, another sample of maternal blood will be taken to evaluate the 
levels of DHA and lactoferrin achieved at the end of the study, the angiogenic factors and the 
level of certain cytokines. Blood will also be collected from the umbilical cord to be able to evaluate 
the levels of DHA and lactoferrin in the baby’s blood, without having to directly prick the baby. 
These samples are biological samples for which all assumptions will be met in accordance with 
the Biomedical Research Lay 14/2007 and RD 1716/2011 of November 18th, which establishes 
the basic requirements for authorization and operation of the biobanks for biomedical research 
purposes and the treatment of biological samples of human origin. By signing this document, you 
agree the use of the samples collected for the purposes of this study.  

FetalBrainCare (December 2022) 
 
28
The simples will be kept stored in the Biobank-IDIBAPS of Maternal-Fetal Medicine at 
Hospital Clínic until they are used for the purposes of this study. Once completed, the remaining 
samples will be Destroyer, unless you sign a specific consent form in order to be stored and used 
in future research (this will be provided separately).  
A code will be used to identify your samples and no data that could reveal your identity 
will be used. Only the study doctor and his collaborators will be able to associate the samples 
with you.  
The data derived from the use of these samples will be treated in the same way as the 
rest of the data obtained during this study.  
The transfer of biological samples for this study is free and voluntary. This means that 
you will not have rights to possible commercial benefits of the findings that could be derived from 
de results of biomedical research.  
If relevant information is obtained that could affect you or your family members health, 
you will be notified. If it is necessary to contact you, the data that appears in your medical history 
will be used. However, your right to not receive that information will be respected. In that case, 
you have to check the specific box found on the consent form.  
 
OTHER RELEVANT INFORMATION 
 
Any new information regarding the treatment used in the study that may affect your 
willingness to participate or that is discovered during your participation, will be communicated to 
you by your doctor as soon as possible.  
 
If you decide to withdraw your consent to participate in this study, no new data will be 
added to the database and you can demand the destruction of all identifiable samples previously 
retained to avoid further analysis.  
 
You should also know that you can be excluded from the study if the promoter and/or the 
study investigators consider it appropriate, either for safety reasons, for any adverse event that 
occurs and is considered to be related to your participation in the study or because they consider 
that you are not complying with established procedures. In either case, you will receive an 
adequate explanation of the reason for your withdrawal from the study.  
 
By signing the attached consent form, you agree to comply with the study procedures that 
have been set forth to you.  
 
 
 
 

FetalBrainCare (December 2022) 
 
29
Participant consent form sheet  
 
Study tittle: FetalBrainCare 
Version 6 (November 2022) 
 
I, (name and surname of the participant) __________________________________________ 
 
- I have read the informational sheet given to me about the study. 
- I have been able to ask questions about the study. 
- I have received enough information about the study. 
- I have spoken with: (name of researcher) ________________________________________ 
- I understand that my participation is voluntary. 
- I understand that I can withdraw from the study: 
- Whenever I want. 
- Without having to explain anything. 
- Without this affecting my medical care. 
- In accordance with the EU Regulation 2016/679 of the European Parliament and the Council of 
April 27th 2016 regarding the protection of natural persons with reference to the processing of 
personal data and the free circulation of data and to the Organic Law 3/2018 of December 5th on 
Protection of Personal Data and Guarantee of digital rights, I declare to have been informed of 
the existence of storage of processing of personal data, of the purpose of the collection of that 
data and of the recipients of the information.  
 
Given this information that the Data Controller has given to me, and having understood it, I offer 
my consent to the treatment of: 
☐ My personal data to carry out the research project. 
☐ My personal data to carry out research projects related to the present or in the same 
research area. 
 
I freely give my consent to participate in the study. 

FetalBrainCare (December 2022) 
 
30
 
 
 
Signature of participant 
 
 
 
 
Signature of researcher 
Date: ____/____/____ 
 
 
 
 
Date: ____/____/____ 
 
I would like to be informed about any information derived from the research that may be relevant 
to my health: 
 
 
 YES           NO                              
 
I would like to be contacted by Pompeu Fabra University to complete the postnatal neurological 
follow-up: 
 
 
 YES           NO                              
 
 
 
Signature of participant 
 
 
 
 
Signature of researcher 
Date: ____/____/____ 
 
 
 
 
Date: ____/____/____ 
 
 
 
 
 
 
 
 
 
 
 
 
 

FetalBrainCare (December 2022) 
 
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