Cardiac Displacement From Third Trimester to Early Childhood
Conditions: IUGR, Fetal Growth Retardation, Intrauterine Growth Restriction
Sponsor: University Hospital, Linkoeping

Study protocol translated from Swedish to English 
CADETTE study 
 
NCT02583763 
Olov Änghagen 
2014-03-18 
 
CADETTE (Cardiac displacement from third trimester to early childhood) 
 
Fetal heart muscle function in growth retardation. 
Significance for the condition of the fetus and for the cardiac function of the newborn and 
older child 
Background 
 
Obstetric ultrasound is an important tool for assessing the fetus during a pregnancy, regarding 
gestational age, growth and possible malformations. Traditionally, in the routine ultrasound 
examination, a general assessment is made that the cardiac anatomy is normal. Certain 
information about the condition of the fetus and placental function is obtained by analyzing 
flows, for example, in the umbilical cord. An unfavorable intrauterine environment, 
disturbances in blood flow or substrate supply etc. can result in growth retardation. During a 
pregnancy with such a complication, repeated considerations are made of the risk of preterm 
birth versus continued or progressive growth retardation. 
New methods for evaluation and treatment of ultrasound data provide improved opportunities 
to analyze the cardiac muscle function of the fetus. 
Our hypothesis is that growth retardation also affects the heart muscle and its function, and 
that with sensitive methodology, the effect on heart function can be evaluated as an indicator 
of the general condition of the fetus. Our hypothesis is also that such cardiac function 
determination can contribute to decision-making when choosing the time of delivery. We also 
plan to study whether an effect on cardiac function can be demonstrated in newborns and 
older children who have been stunted intrauterine. 
 
We also want to set cardiac function parameters in growth-retarded and normal fetuses in 
relation to other data about the fetus/child. 
Material and method 
This study is a prospective case-control study in which fetuses from normal pregnancies will 
be compared with fetuses that have intrauterine growth retardation. Parents will be asked in 
connection with control examinations at the Women's Clinic, where they have been referred 
due to suspicion of fetal growth retardation. A group of fetuses judged to be growth retarded 
by specialist ultrasound examination is compared with a control group. The control group is 
asked among the patients who come for a routine ultrasound in pregnancy weeks 18-20. 
 
Examinations will be carried out in the third trimester and after delivery. During the 
ultrasound examinations, standardized, moving ultrasound sequences of the heart are saved. 
Analysis is done offline with Siemens measurement technology (velocity vector imaging, 
VVI, Siemens medical solutions). With this technique, the chamber wall velocity (velocity), 
displacement and thickening (strain and strain rate) can be quantified 

Study protocol translated from Swedish to English 
CADETTE study 
 
NCT02583763 
Olov Änghagen 
2014-03-18 
 
 
During the evaluation, the walls of the heart are marked and the software can then produce 
movement speed and movement in different directions. The fetuses that are part of the control 
group are examined on 2 occasions, about 4 weeks apart. This takes place during weeks 28-
36. For the fetuses that are assessed as growth retarded, image collection is done during the 
regular ultrasound checks when the pregnancy is followed. 
 
The data we collect about the mother are diseases of the mother and possible treatment. 
Mother's age, smoking, BMI, possible abnormalities in pregnancy, number of pregnancies and 
which pregnancy in order. Method of delivery and possible abnormalities during pregnancy 
such as hypertension, preeclampsia, steroid treatment before birth. 
 
Other data that we plan to collect from the fetus is the flow profile in the umbilical artery, 
ductus venosus and arteria cerebri media in the fetus. Abdominal circumference, estimated 
weight. After delivery, check in the journal entries, the child's height, weight, head 
circumference, gestational age at birth, the acid base of the umbilical vein and the umbilical 
tree, Apgar score, number of days in hospital for care after delivery, possible complications. 
After delivery, we plan to examine the child with ultrasound of the heart at days 1-3, and 
months 4-6 and at 7 years of age. 
Sampling of umbilical cord blood and blood samples at age 7 where growth factors and 
cardiac markers are analyzed. 
We plan to examine between 20-30 fetuses with growth retardation and 40-60 fetuses in the 
control group. 
Inclusion of research subjects: Growth retardation during routine ultrasound control of 
pregnancy, verified during specialist control. Pregnancy length is determined based on the 
Crown Rump Length taken during the first trimester. Growth retardation is defined by a 
deviation more than 22% from the normal curve at a given gestational length or a growth rate 
that deviates more than 10% compared to the previous measurement in relation to expected 
weight. 
Inclusion of control subjects: Control subjects are recruited among mothers who come for 
routine ultrasound check-up at week 18. These are randomly selected and asked 
Exclusion criteria in both research subjects and control cases are demonstrated major 
malformations, twin pregnancy, signs of intrauterine infection during pregnancy, significant 
or treatment-requiring illness in the mother. 

Study protocol translated from Swedish to English 
CADETTE study 
 
NCT02583763 
Olov Änghagen 
2014-03-18 
 
 
1a Mother is referred 
to specialist 
examination due to 
suspected growth 
retardation 
4a Family gets 
information home and 
sends back consent if they 
want to participate 
3b Family takes the 
information home and 
sends back consent if they 
want to participate 
2a The fetus is examined 
in the usual way. During 
an ultrasound 
examination, 4 chamber 
images of the heart are 
saved together with the 
regular flow 
measurements that are 
made. 
6a At delivery, the 
physiological clinic is 
notified that the child 
has now been delivered. 
Sampling of umbilical 
cord blood 
7a Day 1. the child is 
examined with an 
ultrasound heart (ECHO) 
and one saves 4 chamber 
image for later analysis. 
9a At 4-6 months of age Echo 
10a At the age of 7-9, ECHO 
and blood sampling. 
3a Family is asked to 
participate in study  
6b At delivery, the 
physiological clinic is 
notified that the child 
has now been delivered. 
Sampling of umbilical 
cord blood. 
7b Day 1. the child is 
examined with an 
ultrasound heart (ECHO) 
and one saves 4 chamber 
image for later analysis. 
9b At 4-6 months of age Echo 
10b At the age of 7-9, ECHO 
and blood sampling. 
1b Mother comes for 
regular routine 
ultrasound 
examination in 
pregnancy week 18-20 
4+5b Two examinations 
are carried out 4 weeks 
apart during weeks 28-36 
The fetus is examined 
with ultrasound and 
images and flow 
measurements are saved 
for later analysis. 
2b Family is asked to 
participate in study. 
5a Followed with regular 
examinations until 
delivery 

Study protocol translated from Swedish to English 
CADETTE study 
 
NCT02583763 
Olov Änghagen 
2014-03-18 
 
 
Expected results 
 
We hope to increase knowledge about what relationship exists between growth retardation 
and heart function in fetuses? What does the development look like over time closest to birth. 
What is the significance of a possibly early disturbed heart muscle function and in the 
newborn child. 
 
Data regarding myocardial function assessed with our methodology in growth inhibition are 
sparsely investigated in the literature. An own pilot study and literature data indicate that with 
increasing gestational length (and size of the fetus) displacement (movement of the chamber 
wall) and speed in the chamber wall increase by around 40-50% between the period before 
week 27 to the period between week 28-30. 
 
In a recently published study where stunted fetuses were followed until delivery and 
compared to a healthy control group, a significant difference between the stunted fetuses and 
the healthy controls was shown in some measures. 
 
In child populations from 0-18 years, it has been seen that certain myocardial measurements 
have changed over time as the children grow. 
 
Growth-retarded children have been shown in studies to have an impact on their heart 
function while growing up. They also develop cardiovascular disease more easily in 
adulthood than non-retarded children. 
 
Based on the studies done on stunted fetuses, our hypothesis is that displacement and velocity 
are reduced by 10% in stunted fetuses compared to normal fetuses. 
 
 

Study protocol translated from Swedish to English 
CADETTE study 
 
NCT02583763 
Olov Änghagen 
2014-03-18 
 
 
 
Powerberäkning Bilaga 1 
 
1. Usefulness of myocardial tissue Doppler vs conventional 
echocardiography in the evaluation of cardiac dysfunction 
in early-onset intrauterine growth restriction 
Montse Comas, MD; Fàtima Crispi, MD; Rogelio Cruz-Martinez, MD; 
Josep Maria Martinez, MD; Francesc Figueras, MD; Eduard Gratacós, MD 
 
2. Developments in echocardiographic techniques for the evaluation of ventricular function in children. 
Dragulescu A, Mertens LL. 
 
3 Systolic myocardial velocity alterations in the growth-restricted fetus with cerebroplacental 
redistribution. 
Larsen LU, Sloth E, Petersen OB, Pedersen TF, Sorensen K, Uldbjerg N. 
 
Beräkningssida 
http://infovoice.se/fou/bok/statmet/variat/10000042.shtml 
 
 

Study protocol translated from Swedish to English 
CADETTE study 
 
NCT02583763 
Olov Änghagen 
2014-03-18 
 
 
Powercalculation 
 
Artikel 1 
 
 
Left peak anular velocity during early systole (Left PVS cm/s),  
Left peak anular velocity during atrial contraction (Left PVA cm/s) 
Right peak anular velocity during atrial contraction (Right PVA cm/s) 
Right peak anular velocity during early diastole (Right PVE cm/s) 
 
 
Mean 
Control 
Mean 
Studygroup 
SD 
2 sided P 
value 
0,05 
Power 
Sample size 
 
Left 
PVS 
6,9 (1,2) 
5,6 (0,6) 
2.0 
0,05 
0,80 
38 
 
Left 
PVA 
8,5 (1,4) 
6,2 (0,7) 
2,2 
0,05 
0,80 
15 
 
Right 
PVA 
10,8 (1,5) 
9,1 (1,2) 
2,8 
0.05 
0,80 
43 
 
Right 
PVE 
8,5 (1,3) 
6,2 (0,7) 
2,5 
0.05 
0,80 
19 
 
 
In article 2, which is an overview article on the method, a normal variation of the above-mentioned 
measurements is specified, a normal variation of approx. 
 
Article 3 
 
In article 3, they have followed Peak systolic tissue velocity (cm/s) in the left and right ventricles 
 
Mean Control 
Mean study 
group 
SD 
2 sided P 
value 0,05 
Power 
Sample size 
If changed to + 
20 % in SD 
Left 
ventricle 
3,30 (3,05-
3,55) 
2,41 (1,96-
2,86) 
0,7 
0,05 
0,80 
10 
(SD=1,2) 29 
 
Right 
ventricle 
4,16 (3,88-
4,44) 
3,98 (3,43-
4,53) 
1,0 
0,05 
0,80 
485 
(SD=1,6) 1241 
 

Study protocol translated from Swedish to English 
CADETTE study 
 
NCT02583763 
Olov Änghagen 
2014-03-18 
 
Jan Engvall Professor Fysiologiska kliniken Universitetssjukhuset, Linköping 
Tomas Gottvall Medicine Doktor Överläkare Kvinnokliniken Universitetssjukhuet, Linköping 
Eva Nylander Professor Fysiologiska kliniken Universitetssjukhuset, Linköping 
Nina Nelson Professor Barnkliniken Universitetssjukhuset Linköping 
Olov Änghagen Barnläkare Överläkare Barn och ungdomskliniken Motala/Linköping 
 
Christina Johansson, verksamhetschef för Barn och ungdomskliniken Motala/Linköping 
Kjell Jansson, verksamhetschef för Fysiologiska kliniken, US, Linköping 
Ann Josefsson, verksamhetschef för Kvinnokliniken, US, Linköping 
 
 
Contact 
 
 
Olov Änghagen,  
Barnläkare, doktorand 
Barn- och ungdomsmedicinska kliniken  
Linköping/Motala 
Universitetssjukhuset 
581 85 Linköping 
Tel 010-103 00 00 
epost olov.anghagen@regionostergotland.se  
 
 
Tomas Gottvall 
Medicine Doktor Överläkare 
Kvinnokliniken  
Universitetssjukhuset 
581 85 Linköping 
Tel 010-103 00 00 
E-post tomas.gottvall@lio.se’ 

Study protocol translated from Swedish to English 
CADETTE study 
 
NCT02583763 
Olov Änghagen 
2014-03-18 
 
 
Nina Nelson 
Professor, överläkare  
Barn- och ungdomsmedicinska kliniken 
Linköping/Motala 
Universitetssjukhuset 
581 85 Linköping 
Tel 010-103 00 00 
epost nina.nelson@lio.se