European Journal of Obstetrics and Gynecology 298 (2024) 91–97

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European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.journals.elsevier.com/european-journal-of-obstetrics-and-gynecology-and-
reproductive-biology

Full length article

Analysis of MRI brain biometrics in fetuses monitored for intra uterine

growth restriction and their prognostic value: Results of a prospective
multicenter study
Eric Xu a, Jean-Marie Jouannic b, Marianne Alison c, Pierre-Yves Ancel d, e, Stéphanie Friszer b,
Jessica Rousseau d, Lucie Guilbaud b, Catherine Adamsbaum f, François Goffinet d, g,
Eléonore Blondiaux a, *
a
Service de Radiologie Pédiatrique, Hôpital Armand Trousseau, GRC IMAGES, Médecine Sorbonne Université, APHP, Paris, France
b
Service de Médecine Fœtale, Hôpital Armand Trousseau, Médecine Sorbonne Université, APHP, Paris, France
c
Service de Radiologie Pédiatrique, Hôpital Robert Debré, APHP, Université Paris Diderot, Paris France
d
Obstetrical, Perinatal, and Pediatric Epidemiology Team and Biostatistics Sorbonne Paris Cité Research Center (U1153), INSERM and Université Paris Descartes, Paris,
France
e
Unité de recherche clinique, CIC-Mère enfant, AP-HP, FHU PREMA, Hôpital Cochin, F-75014 Paris, France
f
Service de Radiopédiatrie, Hôpital Bicêtre, Université Paris Sud, Le Kremlin-Bicêtre, France
g
Maternité Port Royal, Hôpital Cochin, APHP, DHU Risques et Grossesse, Université Paris Descartes, Paris, France

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: Show a prognostic value of brain changes in fetuses with intra uterine growth restriction (IUGR) on
Fronto-occipital diameter early neonatal outcome.
Transverse cerebellar diameter Study Design: We prospectively recruited pregnant women whose fetuses presented fetal weight < 5th centile. A
MRI
brain MRI was performed between 28 and 32 weeks of gestation (WG). Several brain biometrics were measured
Fetal growth restriction
Neonatal prognosis
(as fronto-occipital diameter (FOD) and transverse cerebellar diameter (TCD)). Neonatal prognosis was evaluated
according to a composite criterion.
Results: Of the 78 patients included, 62 had a fetal brain MRI. The mean centile value of FOD was lower in the
unfavorable outcome group (n = 9) compared to the favorable outcome group (n = 53) (24.5 ± 16.8 vs. 8.6 ±
13.2, p = 0.004). The ROC curve for predicting risk of unfavorable neonatal outcome based on FOD presented an
area under the curve of 0.81 (95 % CI, [0.63–––0.99]) and a threshold determined at the 3rd centile was
associated with sensitivity of 0.78 and a specificity of 0.89. In multivariate analysis, a FOD less than the 3rd
centile was significantly associated with an unfavorable neonatal risk. There also was a reduction in TCD (25.5
± 21.5 vs. 10.4 ± 10.4, p = 0.03) in the unfavorable neonatal outcome group.
Conclusion: We found an association between a reduction in FOD and TCD in fetal MRIs conducted between 28
and 32 WG in fetuses monitored for IUGR with an unfavorable neonatal outcome. Our results suggest that these
biometric changes could constitute markers of poor neonatal prognosis.

Introduction Utero-placental insufficiency is the most frequent cause of intra

uterine growth restriction, resulting in chronic fetal hypoxia. The brain
Intra uterine growth restriction is a public health, with a variable and especially the posterior fossa are structures whose growth is rela­
incidence estimated at nearly 10 % of births in developed countries [1,2] tively unaffected by intra uterine growth restriction due to a brain
and up to 34 % in emerging countries [3] with a recent estimation of sparing mechanism. This compensatory mechanism allows a redistri­
nearly 32 million cases worldwide per year [4,5]. This pathology is bution of blood flow to the cerebral structures so that brain growth can
associated with increased neonatal morbimortality [6]. continue [7–9]. However, this neuroprotective mechanism can

* Corresponding author at: Faculty of Medicine, Sorbonne Université, GRC IMAGES, Department of Imaging, Hôpital Armand-Trousseau, 26 Avenue du Dr Arnold
Netter, 75012 Paris, France.
E-mail address: [email protected] (E. Blondiaux).

https://doi.org/10.1016/j.ejogrb.2024.04.043
Received 27 December 2023; Received in revised form 11 April 2024; Accepted 29 April 2024
Available online 30 April 2024
0301-2115/© 2024 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
E. Xu et al. European Journal of Obstetrics & Gynecology and Reproductive Biology 298 (2024) 91–97

decompensate if the chronic hypoxia is prolonged and/or severe • Periventricular leukomalacia

[10,11]. This results in a reduction in the cranial perimeter [12–14] and
overall brain volume [15], and structural changes (loss of gray matter MRI protocol
volume [13], gyration changes [16,17]).
A few studies on the brain effects in imaging of a fetal growth re­ MRIs were performed with a 1.5 Tesla field intensity on an Achieva
striction have been conducted prenatally. Certain structural changes or Intera system (Philips, Best, The Netherlands) or on an Aera system
such as cortical [18] or white matter [14] development anomalies have (Siemens, Erlangen, Germany). The acquisition protocol primarily con­
been described and could be of prognostic value for long-term psycho­ sisted of conventional T2-weighted anatomic sequences acquired on the
motor development. This is also true for certain biometric changes such three spatial planes (axial, coronal and sagittal), allowing for the
as measurements of the corpus callosum [19,20] or biparietal diameter different brain biometric measurements, such as brain and bone bipar­
growth kinetics [21]. MRI studies have shown a reduced cerebral and/or ietal diameter, transverse cerebellar diameter, fronto-occipital diameter
cerebellar volume in growth-restricted foetuses [11,22,23]. These and vermis heigh (Fig. 1). A skull to brain ratio was defined as the ratio
studies did not evaluate the short-term prognostic. between the width of the pericerebral space and the bone biparietal
Although ultrasound (US) remains the first-line imaging technique
diameter (BonebiparietalBonebiparietal
diameter − Brainbiparietal diameter
).
for prenatal brain assessment, “true” cephalic biometrics are not eval­ diameter

uated by US, but only indirectly by measuring the cranial perimeter. The following acquisition parameters were standardized among the
Prenatal brain MRI allows direct brain measurements. The main objec­ imaging centers: Ultrafast spin echo sequences (single-shot), Repetition
tive of this prospective and multicenter study was to study the prenatal time = 4000 ms, time to echo = 174.7 ms, acquisition matrix = 320 x
MRI brain biometric changes in fetuses with fetal growth restriction with 320 mm2, slice thickness = 4 mm, interslice gap = 0 mm (adjacent
regard to neonatal outcome. slices).
When brain anomalies with a potential impact on the neurological
Material and methods prognosis of the fetus were detected, the results were sent to the
physician in charge of monitoring each patient.
Study population
Statistical analysis
We conducted a prospective multicenter study involving 6 tertiary-
level perinatal centers in the Paris area. The study protocol was vali­ Maternal data, pregnancy-associated complications and fetal and
dated by an independent ethics committee (Institutional Review Board perinatal characteristics were studied in relation with the main com­
2014-A00640-47) and all subjects gave their written informed consent. posite criterion. Brain biometrics were evaluated as centile [26] ac­
The inclusion period ran from November 22, 2016 to September 11, cording to the same composite criterion as favorable or unfavorable
2017. neonatal outcome and were then analyzed in a univariate model. For
The inclusion criteria were: each brain biometrics, ROC curves were plotted, permitting the deter­
mination of the optimal threshold value for discriminating between a
• Singleton pregnancy with an estimated fetal weight < 5th centile favorable or unfavorable neonatal outcome. This threshold value was
[24], between 28 and 32 weeks of gestation. Intra uterine growth determined by finding the minimal distance between the curve and the
restriction corresponded to fetal growth restriction < 5th centile coordinate point (0; 1). The threshold was used to calculate sensitivity,
with criteria in favor of a pathological growth arrest or decrease on at specificity and also the positive predictive values and negative predic­
least 2 measurements 3 weeks apart. tive values.
• No fetal structural abnormality detected by US The association of the brain biometrics with the unfavorable
• Absence of congenital cytomegalovirus infection neonatal outcome was then studied in a multivariate analysis. Adjust­
• Normal fetal karyotype if amniocentesis had been recommended ment variables considered were fetal sex and umbilical artery Doppler
anomalies. Analyses first considered the biometrics as continuous vari­
A fetal brain MRI was conducted within 14 days following inclusion ables and then as a qualitative value using the threshold calculated from
and before the 32nd weeks of gestation. the ROC curves. In the multivariate model, gestational age at birth and
birth weight were not considered in the analysis because they did not
Perinatal data collection represent confusion factors but rather intermediate variables in the
relationship between biometric measurements and neonatal condition
All clinical data for both the mother and the fetus were collected [27].
prospectively. A fetal US was performed within 1 week prior to the MRI Data were presented as mean (±SD) or as proportion (95 % CI).
examination. Quantitative data were tested for their distribution in order to choose
The main indication to opt for the delivery was also collected the appropriate (i.e. parametric or non-parametric) test for comparison.
(abnormal fetal tracing, absent or reversed end-diastolic flow in the Statistical analyses were performed using SAS software (version 9.4).
umbilical artery, fetal growth cessation). All of the neonatal data was
also collected up to discharge from the center. Results

Main assessment criterion: Neonatal outcome Study population

The main assessment criterion was a composite criterion including A total of 78 patients were included (Fig. 2). In 14 cases, the MRI
the main perinatal complications: examination could not be performed because delivery occurred within a
few days following inclusion and before the scheduled date of the MRI.
• Perinatal death at less than 28 days of life. Among the 64 patients for whom MRI examination could be performed,
• Admission to neonatal intensive care unit with need of mechanical two were excluded because of medical termination of the pregnancy for
ventilation for more than 48 h other reasons than intra uterine growth restriction: in one case a
• Ulcerative-necrotizing enterocolitis termination of the pregnancy was performed for a maternal indication.
• Grade III-IV intraventricular hemorrhage according to Papile et al. In the other case, termination of the pregnancy was performed for fetal
[25] brain anomalies detected on the MRI morphological sequences (severe

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Fig. 1. Anatomic sequences from the MRI protocol. T2-weighted sequences focused on the encephalon on a coronal plane (a.; b.) permitting measurement of the
brain and bone biparietal diameter (BPD), on a coronal plain passing through the cerebellum (c.) permitting measurement of the transverse cerebellar diameter
(TCD), and in a median sagittal plane (d.) permitting measurement of the fronto-occipital diameter (FOD) and the vermis height (VH).

anoxic brain injuries non related to intra uterine growth restriction). groups, nor any difference in the occurrence of pregnancy-related
This results in a total of 62 patients with fetal brain MRI examination vascular complications. See (Table 2).
with biometric study.
Among these 62 cases, there was one intrauterine death which Neonatal outcome
occurred at 31 weeks of gestation. In this fetus, the brain MRI was
performed at 28 weeks of gestation and the prenatal US showed an The neonates presenting an unfavorable neonatal outcome were born
umbilical artery resistance index > 95th centile and an estimated fetal significantly earlier, at a mean gestational age of 30.9 ± 1.8 weeks of
weight below the 1st centile. The birth weight was 560 g and the post­ gestation vs. 33.9 ± 3 weeks of gestation (p = 0.004), with a signifi­
mortem examination was declined by the parents. cantly lower birth weight as compared with the neonates with favorable
Among the 61 liveborn neonates, 5 died between days 4 and 24 of outcome.
life. Three neonates were admitted to intensive care unit with need of
mechanical ventilation for more than 48 h, one of them presented with
MRI results
necrotizing enterocolitis. The number of neonates presenting at least one
component of the main assessment criterion for the unfavorable
The fetal brain MRIs were performed at a mean gestational age of
neonatal outcome group was 9/62 (14.6 %; 95 % CI [5.7 % − 23.3 %]).
30.2 weeks of gestation (±1.14) in the favorable neonatal outcome
The favorable neonatal outcome group comprised 53 patients.
group and of 29.2 weeks of gestation (±0.83) in the unfavorable
Maternal characteristics and pregnancy complications are presented
neonatal outcome group, with a significant difference of (p = 0.01).
in Table 1. There was no difference in maternal age or BMI between the
Brain biometrics are presented in Table 3.

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Fig. 2. Flowchart.

neonatal outcome depending on the fronto-occipital diameter centile.

Table 1
The area under the curve (AUC) was 0.81 (95 % CI, [0.63–0.99]) and a
Maternal characteristics and pregnancy complications.
threshold value at the 3rd centile was associated with a sensitivity of
Favorable Unfavorable p 0.78; a specificity of 0.89; a positive predictive value of 0.54 and a
neonatal neonatal outcome
negative predictive value of 0.96. A fronto-occipital diameter below the
outcome(N = (N = 9)
53) 3rd centile was associated with a significant increase risk of unfavorable
neonatal outcome with an odds ratio (OR) of 27.4 (95 % CI, [4.6; 164])
Maternal age (years) 32.5 ± 6.1 31.6 ± 4.9 0.70
in univariate analysis and 52.5 (95 % CI, [4.4; 623]) in multivariate
Body Mass Index at 27.2 ± 5.8 25.5 ± 4.5 0.33 analysis (Table 4).
inclusion (kg/m2) Centile values for brain and bone biparietal diameter were not
Ethnic/geographic * significantly lower in the unfavorable neonatal outcome group. Finally,
origin
we found no significant difference in the skull to brain ratio between the
Caucasian 19/49 (38.8) 5/8 (62.5)
Sub-Saharan 16/49 (32.6) 2/8 (25.0) two groups.
African
Antilles 1/49 (2.0)
Asian 2/49 (4.1)
Cerebellar biometrics
North African 9/49 (18.4) 1/8 (12.5)
Other 2/49 (4.1) Centile values for transverse cerebellar diameter were significantly
Tobacco use during 8/48 (16.7) 3 (33.3) 0.35 reduced in the unfavorable neonatal outcome group (10.4 ± 10.4 vs.
pregnancy
25.5 ± 21.5). Fig. 3b represents the ROC curve for predicting risk of
Primiparity 27 (50.9) 6 (66.7) 0.48
Vascular complications unfavorable neonatal outcome based on transverse cerebellar diameter
Hypertension or 15 (28.3) 3 (33.3) 0.71 centile. This curve presented an AUC of 0.73 (95 % CI, [0.55; 0.9]) and a
pre-eclampsia threshold value set at the 10th centile was associated with a sensitivity
HELLP syndrome 2 (3.8) 1 (11.1) 0.38 of 0.78; a specificity of 0.57; positive predictive value of 0.23 and a
Retroplacental 2 (3.8) 0 (0.0) 1.00
hematoma
negative predictive value of 0.94. In univariate and multivariate anal­
ysis, there was no significant association between a transverse cerebellar
Data were presented as mean ± standard deviation, n/N (%) or n (%). diameter below the 10th and an increased risk of unfavorable neonatal
p: Chi-squared or Fisher’s exact test for the qualitative variables and Mann
outcome.
Whitney test.
Finally, concerning vermis height, a threshold set at the 3rd centile
For the quantitative variables.
was significantly associated with an unfavorable neonatal outcome,
*Comparison tests not performed because of a non-representation of certain
ethnic origins in the unfavorable outcome group. both in univariate analysis (OR = 5.4; 95 % CI, [1.2; 23.7]) and multi­
variate analysis (OR = 13.3; 95 % CI, [1.6; 112]).
Brain biometrics
Discussion
There was a significant reduction in fronto-occipital diameter centile
value in the unfavorable neonatal outcome group (8.6 ± 13.2 vs. 24.5 ± In cases of fetal growth restriction of vascular origin, our prospective
16.8). Fig. 3a represents the ROC curve for predicting risk of unfavorable multicenter study showed an association between a reduction of brain
biometrics measured in fetal MRIs supratentorially (fronto-occipital

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Table 2 Table 3
Fetal characteristics and perinatal issues. Biometrics and neonatal status.
Favorable Unfavorable p Favorable Unfavorable p
neonatal neonatal outcome neonatal outcome neonatal outcome
outcome (N = 53) (N = 9) (N = 53) (N = 9)

Umbilical artery Doppler 16/50 (32.0) 7/9 (77.8) 0.02 Mean (SD) Mean (SD)
anomaly MRI gestational 30.2 (1.1) 29.2 (0.8) 0.01
Cerebroplacental ratio 24/51 (47.1) 6/9 (66.7) 0.47 age (weeks of
anomaly gestation)
Delivery type 1 Interval between 26.5 (20.5) 11.4 (13) 0.02
Spontaneous labor 6 (11.3) 1 (11.1) MRI and birth
Induced labor 10 (18.9) 1 (11.1) (days)
Scheduled caesarian 37 (69.8) 7 (77.8) Brain biparietal 10.8 (13.4) 9.7 (16.2) 0.10
Indication of labor 0.12 diameter
Fetal growth 15/37 (40.6) 0/6 (0.0) (centile)
anomalies Bone biparietal 8.4 (13.4) 5.1 (7.5) 0.29
Fetal tracing anomaly 16/37 (43.2) 4/6 (66.7) diameter
Fetal Doppler 4/37 (10.8) 2/6 (33.3) (centile)
anomalies Skull to brain ratio 0.08 (0.03) 0.08 (0.03) 0.78
Other 2/37 (5.4) 0/6 (0.0) Fronto-occipital 24.5 (16.8) 8.6 (13.2) 0.004
Caesarian (%) 42 (79.2) 8 (88.9) 0.67 diameter
Gestational age at birth 33.9 ± 3 30.9 ± 1.8 0.004 (centile)
Male sex 27 (50.9) 6 (66.7) 0.48 Transverse 25.5 (21.5) 10.4 (10.4) 0.03
Birth weight (g) 1500 ± 588 934 ± 265 0.002 cerebellar
Birth weight Z-score*, − 3.3 (− 4; − 2.5) − 3.7 (− 4.3; − 3.5) 0.04 diameter
median (IQR) (centile)
Vital status <0.001 Vermis height 22 (20) 13.44 (16.8) 0.09
Alive 52 (98.1) 3 (33.3) (centile)
Intrauterine death 0 (0.0) 1 (11.1) p Mann Whitney
Neonatal death before 0 (0.0) 5 (55.6)
day 28 of life
Neonatal death after 1 (1.9) 0 (0.0) restriction should be the brain structure most affected compared with
day 28 of life
fetuses of the same gestational age and with a normal growth [30]. This
5 min APGAR < 7 3 (5.7) 0 (0.0) 1
Arterial cord pH < 7.1 1/51 (2.0) 0 (0.0) 1
differential involvement of the brain structures could be related to the
Main assessment composite encephalic vascular changes associated with fetal chronic hypoxia.
criterion: Hernandez et al. showed encephalic hemodynamic changes depending
Transfer to intensive 38 (71.7) 7/8 (87.5) 0.67 on the severity of the intra uterine growth restriction [8]. A moderate
care unit
intra uterine growth restriction was initially associated with an eleva­
Mechanical 0 (0.0) 3/8 (37.5) 0.002
ventilation ≥ 48 h tion in blood flow in the frontal regions, then with a decrease in the more
Necrotizing 0 (0.0) 1/8 (12.5) 0.13 severe intra uterine growth restriction stages. Moreover, in the early
enterocolitis intra uterine growth restriction stage, the higher cognitive functions of
Leukomalacia 0 (0.0) 0 (0.0) ** the frontal lobes would initially be protected. In cases of severe and/or
Grade III-IV 0 (0.0) 1 (1.9) **
intraventricular
prolonged intra uterine growth restriction and consequently chronic
hemorrhage hypoxia, the brain sparing mechanism favored vital structures (such as
the basal ganglia), at the expense of the frontal regions [8].
* INSERM Epopé curves.
At the subtentorial level, we shown a significant reduction in the
** Sample insufficient for performing a statistical test.
Data were presented as mean ± standard deviation, n/N (%) or n (%). transverse cerebellar diameter in the unfavorable outcome group. In
p: Chi-squared or Fisher’s exact test for the qualitative variables and Mann multivariate analysis, however, this association lacked statistical sig­
Whitney test for the quantitative variables. nificance. The ROC curve for predicting risk of unfavorable neonatal
outcome based on the transverse cerebellar diameter centile presented
diameter) and subtentorially (transverse cerebellar diameter) with an an area under the curve of 0.72 [0.55–0.9], an acceptable level of
unfavorable neonatal outcome. discrimination [28]. These data are in accordance with studies based on
The fronto-occipital diameter measured between 28 and 32 weeks of MRIs in fetuses presenting a intra uterine growth restriction < 5th
gestation was significantly lower in the fetal group whose neonatal centile in which a reduction in the transverse cerebellar diameter was
outcome was unfavorable. The ROC curve based on the fronto-occipital found [11,23]. Our results also agree with prenatal US studies reported
diameter centile reflected an excellent discrimination capacity, with an in the literature: Snijders et al. showed that an intrauterine or neonatal
area under the curve between 0.8 and 0.9 [28]. In the multivariate death was more frequent when the transverse cerebellar diameter was
model and a fronto-occipital diameter < 3rd was associated with a less than − 2SD on prenatal US performed on fetuses with growth re­
significant increased risk of poor neonatal prognosis. This result is in line striction [31]. Moreover, a retrospective monocenter study recently
with other studies. Arthurs et al. demonstrated, using MRI, decreased analyzed, in the general population, the outcome of 408 fetuses with a
brain biometrics (below the 3rd centile) on 30 severe intra uterine transverse cerebellar diameter < 5th centile on US from the 2nd
growth restriction fetuses with umbilical abnormal dopplers, affecting trimester or 3rd trimester [32]. The authors showed in a subgroup of
supratentorial brain biometrics in 2/3 of fetus, and both supra and fetuses with intra uterine growth restriction that an intrauterine or
infratentorial brain biometrics in half of foetuses [11]. neonatal death occurred in 81.8 % of cases with a transverse cerebellar
One study using prenatal MRI (30–34 weeks of gestation) showed an diameter that was between 2.5th and 0.6th centile (n = 102) and in 75 %
overall reduction in brain volume in the fetuses with intra uterine of the cases with a transverse cerebellar diameter < 0.6th centile (n =
growth restriction [23]. And more specifically, a reduction in volume of 99) [32]. In our study, the main assessment criterion was a composite
the frontal lobe in fetuses with intra uterine growth restriction (24–34 criterion including not only perinatal death but also major neonatal
weeks of gestation) was reported in 3D US [29]. From a physiopatho­ complications. This could in part explain why the transverse cerebellar
logical perspective, the frontal lobe of fetuses with intra uterine growth diameter threshold value was higher in our study.

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Fig. 3. ROC curves for predicting risk of unfavorable neonatal outcome based on fronto-occipital diameter (a) and transverse cerebellar diameter (b) centile. AUC:
Area under the curve ROC: Receiver-operating-characteristic.

Table 4
Univariate and multivariate analysis of the association between fetal brain biometrics and unfavorable neonatal outcome depending on the centile values.
Univariate model Multivariate model

OR [95 % CI] p aOR [95 % CI] p

Brain biparietal diameter (centile) 0.99 [0.94–1.05] 0.82 0.99 [0.93–1.06] 0.85
Brain biparietal diameter 0.01 0.006
≤ 2nd centile 7.63 [1.64–35.5] 17.56 [2.29–135]
> 2nd centile 1 − 1 −
Bone biparietal diameter (centile) 0.96 [0.87–1.07] 0.49 0.97 [0.87–1.09] 0.66
Bone biparietal diameter 0.13 0.15
≤ 3rd centile 3.63 [0.69–19.1] 3.67 [0.62–21.9]
> 3rd centile 1 − 1 −
Fronto-occipital diameter (centile) 0.91 [0.84–0.98] 0.02 0.90 [0.82–0.98] 0.02
Fronto-occipital diameter <0.001 0.002
≤ 3rd centile 27.42 [4.59–164] 52.53 [4.43–623]
> 3rd centile 1 − 1 −
Transverse cerebellar diameter (centile) 0.94 [0.88–1.01] 0.07 0.94 [0.88–1.01] 0.09
Transverse cerebellar diameter 0.07 0.11
≤ 10th centile 4.56 [0.87–24.1] 4.22 [0.73–24.2]
> 10th centile 1 − 1 −
Vermis height (centile) 0.97 [0.92–1.02] 0.24 0.96 [0.91–1.02] 0.16
Vermis height 0.03 0.03
≤ 3rd centile 5.37 [1.22–23.7] 6.75 [1.22–37.2]
> 3rd centile 1 − 1 −

Multivariate model: Adjustment for fetal sex and anomalies of the umbilical artery Doppler.
Each aOR is the result of a multivariate analysis adjustment for fetal sex and anomalies of the umbilical artery Doppler. We decided not to present the OR of the
covariates to simplify the table.
Continuous variable effects were evaluated as a 1 centile shift from the mean.
OR: Odds ratio.
CI: Confidence interval.
aOR: Adjusted odds ratio.

This study presents several limitations. First, the measurements we group. This bias was inherent to the population studied complications
used were centiles. It would have been also interesting to study pertaining purely to intra uterine growth restriction and those pertain­
normalized values. This is the case, for example, for the relationship of ing purely to prematurity being interrelated.
the cerebral biometrics with the abdominal perimeter [31,33], or the Finally, in this multicenter protocol, the number of subjects was
relationship between cerebellar volume and cerebral volume [14]. relatively limited. This especially limited our statistical power along
However, these data were lacking. with the number of adjustment variables which could be considered in
Secondly, unfavorable neonatal outcome was defined by a composite the multivariate model, with several biometrics consequently presenting
criterion permitting an overall approach of different neonatal compli­ large confidence intervals.
cations. However, this composite criterion by definition included com­
plications associated both with intra uterine growth restriction and to Conclusion
prematurity. The deliveries occurred at a mean gestational age of 33
weeks (95 % CI, [32–36]) in the favorable outcome group and at 31 Our study showed a significant association between a reduction in
weeks of gestation (95 % CI, [29–32]) in the unfavorable outcome fronto-occipital diameter and transverse cerebellar diameter in fetal

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biomarker of abnormal neurodevelopment in late-onset fetal growth restriction.
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