European Journal of Obstetrics and Gynecology 295 (2024) 18–24

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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

Assessment of the cerebroplacental ratio and uterine arteries in low-risk

pregnancies in early labour for the prediction of obstetric and
neonatal outcomes
Andrea Dall’Asta a, b, *, Tiziana Frusca a, Giuseppe Rizzo c, Ruben Ramirez Zegarra a,
Christoph Lees b, d, Francesc Figueras e, Tullio Ghi a
a
Department of Medicine and Surgery, Obstetrics and Gynaecology Unit, University of Parma, Parma, Italy
b
Department of Metabolism, Digestion and Reproduction, Institute of Reproductive and Developmental Biology, Imperial College London, United Kingdom
c
Department of Obstetrics and Gynaecology, Fondazione Policlinico di Tor Vergata, University of Rome Tor Vergata, Rome, Italy
d
Centre for Fetal Care, Queen Charlotte’s and Chelsea Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
e
Fetal i+D Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Deu),
IDIBAPS, University of Barcelona, Spain

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

Keywords: Background: The evidence-based management of human labor includes the antepartum identification of patients
Uterine artery Doppler at risk for intrapartum hypoxia. However, available evidence has shown that most of the hypoxic-related
Cerebroplacental ratio complications occur among pregnancies classified at low-risk for intrapartum hypoxia, thus suggesting that
Placental insufficiency
the current strategy to identify the pregnancies at risk for intrapartum fetal hypoxia has limited accuracy.
Operative delivery
Objective: To evaluate the role of the combined assessment of the cerebroplacental ratio (CPR) and uterine ar­
Adverse perinatal outcomes
teries (UtA) Doppler in the prediction of obstetric intervention (OI) for suspected intrapartum fetal compromise
(IFC) within a cohort of low-risk singleton term pregnancies in early labor.
Methods: Prospective multicentre observational study conducted across four tertiary Maternity Units between
January 2016 and September 2019. Low-risk term pregnancies with spontaneous onset of labor were included. A
two-step multivariable model was developed to assess the risk of OI for suspected IFC. The baseline model
included antenatal and intrapartum characteristics, while the combined model included antenatal and intra­
partum characteristics plus Doppler anomalies such as CPR MoM < 10th percentile and mean UtA Doppler PI
MoM ≥ 95th percentile. Predictive performance was determined by receiver–operating characteristics curve
analysis.
Results: 804 women were included. At logistic regression analysis, CPR MoM < 10th percentile (aOR 1.269, 95 %
CI 1.188–1.356, P < 0.001), mean UtA PI MoM ≥ 95th percentile (aOR 1.012, 95 % CI 1.001–1.022, P = 0.04)
were independently associated with OI for suspected IFC. At ROC curve analysis, the combined model including
antenatal characteristics plus abnormal CPR and mean UtA PI yielded an AUC of 0.78, 95 %CI(0.71–0.85), p <
0.001, which was significantly higher than the baseline model (AUC 0.61, 95 %CI(0.54–0.69), p = 0.007) (p <
0.001). The combined model was associated with a 0.78 (95 % CI 0.67–0.89) sensitivity, 0.68 (95 % CI
0.65–0.72) specificity, 0.15 (95 % CI 0.11–0.19) PPV, and 0.98 (0.96–0.99) NPV, 2.48 (95 % CI 2.07–2.97) LR +
and 0.32 (95 % CI 0.19–0.53) LR- for OI due to suspected IFC.
Conclusions: A predictive model including antenatal and intrapartum characteristics combined with abnormal
CPR and mean UtA PI has a good capacity to rule out and a moderate capacity to rule in OI due to IFC, albeit with
poor predictive value.

Abbreviations: CPR, cerebroplacental ratio; UtA, uterine artery; OI, obstetric intervention; IFC, intrapartum fetal compromise.
* Corresponding author at: Department of Medicine and Surgery, Obstetrics and Gynaecology Unit, University of Parma, Via Gramsci 14, 43126 Parma, Italy.
E-mail address: andrea.dallasta@unipr.it (A. Dall’Asta).

https://doi.org/10.1016/j.ejogrb.2024.02.002
Received 29 November 2023; Received in revised form 28 January 2024; Accepted 2 February 2024
Available online 5 February 2024
0301-2115/© 2024 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
A. Dall’Asta et al.
Introduction
Intrapartum fetal hypoxia is among the leading causes of perinatal
death and neonatal encephalopathy [1]. The evidence-based manage­
ment of human labour includes the antepartum identification of patients
at risk for intrapartum hypoxia, which is based on the evaluation of
maternal medical and obstetric history in association with antepartum
sonographic parameters, including fetal biometry [2,3]. However,
available data has shown that most cases of hypoxic-related labour
complications occur among pregnancies classified at low-risk [4–6].
Therefore, the current strategies to identify the women who are more
likely to experience intrapartum fetal hypoxia have proven to be inac­
curate [7–9].
Maternal and fetal Doppler represent the mainstay for the moni­
toring and management of pregnancies with an established or suspected
fetal growth restriction [10,11]. Over the last decade fetal and maternal
Doppler has been also investigated in the third trimester and close to
labour in pregnancies with appropriately grown fetuses. In particular,
both the assessment of cerebroplacental ratio (CPR) and uterine artery
Doppler are considered an indicator of placental reserve and have been
proposed at late gestation among normal-sized fetuses to unveil a con­
dition of subclinical placental insufficiency [12],which may eventually
increase the risk of antepartum or intrapartum hypoxic complications
[13–16]. However, the CPR and the UtA Doppler prior to labour have
shown a limited utility in the prediction of adverse perinatal outcomes in
this population [16,17].
Uterine contractions are associated with an up to 60 % reduction of
the flow velocity within the uterine arteries [18]. Therefore, from a
physiological point of view early labour can be seen as the ideal time
span to evaluate the placental function by means of Doppler ultrasound
and to predict the occurrence of intrapartum hypoxic injury. So far, two
studies from our group have shown a limited performance of the CPR
[18] and the mean UtA [19] Doppler as standalone parameters in early
labour in the prediction of adverse perinatal outcomes among appar­
ently low-risk patients. The aim of this study was to evaluate the role of
the combined assessment of the CPR and UtA Doppler in the prediction
of hypoxic-related labour complications within a cohort of low-risk
singleton term pregnancies in early spontaneous labour.
Methods
This was a prospective, multicentre, observational study conducted
at four academic maternity units in Italy (University Hospitals of Parma
and Rome Tor Vergata, Italy), United Kingdom (Queen Charlotte’s and
Chelsea Hospital, London) and Spain (Hospital Clinic, Barcelona). The
data collection was performed by the leading investigator (AD) between
January 2016 and September 2019 across two of the participating units;
in the two other participating centres the data collection unfolded for 12
months each over the same timeframe. The study protocol was approved
by the local institutional ethics committee for all the participating
centres.
Non-consecutive women were approached on admission to the la­
bour ward with spontaneous onset of labour, defined by means of a fully
effaced, 3–4-cm dilated cervix coupled with at least three contractions in
10 min recorded on tocography. The inclusion criteria for the study
included uncomplicated singleton pregnancy with cephalic presenting
fetus at term gestation (37 + 0 to 41 + 6 weeks’ gestation), normal blood
pressure and cardiotocography (CTG) on admission and written consent
for study enrolment. The latter was defined as normal by the senior
physician in charge for the labour ward according to the classification of
the International Federation of Gynecology and Obstetrics (FIGO) [20]
in Italy and Spain and of the National Institute for Health and Care
Excellence (NICE) [21] in the United Kingdom. All the included cases
were eligible for intermittent auscultation during labour at enrolment.
Gestational age was determined by first-trimester crown–rump length
measurement performed between 11 and 13 weeks, or according to head
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European Journal of Obstetrics & Gynecology and Reproductive Biology 295 (2024) 18–24
circumference measurement when the first ultrasound examination was
performed after 14 weeks’ gestation [22,23]. Fetal growth was consid­
ered appropriate based on a growth scan performed between 30 and 37
weeks or on a symphysis–fundal height assessment at 35–37 weeks.
Despite being at low risk for intrapartum hypoxic complications [3] all
the enrolled patients were submitted to continuous CTG as per local
protocols.
The exclusion criteria were represented by: cervical dilatation ≥ 5
cm on admission; multiple pregnancy; pre-existing chronic maternal
medical disorder or poor obstetric history; any complication diagnosed
during the index pregnancy, including hypertensive disorders and
gestational diabetes; morbid obesity as defined by body mass index
(BMI) > 40 kg/m2; previously identified FGR; fetal anomaly, aneuploidy
or genetic syndrome identified either antenatally or postnatally; evi­
dence of intrauterine infection; antepartum haemorrhage; premature
rupture of membranes for > 18 h; scarred uterus due to previous
caesarean section or fibroid removal; and maternal age < 18 years.
Demographic and clinical characteristics were recorded and
included including maternal age and ethnicity, parity, gestational age at
the onset of labour and BMI at booking and at delivery.
In the participating centres, trained practitioners recorded the um­
bilical artery (UA) pulsatility index (PI), the middle cerebral artery
(MCA) PI and the left and right UtA PI in between uterine contractions as
determined on tocography and uterine palpation and in the context of a
normal and stable baseline fetal heart rate. Colour and pulsed-wave
Doppler were used to identify and sample the vessels of interest for
the measurement of the PI, which was performed over three consecutive
waveforms. Doppler parameters were measured following the recom­
mendations by the International Society of Ultrasound in Obstetrics and
Gynecology [24], i.e. using an angle of insonation < 30 degrees, in the
absence of maternal and fetal movements and using an automated trace
of at least three consecutive waveforms, prior to epidural analgesia and
converted into multiples of the median (MoM) based on formerly re­
ported reference ranges to adjust for the gestational age [25,26]. The
CPR was computed by dividing the UA PI and the MCA PI and also
converted into MoMs based on formerly reported reference ranges [25].
The CPR MoM value that selected the lowest 10 % of the values was
chosen as the 10th percentile, and abnormal CPR MoM was defined
based on CPR MoM below this threshold; consistently, the mean UtA PI
MoM that selected the highest 5 % of the values was used as cut off for
the 95th percentile of the study population, and abnormal mean UtA PI
MoM was defined as a value of mean UtA PI MoM above such threshold.
Obstetricians and midwives in charge of intrapartum care were
blinded to the results of the Doppler evaluation, in a way that it would
not affect their clinical management. Deliveries were classified into
spontaneous vaginal delivery, obstetric intervention (OI) due to dystocia
or OI due to suspected intrapartum fetal compromise (IFC). OI was
defined as either caesarean section or instrumental vaginal delivery
using vacuum extraction or forceps. The decision to perform an OI due to
suspected IFC was based on the subjective interpretation of the CTG
features by the clinician in charge for the labour management in the
context of the classification systems proposed by FIGO in Italy and Spain
[20] and NICE in the United Kingdom [21].
Perinatal outcome was assessed by evaluating birthweight, birth­
weight percentile corrected for fetal sex and calculated using INeS charts
[27], 1- and 5-min Apgar scores, cord arterial pH and base excess (BE) at
delivery, obtained routinely either within 60 s after birth or from
double-clamped cord segments, and need for resuscitation at birth or
admission to neonatal intensive care unit (NICU). Data regarding ob­
stetrics and neonatal outcomes were collected from patient records.
The primary outcome of the study was the occurrence of an OI due to
suspected IFC. Secondary outcome was defined as the occurrence of
composite adverse perinatal outcome as defined by one of the following:
neonatal acidaemia at birth, as defined by umbilical artery pH < 7.00
and/or umbilical artery base excess > 12, 5-min Apgar score < 7 and
NICU admission.
A. Dall’Asta et al. European Journal of Obstetrics & Gynecology and Reproductive Biology 295 (2024) 18–24

Statistical analysis was performed using Statistical Package for Social Table 1
Sciences (SPSS) version 22 (IBM Inc., Armonk, NY, USA). Data are Maternal demographics and intrapartum and perinatal outcomes outcome in
presented as mean ± SD, median (interquartile range (IQR)), and 804 low-risk term pregnancies included in the study according to the model of
number (%). Categorical variables were compared using the chi-square delivery: spontaneous vaginal delivery, obstetric intervention due to dystocia
test. Comparison of continuous variables included Student’s t-test for and obstetric intervention due to suspected intrapartum fetal compromise.
normally distributed variables, or Mann-Whitney U test for not-normally Spontaneous Obstetric Obstetric
distributed variables. Two-step forward logistic regression analysis was vaginal intervention due intervention due to
delivery to dystocia intrapartum fetal
performed to build a multivariable model. For the first model, i.e.,
N 659 (82.0 %) N 91 (11.3 %) compromise
baseline model, we entered known antenatal and intrapartum variables N 54 (6.7 %)
associated with OI for suspected IFC: maternal age, BMI at booking,
Age, years 30.9 ± 5.6 30.5 ± 5.2 30.7 ± 6.1
parity, smoking status, oxytocin, and epidural. Next, the baseline model Mean ± SD
was combined with the CPR < 10th percentile and mean UtA ≥ 95th Ethnicity White 545 White 73 (80.2 White 40 (74.1 %)
percentile, i.e., the combined model. The predictive performance of N (%) (82.7 %) %) African 3 (5.6 %)
abnormal CPR MoM and mean UtA PI MoM, as well as of the baseline African 24 (3.6 African 3 (3.3 Asian 6 (11.1 %)
%) %) Other 5 (9.3 %)
and of the combined models for the prediction of OI due to suspected IFC
Asian 45 (6.8 Asian 5 (5.5 %)
and composite adverse perinatal outcomes was determined by recei­ %) Other 10 (11.0
ver–operating characteristics (ROC) curve analysis. The best cut-off Other 45 (6.8 %)
point on the ROC curve was identified by evaluating the Youden’s %)
Parity Nulliparae 339 Nulliparae 63 Nulliparae 39 (72.2
index and the minimum distance from the curve and used to calculate
N (%) (51.4 %) (69.2 %) %)
the sensitivity, specificity, positive predictive value (PPV), negative Booking BMI, kg/m2 24.0 ± 4.3 25.6 ± 4.4 24.2 ± 4.6
predictive value (NPV), positive likelihood ratio (LR + ) and negative Mean ± SD
likelihood ratio (LR-). The DeLong method [28] was used for the com­ Term pregnancy 28.2 ± 4.4 30.2 ± 4.4 28.5 ± 4.9
parison of the areas-under-the-curve (AUCs). p-values < 0.05 were BMI, kg/m2
Mean ± SD
considered to indicate statistical significance. The study was reported
Smoking 57 (8.6 %) 10 (11.0 %) 4 (7.4 %)
following the STROBE guidelines [29]. N (%)
Gestation at 39 +6
±1 +1
40 +0
±1
+0
39+5 ± 1+0
Results delivery,
weeks+days
Mean ± SD
Overall, 804 women were included. In all cases delivery occurred PROM 178 (27.0 %) 28 (30.8 %) 13 (24.1 %)
within 24 h after enrolment. CPR MoM within the lowest decile corre­ N (%)
sponded to 0.62 and was found in 75 (9.3 %) women, while mean UtA PI Umbilical PI MoM 1.04 ± 0.21 1.12 ± 0.23 1.12 ± 0.23
MoM above the 95th percentile corresponded to 1.66 and was recorded Mean ± SD
Middle cerebral 0.98 ± 0.22 0.99 ± 0.20 0.89 ± 0.20
in 40 (5 %) cases. The characteristics of the study population are sum­ artery PI MoM
marized in Table 1. OI for suspected IFC occurred in 54 cases (6.7 %), Mean ± SD
among whom caesarean section was performed in 25 (3.1 %). No case of CPR MoM 0.96 ± 0.29 0.90 ± 0.25 0.76 ± 0.27
stillbirth or neonatal death was recorded in our cohort. Mean ± SD
Mean UtA PI MoM 1.10 ± 0.27 1.18 ± 0.32 1.23 ± 0.39
The characteristics of the study population in relation to the occur­
Mean ± SD
rence of the primary outcome are shown in Table S1. At logistic Labour length, 355 ± 182 598 ± 194 456 ± 221
regression analysis comparing the cases undergoing OI due to suspected minutes
IFC and those who did not, the CPR MoM < 10th percentile (aOR 1.269, Mean ± SD
95 % CI 1.188–1.356, P < 0.001), the mean UtA PI MoM ≥ 95th Fetal sex Male 345 (52.4 Male 41 (45.1 Male 29 (53.7 %)
N (%) %) %)
percentile (aOR 1.012, 95 % CI 1.001–1.022, P = 0.04) and parity (aOR Birthweight, grams 3369 ± 419 3442 ± 437 3352 ± 461
0.390, 95 % CI 0.193–0.788, P = 0.009) were independently associated Mean ± SD
with OI for suspected IFC (Table 2). At ROC curve analysis, the com­ Birthweight 50.0 ± 28.3 52.4 ± 29.7 48.3 ± 30.4
bined model showed an AUC of 0.78 (95 % CI 0.71–0.85, p < 0.001), percentile
Mean ± SD
which was higher compared to that of the baseline model, which yielded
Apgar at 1 min 9 (3–10) 9 (2–10) 9 (1–10)
an AUC of 0.61 (95 %CI 0.54–0.69, p = 0.007) (DeLong, p < 0.001) Median (range)
(Fig. 1). The combined model was associated with 0.78 (95 % CI Apgar at 5 min 9 (8–10) 9 (7–10) 9 (7–10)
0.67–0.89) sensitivity, 0.68 (95 % CI 0.65–0.72) specificity, 0.15 (95 % Median (range)
CI 0.11–0.19) PPV, 0.98 (95 % CI 0.96–0.99) NPV, 2.48 (95 % CI Cord arterial pH 7.26 ± 0.09 7.27 ± 0.07 7.19 ± 0.10
Mean ± SD
2.07–2.97) LR + and 0.32 (95 % CI 0.19–0.53) LR- for OI due to sus­ N 699
pected IFC. Cord arterial base 5.68 ± 2.83 5.59 ± 2.68 7.43 ± 4.04
Composite adverse perinatal outcome was recorded in 45 cases (5.6 excess
%). At logistic regression analysis, the CPR MoM < 10th percentile (aOR Mean ± SD
N 673
3.061, 95 % CI 1.385–6.764, p = 0.006), the mean UtA PI MoM ≥ 95th
Amniotic fluid MSAF 55 (8.3 MSAF 11 (12.1 MSAF 9 (16.7 %)
percentile (aOR 3.274, 95 % CI 1.145–9.366, p = 0.03) and parity (aOR characteristics in %) %)
0.302, 95 % CI 0.132–0.691, p = 0.005) were independently associated labour
with composite adverse perinatal outcome (Table 3). At ROC curve N (%)
analysis, the combined model showed an AUC of 0.77 (95 % CI Oxytocin Yes 243 (36.8 Yes N 68 (74.7 Yes 29 (53.7 %)
augmentation %) %)
0.71–0.84, p < 0.001), which was higher compared to that of the N (%)
baseline model, which yielded an AUC of 0.73 (95 % CI 0.66–0.79, p < Epidural in labour Yes 362 (54.9 Yes 77 (84.6 %) Yes 36 (66.7 %)
0.001) (DeLong, p = 0.046) (Fig. 2). The combined model was associ­ N (%) %)
ated with 0.77, 95 %CI(0.61–0.88) sensitivity, 0.68, 95 %CI(0.65–0.72) Birthweight < 10th 45 (6.8 %) 9 (9.9 %) 5 (9.3 %)
centile for
specificity, 0.12, 95 % CI(0.09–0.17) PPV, 0.98, 95 %CI(0.96–0.99)
NPV, 2.42, 95 %CI (1.99–2.95) LR + and 0.34, 95 % CI(0.20–0.59) LR- (continued on next page)

for composite adverse perinatal outcome.

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A. Dall’Asta et al. European Journal of Obstetrics & Gynecology and Reproductive Biology 295 (2024) 18–24

Table 1 (continued )
Spontaneous Obstetric Obstetric
vaginal intervention due intervention due to
delivery to dystocia intrapartum fetal
N 659 (82.0 %) N 91 (11.3 %) compromise
N 54 (6.7 %)

gestation
N (%)
APGAR < 7 at 1 min 4 (0.6 %) 5 (5.5 %) 10 (18.5 %)
N (%)
APGAR < 7 at 5 min – – –
N (%)
Cord arterial pH < 130 (23.0 %) 16 (19.3 %) 26 (52.0 %)
7.20
N (%)
N 699
Cord arterial pH < 11 (1.9 %) 0 (0 %) 10 (20.0 %)
7.10
N (%)
N 699
Cord arterial pH < 1 (0.2 %) 0 (0 %) 2 (4.0 %)
7.00
N (%)
N 699 Fig. 1. Receiver–operating characteristics curve analysis for obstetric inter­
Cord arterial base 92 (16.9 %) 13 (16.2 %) 20 (41.7 %) vention due suspected intrapartum fetal compromise in low risk pregnancies
excess > 8 according to the antenatal model (maternal age, body mass index at booking,
N (%) parity, smoking status, oxytocin use and epidural use) (blue line), and the
N 673
combined model including the antenatal model plus abnormal CPR and mean
Cord arterial base 77 (14.5 %) 10 (12.5 %) 15 (31.2 %)
uterine arteries pulsatility index (red line). (For interpretation of the references
excess > 8 and ≤
12
to colour in this figure legend, the reader is referred to the web version of
N (%) this article.)
N 673
Cord arterial base 15 (2.8 %) 3 (3.8 %) 5 (10.4 %)
excess > 12 Table 3
N (%) Multivariable logistic regression analysis (combined model) for the association
N 673
of antenatal and intrapartum parameters and Doppler assessment with com­
NICU admission or 6 (0.9 %) 1 (1.1 %) 5 (9.3 %)
posite adverse perinatal outcomes, defined as one of the following: Apgar at 5
need for
resuscitation at min < 7, umbilical artery pH < 7.10, umbilical artery base excess > 12 and
birth admission to the neonatal intensive care unit, in 804 low-risk term pregnancies.
N (%) Variable aOR (95 % CI) p
Hypoxic-ischemic – – –
encephalopathy Maternal age 1.026 (0.966–1.089) 0.40
N (%) Booking BMI 0.959 (0.889–1.035) 0.29
Multiparity 0.302 (0.132–0.691) 0.005
MSAF, meconium-stained amniotic fluid; NICU, neonatal intensive care unit; Smoking 0.205 (0.027–1.536) 0.12
CPR, cerebroplacental ratio; BMI, body mass index; PROM, premature rupture of Cerebroplacental ratio MoM < 10th percentile 3.061 (1.385–6.764) 0.006
the membranes. Mean uterine artery PI MoM ≥ 95th percentile 3.274 (1.145–9.366) 0.03
Epidural in labour 1.585 (0.662–3.796) 0.30
Oxytocin in labour 1.916 (0.849–4.323) 0.12
Table 2 Note. χ2(8) = 42.691, p < 0.001. Cox & Snell R2 = 0.05. Nagelkerke R2 = 0.15.
Multivariable logistic regression analysis (combined model) for the association BMI, body mass index; PI, pulsatility index; MoM, multiples of the median; aOR,
of antenatal and intrapartum characteristics and Doppler assessment, with ob­ adjusted odds ratio; CI, confidence interval.
stetric intervention for suspected intrapartum fetal compromise in 804 low-risk
term pregnancies.
fetal Doppler in early labour with the occurrence of OI due to suspected
Variable aOR (95 % CI) p IFC and composite adverse perinatal outcomes. More specifically, within
Maternal age 1.002 (0.947–1.061) 0.94 a population considered at low risk for intrapartum hypoxia the com­
Booking BMI 0.978 (0.912–1.049) 0.54 bination of abnormal CPR and of mean UtA Doppler assessed in early
Multiparity 0.390 (0.193–0.788) 0.009
labour with baseline maternal and pregnancy characteristics allows the
Smoking 0.916 (0.296–2.840) 0.88
Cerebroplacental ratio MoM < 10th percentile 1.269 (1.188–1.356) <0.001 identification of over three out of four women submitted to OI due to
Mean uterine artery PI MoM ≥ 95th percentile 1.012 (1.001–1.022) 0.04 suspected IFC and of neonates with adverse outcome. For screen-
Epidural in labour (Yes/No) 1.095 (0.515–2.330) 0.81 positive cases the risk of adverse events is three times higher than the
Oxytocin in labour (Yes/No) 1.006 (0.486–2.083) 0.99 background risk of the population. Overall, the predictive model
Note. χ2(8) = 57.716, p < 0.001. Cox & Snell R2 = 0.07. Nagelkerke R2 = 0.19. including antenatal and intrapartum characteristics combined abnormal
BMI, body mass index; PI, pulsatility index. MoM, multiples of the median; aOR, CPR and mean UtA PI has a good capacity to rule out and a moderate
adjusted odds ratio; CI, confidence interval. capacity to rule in OI due to IFC and composite adverse perinatal
outcome, albeit with poor predictive value.
Discussion
Interpretation of the study findings in the context of what is known
Main findings
Placental insufficiency is the most common determinant of impaired
In this study we demonstrate an association between maternal and fetal growth [30,31], which represents a major risk factor for stillbirth
and poor labour and perinatal outcomes [32–34]. Based on this

21
A. Dall’Asta et al.
Fig. 2. Receiver–operating characteristics curve analysis for composite adverse
perinatal outcomes, defined as one of the following: Apgar at 5 min < 7, um­
bilical artery pH < 7.10, umbilical artery base excess > 12 and admission to the
neonatal intensive care unit according to the antenatal model (maternal age,
body mass index at booking, parity, smoking status, oxytocin use and epidural
use) (blue line), and the combined model including the antenatal model plus
abnormal CPR and mean uterine arteries pulsatility index (red line). (For
interpretation of the references to colour in this figure legend, the reader is
referred to the web version of this article.)
assumption, fetal smallness has been considered a proxy of placental
insufficiency and the leading cause of adverse perinatal outcomes due to
antepartum or intrapartum hypoxia [35,36]. However, most of the
adverse perinatal events due to placental insufficiency at or close to term
have been shown to occur in normal sized fetuses, hence considered at
low-risk of hypoxia [5,35,37]. The fetal respiratory demands increase
exponentially towards the end of the pregnancy, while fetal nutritional
demands begin to plateau by this period. On this basis, appropriately
grown term fetuses whose placental function becomes inadequate for
their metabolic needs may suffer hypoxic-related adverse outcomes long
before the fetal growth is impaired [38]. In such context, maternal and
fetal Doppler has been proposed as earlier and more reliable indicator of
the placental function in respect of the fetal biometry and ultrasound
findings consistent with cerebral redistribution (i.e. < CPR) and/or
reduced maternal perfusion of the placental bed (i.e. > Ut artery resis­
tance) [11,16,39] have been found to be associated with adverse peri­
natal outcomes related to fetal hypoxia also among apparently grown
fetuses [13–16].
Additionally, in fetuses with subclinical placental insufficiency fetal
hypoxia may become evident only during labour due to the intermittent
reduction of the blood flow to the placenta during uterine contractions.
Human labour represents a challenge for the feto-placental unit given
that uterine contractions result in a reduction of blood flow towards the
fetus [18]. Therefore, the onset of labour may further diminish placental
performance leading to an increased incidence of hypoxic perinatal
events. On this basis, it is reasonable to hypothesize that the antepartum
Doppler examination may overlook conditions of subclinical placental
insufficiency that may become evident only after the onset of labour.
The evaluation of maternal and fetal Doppler in early labour may
improve the detection of fetuses affected by subclinical placental
insufficiency. Two studies from our group evaluating low-risk women
demonstrated an association between abnormal CPR [15] and mean UtA
Doppler [19] in early labour and OI due to suspected IFC and adverse
neonatal outcomes, albeit with limited sensitivity and poor predictive
value of the Doppler parameters. Therefore, both studies concluded that
the use of CPR and mean UtA as standalone parameters is not well-suited
for the identification of fetuses at experiencing adverse outcomes
22
European Journal of Obstetrics & Gynecology and Reproductive Biology 295 (2024) 18–24
associated with intrapartum hypoxia.
In such context, the present study shows that the identification of
such perinatal events may be improved by combining the maternal and
fetal Doppler parameters. Cerebral redistribution (i.e., abnormal or
reduced CPR) indicates the implementation of adaptive mechanisms for
the prevention of cerebral hypoxia, while increased impedance in the
uterine circulation (i.e., abnormal or raised mean UtA PI) is associated
with reduced perfusion of the placental bed. Such Doppler findings may
witness a suboptimal fetal oxygen supply during labour. Consistently,
this study has shown an independent association of abnormal CPR and
mean UtA PI and OI due to suspected IFC and adverse neonatal outcome,
which is not consistent with one previous study evaluating cases sub­
mitted to third trimester routine prenatal ultrasound including Doppler
assessment prior to the onset of labour [40]. Of note, in this present
study the birthweight was not a significant determinant of both out­
comes, which seems to support the concept that subclinical placental
insufficiency (i.e., abnormal Doppler with normal fetal size) is more
commonly implicated than its overt form (i.e., abnormal Doppler with
reduced fetal size) in the hypoxic-related complications occurring at
term gestation or during labour. In the event of subclinical insufficiency,
the placenta may be unable to sustain the oxygen needs of the fetus as
soon as uterine activity becomes spontaneously regular or is augmented.
This is accounted as the determinant of the wide and deep decelerations
of the fetal heart rate featuring the so-called relative utero-placental
insufficiency, which typically disappear or attenuate immediately after
the uterine contractions stop.
Clinical and research implications
Our study conducted on a selected cohort of women at low risk for
intrapartum hypoxic-related complications has confirmed that a com­
bination of antenatal variables and labour Doppler evaluation into a
multivariable regression model albeit with a poor PPV is associated with
higher detection rates for OI due to suspected IFC or adverse neonatal
outcomes compared to any of the included parameters by itself [41–43].
Of note, the association with compositive adverse outcome was also
significant, which suggests that intrapartum maternal and fetal Doppler
may help in the identification of clinically relevant outcomes such as
neonatal acidaemia.
The implementation of intrapartum CTG among low-risk pregnan­
cies for the monitoring of the fetal wellbeing during labour has resulted
in a dramatic increase of OI for concerns related to the fetal oxygenation
status but not in a decreased occurrence of perinatal complications [7].
The current evidence-based approach for the labour management relies
on the identification of the pregnancies at low vs those at high-risk for
intrapartum hypoxic-related complications and on the adoption of
intermittent auscultation in low-risk cases [3,20]. However, available
evidence from the literature suggests that the current strategy for the
triage of the obstetric risk for hypoxic-related complications in labour
performs suboptimally in identifying those fetuses who are not able to
cope with uterine contractions, hence are at risk to suffer an intrapartum
hypoxic injury [7–9].
In our study, which was conducted on a selected cohort of women
potentially eligible for intermittent auscultation, the use of maternal and
fetal Doppler showed a good capacity to rule out the occurrence of OI
due to IFC and of adverse perinatal outcome among the patients who
screened negative at early labour assessment. This capacity was better
than that yielded by the obstetric history and admission CTG alone.
Therefore, women admitted in labour after an apparently low risk
pregnancy can be safely allocated to intermittent auscultation if fetal
and maternal Doppler findings are favourable.
A phase-2 randomized clinical trial has shown a reduced frequency
of hypoxic-related adverse peripartum events following the intrapartum
administration of Sildenafil Citrate to improve the placental perfusion in
women with normally grown fetuses [44], and a recent meta-analysis
has demonstrated the safety of the antenatal administration of Sildenafil
A. Dall’Asta et al.
Citrate [45]. In such context, a Doppler-based screening strategy to
evaluate the placental function/reserve in early labour could help in
selecting those cases who may benefit from the administration of Sil­
denafil Citrate to improve labour outcomes. More insights will be
available at the end of a currently ongoing large RCT comparing Sil­
denafil Citrate versus placebo in reducing labour complications [46].
Strengths and limitations
The strengths of our study are represented by its prospective design,
the large number of patients enrolled, the short interval between ul­
trasound and delivery precluding the opportunity of supervening
placental insufficiency following enrolment, the strict inclusion criteria
for the study and, most notably, by the fact that the clinicians in charge
for the labour management were blinded with respect to the Doppler
recordings. On the other hand, we are aware that the inclusion of a less
selected cohort of patients with risk factors for labour complications
could have increased the number of relevant outcomes, the statistical
power and the clinical relevance of the study findings.
We acknowledge that the multicentre design of the study may
represent a limitation, as labour ward practice may differ across in­
stitutions. However, such design may increase generalizability and
external validity of the study findings. Other limitations are that infor­
mation on the arterial cord blood pH and BE is missing in approximately
one in ten cases, and the non-consecutive enrolment may be another
determinant of selection bias. Additionally, the primary outcome of the
study–i.e. obstetric intervention due to intrapartum fetal distress–was
subjectively defined based on CTG assessment, which has been found to
have a high false positive rate [47] and interobserver and intraobserver
variability [48]. Although patients undergoing OI were candidates for
IFC, the course of intrapartum hypoxia was interrupted, since an inter­
vention was applied. Hence, our model cannot predict the actual risk of
IFC. However, our combined model proved to have a fair predictive
value for the occurrence of adverse perinatal outcomes, which are
known to be associated with labour hypoxia and associated complica­
tions [6].
Finally, we acknowledge that most of the parameters included in the
prediction models were not independently associated with the investi­
gated outcomes. However, the purpose of this study was to show the
actual added value of maternal and fetal Doppler in early labour in
predicting labour complications in the context of a highly selected
population at low-risk for intrapartum hypoxia. In such context, the
variables included in the logistic regression analysis were used to
simulate a baseline history-based risk, which is consistent with the
approach commonly adopted for the risk assessment in the clinical
practice.
Conclusion
In conclusion, our research conducted on a selected cohort of low-
risk term pregnancies enrolled in early spontaneous labour has shown
that a prediction model including antenatal and intrapartum baseline
characteristics combined with CPR and UtA Doppler findings in early
labour has a good sensitivity in the identification of the cases submitted
to OI due to IFC and experiencing adverse perinatal outcome, albeit with
poor predictive value. Such model may be used as a screening test of
reduced placental reserve in early labour or as a tool to select more
appropriately the women who are eligible to IA due to an actual low risk
of intrapartum hypoxia. Further studies are warranted to confirm
whether the assessment of maternal and fetal Doppler in early labour
alone followed by a medical treatment with Sildenafil Citrate of screen-
positive cases can improve labour outcome.
Funding
None.
23
European Journal of Obstetrics & Gynecology and Reproductive Biology 295 (2024) 18–24
CRediT authorship contribution statement
Andrea Dall’Asta: Writing – review & editing, Writing – original
draft, Investigation, Formal analysis, Data curation, Conceptualization.
Tiziana Frusca: Writing – review & editing, Supervision, Conceptuali­
zation. Giuseppe Rizzo: Writing – review & editing, Investigation.
Ruben Ramirez Zegarra: Writing – original draft, Formal analysis.
Christoph Lees: Writing – review & editing, Investigation. Francesc
Figueras: Writing – review & editing, Investigation. Tullio Ghi: Writing
– review & editing, Supervision, Investigation, Conceptualization.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
None.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.ejogrb.2024.02.002.
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