J. Perinat. Med.
2016; 44(2): 249–256
Review article
Ahmed Abobakr Nassr*, Ahmed M. Abdelmagied and Sherif A.M. Shazly
Fetal cerebro-placental ratio and adverse perinatal
outcome: systematic review and meta-analysis of
the association and diagnostic performance
DOI 10.1515/jpm-2015-0274
Received August 3, 2015. Accepted November 23, 2015. Previously
published online January 12, 2016.
Abstract
Objective: The objective of this meta-analysis is to assess
the value of fetal cerebro-placental Doppler ratio (CPR) in
predicting adverse perinatal outcome in pregnancies with
fetal growth restriction (FGR).
Methods: Three databases were used: MEDLINE, EMBASE
(with online Ovid interface) and SCOPUS and studies from
inception to April 2015 were included. Studies that reported
perinatal outcomes of fetuses at risk of FGR or sonographi-
cally diagnosed FGR that were evaluated with CPR were
considered eligible. Perinatal outcomes include cesarean
section (CS) for fetal distress, APGAR scores at 5 min, neo-
natal complications and admission to neonatal intensive
care unit (NICU). Pooled data were expressed as odds
ratio (OR) and confidence intervals (CI), and the summary
receiver operating characteristic (SROC) curve was used to
illustrate the diagnostic accuracy of CPR.
Results: Seven studies were eligible (1428 fetuses).
Fetuses with abnormal CPR were at higher risk of CS for
fetal distress (OR = 4.49, 95% CI [1.63, 12.42]), lower APGAR
scores (OR = 4.01, 95% CI [2.65, 6.08]), admission to NICU
(OR = 9.65, 95% CI [3.02, 30.85]), and neonatal complica-
tions (OR = 11.00, 95% [3.64, 15.37]) than fetuses who had
normal CPR. These risks were higher among studies that
included fetuses diagnosed with FGR than fetuses at risk
of FGR. Abnormal CPR had higher diagnostic accuracy
*Corresponding author: Ahmed Abobakr Nassr, Department of
Obstetrics and Gynecology, Mayo Clinic College of Medicine,
Rochester, MN, USA; and Women’s Health Hospital, Assiut
University Hospitals, Assiut, Egypt, Tel.: +1 507 319 2332,
E-mail: Nassr.Ahmed@mayo.edu; ahmedabobakr@aun.edu.eg
Ahmed M. Abdelmagied and Sherif A.M. Shazly: Department
of Obstetrics and Gynecology, Mayo Clinic College of Medicine,
Rochester, MN, USA; and Women’s Health Hospital, Assiut
University Hospitals, Assiut, Egypt
for adverse perinatal outcomes among “sonographically
diagnosed FGR” studies than “at risk of FGR” studies.
Conclusion: Abnormal CPR is associated with substan-
tial risk of adverse perinatal outcomes. The test seems to
be particularly useful for follow up of fetuses with sono-
graphically diagnosed FGR.
Keywords: Cerebro-placental ratio; intrauterine growth
restriction; middle cerebral artery Doppler; perinatal
outcome; umbilical artery Doppler.
Introduction
By definition, fetal growth restriction (FGR) complicates
about 10% of all pregnancies [1]. Despite advances in
the antenatal surveillance tests, FGR remains among the
leading causes of perinatal morbidity, mortality with post-
natal adult consequences [2, 3].
Controversies surround the optimal strategy for fetal
surveillance and the timing of delivery of pregnancies
complicated by FGR [4]. Current American College of
Obstetrician and Gynecologists (ACOG) guidelines of fetal
arterial Doppler evaluation in FGR utilize umbilical artery
Doppler exclusively to determine the timing of delivery [5].
Although the circulatory redistribution phenomenon and
brain sparing effect are well understood in FGR compli-
cated pregnancies, the abnormal middle cerebral artery
(MCA) Doppler findings has demonstrated limited predic-
ative value for poor perinatal outcome [6].
The fetal cerebro-placental ratio (CPR) is a unique
fetal Doppler parameter to objectively quantify circula-
tory redistribution that could be attributed to increased
placental resistance and brain sparing effect which
occurs as a compensatory mechanism to chronic hypoxia
and results in increased cerebral blood flow [7]. A study
on lamb fetuses demonstrated that the CPR was most
valuable for detection of early hypoxia in the setting of
acute deterioration in PO2 [8]. Several small studies have
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250      Nassr et al., Utility of cerebro-placental ratio in FGR
shown that CPR has higher predictive value for adverse
perinatal outcomes than individual Doppler components
[9–11].
CPR can be calculated by dividing the MCA pulsatility
index (PI) by the umbilical artery PI. Abnormal CPR may
reflect abnormal blood flow in the umbilical artery, MCA
or both. However, the ratio may be abnormal while the PIs
of both arteries are still within the limits of normal values
[12]. The objective of this meta-analysis is to investigate
the utility of fetal CPR for predication of adverse perinatal
outcome in fetuses with sonographically diagnosed FGR
or at risk of FGR.
Methods
In collaboration with an expert librarian, we conducted a search for
studies that evaluated the role of fetal CPR in evaluating FGR and
the risk of adverse perinatal outcome among neonates with previous
abnormal CPR. Three databases were used: MEDLINE, EMBASE (with
online Ovid interface) and SCOPUS. The search included studies from
inception to April 2015; we used the terms: “Fetal Doppler” or “fetal
cerebro-placental ratio” and “FGR, small for gestational age (SGA)
or IUGR” and “perinatal outcome” to identify eligible studies. A
search on related references from review articles and selected studies
was performed. No language restriction was applied during search.
Detailed research strategy is explained in Appendix I.
Eligibility criteria and study selection
Studies that reported perinatal outcomes of fetuses at risk of FGR or
sonographically diagnosed FGR that were evaluated with CPR were
considered eligible. Studies that did not address our primary out-
comes were excluded, namely; Cesarean section (CS) for fetal distress,
APGAR scores at 5 min, neonatal complications, and admission to
neonatal intensive care unit (NICU). Studies on multiple gestations
were also excluded. Both prospective and retrospective studies were
considered. A sample size was not a basis of exclusion. Two inde-
pendent reviewers screened initially included abstracts and reviewed
the full text of the selected articles. For purposes of analysis, studies
were categorized according to their selection frame to either: at risk
of FGR (having one or more risk factors for FGR) or sonographically
diagnosed FGR (estimated fetal weight  < 10th percentile or abdominal
circumference  < 5th percentile for gestational age) [4].
Data abstraction
Data was abstracted using a standardized form that included the
authors, the year of the study, the publishing journal, the origin and
the type of the study, the time frame of data recruitment, the sample
size, the cutoff point for abnormal CPR, and perinatal outcomes. Data
were abstracted from text, tables or figures. Discrepancies in study
selection and data abstraction were minor and were adjusted by
consensus among reviewers. The Newcastle-Ottawa Scale (NOS) was
used to evaluate the risk of bias [13].
Data analysis
Odds ratios (OR) and 95% confidence interval (CI) were used to
express perinatal outcomes [CS for fetal distress, low APGAR scores
at 5 min ( < 7), neonatal complications, and admission to NICU]. Pool-
ing of diagnostic accuracy of abnormal CPR was performed using
Littenberg-Moses summary receiver operating characteristic (SROC)
curve. Due to anticipated heterogeneity, a random-effect model was
selected to pool outcomes [14]. I squared statistic and Cochrane
Q test were used to assess heterogeneity. A substantial heterogeneity
was considered if I squared value  > 50% or Q test P-value  < 0.10 [15].
­Statistical analysis was performed using Review Manager (RevMan)
Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane
Collaboration, 2014) [16].
Results
An initial database search identified 124 abstracts. Ninety
one were initially excluded for irrelevance. Of the remain-
ing 33 studies, 26 did not meet our eligibility criteria based
on reviewers’ consensus. Seven studies were eventually
selected for analysis [9, 10, 12, 17–20]. The study selection
flowchart is summarized in Figure 1.
The characteristics of selected studies are summarized
in Table 1. These studies were published between 1992 and
2014. Overall, the quality of methodology and the risk of
bias of the 7 studies were acceptable (­Appendix II). Five of
these studies were prospective and two were retrospectively
Studies abstracted from EMBASE,
MEDLINE and SCOPUS databases
(n=124)
Irrelevant abstracts
(n=91)
Retrieved full texts
(n=33)
Full texts excluded for not
meeting the inclusion criteria
(n=26)
Eligible studies
(n=7)
Figure 1: Flow chart of study selection.
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 Table 1: Characteristics of the selected studies.

Author and year   Country   Journal   Type of the study   Time frame   Eligibility criteria (studied   Cut-off point   Sample size
of origin population)

I. Sonographically diagnosed FGR

 Regan et al.   USA   Journal of Perinatology   Retrospective study   Between March   Suspected FGR (EFW  < 10th   1.08   Normal umbilical artery
2014 2011 and 2014 percentile and/or an estimated (n = 178), abnormal
fetal AC  < 5th percentile) UA and normal CPR
(n = 52), abnormal UA
and CPR (n = 40)
 Habek et al.   Croatia   Fetal Diagnosis and Therapy   Prospective study   Between 1997   Singleton pregnancies and FGR   1   87
2003 and 1999 at 28–42 weeks of gestation
(criteria for FGR diagnosis not
reported)
 Makhseed   Kuwait   International Journal of   Prospective study   N/A   Between 29 and 42 weeks   1.05   70
et. al. 2000 Gynecology and Obstetrics of gestation with clinically
suspected fetal growth
restriction (EFW  < 10th
percentile)
 Gramellini   Italy   Obstetrics and Gynecology   Retrospective study   N/A   Singleton fetuses who had   1.08   90 (45 with
et. al. 1992 Doppler between 30–41 weeks uncomplicated
(FGR AC  < 5th percentile) pregnancies and
45 with ultrasound
diagnosis of FGR)
II. At risk of FGR
  Singh et al.   India   National Journal of Medical   Prospective study   Between March   Pregnant patients with   1   50 (30 had FGR)
2013 Research 2008 and March preeclampsia at  ≥ 32 weeks
2009 gestation
  Shahinaj   Albania   Journal of Prenatal Medicine   Prospective study   Between January  All pregnant women with   1   738
et al. 2010 2008 and preeclampsia and gestational
January 2009 hypertension
  Bahado-Singh  USA   American Journal of   Prospective study   Between January  Fetuses at risk for FGR who were   0.5 Multiples   123
et al. 1999 Obstetrics and Gynecology 1994 and delivered  < 3 weeks after the of the normal
September 1997 last Doppler examination median

FGR = fetal growth restriction, CPR = cerbro-placental ratio, PI = pulsatility index.

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Nassr et al., Utility of cerebro-placental ratio in FGR      251
252      Nassr et al., Utility of cerebro-placental ratio in FGR
conducted. Three studies used a cutoff point of 1, two studies
used a cutoff point of 1.08, one used 1.05, and one used mul-
tiples of median to define abnormal CPR. These studies were
conducted in the USA [9, 18], Italy [12], Croatia [17], Albania
[19], India [20] and Kuwait [10]. The total pooled population
was 1428 fetuses, 497 of them had abnormal CPR.
Odds analysis
All included studies reported the rate of CS for fetal dis-
tress among women with normal and abnormal CPR (931
vs. 497 fetuses, respectively). Fetuses with abnormal CPR
had significantly higher rate of CS for fetal distress as
opposed by fetuses with normal CPR (304/497 vs. 366/931,
respectively, OR = 4.49, 95% CI [1.63, 12.42]). This ratio was
higher in the subset of studies that evaluated fetuses
with sonographically diagnosed FGR (81/118 vs. 80/399,
OR = 7.40, 95% CI [2.54, 21.51]). However, the pooled odds
ratio was less, and was not significant in the subset of
studies that included fetuses at risk of FGR (223/379 vs.
286/532, OR = 2.23, 95% CI [0.66, 7.56]).
Five studies reported the rate of low APGAR scores ( < 7)
at 5 min among neonates with or without previous abnor-
mal CPR. Fetuses with abnormal CPR had higher rate of
low 5-min APGAR scores at birth than fetuses with normal
CPR (203/439 vs. 111/629, respectively, OR = 4.01, 95% CI
[2.65, 6.08]). The risk was higher and close to significance
in the subset with sonographically diagnosed FGR (19/60
vs. 6/97, OR = 6.88, 95% CI [0.96, 49.10]) and was lower,
yet significant, in the subset with risk of FGR (184/379 vs.
105/532, OR = 3.69, 95% CI [2.73, 4.97]).
The rate of admission to NICU among neonates was
evaluated in six studies. Fetuses with abnormal CPR
were significantly more liable to NICU admission at birth
(314/472 vs. 278/869, OR = 9.65, 95% CI [3.02, 30.85]). Odds
ratio is higher in the subset with sonographically diag-
nosed FGR (72/93 vs. 68/337, OR = 12.96, 95% CI [6.03,
27.87]) and lower in the subset with risk of FGR (242/379
vs. 210/532, OR = 7.06, 95% CI [1.00, 50.00]).
The pooled estimate of the four studies, which addressed
the risk of serious neonatal complications, also revealed
significantly higher rates among neonates with previous
abnormal CPR as compared to those who had normal CPR
(56/123 vs. 60/410, respectively, OR = 11.00, 95% [3.64, 15.37]).
The odds ratio was almost doubled in the subset of studies
that included fetuses with sonographically diagnosed FGR
(40/58 vs. 44/302, OR = 20.35, 95% CI [8.71, 47.56]). The risk
was lower among studies that included fetuses at risk of
FGR (16/65 vs. 5/108, OR = 4.76, 95% CI [1.55, 14.67]). Forest
plots are summarized in Figure 2.
Analysis of diagnostic accuracy
Among selected studies, the sensitivity of abnormal CPR
for CS due to fetal distress ranged from 0.44 to 0.70, and
ranged from 0.50 to 0.80 for low 5  min APGAR scores,
0.40–0.81 for NICU admission, and 0.39–0.86 for neona-
tal complications. In terms of specificity, abnormal CPR
ranged from 0.56 to 0.93 for CS due to fetal distress, 0.54–
0.80 for low APGAR scores, 0.53–0.96 for NICU admission,
and 0.53–0.97 for neonatal complications (Appendix III).
These data were explicated using SROC curve (Figure 3).
As illustrated, the diagnostic accuracy of abnormal CRP
was more prominent for neonatal complications and NICU
admission. CPR among the subset of population with
sonographically diagnosed FGR showed higher diagnostic
curves than those at risk of FGR.
Discussion
To the best of our knowledge, this is the first meta-­analysis
that evaluates the value of abnormal fetal CPR in pre-
dicting poor perinatal outcome among fetuses at risk or
sonographically diagnosed FGR. We found that abnormal
CPR is associated with substantial increase in the risk of
perinatal adverse outcomes particularly among fetuses
that were sonographically diagnosed with FGR. It exhibits
higher diagnostic accuracy for subsequent NICU admis-
sion and neonatal complications in these fetuses.
CPR is a unique Doppler index that has been evalu-
ated in the literature for around quarter a century. Yet,
it has not been integrated in antenatal surveillance
protocols and management strategies for FGR through
these years. Relying on umbilical artery Doppler alone
in assessment of high risk pregnancies is usually inad-
equate for predicting the perinatal outcome [21]. A meta-
analysis conducted by Morris et  al. showed a moderate
utility of umbilical artery Doppler alone in prediction of
fetal compromise and poor perinatal outcome [22]. On the
other hand, interpreting fetal MCA in isolation usually
gives limited predicative accuracy for poor perinatal
outcome [6] and may indicate early stages of hypoxia in
fetuses that still have reserves to overcome the stress of
normal labor [23].
In this review, we found that abnormal CPR is associ-
ated with high rates of adverse perinatal outcomes. The
sensitivity and specificity of CPR ranged from moderate to
high among selected studies with slightly higher specific-
ity than sensitivity. Among perinatal adverse events, CPR
was more diagnostic for neonatal complications and NICU
admission.
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Figure 2: Forest plots for perinatal outcomes among neonates with normal and abnormal cerbroplacental ratio.
Also, we found that abnormal CPR was associated
with higher odds of poor perinatal outcomes among the
subsets of fetuses with sonographically diagnosed FGR
than those clinically at risk for FGR. Accordingly, CPR
seems to perform more efficiently as a method for surveil-
lance and management for FGR fetuses than as a method
for screening of fetuses at high risk for FGR.
Nassr et al., Utility of cerebro-placental ratio in FGR      253
However, there are some limitations that should be
addressed. The cutoff for abnormal CPR was variable
among studies and one study used multiple of median to
define abnormal test. However, abnormal CPR has been
described using two methods. One method used fixed
cut-off levels throughout gestation. These levels showed
very small variations among different studies and most
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254      Nassr et al., Utility of cerebro-placental ratio in FGR
Figure 2 (continued)
commonly used levels have been 1.08, 1.05, and 1.00 [12,
21, 24]. Another method considered that CPR values are
not fixed throughout gestational age and abnormal CPR
has been described when it is  < 5th percentile for gesta-
tional age [7]. Odibo et al. compared both methods con-
sidering the fixed level at 1.08 and concluded that both
yielded similar results in prediction of adverse perinatal
outcomes [11]. Also, studies were inconsistent in terms
of gestational age and pregnancy risk. Nevertheless,
all fetuses were evaluated within the third trimester
(28–42 weeks) and they were all included for suspicion
of FGR.
In the view of these findings, we believe that CPR is
a potentially useful tool for assessing perinatal outcomes
in pregnancies with established diagnosis of or at risk for
fetal growth restriction. It is particularly valuable for sug-
gesting poor outcomes in pregnancies sonographically
diagnosed with FGR. These findings warrant further eval-
uation of CPR by large randomized trials that could justify
future integration of this tool in clinical practice.
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 Nassr et al., Utility of cerebro-placental ratio in FGR      255

All studies
A 1

0.9

0.8

0.7

0.6
Sensitivity
0.5

0.4

0.3

0.2

0.1

0
1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
Specificity
Legend
CS for fetal distress 5 min APGAR score NICU admission Neonatal complications

Sonographically diagnosed FGR C At risk of FGR

B 1 1

0.9 0.9

0.8 0.8

0.7 0.7

0.6 0.6
Sensitivity

0.5 0.5
Sensitivity

0.4 0.4

0.3 0.3

0.2 0.2

0.1 0.1

0 0
1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
Specificity Specificity
Legend Legend
CS for fetal distress NICU admission CS for fetal distress NICU admission
5 min APGAR score Neonatal complications 5 min APGAR score Neonatal complications

Figure 3: The SROC curve of abnormal CPR for perinatal outcomes.

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Supplemental Material: The online version of this article (DOI:
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The authors stated that there are no conflicts of interest regarding
the publication of this article.
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