385ee6cd-3f7c-438d-a02eca12dec38bb1

UOG Journal Club: April 2019
Reference ranges for Doppler indices of umbilical and fetal middle

cerebral arteries and cerebroplacental ratio: systematic review
D. OROS, S. RUIZ-MARTINEZ, E. STAINES-URIA, A. CONDE-AGUDELO,

J. VILLAR, E. FABRE and A. T. PAPAGEORGHIOU
Volume 53, Issue 4
Journal Club slides prepared by Dr Fiona Brownfoot

(UOG Editor for Trainees)
Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental
ratio: systematic review
Oros et al., UOG 2019
Introduction
• Doppler velocimetry is used to assess small-for-gestational-age (SGA) fetuses at risk of
adverse perinatal outcome.
• Doppler abnormalities in the umbilical artery (UA) are related closely to placental disease
whilst changes in the fetal middle cerebral artery (MCA) reflect fetal cardiovascular
adaptations to hypoxia or blood flow redistribution.
• The ratio of MCA-PI to UA-PI (cerebroplacental ratio (CPR)) is an independent predictor of
fetal compromise, Cesarean section and adverse perinatal outcome.
• UA and MCA Doppler indices and CPR are currently used to modify the scheduling of
antepartum surveillance and, in some cases, to time delivery of the compromised fetus.
• References ranges for UA, MCA and CPR differ between studies.
Aim of the study
To evaluate reference ranges for UA and MCA Doppler indices and CPR.
Specifically, to assess the methodological quality of studies on which
these are based using a set of predefined quality criteria and to estimate
the clinical impact of using different reference charts.
Methods
• Study design
– Systematic review.
• Study selection
– Studies were identified through a search of MEDLINE, EMBASE, CINAHL and
the Web of Science databases, including studies reported from 1954 to
December 2016 in English or Spanish.
– Included: Observational (cohort or cross-sectional) studies aimed to create
reference ranges for UA and MCA Doppler indices and CPR.
– Excluded: Case–control studies, studies in which the primary aim was not to
construct Doppler reference ranges or they were limited to pregnancies < 20 or >
40 weeks’ gestation.
Methods
• Inclusion criteria
– Made clear that women at high risk of pregnancy complications were not included and
that women with abnormal outcome were excluded, i.e. an effort was made to include
as normal an outcome as possible.
• Exclusion criteria
– Multiple pregnancy; fetuses with congenital, structural or chromosomal anomaly; fetal
death/stillbirth; women with disorders that may affect fetal growth or Doppler (at least
should specify exclusion of women with pre-existing hypertension, diabetes mellitus,
renal disease and smokers); pregnancy complications (at least pre-eclampsia,
SGA/IUGR, prematurity, diabetes mellitus); delivery prior to 37 weeks.
• Outcomes
– To evaluate reference ranges for UA and MCA Doppler indices and CPR.
– To assess the methodological quality of studies on which these are based.
Methods
• Methodological quality assessment
– The methodological quality of the full-text versions of eligible studies was
assessed independently by the same reviewers and a medical statistician
– A list of methodological quality criteria (next 2 slides) was initially developed by
one of the authors, modified for use in the setting of Doppler, and agreed by the
team not involved in data extraction.
– Every study was assessed against each of the criteria within the checklist and
was scored as either 0 or 1 if there was a high or low risk of bias, respectively.
The overall quality score was defined as the sum of low risk of bias marks, with
the range of possible scores being 0 – 24.
– Multiple regression analysis were performed to assess the association between
quality score and study characteristics that were not part of the scoring
algorithm.
Methods – Risk of bias due to study design

Domain Low risk of bias High risk of bias
Study design Clearly described as either cross-sectional or Not reported

longitudinal Mixture of cross-sectional and longitudinal data
Population Women reported as coming from population of low Women from unselected population; or selected; or at
risk of pregnancy complications high risk of pregnancy complications
Prospective data collection Prospective study and ultrasound data collected Retrospective study, data not collected specifically for
specifically for purpose of constructing charts of purpose of constructing charts of fetal Doppler, or
fetal Doppler unclear (e.g. use of routinely collected data)
Specific scan Specific scan for research purposes Routine scan in context of pregnancy assessment
Sample size A-priori determination or calculation of sample size Lack of a-priori sample size determination or
and justification calculation and justification
Recruitment period Reported Not reported
Consecutive enrolment Consecutively included patients Did not include patients consecutively
Inclusion/exclusion criteria Made clear that women at high risk of pregnancy Study population included both low- and high-risk
complications were not included and that women pregnancies
with abnormal outcome were excluded,
Method of dating pregnancy Clearly described known LMP and sonogram before Not described clearly
14 weeks’ gestation
Multicenter study Study performed with more than one center Performed at only one hospital
collaborating
Do
Methods – Risk of bias due to reporting and statistical methods

Domain Low risk of bias High risk of bias
Perinatal outcome Collected and reported prospectively Not reported

Gestational age range Reported Not reported
Ultrasound machines and probe type used Clearly specified Not clearly specified
Reported sonographers Number of sonographers reported Not clearly specified
Sonographer experience Experienced or specifically trained sonographers clearly reported Not clearly specified
Blinded measurements Sonographers were blinded Not clearly specified
Ultrasound quality control measures Should include the following: assessment of intraobserver variability; Does not contain quality control
assessment of interobserver variability; image review; image scoring; measures
image storage
Protocol Study described sufficient and unambiguous details of measurement Not described sufficiently and
techniques used for fetal Doppler parameters unambiguous details of measurement
Number of measurements taken for each At least three measures per fetus per scan Single measure or not specified
Doppler variable
Angle correction Clearly specified Not clearly specified
Statistical methods Clearly described and identified Not clearly described and identified
Report of mean and SD of each measurement Presented in a table or clearly described Not presented in a table or not clearly
and sample size for each week of gestation described
Report of regression equations for mean (and Reported Not reported

SD if relevant) for each measurement
Scatter diagram Study included Doppler chart with mean and SD or centiles (at least Doppler charts not included
5th, 50th and 95th centiles)
Results
• A total of 38 studies from 22 countries met

the inclusion criteria and were included in
the final analysis.
• The median sample size of participating
women was 206 (range, 13–2323;
interquartile range (IQR), 70.75–675.25).
• The median number of ultrasound
examinations was 400 (range, 60–2323;
IQR, 183.5–952).
• The earliest included study was published in
1987 and the latest in 2016.
Results
• Data collection was prospective in 34 studies, but in only 19 studies was data collection
explicitly for research purposes.
• Low-risk pregnancies were included in 22 (57.9%) studies.
• Dopplers reported:
-UA and MCA Doppler reference ranges were reported in 30 and 19 studies, respectively.
-11 studies reported reference ranges for both UA and MCA.
-4 studies reported reference ranges for CPR.
-PI was reported in 31 studies.
-Resistance index in 22 studies.
-Systolic-diastolic ratio in 21 studies.
• An equation for the mean and SD was reported in 23 of 38 studies, whereas

printed charts of the median and centile curves were seen in 25 publications.
Results
• Overall mean quality score for the included studies was 51.4% (95% CI, 47.1–55.8%).
• Quality scores for study design and statistical and reporting methods were 47.4% (95%
CI, 42.6–52.1%) and 54.3% (95% CI, 48.8–59.7%), respectively.
• The overall methodology score was similar for the studies focused on:
-UA (median, 49.0%; range, 20.8 – 70.8%),
-MCA (median, 55.0%; range, 29.1 – 79.1%),
-CPR (median, 54.1%; range, 41.6–62.5%).
• Year of publication (P = 0.506), sample size of participating women (P = 0.119),

ultrasound examinations (P=0.215), study duration (P=0.251), teaching hospital
(P=0.395), number of participating sites (P = 0.278) or number of sonographers (P =
0.447) were not significant predictors of quality score on univariate or multiple regression
analysis.
Results
Despite high methodological quality, all studies reported quite variable reference ranges.
Discussion
There is considerable heterogeneity in the methodological quality of ultrasound
studies aimed at creating reference ranges for UA and MCA Doppler indices and
CPR.
These differences may at least partly explain the differences in reported reference
ranges and these may in turn explain some of the discrepancies seen in perinatal
research based on Doppler.
Even when assessing only those studies with the highest scores of methodological
quality, clinical cut-offs varied significantly and could lead to important differences in
clinical management, demonstrating that about 40–50% of fetuses may be
misclassified by using one chart rather than another.
Study limitations
Inclusion of studies published in only the English or Spanish language; it is possible
that biological variations might account for differences in Doppler results.
Conclusion
• This systematic review has identified many ultrasound studies with poor
methodology and reporting of reference ranges for UA and MCA Doppler
indices and CPR.
• These should be taken into account in future studies and we recommend using
a checklist of methodological good practices in further studies aimed at creating
reference ranges for UA and MCA Doppler parameters and CPR.
• Our aim was to recommend reference ranges for use in clinical services based
on the lowest risk of methodological bias, however, even among these studies
there are differences of clinical importance with what is considered normal and
what is not; urgent research is needed to reach consensus on this issue or
create charts of optimal quality for widespread use.
Discussion points
• Given the large variability between studies, perhaps Doppler indices

change depending on the population.
• It would be interesting to see whether the different Doppler ranges

result in differences in the clinical outcome of the pregnancies.
• Do fetal growth differences e.g. macrosomia change the Doppler

range?

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UOG Journal Club: April 2019

Reference ranges for Doppler indices of umbilical and fetal middle

D. OROS, S. RUIZ-MARTINEZ, E. STAINES-URIA, A. CONDE-AGUDELO,

Volume 53, Issue 4

Journal Club slides prepared by Dr Fiona Brownfoot

Aim of the study

Methods – Risk of bias due to study design

Study design Clearly described as either cross-sectional or Not reported

Recruitment period Reported Not reported

Methods – Risk of bias due to reporting and statistical methods

Perinatal outcome Collected and reported prospectively Not reported

Reported sonographers Number of sonographers reported Not clearly specified

Blinded measurements Sonographers were blinded Not clearly specified

Angle correction Clearly specified Not clearly specified

Report of regression equations for mean (and Reported Not reported

• A total of 38 studies from 22 countries met

• An equation for the mean and SD was reported in 23 of 38 studies, whereas

• Year of publication (P = 0.506), sample size of participating women (P = 0.119),

• Given the large variability between studies, perhaps Doppler indices

• It would be interesting to see whether the different Doppler ranges

• Do fetal growth differences e.g. macrosomia change the Doppler

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