Ultrasound Obstet Gynecol 2008; 32: 160–167
Published online 15 July 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.5386
Progression of Doppler abnormalities in intrauterine growth
restriction
O. M. TURAN*, S. TURAN*†, S. GUNGOR* C. BERG‡, D. MOYANO†, U. GEMBRUCH‡,
K. H. NICOLAIDES†, C. R. HARMAN* and A. A. BASCHAT*
*Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland, Baltimore, MD, USA, †Harris Birthright
Research Centre for Fetal Medicine, King’s College Hospital, London, UK and ‡Department of Obstetrics and Prenatal Medicine,
Friedrich-Wilhelm University, Bonn, Germany
K E Y W O R D S: ductus venosus; intrauterine growth restriction; longitudinal analysis; middle cerebral artery; umbilical artery
ABSTRACT
Objective To identify the sequence of progression of
arterial and venous Doppler abnormalities from the onset
of placental insufficiency in intrauterine growth restriction
(IUGR).
Methods Prospective observational study of singletons
with IUGR (abdominal circumference < 5th percentile)
who underwent serial standardized umbilical artery (UA),
middle cerebral artery (MCA), ductus venosus (DV) and
umbilical vein (UV) Doppler surveillance. Time intervals
between progressive Doppler abnormalities and patterns
of deterioration were related to UA Doppler status and
gestational age.
Results Six hundred and sixty-eight longitudinal examinations were performed in 104 fetuses, identifying three
patterns of progression: (1) Mild placental dysfunction
(n = 34) that remained confined to the UA/MCA. The
UA became abnormal at a median of 32 weeks’ gestation
but the pulsatility index never exceeded 3 SD above
normal. Progression took a median of 33 days, requiring
delivery at a median of 35 weeks. (2) Progressive
placental dysfunction (n = 49). Initially normal UA
Doppler PI at 29 weeks’ gestation increased beyond
3 SD, progressing to abnormal MCA, absent/reversed UA
diastolic flow, abnormal DV, UV pulsations in 9-day
intervals requiring delivery by 33 weeks. (3) Severe earlyonset placental dysfunction (n = 21). Markedly elevated
UA PI established by 27 weeks’ gestation was associated
with rapid (7-day intervals) progression to abnormal
venous Doppler with median delivery at 30.6 weeks.
Gestational age at onset, time to delivery and progression
intervals were different between patterns (all P < 0.05).
Conclusion The characteristics of cardiovascular manifestations in IUGR are determined by the gestational age
at onset and the severity of placental disease. Recognition
of these factors is critical for planning fetal surveillance
in IUGR. Copyright 2008 ISUOG. Published by John
Wiley & Sons, Ltd.
INTRODUCTION
Placenta-based intrauterine growth restriction (IUGR) is
predominantly a vascular disorder. It starts with abnormal
tertiary villous vessels and ends with characteristic fetal
multi-vessel cardiovascular manifestations1 . These effects
can be documented with Doppler ultrasound examination
of a number of vessels: maternal uterine arteries and
the fetal umbilical arteries for the placenta; middle
cerebral artery (MCA) for preferential brain perfusion;
and precordial veins for the cardiac effects of placental
dysfunction. As IUGR worsens, Doppler abnormalities in
these vascular territories also deteriorate2 , suggesting a
sequential pattern of disease progression. This presumed
sequence and the anticipation of fetal deterioration form
the basis for Doppler surveillance in IUGR. Deterioration
in Doppler findings typically leads to several changes
in clinical IUGR management: increased monitoring
frequency, administration of antenatal steroids and
delivery3 .
Relationships between fetal Doppler findings and perinatal risks have been defined in numerous cross-sectional
studies4 . While these studies are useful for suggesting
outcome relationships, a sequence of Doppler changes is
inferred, rather than proven, from cross-sectional data.
Cross-sectional studies define an anticipated range of
observations for individual members of a cohort. With
Correspondence to: Dr A. A. Baschat, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland, Baltimore,
405 West Redwood Street, 4th floor, Baltimore, MD 21201, USA (e-mail: abaschat@umm.edu)
Accepted: 21 March 2008
Copyright 2008 ISUOG. Published by John Wiley & Sons, Ltd.
ORIGINAL PAPER
Longitudinal Doppler in IUGR
large sample sizes such studies may provide reasonably
reliable estimates of group behavior. However, the inherent variability of each individual and the true longitudinal
progression from a specific entry point cannot be determined. In contrast, appropriately constructed longitudinal
studies can evaluate the progression in individual fetuses
from a predefined entry point and therefore provide narrower confidence limits and a more accurate description of
biological behavior5 . Only a handful of longitudinal studies specific to IUGR have evaluated the arterial and venous
circulations6 – 10 . Our understanding of the progression of
fetal cardiovascular responses to placental dysfunction is
therefore largely based on weaker scientific evidence from
cross-sectional observations4 . This evidence is weakened
further because neither the Doppler techniques nor the
characteristics of fetuses studied were consistent between
studies. Moreover, in focusing on referred cases of endstage IUGR, investigators may not have fully evaluated
the progression of mild or moderate placental disease.
Placenta-based IUGR often first becomes apparent at a
less developed stage, when customizing surveillance is key
and moving towards delivery is not yet appropriate3 .
The aim of this study was to evaluate the longitudinal
progression of arterial and venous Doppler parameters
from the clinical onset of IUGR in individual pregnancies.
It was our hypothesis that arterial and venous Doppler
parameters progress in a predictable sequence in these
fetuses.
PATIENTS AND METHODS
This prospective multicenter study of singleton pregnancies complicated by IUGR was conducted from January
2000 to March 2006. Fetuses at an early stage of placentabased growth restriction were defined by the following
inclusion criteria: (1) gestational age determined by sure
date of last menstrual period confirmed by ultrasound
examination at < 20 weeks’ gestation; (2) abdominal circumference (AC) < 5th percentile; and (3) early placental
insufficiency as defined by umbilical artery (UA) pulsatility index (PI) elevation more than 2 SD above the
mean and/or cerebroplacental ratio (CPR) more than 2 SD
below the mean11 . To be eligible for longitudinal analysis, it was necessary for patients to have had at least
three Doppler examinations prior to delivery, including a complete set of study variables at both the first
and last examination. Exclusion criteria were: (1) fetuses
with chromosomal abnormalities or structural anomalies;
and (2) fetuses with advanced fetal vascular disease at
recruitment (brain sparing, absent or reversed flow in
UA, elevated ductus venosus (DV) PI, absent or reversed
a-wave in DV and umbilical vein (UV) pulsation).
Patients gave informed written consent, and the study
protocol was approved by the Institutional Review Board
at each participating center.
Doppler parameters were obtained from the UA, MCA,
DV and UV according to uniform standards provided by
the originating institution3 . UA end-diastolic velocity was
classified as present, absent (AEDV) or reversed (REDV).
Copyright 2008 ISUOG. Published by John Wiley & Sons, Ltd.
161
The CPR was calculated as previously described11 . DV
velocity during atrial systole was characterized as forward
or absent/reversed (DV-RAV). Pulsations in the UV were
noted. The pulsatility index for each vessel was converted
to its Z-score to exclude the effect of gestational age. For
the UA and DV, a two-SD elevation of the Doppler index
was considered abnormal. Redistribution was defined as
a two-SD decrease in the CPR11 , and brain sparing was
defined as a two-SD decline in MCA-PI12 .
Determination of monitoring intervals and delivery
timing were at the discretion of the attending obstetrician.
Perinatal characteristics and delivery details such as
indication, route, gestational age, birth weight, Apgar
scores, and UA blood gases were ascertained. Neonatal
mortality and the presence of major neonatal morbidity
were noted.
Longitudinal progression of Doppler abnormalities was
evaluated in several ways. The day of delivery was used
as the primary reference point for describing Doppler
changes (Figure 1). Three time intervals were defined
to assess progression: (1) enrollment-to-delivery interval;
(2) progression interval, defined as the time between two
successive Doppler abnormalities; and (3) duration of
each individual Doppler abnormality, calculated as the
interval from its first appearance to delivery.
Doppler index Z-scores were related to duration of
abnormality for each vessel to give a mathematical
description of longitudinal progression for each fetus.
This analysis defined the sequence of categorical
Doppler abnormalities. Patterns were categorized by their
consistent sequence of Doppler abnormalities. For this
analysis the sequence of categorical Doppler abnormalities
was noted for each fetus. This sequence of categorical
Doppler abnormalities was independently reviewed by
five authors (O.M.T., S.T., S.G., C.R.H. and A.A.B.)
and defined the pattern of progression. Patterns were
compared for their gestational age at onset, difference
in intervals between Doppler changes and severity of
placental disease.
Enrollment day
Delivery day
Enrollment to delivery
interval
1st Doppler abnormality
Interval to delivery
2nd Doppler
abnormality
Interval to delivery
Progression
interval
−56
−49
−42
−35
−28
−21
Days before delivery
−14
−7
0
Figure 1 Time intervals (days) that were used to analyze the
longitudinal progression of Doppler abnormalities. The time
interval between the appearance of two consecutive Doppler
abnormalities was termed the progression interval, and for each
individual Doppler abnormality the interval to delivery was
calculated.
Ultrasound Obstet Gynecol 2008; 32: 160–167.
Turan et al.
162
Continuous variables were analyzed with the Mann–
Whitney U-test after evaluation for normal distribution
by the Kolmogorov–Smirnov test. Logarithmic transformation of PI Z-scores was performed where appropriate.
Categorical variables were analyzed with Chi-square or
Fisher’s exact test depending on cell size. Regression analysis was performed to describe the determinants of clinical
progression, and variances of the intervals in the Doppler
abnormalities were analyzed by ANOVA. SPSS 13.0 (SPSS
Co., Chicago, IL, USA) was used for these analyses.
Finally, differences in the slopes of regression lines for
various Doppler indices were analyzed using Statgraphics Centurion software (Statpoint, Herndon, VA, USA).
P < 0.05 was considered as statistically significant.
RESULTS
In the study period a total of 177 pregnant women
were recruited for longitudinal evaluation. Of these, 104
pregnancies met the specific inclusion criteria of earlyonset placental dysfunction. The maternal characteristics
and delivery details are displayed in Tables 1 and 2. In
these patients 668 Doppler examinations were performed
with a median of 8 (range, 3–26) examinations per
patient. The distribution of Doppler abnormalities at
enrollment and delivery are displayed in Table 3. By the
time of delivery almost all patients had elevated UA blood
flow resistance (n = 97, 93.3%), the majority had brain
sparing (n = 61, 58.7%) and approximately one third had
an elevated DV Doppler index (n = 30, 28.8%).
Individual Doppler abnormalities had successively
shorter duration (ANOVA P < 0.0001). The duration
of each individual Doppler abnormality is displayed in
order in Figure 2. The rate of progression for Doppler
abnormalities was significantly related to gestational age.
When the abnormality presented early in gestation, it
progressed more rapidly; when an abnormality emerged
later, progression was slower. This was true for the UA,
MCA and DV (Figure 3).
When the sequence of Doppler abnormalities was
categorized, three principal patterns of deterioration
were identified (Figure 4). In the first pattern Doppler
abnormalities were confined to the umbilical/cerebral
Table 1 Maternal demographics (n = 104)
Parameter
Maternal age (years, mean (range))
Parity (n (%))
0
1
2
3
Ethnicity (n (%))
Caucasian
African American/Afro-Caribbean
Asian
Gestational age at enrollment (weeks,
median (range))
Value
28 (14–45)
Table 2 Delivery and postpartum characteristics (n = 104)
Parameter
Value
Indication for delivery (n (%))
Non-reassuring fetal status
Pre-eclampsia
Abruption
Oligohydramnios
Spontaneous vaginal delivery
Elective (breech presentation)
Mode of delivery (n (%))
Vaginal
Cesarean section
Gestational age at delivery (weeks,
median (range))
Birth weight (g, median (range))
5-min Apgar score < 7 (n (%))
Umbilical artery pH < 7.20 (n (%))
Antepartum death (n (%))
Major morbidity (n (%))*
Intact survival (n (%))†
61 (59.8)
11 (10.8)
2 (2)
2 (2)
18 (17.6)
8 (7.8)
26 (25)
78 (75)
33.4 (26.4–40.3)
1235 (420–2790)
5 (4.9)
29 (27.9)
2 (1.9)
12 (11.5)
90 (86.5)
*Major morbidity defined as neonatal bronchopulmonary
dysplasia, necrotizing enterocolitis or Grade III–IV intraventricular
hemorrhage. †No major morbidity and neonatal death.
Table 3 Distribution of ultrasound and Doppler abnormalities at
enrollment and delivery
Parameter
Value
Gestational age at enrollment (weeks, median
27 (23–33.6)
(range))
Doppler examination
Total number of scans (n)
668
Number of scans per patient (median
8 (3–26)
(range))
Interval of Doppler examination (days,
5 (1–56)
median (range))
Ultrasound findings at enrollment (n (%))
AC < 5th percentile without Doppler
49 (47.1)
abnormality
AC < 5th percentile + elevated umbilical
32 (30.8)
artery PI
AC < 5th percentile + elevated umbilical
23 (22.1)
artery PI + reduced CPR
Frequency of Doppler abnormalities at delivery (n (%))
Elevated umbilical artery PI
97 (93.3)
Reduced CPR
82 (78.8)
Brain sparing
61 (58.7)
Elevated ductus venosus PI
30 (28.8)
Umbilical artery AEDV
24 (23.1)
Umbilical artery REDV
18 (17.3)
Umbilical vein pulsation
19 (18.3)
Ductus venosus absent/reversed a-wave
5 (4.8)
77 (74)
19 (18.3)
7 (6.7)
1 (1)
AC, abdominal circumference; PI, pulsatility index; CPR,
cerebroplacental ratio; AEDV, absent end-diastolic velocity; REDV,
reversed end-diastolic velocity.
70 (67.3)
32 (30.8)
2 (1.9)
27 (23–33.6)
circulation. In the other two patterns, Doppler abnormalities progressed to the venous system, following very
different time courses. These three patterns were characterized as mild, progressive or severe early-onset placental
dysfunction according to the following criteria:
Copyright 2008 ISUOG. Published by John Wiley & Sons, Ltd.
Ultrasound Obstet Gynecol 2008; 32: 160–167.
Longitudinal Doppler in IUGR
163
Elevated UA-PI
Reduced CPR
UA-AEDV
Brain sparing
UA-REDV
Elevated DV-PI
UV pulsation
DV-RAV
91 84 77 70 63 56 49 42
35
28
21
Interval to delivery (days)
14
7
0
Figure 2 Sequence of Doppler abnormalities determined by the interval to delivery in the whole study population. The minimum and
maximum values with interquartile range and median are displayed. The median intervals from the occurrence of an elevated umbilical
artery (UA) pulsatility index (PI), reduced cerebroplacental ratio (CPR), UA absent end-diastolic velocity (AEDV), brain sparing, UA
reversed end-diastolic velocity (REDV), elevated ductus venosus (DV)-PI, umbilical vein (UV) pulsation and DV reversed a-wave (RAV) were
21, 13, 10, 6, 5, 3, 1 and 0 days, respectively, with a statistically significant difference overall (ANOVA P < 0.0001).
Deterioration interval (days)
(a)
(b)
(c)
50
50
50
45
45
45
40
40
40
35
35
35
30
30
30
25
25
25
20
20
20
15
15
15
10
10
10
5
5
5
0
26
30
34
38
Gestational age at sonogram (weeks)
0
26
30
34
Gestational age at sonogram (weeks)
38
0
26
30
34
38
Gestational age at sonogram (weeks)
Figure 3 Relationship between deterioration interval and gestational age in the umbilical artery (a), middle cerebral artery (b) and ductus
venosus (c). The graphs illustrate that the deterioration interval for the progression of Doppler abnormalities is shorter at early gestational
ages and increases with advancing gestation. The relationships between deterioration interval (DI) and gestational age (GA) are:
(a) DI = 0.2 × GA2 − 9.6 × GA + 129.9; R2 = 0.35, P < 0.0001.
(b) DI = 0.1 × GA2 − 3.4 × GA + 28.8; R2 = 0.36, P < 0.0001.
(c) DI = 0.1 × GA2 − 2.5 × GA; R2 = 0.48, P < 0.0001.
• Mild placental dysfunction: Mild onset and nonprogressive abnormalities characterize this pattern. Of
the 34 fetuses in this category, 11 (32.4%) presented
with an elevated UA-PI, two (5.9%) with reduced
CPR and four (11.8%) with isolated brain sparing.
The patients were enrolled at a median gestational
Copyright 2008 ISUOG. Published by John Wiley & Sons, Ltd.
age of 27.4 (range, 23.0–33.4) weeks, and the initial
Doppler abnormality was detected at 31.5 (range,
23.3–40.2) weeks’ gestation. The median gestational
age at delivery was 35.3 (range, 28.0–40.3) weeks.
The UA-PI Z-score was typically normal at initial
presentation and never rose above three SD elevations.
Ultrasound Obstet Gynecol 2008; 32: 160–167.
Turan et al.
164
Placental
insufficiency
Sequence of Doppler abnormalities
Mild
n = 34
UA
Progressive
n = 49
UA
19
days
CPR
14
4
14
UA
Brain
days sparing days A/REDV days
DV
Severe early-onset
n = 21
UA
7
days
CPR
UA
7 Brain
11
9
days A/REDV days sparing days
DV
33
CPR
days
8
DV-RAV/
days UV pulsation
5
days
DV-RAV/
UV pulsation
Figure 4 Categorization of placental insufficiency according to the sequence of Doppler abnormalities. The progression interval is expressed
as median (days). UA, umbilical artery; CPR, cerebroplacental ratio; A/REDV, absent or reversed end-diastolic velocity; DV, ductus venosus;
RAV, absent/reversed a-wave; UV, umbilical vein.
Copyright 2008 ISUOG. Published by John Wiley & Sons, Ltd.
The median gestational age at delivery was 30.6
(range, 27.1–36.3) weeks. The UA-PI Z-score always
showed a greater elevation than 3 SD and increased
progressively. The enrollment-to-delivery interval was
23 (range, 8–86) days and the median progression
interval between successive Doppler abnormalities was
7 (range, 1–48) days. No antepartum death was
observed in this group. Two patients (9.5%) developed
pre-eclampsia and 17 (81.0%) were delivered for fetal
indications (P < 0.05 compared to patients with mild
placental dysfunction). The progression interval from
elevated UA-PI to reduced CPR was a median of 7 days
(range, 2–30).
Once the patterns had been defined their characteristics were compared. The primary differentiating factor
between the patterns was the way UA Doppler abnormality progressed (Figure 5). The terminology for the three
patterns was chosen because it emphasizes the impact
of placental dysfunction on the progression of Doppler
Umbilical artery pulsatility index
Z-score
This group had the longest enrollment-to-delivery
interval (median 46 days, range 7–97). No antepartum
death was observed. Two patients (5.9%) developed
pre-eclampsia and 15 (44.1%) were delivered for fetal
indications. Progression from an elevated UA-PI to
a reduced CPR took a median of 33 (range, 4–96)
days, significantly longer than in the progressive and
severe early-onset groups (P = 0.02 and P < 0.0001,
respectively).
• Progressive placental dysfunction: Mild onset but
progressive cardiovascular compromise were the main
characteristics of this pattern, observed in 49 fetuses.
The sequence of abnormal Doppler findings was
elevated UA-PI, reduced CPR, brain sparing, UAAEDV, UA-REDV, elevated DV-PI, and DV-RAV/UV
pulsation. The patients were diagnosed at a median
gestational age of 27.0 (range, 24.0–33.6) weeks
and the initial Doppler abnormality was diagnosed
at a gestational age of 29.1 (range, 24.0–38.0)
weeks. The median gestational age at delivery was
33.4 (range, 26.4–39.5) weeks. The UA-PI Z-score
was typically normal at enrollment but progressively
increased beyond 3 SD. The enrollment-to-delivery
interval was 38 (range, 7–90) days and the median
progression interval was 9 (range, 0–75) days. Two
antepartum deaths were observed, seven patients
(14.3%) developed pre-eclampsia and 29 (59.2%) were
delivered for fetal indications. Progression from an
elevated UA-PI to reduced CPR took a median of 19
(range, 2–75) days, significantly slower than in severe
early-onset placental dysfunction (P = 0.005).
• Severe early-onset placental dysfunction: This pattern
was typified by severe cardiovascular compromise,
presenting early in gestation and progressing rapidly,
and was observed in 21 fetuses. Although most fetuses
showed a typical progression pattern (elevated UA-PI,
reduced CPR, UA-AEDV, UA-REDV, brain sparing,
elevated DV, DV-RAV/UV pulsation), an elevated DV
was the initial finding in five of them. Patients were
diagnosed at a median gestational age of 26.3 (range,
24.0–33.4) weeks, and the initial Doppler abnormality
presented at 27.1 (range, 24.1–36.3) weeks’ gestation.
7
6
5
4
3
2
1
0
−1
−2
–56
–49
–42 –35 –28 –21 –14
Interval to delivery (days)
−7
0
Figure 5 Regression lines for the umbilical artery (UA) Doppler
pulsatility index (PI) Z-score in the three different progression
patterns. Regression lines were created using the interval to delivery
in days as the independent variable and the UA-PI Z-score as the
dependent variable. The slopes of these regression lines were
significantly different from each other (P < 0.0001 for all
,
comparisons). The shaded area indicates the normal range.
3 SD elevations;
, mild insufficiency;
, progressive
insufficiency;
, severe early-onset insufficiency.
Ultrasound Obstet Gynecol 2008; 32: 160–167.
Longitudinal Doppler in IUGR
165
Table 4 Characteristics of placental insufficiency patterns
Degree of placental insufficiency
Characteristic
Gestational age at enrollment (weeks)
Gestational age at detection of first Doppler abnormality (weeks)
Gestational age at delivery (weeks)
Time from enrollment to delivery (days)
Progression interval (days)
Mild
Progressive
Severe early-onset
27.4 (23.0–33.4)
31.5 (23.3–40.2)*
35.3 (28.0–40.3)*
46 (7–97)
—
27.0 (24.0–33.6)
29.1 (24.0–38.0)§
33.4 (26.4–39.5)§
38 (7–90)§
9 (0–75)§
26.3 (24.0–33.4)
27.1 (24.1–36.3)†
30.6 (27.1–36.3)‡
23 (8–86)†
7 (1–48)
Degree of Doppler abnormality
Data are given as median (range). *Mild vs. progressive, P < 0.05. †Mild vs. severe, P < 0.05. ‡Mild vs. severe, P < 0.001. §Progressive vs.
severe early-onset, P < 0.05.
3
2
1
27
29
31
33
35
37
39
Gestational age (weeks)
Figure 6 Relationship between gestational age, degree and rate of
Doppler escalation. Each step in the cluster graph indicates
progression to a new Doppler abnormality. The graph illustrates
that severe progressive placental dysfunction (3) has an earlier
onset and a more extensive and rapid deterioration than do
progressive (2) and mild non-progressive (1) placental dysfunction.
abnormalities. Significant differences in enrollment-todelivery interval, progression interval and gestational age
at delivery were observed between the three patterns
(Table 4). The relationships between gestational age and
rate and degree of Doppler escalation are displayed in
Figure 6.
DISCUSSION
Numerous cross-sectional studies have shown associations between abnormal Doppler findings and adverse outcomes in IUGR that help frame delivery decisions2,4,7 – 9 .
At the end of IUGR progression, arterial and venous
Doppler ultrasonography can provide an estimate of
imminent fetal risk, thereby indicating immediate management. However, most of these associations are derived
from studies of end-stage IUGR – they do not describe
the pathway of deterioration. Therefore, cross-sectional
observations do not specify how to monitor individual
fetuses that are not yet compromised. In this context,
longitudinal assessment may provide key information, if
patterns can be discerned that predict progression from
the onset of clinical disease. The goal of antenatal surveillance, of course, is not to prove that the associations are
true by allowing adverse outcomes, but to avoid them
Copyright 2008 ISUOG. Published by John Wiley & Sons, Ltd.
by anticipating changes. By examining early factors and
allowing that anticipation, our longitudinal observations
clarify crucial monitoring decisions in IUGR.
Choices for monitoring intervals, determinants of accelerating disease and expected patterns of progression
have been extrapolated from cross-sectional studies, most
recently in both arterial and venous systems. Several longitudinal studies have utilized various approaches for
analyzing these Doppler abnormalities in IUGR. For
example, Rigano et al. found that a persistent reduction in
umbilical venous volume flow precedes the development
of growth delay13 . Similarly, Harrington et al. showed
that the degree of growth delay mirrors the increase in
UA pulsatility14 . Several studies have shown that cerebral blood flow abnormalities become more prevalent
as growth restriction progresses15 . Worsening arterial
Doppler results do parallel worsening fetal status, but only
the addition of venous Doppler has allowed a comprehensive understanding of cardiovascular deterioration16,17 .
Our study is another step in understanding IUGR, as the
first longitudinal study of arterial and venous Doppler
parameters documenting progression from its early onset.
Based on the defined entry point of first clinical diagnosis,
our observations illustrate the sequence and character of
progression, before the phase of fetal compromise.
How IUGR progresses is determined by when it starts
and how it starts, i.e. gestational age and degree of UA
abnormality at onset. In patients presenting much before
30 weeks, a pattern of worsening UA Doppler established
in the first 7–10 days reliably predicts progression to
venous Doppler abnormalities and very early intervention
(severe early-onset placental dysfunction). In those
presenting closer to 30 weeks with decreased (but still
present) UA end-diastolic velocity, Doppler progression
is also typically forecast within the first 2 weeks of
monitoring and falls into one of two patterns. If initial
Doppler abnormalities have not worsened in that first
interval, they are unlikely to do so. Abnormalities remain
confined to umbilical and mild cerebral changes. These
fetuses do not develop venous Doppler abnormalities and
are likely to deliver near term (mild placental dysfunction).
If the first few weeks of monitoring show progressive
elevation of UA Doppler indices, progression to abnormal
venous Doppler findings and preterm delivery become
more likely (progressive placental dysfunction).
Ultrasound Obstet Gynecol 2008; 32: 160–167.
Turan et al.
166
Previous studies that focused on associations with outcome analyzed steps in final deterioration by examining
events backward from the time of delivery. Senat et al.
correlated arterial and venous Doppler waveforms in 75
IUGR singleton pregnancies10 . They documented parallel
progression of cerebral and precordial venous Doppler
abnormalities. Ferrazzi et al. analyzed the percentage of
Doppler abnormalities and longitudinal cumulative onset
time of Doppler abnormalities in 26 fetuses with severe
early-onset growth restriction6 . Early Doppler changes of
brain sparing and UA end-diastolic velocity were present
in 50% of fetuses up to 16 days prior to delivery. Late
Doppler changes including an elevated DV Doppler index
and reversed UA end-diastolic velocity were observed
in the week prior to delivery in up to 40% of fetuses.
The daily incidence of these Doppler abnormalities was
0.052 and 0.046. Bilardo et al.7 and Hecher et al.8 also
studied trends in IUGR Doppler leading to a delivery
decision7,8 . Both studies confirmed the proposed sequence
of Doppler abnormalities, but also noted a higher probability of escalation at earlier gestational ages and a
cumulative impact on perinatal outcome. However, our
group, and later Cosmi and colleagues18 have shown that
many growth-restricted fetuses do not follow the classical
Doppler progression.
These studies documented components of IUGR
deterioration in already established disease. By starting
earlier, and analyzing behavior prospectively, we have
illustrated differing patterns of progression. In fact,
many fetuses progress slowly or not at all from the
onset of IUGR. Further, these patterns of progression
determine the structure of antenatal surveillance. First,
primary consideration is given to gestational age at
onset and the trends observed in short-term serial
evaluation of UA Doppler. Early-onset IUGR carries
a risk for rapid parallel progression of umbilical and
venous Doppler abnormalities. Late-onset disease is less
likely to progress in such a way. At identical gestational
ages progression from isolated UA Doppler abnormality
to brain sparing doubles the rate of progression, and
DV Doppler abnormalities are associated with a tenfold acceleration of deterioration. The progression of
UA Doppler abnormalities is the primary tool for
distinguishing between these patterns of anticipated
progression. This role of the progression of UA Doppler
abnormality has not been accounted for in previous
studies. Therefore, differences in the prevalence of venous
Doppler abnormalities and in the patterns of progression
have remained unexplained. Our observations clarify that
the prevalence of venous Doppler abnormalities and their
rate of progression is highest in preterm IUGR and very
rare among fetuses presenting with growth restriction
beyond 30 weeks’ gestation.
Our observations suggest a schedule for IUGR
surveillance. Once IUGR has been diagnosed weekly
UA Doppler examination is suggested to determine the
pattern of progression. After the initial 14 days, rapidly
progressive severe disease will be revealed by definitive
deterioration of UA Doppler and the emergence of
Copyright 2008 ISUOG. Published by John Wiley & Sons, Ltd.
additional vessel abnormalities. For the remainder, a less
fulminant course is expected. If there is still no change
over the next 2 weeks then venous Doppler monitoring is
unlikely to yield abnormal results. Of interest, this nonprogressive subset may show isolated increased cerebral
diastolic blood flow near term. The significance of this
isolated Doppler finding in near-term IUGR has been
emphasized previously19 and merits further study. Those
fetuses that do progress in subsequent intervals require
frequent, serial, arterial and venous testing, but often
may gain many weeks of valuable maturation time before
delivery. Further study needs to address whether there
are additional factors such as UA Doppler status or the
development of pregnancy-induced hypertensive disorders
that impact on this anticipated progression.
In conclusion, the characteristics of cardiovascular
manifestations in IUGR are determined by the gestational
age at onset and the severity of placental disease,
identified by UA Doppler alone. The precise mechanisms
mediating these differences require further study. These
associations are not recognized when extrapolated from
cross-sectional studies. Recognition of these factors is
critical for planning fetal surveillance in IUGR. Serial
observations of UA Doppler status remain a cornerstone
for determining monitoring intervals in IUGR. At early
gestation escalation of UA Doppler parameters and
elevation of the DV Doppler index are relevant modifiers
of testing. Near-term progression beyond an abnormal
MCA Doppler is not observed.
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