Keywords
fetal growth restriction - ductus venosus waveform - feta heart rate monitoring -
biophysical profile - middle cerebral artery waveform
In 2020 both the International Society of Ultrasound in Obstetrics and Gynecology
(ISUOG) and the Society for Maternal–Fetal Medicine (SMFM) published practice guidelines
regarding the diagnosis and management of fetal growth restriction (FGR).[1]
[2] The differences between these two documents, representing a primarily European versus
American approach, have generated a great deal of controversy.[3]
[4] The ISUOG document places a greater emphasis on the use of Doppler in fetal surveillance,
relying in large part on the 2015 TRUFFLE trial.[5] However, a careful analysis of the results of this important trial leads us to conclusions
that are quite different from those of its authors.
The purpose of this paper is to suggest a clinical approach based on the data presented
in the TRUFFLE trial and several other studies and to address some other clinical
questions that frequently arise. Our goal is to provide an evidence-based framework
for management that can augment the ISUOG and the SMFM guidelines.
Definition and Diagnosis of Fetal Growth Restriction
Definition and Diagnosis of Fetal Growth Restriction
The likelihood of stillbirth is related to the degree of growth restriction in an
exponential manner. Fetuses at less than the third percentile are clearly at the greatest
risk and most often present early in pregnancy, compared with those between the 3rd
and 10th percentiles. However, even fetuses between the 10th and 25th percentiles
are at slightly increased risk compared with larger fetuses.[6]
[7] As is the case with many other diseases such as chronic hypertension and gestational
diabetes, there is a continuum of risk, and rigid adherence to an arbitrary cutoff
that dichotomizes patients to a diseased or nondiseased state can sometimes be disadvantageous.
Titrating the response to the anticipated degree of risk may be the best approach.
SMFM defines FGR as estimated fetal weight (EFW) or abdominal circumference (AC) < 10th
percentile.[2] ISUOG defines FGR as EFW or AC < 3rd percentile or between the 3rd and 10th percentile
with abnormal Doppler measurements of the uterine, umbilical, or middle cerebral arteries
(e.g., umbilical artery [UA] pulsatility index > 95 percentile).[1] Both documents recognize that early-onset FGR, diagnosed before 32 weeks, is more
closely associated with maternal hypertensive disorders and perinatal mortality than
late-onset FGR recognized after 32 weeks. ISUOG also discusses a third category of
small fetuses (e.g., between the 3rd and 10th percentiles) categorized in their document
as “small for gestational age” with normal Doppler findings but that are nonetheless
at increased risk for various surrogates for adverse outcome, consistent with the
epidemiological studies cited above.
Since fetuses between the 3rd and 10th percentiles with normal Doppler studies are
identified as FGR by the SMFM criteria but not ISUOG, the SMFM criteria would be expected
to have a higher sensitivity but lower specificity for adverse outcomes compared with
the ISUOG criteria. This was recently confirmed by a study demonstrating the sensitivity
and specificity for a composite of adverse neonatal outcomes were (only) 15 and 87%,
respectively, using the SMFM criteria, compared with 10 and 95% using the ISUOG criteria.[8]
Both documents rely on assignment of a percentile for the EFW, which depends on:
-
Normative data. The Hadlock curve, based on ultrasound measurements obtained 35 years
ago of 392 women from Southwestern United States,[9] is favored by SMFM, whereas the ISUOG refers to their previous document,[10] which favors carefully obtained international data from INTERGROWTH-21[11] or World Health Organization.[12] Comparison of these reference standards shows significant differences ([Tables 1] and [2]): at 24 weeks, the INTERGROWTH curve identifies a greater number of fetuses as FGR
compared with Hadlock, whereas the reverse is true at 32 weeks. Use of any of these
charts ignores the effect of fetal sex, maternal parity, twin pregnancy, and (more
controversially) racial/ethnic variation.
-
Accurate sonographic biometry is obviously important, as is also evident in [Tables 1] and [2]. For example, according to the INTERGROWTH-21, the difference between the 3rd and
10th percentile at 24 weeks is only 27 g.
-
A very precise estimate of gestational age is of utmost importance, as an error of
just a few days can make a significant difference in the weight percentile in the
second and early third trimester. For example, according to the Hadlock curve, a 652 g
fetus would be at the 10th percentile at 250/7 weeks but the 25th percentile at 243/7 weeks; a 589 g fetus would be at the 3rd percentile at 250/7 weeks but the 18th percentile at 240/7 weeks. Similarly, a 602 g fetus would be at the 10th percentile at 24 weeks on the
INTERGROWTH-21 curve but > 50th percentile at 23 weeks. At earlier gestational ages,
the need for a precise estimate of gestational age is even greater. For example, on
the Hadlock curve, 398 g is the 10th percentile at 22 weeks but the 28th percentile at 213/7 weeks.
Table 1
Third percentile for fetal weight according to the Hadlock[8] the INTERGROWTH-21[11] standards, and 2.5 percentile according to the World Health Organization[12] standards
|
Gestational age (wk)
|
Hadlock 1991 (g)
|
INTERGROWTH-21 (g)
|
WHO (g)
|
|
24
|
503
|
575
|
523
|
|
26
|
685
|
716
|
707
|
|
28
|
908
|
892
|
929
|
|
30
|
1,169
|
1,106
|
1,185
|
|
32
|
1,465
|
1,357
|
1,473
|
Table 2
Tenth percentile for fetal weight according to the Hadlock,[8] the INTERGROWTH-21,[11] and the World Health Organization[12] standards
|
Gestational age (wk)
|
Hadlock 1991 (g)
|
INTERGROWTH-21 (g)
|
WHO (g)
|
|
24
|
556
|
602
|
576
|
|
26
|
758
|
757
|
780
|
|
28
|
1,004
|
951
|
1,026
|
|
30
|
1,294
|
1,190
|
1,313
|
|
32
|
1,621
|
1,473
|
1,635
|
Abbreviation: WHO, World Health Organization.
The American College of Obstetricians and Gynecologists guideline for establishing
the due date[13] bases the estimate of the gestational age on the last menstrual period unless the
sonographic biometry differs by >5 days prior to 9 weeks, > 7 days between 9 and 16
weeks, and by a larger amount if the first ultrasound is done later in pregnancy.
This degree of accuracy is not always sufficient. Delayed ovulation is common, and
therefore the menstrual history must consider changes in the timing of conception
due to long or irregular cycles or the use of hormonal contraception. While some patients
are unsure of the exact date of their last menstrual period, others reliably know
their date of ovulation or conception, which is not always day 14. Failure to consider
any of these factors can easily result in an error of a few days, potentially changing
the classification between “normal” and FGR. At the time of registration, a carefully
obtained history should be accompanied by a low threshold for early first-trimester
ultrasound, if resources permit.
Management of Fetal Growth Restriction
Management of Fetal Growth Restriction
Neither the ISUOG and SMFM documents discuss the importance of preexisting comorbidities
such as hypertension, acquired thrombophilia, renal and autoimmune diseases, advanced
age, elevated body mass index, and a complicated prior pregnancy. The presence or
absence of comorbidities such as hypertension plays a major role in the likelihood
that a particular EFW represents placental insufficiency and the likelihood that a
given set of findings will result in stillbirth.[14]
Both documents recognize that the degree of growth restriction and evaluation of the
UA waveform are of great importance in the management of FGR and recommend the use
of electronic fetal heart rate monitoring (FHRM). The ISUOG document suggests that
this should be every 2 or 3 days if the UA waveform demonstrates absent or reversed
diastolic flow.[1] The SMFM document suggests that FHRM should be weekly if the UA waveform is normal,
once or twice a week if there is decreased end diastolic velocity, at least twice
a week if there is absent end diastolic flow, and at least daily if there is reversed
diastolic flow.[2]
The ISUOG document prefers computerized rather than visual interpretation of FHRM,
since it allows quantification of short-term variability (STV), whereas the SMFM document
does not mention computerized interpretation. However, the difference between the
two approaches that has generated the most controversy involves the role of Doppler
evaluation of the ductus venosus (DV) and middle cerebral artery (MCA).
Ductus Venosus Waveform
The ISUOG recommendation that DV waveform should be monitored for early-onset FGR
when there is an abnormal UA waveform relies heavily on the TRUFFLE trial.[5] This was a randomized controlled trial of three groups of fetuses between 26 and
32 weeks' gestation with FGR defined as AC < 10th percentile and UA pulsatility index > 95
percentile. Surveillance in one group was by computerized analysis of STV and UA Doppler
velocimetry; the other two groups also incorporated evaluation of the DV waveform
but used more stringent STV positivity criteria. The primary outcome was survival
without neurodevelopmental impairment at 2 years of age, and the secondary outcome
was survival without severe neonatal morbidity.
It is perhaps not widely recognized that there was no statistically significant difference
in either the primary or secondary outcome among the three groups. The number of survivors without neurodevelopmental impairment was slightly less in
the DV groups (p = 0.09), and there was an identical number of survivors without severe neonatal morbidity
in each group. A post hoc analysis identified a statistically significant decrease
in neurodevelopmental impairment in survivors of the two groups that were managed
with DV waveform and the more stringent STV positivity criteria: 47/299 (16%) versus
33/144 (23%), which was partially offset by a small increase in stillbirths. However,
it must be remembered that clinical management should not be determined by a statistically
significant finding based on a post hoc analysis of the data rather than a prespecified
hypothesis.[15]
The similarity in outcomes among the three groups should not be surprising, as the
DV waveform had a rather limited role in management. As has been previously pointed
out, only 45/205 (22%) women allocated to the DV groups with a live-born baby were
delivered due to an abnormal DV waveform; 87 (42%) were delivered due to FHR abnormalities,
and the remaining 73 (36%) were delivered for other fetal indications or maternal
deterioration (mainly hypertension).[16]
These findings are consistent with a more recent study of 132 fetuses with FGR between
26 and 34 weeks with absent or reversed diastolic flow in the UA.[17] Only 15 fetuses (11%) were delivered due to an abnormal DV waveform compared with
81 (61%) that were delivered due to FHR abnormalities and 36 (27%) that were delivered
for other fetal or maternal indications.
Furthermore, reliance on a normal DV waveform for continuing the pregnancy can result
in stillbirth. In the TRUFFLE trial five of seven stillbirths had a normal DV waveform;[18] stillbirth shortly after a normal DV waveform has also been reported elsewhere.[19]
Finally, false-positive DV waveform results are possible ([Fig. 1]). This can occur if the hepatic vein, which is in close proximity to the DV and
typically demonstrates reversed waves,[20] is mistakenly sampled.
Fig. 1 False positive ductus venosus waveform. This image was taken at 26 weeks. Subsequent
waveforms were normal, and the patient delivered a 2,400 g (5th percentile) baby at
37 weeks with a normal course in the nursery.
Fetal Heart Rate Monitoring
Fetal Heart Rate Monitoring
Importantly, the TRUFFLE trial demonstrated an unexpectedly good outcome in all three
groups.[21] The authors attribute this in part to frequent FHRM, which was daily in 17 of 20
participating centers and at least every other day in the rest.[22] The daily risk of abnormal STV and/or recurrent decelerations was 5%, and most decreases
in STV occurred suddenly and unexpectedly within 24 hours of delivery.
The components of FHRM include presence or absence of accelerations or decelerations
and evaluation of variability. The ISUOG document stresses the importance of STV,
stating that when computerized FHRM is available, STV should be the main parameter
assessed.[1] However, in the TRUFFLE trial, of the 79/165 (48%) patients who were delivered for
an abnormal FHR tracing, the indication for delivery was decelerations rather than
decreased STV.[16] The findings of Fratelli et al were again similar: 76/132 (58%) patients were delivered
due to decelerations on FHRM compared with only 5/132 (4%) who were delivered due
to decreased STV.[17]
The superiority of computerized over visual evaluation of STV is unproven.[22]
[23]
[24] The correlation with fetal acidemia is not robust, as there is a large overlap with
normal fetuses,[25] especially if decelerations are absent,[26] and there is disagreement regarding which criterion is optimal.[24]
[25] Finally, in the TRUFFLE trial the STV positivity criteria were different in the
groups that were monitored by DV waveform compared with the group that was not.
It appears that frequent FHR monitoring, rather than computerized assessment, is the
critical variable. This conclusion is supported by a recent study involving 367 FGR
pregnancies managed by daily visual FHR monitoring who were delivered with a median
birth weight of 900 g at 30 weeks. There were 347 live births and only 6 unanticipated
fetal deaths.[27]
Other Modes of Surveillance
Other Modes of Surveillance
Use of the biophysical profile (BPP) is well established[28] and is the mainstay of fetal surveillance in many institutions. However, BPP was
not utilized in the TRUFFLE trial, and the ISUOG recommendation regarding its use
was considered a “good practice point” defined as “Recommended best practice based
on clinical experience of the Guideline Development Group,” its lowest level of evidence.[1] Similarly, the SMFM document states that “further studies are required to prove
the usefulness of BPP,[2] citing a series of 48 fetuses < 1,000 grams with daily BPP in which stillbirths
occurred in 3/13 fetuses with a BPP score of 6/8 and in 3/27 fetuses with a BPP score
of 8/8.[29]
The role of MCA Doppler, and the ratio of MCA/UA pulsatility index called the cerebroplacental
ratio (CPR) is also unclear. There is uncertainty about normative data, two meta-analyses
were unable to demonstrate its utility[30]
[31] and it was of no benefit in fetuses less than 32 weeks in the TRUFFLE trial.[32] Nonetheless, the ISUOG gave multimodal assessment for monitoring fetuses with early
FGR, including MCA Doppler, its highest grade of assessment.[1] Regarding late-onset FGR, they state that “MCA-PI and its ratios to UA-PI are the
most important Doppler parameters.” However, they only recommend delivery for abnormal
MCA Doppler after 38 to 39 weeks. Conversely, SMFM states that additional clinical
trials are needed to evaluate the effectiveness of CPR in guiding clinical management.[2] The ongoing TRUFFLE 2 study[33] may provide these data.
Conclusion
It is imperative that all providers obtain a very careful history at the first prenatal
visit that in an attempt to determine the precise date of conception. This entails
inquiring about the length and regularity of the menstrual cycle, the use of hormonal
contraception, and if the patient was using other methods of tracking ovulation or
conception. In resource-rich settings, there should be a low threshold for an early
first-trimester ultrasound.
There is a continuum of risk for small fetuses, depending on the certainty of dates,
comorbidities, the EFW percentile, and the UA Doppler waveform. A greater degree of
risk warrants closer surveillance. On one extreme a healthy patient whose fetus is
near the 10th percentile by less than certain dates should have at least a follow-up scan at a
reasonable interval, perhaps 2 to 4 weeks. On the other extreme, fetuses at highest
risk due to size or comorbidities should undergo intensive surveillance with frequent
FHRM ([Table 3]). It is probably unimportant whether it is visual or computerized; what is essential
is that it is frequent; daily if the UA waveform has a pulsatility index > 95 percentile.
Monitoring DV waveform, BPP and MCA Doppler appears to be less important and perhaps
less reliable, so both positive and negative results should be interpreted with caution.
Table 3
Recommended surveillance of pregnancies complicated by fetal growth restriction and
abnormal umbilical artery waveform < 32 weeks
|
Electronic FHRM
|
Ductus venosus waveform
|
Biophysical profile
|
Middle cerebral artery waveform
|
|
SMFM
|
Diminished EDV: 1–2 × per week
absent EDV: at least 2 × per week
reversed EDV: 1–2 × per day
|
Not recommended
|
No definite statement either for or against
|
Not recommended
|
|
ISUOG
|
Diminished EDV: no statement
absent EDV: every 2–3 d
reversed EDV: every 2–3 d
computerized FHRM is preferred
|
Recommended
|
If computerized FHRM is unavailable; every 2–3 d for absent or reversed EDV
|
Useful to guide monitoring but not timing of delivery
|
|
This review
|
Diminished EDV: daily
absent EDV: at least daily
reversed EDV: at least daily
|
Optional; interpret with caution
|
Optional; interpret with caution
|
Optional; interpret with caution
|
Abbreviations: EDV, end diastolic flow in the umbilical artery; FHRM, fetal heart
rate monitoring; ISUOG, International Society of Ultrasound in Obstetrics and Gynecology;
SMFM, Society for Maternal-Fetal Medicine.
Note: Diminished EDV implies a pulsatility index > 95 percentile.
Finally, shared decision-making is essential. Especially in cases of extreme prematurity,
it is essential to understand the value that prospective parents place on avoiding
stillbirth even at the risk of neurodevelopmental impairment versus their desire to
optimize long-term outcomes.
