Professional Documents
Culture Documents
Key Words agement of FGR and the decision to deliver aims at an opti-
Fetal growth restriction update Stage-based management mal balance between minimizing fetal injury or death versus
protocol Constitutional small-for-gestational age the risks of iatrogenic preterm delivery. We propose a proto-
Early-severe versus late-mild fetal growth restriction col that integrates current evidence to classify stages of fetal
deterioration and establishes follow-up intervals and opti-
mal delivery timings, which may facilitate decisions and re-
Abstract duce practice variability in this complex clinical condition.
Small fetuses are defined as those with an ultrasound esti- 2014 S. Karger AG, Basel
mated weight below a threshold, most commonly the 10th
centile. The first clinically relevant step is the distinction of
true fetal growth restriction (FGR), associated with signs of Introduction
abnormal fetoplacental function and poorer perinatal out-
come, from constitutional small-for-gestational age, with a Fetal growth restriction (FGR) is defined as a failure to
near-normal perinatal outcome. Nowadays such a distinc- achieve the endorsed growth potential. The diagnosis of
tion should not be based solely on umbilical artery Doppler, fetal smallness is currently performed on the basis of an
since this index detects only early-onset severe forms. FGR estimated fetal weight (EFW) below a given threshold,
should be diagnosed in the presence of any of the factors most commonly the 10th centile. It is likely that this def-
associated with a poorer perinatal outcome, including inition lacks sensitivity, so that it misses cases of growth
Doppler cerebroplacental ratio, uterine artery Doppler, a restriction that do not fall below the 10th centile, but it
growth centile below the 3rd centile, and, possibly in the identifies a subset of pregnancies at high risk of poorer
near future, maternal angiogenic factors. Once the diagnosis perinatal outcome. Thus, detection of small fetuses is
is established, differentiating into early- and late-onset FGR clinically relevant because as a whole this group of fetuses
is useful mainly for research purposes, because it distin-
guishes two clear phenotypes with differences in severity,
association with preeclampsia, and the natural history of fe-
tal deterioration. As a second clinically relevant step, man- E. Gratacs and F. Figueras contributed equally to this work.
190.232.73.115 - 1/11/2017 2:10:29 AM
120
100
80
60
40
20
0
a 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41
160
No sign of FGR
Any sign of FGR
140
120
100
80
Fig. 1. Distribution of a large population of
small fetuses (n = 656) in FGR or SGA. 60
a FGR is defined by an UA PI >95th centile
only. b FGR is defined using a combination 40
of CPR <5th centile, UtA PI >95th centile
and an EFW <3rd centile. Note how a re- 20
markable proportion of SGA defined by
UA PI are reclassified as true FGR when the 0
combined definition is used, particularly b 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41
among late-onset FGR fetuses.
Table 1. Summary of the main differences between early- and late-onset forms of FGR
CPR <p5
Growth restriction
Fig. 2. Fetal deterioration and monitoring in early-severe FGR. Pla- average temporal relation among changes in parameters, but the
cental disease affects a large proportion of the placenta, and this is actual duration of deterioration is influenced by severity. Regard-
reflected in changes in the UA Doppler in a high proportion of less of the velocity of progression, in the absence of accompanying
cases. The figure depicts in a schematic and simplified fashion the PE this sequence is relatively constant, particularly as regards end-
pathophysiologic progression with the main adaptation/conse- stage signs and the likelihood of serious injury/death. However,
quence in placental-fetal physiology, and the accompanying cas- severe PE may distort the natural history and fetal deterioration
cade of changes in Doppler parameters. The sequence illustrates the may occur unexpectedly at any time (see text for abbreviations).
95% centile is associated with higher risks but not as con- AoI has a strong association with both adverse perina-
sistently as when atrial flow is reverse. Overall, the sensi- tal [62] and neurological outcome [59]. However, longi-
tivity for perinatal death is still 4070% [28, 55, 57]. A tudinal studies show that the AoI precedes DV abnor-
systematic review of 18 observational studies (including malities by 1 week [29, 63], and consequently it is not as
2,267 fetuses) found that DV Doppler has predictive ca- good to predict the short-term risk of stillbirth [41]. In
pacity for perinatal mortality [58]. In about 50% of cases, contrast, AoI seems to improve the prediction of neuro-
abnormal DV precedes the loss of short-term variability logical morbidity [59]. Among early-onset FGR with pos-
(STV) in computerized cardiotocography (cCTG) [27], itive DV atrial velocities, a reverse AoI indicated a very
and in about 90% of cases it is abnormal 4872 h before high risk of late neonatal neurological injury (57 vs. 9.7%)
the biophysical profile (BPP) [53]. Hence, it is considered [41]. In the opinion of the authors, reverse AoI could al-
to provide a better window of opportunity for delivering ready be incorporated in clinical protocols as a sign of
fetuses in critical conditions at very early gestational ages. severe placental insufficiency and could justify consider-
ing elective delivery beyond 34 weeks of gestation. If fu-
Aortic Isthmus Doppler ture studies confirm the strong association with neuro-
The aortic isthmus (AoI) Doppler is associated with logical morbidity, reverse AoI flow could be used to indi-
increased fetal mortality and neurological morbidity in cate delivery even earlier, but more data are required.
early-onset FGR [59]. This vessel reflects the balance be-
tween the impedance of the brain and systemic vascular Fetal Heart Rate Analysis by Conventional and
systems [60, 61]. Reverse AoI flow is a sign of advanced Computerized Cardiotocography
deterioration and a further step in the sequence starting Early studies on high-risk pregnancies showed that,
with the UA and MCA Dopplers (fig.2, 3). Remarkably, though highly sensitive, CTG has a 50% rate of false pos-
the AoI can be found abnormal also in a small proportion itives for the prediction of adverse outcome [64]. In addi-
of late-onset FGRs [29]. tion, a meta-analysis [65] on high-risk pregnancies failed
190.232.73.115 - 1/11/2017 2:10:29 AM
Biophysical Profile
CTG decelerations
BPP is calculated by combining ultrasound assessment
of fetal tone, respiratory and body movements, with am-
niotic fluid index and a conventional CTG. It was de-
Growth restriction
signed to improve the performance of FHR. Observation-
al studies show an association between abnormal BPP
Fig. 3. Fetal deterioration and monitoring in late-mild FGR. Pla- and perinatal mortality and cerebral palsy [69]. Studies in
cental disease is mild and UA Doppler values are not elevated which a cordocentesis was performed demonstrated a
above the 95th centile. The effects of fetal adaptation are best de-
tected by the CPR, which can pick up mild changes in the AU and
good correlation with acidosis [70], with fetal tone and
MCA Doppler. An important fraction of cases do not progress to gross motor movements the best correlated components.
baseline hypoxia so that they remain only with abnormal CPR. However, as with FHR, a high false-positive rate (50%)
Once baseline hypoxia is established, placental reserve is minimal limits the clinical usefulness of the BPP [71]. Early obser-
and progression to fetal deterioration may occur quickly, as sug- vational studies reported a very low risk of false positives
gested by the high risk of severe deterioration or intrauterine fetal
death after 37 weeks in these cases, possibly due to a combination
for acidosis and perinatal death, but more recent studies
of a higher susceptibility to hypoxia of the term-mature fetus and on early-onset very preterm FGR fetuses raise concerns
the more common presence of contractions at term (see text for over the false-positive rate, with up to 23% of instances of
abbreviations). intrauterine fetal death in fetuses with BPP >6 and 11%
in those with BPP >8 [72]. A meta-analysis [73] showed
no significant benefit of BPP in high-risk pregnancies.
Consequently, whenever Doppler expertise and/or cCTG
to demonstrate any beneficial effect in reducing perinatal are available, the incorporation of BPP in management
mortality. Hence, there is no evidence to support the use protocols of FGR is questionable.
of traditional fetal heart rate (FHR) monitoring or non-
stress tests in FGR fetuses. We must acknowledge that Amniotic Fluid Index
these studies were conducted in the early 1980s, and the Amniotic fluid index (AFI) is used essentially as part
control group had no fetal well-being assessment or out- of BPP. Amniotic fluid volume is believed to be a chronic
dated techniques such as biochemical tests. However, in parameter. In fact, among the components of BPP, it is
general, a silent FHR pattern or the presence of spontane- the only one that is not considered acute. A meta-analysis
ous decelerations represent a very late event preceding [74] of 18 randomized studies demonstrated that a re-
fetal demise, and consequently measures that allow ear- duced AFI is associated with an abnormal 5-min Apgar
lier identification and delivery must be used. A main lim- score, but there was no association with acidosis or peri-
itation of conventional CTG is the subjective interpreta- natal death in SGA (RR 1.6, 95% CI 0.92.6). Longitudi-
tion of the FHR, which is extremely challenging in very nal studies in early-onset FGR fetuses have shown that the
preterm fetuses with a physiologically reduced variability. AFI fluid index progressively decreases [27, 38]. One
cCTG has represented a step forward and has provided week before acute deterioration, 2030% of cases have
new insights into the pathophysiology and management oligohydramnios [38, 53]. There is limited evidence on
of FGR. cCTG evaluates STV of the FHR, an aspect that the role of oligohydramnios to predict perinatal compli-
subjective evaluation cannot assess. Current evidence cations in FGR fetuses managed with Doppler so that its
suggests that cCTG is sensitive to detect advanced fetal inclusion in management protocols is questionable.
deterioration, and it provides a value similar to DV re-
190.232.73.115 - 1/11/2017 2:10:29 AM
Labor induction
or mean UtA pulsatility index >95th centile
No
No Yes
6*$40 weeks
Fig. 4. Stage-based decision algorithm for the management of FGR (see text for abbreviations).
All Doppler signs described above should be confirmed at least twice, ideally at least 12 h apart. GA = Gesta-
tional age; LI = labor induction; CS = cesarean section. * Recommended intervals in the absence of severe preeclamp-
sia. If FGR is accompanied by this complication, strict fetal monitoring is warranted regardless of the stage.
** Lower GA threshold recommended according to current literature figures reporting at least 50% intact survival.
Threshold could be tailored according to parents wishes or adjusted according to local statistics of intact survival.
190.232.73.115 - 1/11/2017 2:10:29 AM
References
1 Lindqvist PG, Molin J: Does antenatal identi- 8 Oros D, et al: Longitudinal changes in uter- 15 Ghosh GS, Gudmundsson S: Uterine and um-
fication of small-for-gestational age fetuses ine, umbilical and fetal cerebral Doppler in- bilical artery Doppler are comparable in pre-
significantly improve their outcome? Ultra- dices in late-onset small-for-gestational age dicting perinatal outcome of growth-restrict-
sound Obstet Gynecol 2005;25:258264. fetuses. Ultrasound Obstet Gynecol 2011;37: ed fetuses. BJOG 2009;116:424430.
2 Gardosi J, et al: Maternal and fetal risk factors 191195. 16 Vergani P, et al: Prognostic value of uterine
for stillbirth: population-based study. BMJ 9 Doctor BA, et al: Perinatal correlates and neo- artery Doppler velocimetry in growth-re-
2013;346:f108. natal outcomes of small for gestational age in- stricted fetuses delivered near term. Am J Ob-
3 Figueras F, et al: Predictiveness of antenatal fants born at term gestation. Am J Obstet Gy- stet Gynecol 2002;187:932936.
umbilical artery Doppler for adverse preg- necol 2001;185:652659. 17 Savchev S, et al: Estimated weight centile as a
nancy outcome in small-for-gestational-age 10 McCowan LM, Harding JE, Stewart AW: Um- predictor of perinatal outcome in small-for-
babies according to customised birthweight bilical artery Doppler studies in small for ges- gestational-age pregnancies with normal fetal
centiles: population-based study. BJOG 2008; tational age babies reflect disease severity. and maternal Doppler indices. Ultrasound
115:590594. BJOG 2000;107:916925. Obstet Gynecol 2012;39:299303.
4 Skovron ML, et al: Evaluation of early third- 11 Severi FM, et al: Uterine and fetal cerebral 18 Savchev S, et al: Late-onset fetal growth re-
trimester ultrasound screening for intrauter- Doppler predict the outcome of third-trimes- striction vs. small-for-gestational age: diag-
ine growth retardation. J Ultrasound Med ter small-for-gestational age fetuses with nor- nostic criteria and classification (in prepara-
1991;10:153159. mal umbilical artery Doppler. Ultrasound tion).
5 Richardus JH, et al: Differences in perinatal Obstet Gynecol 2002;19:225228. 19 Lobmaier SM, et al: Angiogenic factors versus
mortality and suboptimal care between 10 12 Bahado-Singh RO, et al: The Doppler cere- Doppler follow-up in the prediction of ad-
European regions: results of an international broplacental ratio and perinatal outcome in verse outcome among late pregnancy small-
audit. BJOG 2003;110:97105. intrauterine growth restriction. Am J Obstet for-gestational-age fetuses. Ultrasound Ob-
6 Alfirevic Z, Stampalija T, Gyte GM: Fetal and Gynecol 1999;180:750756. stet Gynecol 2013, Epub ahead of print.
umbilical Doppler ultrasound in high-risk 13 Gramellini D, et al: Cerebral-umbilical Dopp- 20 Sanz-Cortes M, et al: Fetal brain MRI texture
pregnancies. Cochrane Database Syst Rev ler ratio as a predictor of adverse perinatal analysis identifies different microstructural
2010:CD007529. outcome. Obstet Gynecol 1992;79:416420. patterns in adequate and small for gestational
7 Soothill PW, Bobrow CS, Holmes R: Small for 14 Baschat AA, Gembruch U: The cerebropla- age fetuses at term. Fetal Diagn Ther 2013;33:
gestational age is not a diagnosis. Ultrasound cental Doppler ratio revisited. Ultrasound 122129.
Obstet Gynecol 1999;13:225228. Obstet Gynecol 2003;21:124127.
190.232.73.115 - 1/11/2017 2:10:29 AM