Early onset fetal growth restriction

Dr Aamod Nawathe PhD, MRCOG

Queen Charlotte’s and Chelsea Hospital, London, W120HS

Email: anawathe@imperial.ac.uk

Tel – 02033131111

Mr Christoph Lees MD, MRCOG *

Queen Charlotte’s and Chelsea Hospital, London, W120HS

Email: christoph.lees@imperial.nhs.uk

Tel – 02083835086

* = corresponding author

Abstract

Fetal growth restriction remains a challenging entity with significant variations in clinical practice

around the world. The different etiopathogenesis of early and late fetal growth restriction with their

distinct progression of fetal severity and outcomes, compounded by doctors and patient anxiety

adds to the quandary involving its management. This review is aimed at reviewingsummarises the

literature in a viewaround to diagnose diagnosing and monitoring early onset fetal growth restriction

(early onset FGR) with special emphasis on optimal timing of delivery as guided by recent research

advances.

Key words: early onset fetal growth restriction, fetal growth, umbilical artery Doppler, middle

cerebral artery Doppler, ductus venosus Doppler

Introduction

The diagnosis and management of fetal growth restriction (FGR) still remains an unravelled

unresolved dilemma in modern day obstetrics. This is due to several reasons such as unclear

diagnostic criteria, variable monitoring methods, complex confounding factors affecting different

gestational ages and obstetrician and patient anxiety. These factors are further compounded by lack

of robust evidence although recently progress has been made in this regard [1,2]. FGR is known to

be associated with significant neonatal morbidity and mortality [3,4] which has large economic

implications on for the health service. It has been shown that improved detection of FGR could

potentially save upto 360000£ £360,000 a year in a unit with 3000 births (www.perinatal.org.uk). As

our understanding continues to evolve, and given that there is no treatment for this condition, it is

crucial to make an accurate diagnosis at a correct gestational age as this will determine the timing of

delivery and the perinatal outcomes associated with it. Over the last couple of decades, it has

become clear that FGR can start early in the gestation called when it is termed early onset fetal

growth restriction (early onset FGR); and this follows a more severe trajectory in terms of neonatal

outcome as compared to late onset fetal growth restriction (late onset FGR) [5]. Studies have shown

that early onset FGR can rapidly deteriorate from umbilical artery and venous abnormalities to

abnormal biophysical profile leading to interventions and significant neonatal morbidity and

mortality [6–8].Furthermore, early onset FGR has shown to be associated with other pathologies

such as preeclampsia (PET) and increased perinatal mortality as compared to late onset FGR which is

associated with a milder form of PET [9,10]. Therefore, there is a it is a clear need to identify the

gestational age cut off to be able to label FGR as early or late, given the wider implications for

antenatal management and delivery. Unfortunately, studies done until now have used arbitrary cut

off gestational ages [7,8,11–13] to diagnose early onset FGR. However, this wide difference in the

gestational age cut off could bemight be considered acceptable in the broader medical fraternity

community, given the variable guidance followed and the logistics of available diagnostic tools. Also

Also, given the lack of robust research in early onset FGR, it is likely that the different gestational age

ranges could be a result of consensus rather than scientific reasoning. However, a recent large

prospective study evaluated the gestational age cut off according to perinatal mortality and adverse

perinatal outcome in a cohort of 656 pregnancies with FGR [14]. They identified 32 weeks as the

diagnostic cut off for maximising differences between early onset FGR and late onset FGR,

particularly especially in the absence of umbilical artery Doppler information.

Definition

The agreed definition by of the American College of Obstetricians and Gynaeoclogists (ACOG) and

the Royal College of Obstetricians and Gynaecologists (RCOG) to identify a growth restricted fetus is

based on either the estimated fetal weight (EFW) or abdominal circumference (AC) < 10 th centile.

However it became imperative to ascertain exactly which sonographic findings are truly associated

with adverse perinatal outcomes. In this regard, the PORTO study [15]analysed 1100 pregnancies

with EFW < 10th centile and looked at various sonographic biometric and Doppler flow markers. The

authors and concluded that EFW < 3rd centile along with abnormal umbilical artery Doppler

velocimetry was consistently associated with adverse perinatal outcome and therefore could be

taken as a definition of IUGRFGR. This definition gets gains further credence by from the multicentre

TRUFFLE study [5]where 503 women with IUGR FGR fetuses were recruited and followed untill

delivery to describe the perinatal morbidity and mortality depending on the sonographic features

and gestational age of diagnosis. More recently in an attempt to accurately define FGR by

international consensus, a Delphi consensus methodology was used. Experts provided there opinion

on various parameters to diagnose both early and late onset FGR. For early FGR, three solitary

parameters of AC or EFW < 3rd centile and absent umbilical end diastolic flow and four contributory

markers of AC or EFW < 10th centile with a PI > 95th centile in either umbilical or uterine flow were

agreed upon (will add Delphi reference).

Etiopathogenesis

It is imperative to understand the pathogenesis resulting in early onset FGR and late onset FGR to be

able to guide management and delivery delivery, particularlyespecially since they are governed by

different placental disorders. Early onset FGR stems from the reduction of the villous vascular area,

typically more than 30%, occurring in the second trimester and resulting in increased resistance to

the umbilical arterial flow [16]. This affects usually causes fetal biometry less than the 10th centile

and which, in conjunction with raised umbilical artery resistance constitutes the diagnosis of early

onset FGR [17]. Early onset FGR constitutes up to 30% of all FGRs and is more less common than late

onset FGR which constitutes up to 70% of all FGRs [18]. Late onset FGR on the other hand occurs in

the third trimester and is more associated with impaired maturation of the villi rather than reduction

in the surface area. As a result result, the umbilical arterial blood flow may not be necessarily

beimpeded as the villous immaturity does not impact on the resistance; rather, but it hampers the

gaseous and nutrient exchange [19]. The fetus senses the hypoxic conditions and responds by

reducing the impedance in the middle cerebral artery (MCA) [20]. Therefore, whilst umbilical artery

Doppler is crucial in the diagnosis and monitoring of early onset FGR, the middle cerebral artery

(MCA) Doppler is probably more important useful to diagnose late onset FGR. The progression of

adverse eventsthe condition in early onset FGR can take many weeks unoless pre-eclampsia

supervenes, and is more variable incould take a month whilst it could take upto 2 months in case of

late onset FGR (Figure 1). The disease progression in early onset FGR and late onset FGR is also

different. In early onset FGR the sequence is usually starting starts from abnormal Doppler

velocimetry in the umbilical artery, MCA, ductus venosus (DV) followed by abnormal

cardiotocograph (CTG) findings while in late onset FGR it is mainly abnormal MCA or abnormal

umbilical artery Doppler velocities [21]. However it has been reported that the time interval

between absent or reversed DV ‘a’ wave velocity to fetal death could be up to a week [22].

Histopathological findings associated with early onset FGR and clinical correlations

The pathological basis for early onset FGR is classically related to the impaired trophoblastic invasion

by the spiral arteries thus so it is termed as an abnormality of the villous vessels causing massive

lesions of the placental structure [23]. Although this is the basis of the association of early onset FGR

with other diseases which also affect placental vessels like such as preeclampsia [24], a rather

tenuous relationship between histopathological placental lesions with FGR and PET have has also

been reported [25]. Abnormal uterine artery Doppler velocimetry reflects uterine malperfusion

further confirmed by placental bed biopsies showing defective spiral artery remodelling and fibrinoid

necrosis[26]. Abnormal uterine artery resistance is associated with defective trophoblastic migration

on placental bed biopsies is also seen in preterm PET, thus underlying the extent of similarity

between these conditions [27]. In fact convincing evidence from a recent meta-analysis has shown

that uterine artery Doppler abnormalities not only reflects abnormal placental vasculature but can

anticipate its progression[28]. Studies have also reported an association between umbilical artery

pulsatility index and the proportion of increase in abnormal fetal stem artery thickness

[29]sometimes present in up to 90% of cases with absent EDF [30].It is interesting that further

reports have not only confirmed this finding but also shown that changes in the fetal stem arteries

progress in parallel with umbilical artery Doppler abnormalities and in most cases precede abnormal

uterine artery Doppler abnormalities [31–34].

Histopathological findings associated with late onset FGR and clinical correlations

Unlike the similarity in the clinical and pathological findings of early onset FGR and preterm PET, the

same association between late onset FGR and PET is noted at a lower frequencyless common [35].

Late onset FGR represents the a failure of the fetus to achieve its optimal growth potential, likely

secondary to placental insufficiency[36]. Studies have shown a much lower incidence of

uteroplacental lesions in late onset FGR, and in the majority of cases they were deemed as

unremarkable [37]. The placental lesions generally are generally not significant enough to translate

into increased uteroplacental and fetal vascular resistance [38]. Other villous lesions reported were

include fibrosis, hypovascularity and avascularity avascularity, suggestive of fetal thrombotic event

but no clinical correlation has been notedfound[39].

Maternal Cardiovascular Function and FGR

Whether placental lesions are a cause of FGR or an effect of systemic maternal cardiovascular

dysfunction remains controversial. There is emerging evidence suggesting that abnormal uterine

artery Doppler may reflect maternal arterial function [40] and the contribution of placental and

cardiovascular components lead to the abnormal expression of the waveform. Furthermore, fetal

growth restriction FGR is associated with low maternal cardiac output and high vascular resistance

[41,42]. It is therefore likely that the combination of reduced placental perfusion and abnormal

placental function are implicated in the pathogenesis of fetal growth restrictionFGR.

Investigations

Uterine artery Doppler

Impaired placentation with aberrations of trophoblastic spiral arterial invasion has been shown to

beis the underlying pathophysiology inassociated with FGR, pregnancy induced hypertension and

PET [43]. In the first trimester uUterine artery Doppler notches are associated in first trimesterfound

in up to 65% cases inof normal pregnancies but even persistent notching beyond 20 weeks has a

lower positive predictive value for both PET and FGR in a high risk population as compared to

women at lower risk of these conditions[43]. On the contrary, its negative predictive value is high at

97% in the high risk population. Predictive models by developed by the Fetal Medicine Foundation

researchers in which where uterine artery doppler Doppler velocimetry was combined with various

biochemical markers in the first trimester have shown variable detection rates of 52.3% and 73%

with for a 10% false positive rate [44,45]. Furthermore, a systematic review of 74 studies of PET and

61 studies of FGR has shown that Uterine artery doppler Doppler abnormalities are better predictors

of PET than FGR [44,45]. A recent meta-analysis involving 55,974 women [28] investigating the

accuracy of Uterine artery doppler Doppler in predicting FGR has shown the that its sensitivity to

identifyfor identifying early onset FGR was only 39% andwhile the sensitivity to predictfor predicting

stillbirth was 14.5%. Therefore, risk prediction with Uterine artery doppler Doppler screening is not

differentno better than the risk prediction due tousing other risk factors. The poor reproducibility of

first trimester Uterine artery doppler and variable results from past studies has have resulted in

focus on other impedenceimpedance markers as predictors of FGR rather than Uterine artery

doppler alone. Combining Uterine artery doppler Doppler flow studies with biochemical markers

may improve the prediction of FGR as shown in a recent study [18].

Second trimester uterine artery Doppler studies have shown better predictive performance than first

trimester studies[46,47], in particular for early onset disease PET and FGR [48]. The concept of

individualised risk prediction based on uterine artery Doppler and maternal factors was first

described following uterine artery Doppler assessment in the late second trimester [49]. Uterine

artery Doppler remains a useful modality for assessing the aetiology of FGR in the second trimester.

Umbilical artery Doppler

There is clear evidence of the benefit of umbilical artery Doppler measurement in reducing order to

reduce perinatal deaths which has been shownwith a reduction of to be up to 29% in high risk

pregnancies [50]. While increased resistance to umbilical artery flow helps in the diagnosis of FGR,

reversed flow can correlate with neonatal mortality [51]. In early onset FGR, uUmbilical artery

Doppler is crucial in the diagnosis of early onset FGR [52] especially since as it is difficult to interpret

cardiotocograph (CTG) findings in fetuses under 28 weeks of gestation. Unfortunately, in common

clinical practice there is still heavy reliance on CTG findings beyond 28 weeks of gestation and, by the

time the tracing becomes pathological, up to 80% of fetuses are already hypoxic [53]. There is

evidence from 9 nine randomised trials that perinatal mortality and length of hospital stay is are

reduced when umbilical artery Doppler monitoring is used along with CTG tracings [54]. A European

trial further noted the positive correlation between worsening changes in the umbilical artery

Doppler velocimetry and worst perinatal outcomes [55]. Early changes in umbilical artery Doppler

velocimetry was shown to bewere present about around 15 days prior to deterioration, whilst, the

end of the spectrummost severe abnormalities i.e. reversed flow, has been shown to bewere

present about around 4-5 days before delivery [13]. The progression of the abnormal changes in the

umbilical artery Doppler can be rapid in early onset FGR [32] but absent or reversed umbilical artery

Doppler blood flow after 26 weeks of gestation has been shown to have an independent impact on

neurodevelopment after 26 weeks [56]. Children born with these abnormalities have been further

shown to have impaired cognitive impairment and have a lower motor development at the age of 2

years [57]. Umbilical artery Doppler, whilst signifying an ‘at risk’ fetus, is not good at predicting nor

informing timing of delivery in early onset IUGRFGR.

Middle cerebral artery Doppler

Unlike umbilical artery Doppler, MCA Doppler is a proxy hallmark offor hypoxia and may be

abnormal for many weeks in early onset FGR. The MCA Doppler may be useful in tracking late onset

FGR independent of umbilical artery Doppler findings, as there is an association with with adverse

perinatal adverse outcomes [58]. It can also be used to predict emergency Caesarean section;s

where a raised lower MCA pulsatility index (PI) ) and cerebro-placental ratiois associated with an

increaseds the risk of abdominal delivery by a factor of 6 times as compared to MCA with a normal PI

[59]. These children have also been shown to have impaired neurodevelopment at 2 years of age

[60]. Since early onset FGR is associated with brain sparing, the interpretation of the MCA Doppler

findings is unclear especially in relation to timing of delivery is unclear. Nevertheless, MCA PI less

than the 5th centile is an efficient tool in forcan evaluateing cerebral vasodilatation and a recent

study has shown that CPR <1 isin a recent study has been shown to be associated with a worse

perinatal outcome as shown by the PORTO study[61]. Similarly, the cerebroplacental ratio (CPR),

which is the ratio of MCA PI and to the umbilical artery PI, is more useful in late onset FGR, as

impaired CPR has been shown to be associatedis in up to 25% of late onset FGRs prior to delivery

[62]and is associated with a worse outcome at delivery as compared to using MCA Doppler

alone[59]. Although one recent study has shown that CPR to correlates with adverse perinatal

outcomes, even in early onset FGR [63], CPR alone may not be predictive for adverse outcome nor

give information regarding the optimal time of delivery, leaving uncertainty as to on what basiswhat

factors should trigger delivery is indicated in late onset FGR [38,56].

Ductus venosus (DV) Doppler

There is strong evidence to suggest that (DV) Doppler predicts the risk of fetal death in early onset

FGR [6,12,13] and absent or reversed ‘a’ waves are associated with perinatal mortality irrespective

of gestational age, with a risk up to 100% in early onset FGR [64–66]. A systematic review of 18

observational studies has also shown the importance of DV Doppler velocimetry in predicting

perinatal mortality [67]. It has been shown that DV abnormalities precede changes in computerised

CTG in 50% of cases [6] whilst it predates abnormal biophysical profile (BPP) by up to 3 days [8]. It is

therefore considered a better investigation for delivering criticaldetermining the timing ofdelivery of

fetuses especially after steroid administration. There have been 2 multicentre randomised controlled

trials (RCTs) investigating timing of delivery in early onset FGR FGR,and namely GRIT and TRUFFLE

[1,2]. The growth restriction intervention trial (GRIT) although included women before and after 30

weeks of gestation but has been criticised for timing delivery based on clinicians judgment rather

than on objective signs[1]. It did not specifically evaluate Doppler findings. The outcomes at 2 years

of age in both the groups, i.e. immediate or deferred delivery following signs of fetal distress, were

similar and the optimum timing of delivery was unclear. In the most more recent TRUFFLE trial the

average age of entry was 29 weeks of gestation and the women were divided randomised in one of

the three groupsto 3 objective timing of delivery plans, i.e. reduced CTG short term variation (STV),

early and or late DV changes respectively. They found that, although the survival without

neurological impairment was similar in all three all groups, the timing of delivery according to late

changes in DV might bewas associated with an improvement in developmental outcomes at 2 years

of age [2]. This trial reinforces the importance of abnormal DV changes in the management of early

onset FGR.

Aortic isthmus Doppler

The oxygenated blood from the placenta enters the left atrium via the DV, left hepatic vein, inferior

vena cava, right atrium and foramen ovale, and the deoxygenated blood enters the right atrium

through the inferior and superior vena cava. The aortic isthmus (AI) is important because it acts as a

crucial interface connecting the oxygenated and deoxygenated circulation [68]. From there, it passes

into the right ventricle and is pumped out through the pulmonary artery. It passes through the

ductus arteriosus to reach the aorta at the aortic isthmus. Thus, these two streams, the oxygenated

and deoxygenated blood, meet substantively for the first time in the aortic isthmus. The aortic

isthmus (AI) is therefore very important because it acts as a crucial interface connecting the

oxygenated and deoxygenated circulations [68]. Animal studies have shown that not only does the

AI blood flow become retrograde prior to a decrease in cerebral blood flow [69], but in fact changes

in AI flow become apparent even before changes in UA umbilical artery velocimetry[70]. Human

studies have also reported an association between abnormal changes in AI velocimetry and neonatal

mortality and neurological morbidity in early onset FGR [71]. Reversed AI flow could be seen as an

advanced late step in the spectrum of Doppler abnormalities however AI flow abnormalities have

also been shown to be associatedfound in some cases of late onset FGR [72]. Furthermore, abnormal

AI flow precedes abnormal DV flow by a week and therefore deemed not a suitable marker to

predict fetal death in early onset FGR [72–74]. Abnormal AI flow in early onset FGR might be of value

in predicting neurological injury [66] but more research and training is required to incorporate it

ininto clinical practice.

Cardiotocography

Routine CTG in FGR fetuses has been reported to have a high (50%) false positive rate [75].

Furthermore, interpretation of the fetal heart rate (FHR) poses a challenge especially in extremely

small fetuses. However, significantly reduced and prolonged variability or unprovoked decelarations

are considered preterminal events and therefore not useful for early identification [51]. Bracero et

al [76] reported that computerised CTG (cCTG) could lead to 5 times fewerfever interventions as

compared to the routinenon-computersied CTG use . They showed that the cCTG group would need

5 times less intervention as compared to the visual CTG group (9% vs. 49%). Furthermore, although

the perinatal outcome was similar in two both groups, patients spent less time per test in the cCTG

than in the visual interpretation group. while the NICU stay was also slightly shorter in the cCTG

group than in the visual CTG group, although this wasthis difference could be attributed to chance.

There is evidence suggesting that the ability to predict fetal death is similar for predictability of the

short term variability (STV) which is evaluated by cCTG is similar to the predictability of fetal death as

suggested by late changes in DV [51]. A Cochrane database review [77] suggested that STV

correlates with acidosis and severe hypoxia, and a longitudinal study has reinforced its role as an

acute marker of acute compromise, which coincides with coinciding with abnormal DV flow

velocimtery [6].

Amniotic fluid index

Oligohydramnios is a chronic marker and has been shown to be associated with low Apgar score in a

meta-analysis of 18 RCTs [78]. There is no strong evidence relating reduced amniotic fluid index (AFI)

to acidosis [6,12] and therefore its role in the management of early onset FGR is undefineduncertain.

Monitoring and management

The aim of antenatal surveillance is to prevent fetal morbidity and mortality. However, the

frequency of monitoring and decision to deliver has always been a matter of debate,

particularlyespecially in the absence of robust researchevidence. However, the recent multicentre

TRUFFLE trial [2] has shown that clear objective assessments along with standardised antenatal

surveillance could improve perinatal outcome. However Nevertheless, in the absence of a universal

protocol and given the complexity of early onset FGR, the monitoring and decision of to delivery

should revolve around the pathogenesis and progression of early onset FGR which is distinctly

different than to that of late onset FGR. As mentioned earlier, the umbilical artery Doppler is a

crucial critical tool in the diagnosis of early onset FGR. H however, there is evidence of the

importance of abnormal DV velocimetry which plays an important role in predicting fetal academia

and death. Therefore DV velocimetry should be included as a routine tool, along with umbilical

artery Doppler analysis, during surveillance of these compromised fetuses.tool of surveillance along

with umbilical artery Doppler analysis [2,79,80]. Monitoring should commence from 24 weeks in

women screened identified as high risk during screening at booking with an early multidisciplinary

input by from the neonatal team. A useful algorithm is shown below in (Figure 2).

Planning delivery – the dilemma between birthweight centile and gestational age?

Although neonatal morbidity and mortality has significantly improved significantly in the past

decade, there is still uncertainty between choosing the birthweight centile or gestational age as a

parameter to guide the timing of delivery. In this regard the PREM scoring system [81] has shown a

positive correlation between decreasing neonatal survival with and lower birthweight centiles. The

PREM scoring system has also been recently validated [82] and it has been suggested that it

shouldmight be used in combination with the “Clinical Risk Index for babies” (CRIB) scoring system

for neonatal mortality risk adjustment [83,84]. It has been suggested that the outcome for growth

restricted neonates below 29 weeks is similar to that of neonates who are appropriately grown but

at 2 weeks earlier gestational age [85]. Timing of delivery should not only take into account not only

the neonatal survival but also the risk of ensuing morbidity such as bronchopulmonary dysplasia,

intraventricular haemorrhage, necrotising enterocolitis and cerebral palsy. Neonatal survival has

been shown to be 13% at 24 weeks, 43% at 25 weeks, up to 76% at 26 weeks and up to 90% at 30

weeks’ gestation [2,85],. wWhile the intact neonatal survival progressively increases with increasing

gestational age, as reported in the TRUFFLE study (Figures 3 and 4)[5] .

Classical Caesarean section is often indicated before 26 weeks with an estimated fetal weight of

<600g. This allows for atraumatic delivery of the baby but does commit the mother to further to

future delivery by Caesarean section at 36 weeks because of the risk of uterine scar rupture. The

risks of subfertility, infection and haemorrhage following a classical incision is almost certainly likely

to beexaggerated greater than following lower segment Caesarean section, butand very few data

exist to inform the clinician or patient.

Concluding remarks

In early onset FGR Tthe neonatal morbidity and mortality is considerably better lower than is often

assumed, in early onset FGR with over 80% of those presenting between 26-32 weeks surviving

intact at 2 years [2]. There is, however, evidence that neonates born with abnormal Doppler flow

before 30 weeks’ gestation, when matched to appropriately grown neonates that delivered at that

gestation, not only have a lower survival but also had higher rates of chronic lung disease,

retinopathy, gastrointestinal disturbances, severe motor impairment and they were further shown

to have increased cognitive impairment at school age [57,86–88]. Given the evidence suggesting that

outcomes for SGA FGR neonates are comparable to outcomes for appropriately grown neonates

born 2 weeks earlier, delivery may not be recommended earlier than 26 weeks’ gestation unless it is

directed by informed parental choice [85]. Also, given the evidence that cerebral palsy is not any

more frequent in FGR preterm infants as compared tothan it is in appropriately grown preterm

infants [87,89,90] and around 1% in early onset FGR (TRUFFLE), it underlines the importance of

allowing gestational maturity even while acknowledging the associated risk of intrauterine death,

while waiting to determine delivery the timing of delivery. This management plan gains more

credence in the light of the evidence showing a better outcome in subsequent pregnancies [91,92]

especially when treated with aspirin in early pregnancy. Although corticosteroids are recommended

between 24-34 weeks of gestation if delivery is anticipated, there is in fact no evidence of theirits

benefit in IUGR FGR infants [93]. This is supported by the evidence that IUGR FGR neonates have

significant lung problems despite showing accelerated indices of fetal lung maturation [94].

Therefore management of early onset FGR revolves around understanding its pathogenesis, evolving

phenotype with corresponding changes in Doppler velocimetries, understanding the perinatal risks

involved at delivering at various gestational ages, active involvement of the neonatal team and

taking patient choice into consideration.

Practice points

Early onset FGR and late onset FGR have different patterns of placental and maternal

cardiovascular pathologies

Umbilical artery and ductus venosus Doppler velocimetries play an important role in diagnosis

and prognosis of early onset FGR

Delivery of FGR babies at very preterm gestational ages are is associated with higher morbidity

but not significantly different risks of mortality compared to appropriately grown fetuses

Delivery in early onset fetal growth restrictionFGR should be in tertiary care centre given the high

perinatal morbidity

The trigger for delivery in early onset fetal growth restrictionFGR should be based on late ductus

venosus changes or abnormal CTG

Identification and monitoring of late onset FGR is less clearly defined however given the much

lower morbidity after 32 weeks, a lower threshold for delivery applies should any of the Doppler,

CTG or biophysical tests become abnormal

Research agenda

Determining the value of monitoring of aortic isthmus flow studies along with ductus venosus

Doppler flow studies in timing delivery

Developing methods of reliably defining lateearly onset FGR reliably

Robust prospective studies designed to establish appropriate triggers for delivery in late onset

FGR

Establishing the roles of placental and cardiovascular dysfunction in FGR

Conflicts of interest - none

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