DRIGITAT: Doppler Ratio In fetal Growth restriction Intervention Trial At (near) Term

Fetal Growth Restriction (FGR) is often defined as small for gestational age
(SGA), a definition based on size, usually the 10th percentile on growth
centiles, and thus affects 10% of all fetuses. Among SGA fetuses is a
considerable group of fetuses that is constitutionally small and healthy and
among the appropriate for gestational age (AGA) fetuses is a group of fetuses
that are growth restricted despite a *normal* weight. The pathophysiological
mechanism in FGR is uteroplacental insufficiency that leads to failure of the
placental exchange unit to serve the fetal needs. When the growth restricted
fetus remains undelivered the insufficiency progresses and the prolonged
placental restraints put the fetus at risk for fetal demise.Also, whilst
remaining in utero, permanent alterations in fetal physiology increases the
fetus* chances of disease in adulthood. On the other hand, when delivered
timely, usually in the late preterm period, the baby is at risk for neonatal
transitional disease and gross morbidity.

Because of the diagnostic substitution of SGA with FGR, the effect of any
approach is diluted by the inability to identify fetuses with true placental
growth restriction and identify the fetuses that may benefit from timely
interventions by avoiding fetal risks that surpass the neonatal disadvantages.
A major challenge is to find the FGR fetus in the SGA group.

Functional parameters, such as Doppler ultrasound and serum biomarkers can help
distinguish the FGR fetuses from healthy SGA fetuses. Redistribution of the
fetal circulation, signalled by an increased umbilicocerebral ratio (UCR)
caused by a decrease in resistance in the middle cerebral artery (MCA,
reflecting cerebral flow) and an increased resistance in the umbilical artery
(UmbA reflecting placental flow) is an adaptation to scarcity with long-term
adverse consequences in survivors. Serum biomarkers, including sFlt and PlGF,
have received attention as markers for placental function, as they have
considerable association with relevant outcomes. This also holds true for the
clear associations of late prematurity and significant adverse
neurodevelopmental outcomes. Even in the absence of severe neonatal morbidity,
uncommon in late prematurity, there are significant effects from gestational
age. These may be related to a simple effect from gestational age, but are more
likely due to the underlying reason for premature delivery.

The dilemma is obvious: previous studies clearly show diagnostic accuracy,
resulting in many (doctors) to believe in an *obvious* effective test-treatment
combination in SGA fetuses. Intuitively, physicians balance the effect on
outcomes from cohort evidence of associations of the diagnostic tools with the
cohort evidence of the effect of gestational age. This leads to practice
variation due to different perceptions of risk. However, prospective
comparative evidence is lacking. There is international consensus that a RCT on
intervention on abnormal UCR is now opportune, and that serum biomarkers should
be further investigated for their potential added value in guiding timing of
delivery. This study is embedded in an international initiative.

For references, see chapter 1 of the study protocol.

Does, in late preterm fetuses identified as small-for-gestational-age (SGA),
timing of delivery based on abnormal umbilicocerebral ratio (UCR) improve
neurodevelopmental outcome?

Cohort of women with identified SGA pregnancies (EFW/FAC < p10) with a nested
RCT in fetuses with abnormal UCR (> 0.8)

Delivery at 36 weeks when UCR is abnormal and fetal growth is mildly abnormal
(EFW/FAC p3-p10) and delivery at 34 weeks when UCR is abnormal and fetal growth
is severely abnormal (EFW/FAC below p3).

Patients participating in the cohort and in the non-interventional arm of the
RCT do not incur additional risks compared to patients not participating in
this study. They receive standard care and follow-up according to local
protocol. The additional study-related procedures patients undergo in these
groups (blood sampling, fill out questionnaires) do not oppose additional risks
and the burden of these procedures are considered minimal.
In case of an abnormal UCR, patients could be randomized for timely delivery.
In previously conducted cohort studies the relevance (diagnostic accuracy) of
abnormal UCR has been signalled extensively and there is general consensus that
an abnormal UCR is a signal of FGR with strong association with poor outcomes:
stillbirth, inability to withstand uterine contractions, neonatal morbidity and
long-term neurodevelopmental
delay.[5-9] Patients in the interventional arm of the RCT are therefor likely
to have a benefit from early delivery with less exposure to the placental
insufficiency.