<div class="section">
<a class="named-anchor" id="d6146660e191">
<!--
named anchor
-->
</a>
<h5 class="section-title" id="d6146660e192">Background</h5>
<p id="d6146660e194">Fetal growth restriction is a major determinant of perinatal
morbidity and mortality.
This condition has no gold standard definition, but a widely used proxy is delivery
of a small for gestational age infant (<10th percentile) combined with an adverse
pregnancy outcome. Effective screening for fetal growth restriction is an area of
unmet clinical need. We aimed to determine the diagnostic effectiveness of a combination
of ultrasonic fetal biometry and measurement of the ratio of soluble fms-like tyrosine
kinase receptor 1 (sFLT1) to placental growth factor (PlGF) in predicting adverse
pregnancy outcomes associated with delivery of a small for gestational age infant.
</p>
</div><div class="section">
<a class="named-anchor" id="d6146660e196">
<!--
named anchor
-->
</a>
<h5 class="section-title" id="d6146660e197">Methods</h5>
<p id="d6146660e199">In this prospective cohort study, using serial antenatal blood
sampling and blinded
ultrasound scans, we investigated the association between the combination of an elevated
sFLT1/PlGF ratio (>85th percentile) and ultrasonically suspected small for gestational
age (<10th percentile) at both 28 and 36 weeks of gestational age. The outcome
following
the 28 week measurement was preterm delivery of a small for gestational age infant.
The outcome following the 36 week measurement was subsequent delivery of a small for
gestational infant associated with maternal pre-eclampsia or perinatal morbidity or
mortality. All definitions of exposure and outcome were predefined before we did our
data analysis.
</p>
</div><div class="section">
<a class="named-anchor" id="d6146660e201">
<!--
named anchor
-->
</a>
<h5 class="section-title" id="d6146660e202">Findings</h5>
<p id="d6146660e204">Between Jan 14, 2008, and July 31, 2012, we recruited 4512 nulliparous
women. 4098
women (91%) had a sFLT1/PlGF ratio measurement and estimated fetal weight at 28 or
36 weeks of gestational age, and outcome data available. 3981 women were analysed
for 28 weeks of gestational age measurements and 3747 women were analysed for 36 weeks
of gestational age measurements. At 28 weeks, 47 (1%) of 3981 women had the combination
of ultrasonic small for gestational age and an elevated sFLT1/PlGF ratio. The positive
likelihood ratio for preterm delivery of a small for gestational age infant associated
with this combination was 41·1 (95% CI 23·0–73·6), the sensitivity was 38·5% (21·1–59·3),
the specificity was 99·1% (98·7–99·3), and the positive predictive value was 21·3%
(11·6–35·8). At 36 weeks, 102 (3%) of 3747 women had the combination of ultrasonic
small for gestational age and an elevated sFLT1/PlGF ratio. The positive likelihood
ratio for delivery of a small for gestational age infant associated with maternal
pre-eclampsia or perinatal morbidity or mortality was 17·5 (95% CI 11·8–25·9), the
sensitivity was 37·9% (26·1–51·4), the specificity was 97·8% (97·3–98·3), and the
positive predictive value was 21·6% (14·5–30·8). The positive likelihood ratios at
both gestational ages were higher than previously described definitions of suspected
fetal growth restriction using purely ultrasonic assessment.
</p>
</div><div class="section">
<a class="named-anchor" id="d6146660e206">
<!--
named anchor
-->
</a>
<h5 class="section-title" id="d6146660e207">Interpretation</h5>
<p id="d6146660e209">The combination of ultrasonically suspected small for gestational
age plus an elevated
sFLT1/PlGF ratio in unselected nulliparous women identified a relatively small proportion
of women who have high absolute risks of clinically important adverse outcomes. Screening
and intervention based on this approach could result in net benefit and this could
be an appropriate subject for a randomised controlled trial.
</p>
</div><div class="section">
<a class="named-anchor" id="d6146660e211">
<!--
named anchor
-->
</a>
<h5 class="section-title" id="d6146660e212">Funding</h5>
<p id="d6146660e214">NIHR Cambridge Comprehensive Biomedical Research Centre, Medical
Research Council,
and Stillbirth and neonatal death society (Sands).
</p>
</div>