Diagnostic accuracy of placental growth factor and ultrasound parameters to predict the small-for-gestational-age infant in women presenting with reduced symphysis–fundus height M. Griffin, P. T. Seed, L. Webster, J. Myers, L. MacKillop, N. Simpson, D. Anumba, A. Khalil, M. Denbow, A. Sau, K. Hinshaw, P. von Dadelszen, S. Benton, J. Girling, C. W. G. Redman, L. C. Chappell and A. H. Shennan Volume 46, Issue 2, pages 182–190, August 2015 Link to free-access article: http://onlinelibrary.wiley.com/doi/10.1002/uog.14860/full

1. UOG Journal Club: August 2015
Diagnostic accuracy of placental growth factor and
ultrasound parameters to predict the small-for-gestational-
age infant in women presenting with reduced symphysis–
fundus height
M Griffin, PT Seed, L Webster, J Myers, L Mackillop, N Simpson, D Anumba, A Khalil, M Denbow, A
Sau, K Hinshaw, P Von Dadelszen, S Benton, J Girling, CWG Redman, LC Chappell and AH Shennan
Volume 46, Issue 2, Date: August (pages 182–190)
Journal Club slides prepared by Dr Shireen Meher
(UOG Editor for Trainees)

2. Introduction
• Identifying small-for-gestational-age (SGA) infants is challenging in the low-risk
population, as it relies on imprecise techniques such as symphysis–fundus
height (SFH) measurement.
• UK guidelines do not advocate routine ultrasound in the third trimester as a
screening tool for SGA because of poor predictive value (sensitivity, 38–51%)
and no evidence of improved neonatal outcome.
• As placental insufficiency is causative in many cases of growth restriction,
markers of placental function could provide adjuncts to currently used methods.
• Previous studies have shown that low levels of maternal serum placental
growth factor (PlGF) can distinguish placental SGA from constitutionally small
fetuses.
PlGF to predict SGA
Griffin et al., UOG 2015

3. Aim of the study
PlGF to predict SGA
Griffin et al., UOG 2015
To assess the diagnostic accuracy of PlGF levels and
ultrasound parameters to predict delivery of a small-for-
gestational-age infant in women presenting with reduced
symphysis–fundus height.

4. • Study design: multicenter prospective observational study
• Setting: 11 sites in the UK and Canada, from December 2011 to July 2013
• Participants
• Inclusion criteria:
• women ≥ 16 years of age
• singleton pregnancy between 24+0 and 36+6 weeks’ gestation
• reduced SFH (>2cm or <10th centile on customized SFH charts)
• Excluded: confirmed SGA or rupture of membranes, major fetal anomaly
• Intervention: plasma PlGF concentration and ultrasound scan
Methods
PlGF to predict SGA
Griffin et al., UOG 2015

5. • Outcome:
Diagnostic accuracy of the following (in isolation and combination)
• Low plasma PlGF < 5th centile
• Estimated fetal weight (EFW) < 10th centile
• Umbilical artery Doppler pulsatility index (UA-PI) > 95th centile
• Oligohydramnios (AFI < 5cm)
To predict
• Primary outcome: delivery of SGA infant < 3rd customized birth-weight
centile
• Secondary outcomes: SGA < 10th customized birth-weight centile
and adverse perinatal outcomes
PlGF to predict SGA
Griffin et al., UOG 2015
Methods

6. • Blinding of laboratory staff to clinical diagnosis and clinical staff to PlGF levels
• Sample size: 55 cases needed for 90% power at 5% significance to
distinguish reliably good (80%) from moderate (60%) sensitivity: met for all
endpoints by recruiting 601 women (78 SGA babies)
• Statistical analysis: sensitivity, specificity, PPV, NPV, ROC curves, Fisher’s
exact test to evaluate event rate (STATA statistical package)
• Reporting as per STARD guidelines
PlGF to predict SGA
Griffin et al., UOG 2015
Methods

7. Results
PlGF to predict SGA
Griffin et al., UOG 2015
• 601 women
recruited, complete
data available for
592 women
• 78 SGA infants
with birth weight
<3rd customized
centile
• 192 SGA infant with
birth weight <10th
customized centile

8. Results
PlGF to predict SGA
Griffin et al., UOG 2015
• EFW had the highest sensitivity (58%) and NPV (93%) among parameters
assessed alone for determining SGA <3rd centile.
• Low PlGF alone had a sensitivity of 37% and NPV of 90%.
• Addition of PlGF to EFW increased the sensitivity from 58% to 69% in
determining SGA <3rd centile (NPV unchanged at 93%) and from 47% to
57% in determining SGA <10th centile (NPV increased from 77% to 78%).
• For women with EFW ≥10th centile, low PlGF at the time of scanning would
have detected an additional nine women with subsequent SGA <3rd centile.
• The difference in SGA <3rd centile between those with normal PlGF (5.9%)
compared with those with low PlGF (20.5%) is significant (P=0.002).

9. Results: Prediction of SGA <3rd centile
PlGF to predict SGA
Griffin et al., UOG 2015
Biomarker/test Sensitivity
(% (95% CI))
Specificity
(% (95% CI))
PPV
(% (95% CI))
NPV
(% (95% CI))
EFW <10th centile 57.9 (46.0–69.1) 78.8 (75.0–82.3) 28.9 (21.9–36.8) 92.6 (89.8–94.9)
AFI <5cm 3.7 (0.5–12.7) 99.0 (97.0–99.8) 40.0 (5.3–85.3) 84.8 (80.5–88.4)
UA-PI >95th
centile
16.4 (8.2–28.1) 96.0 (93.5–97.7) 38.5 (20.2–59.4) 88.2 (84.8–91.1)
PlGF <5th centile 37.2 (26.5–48.9) 88.7 (85.7–91.3) 33.3 (23.6–44.3) 90.3 (87.4–92.7)
Abnormal AFI or
EFW
57.7 (43.2–71.3) 79.0 (73.9–83.6) 33.0 (23.5–43.6) 91.3 (87.1–94.4)
Abnormal PlGF
or AFI or EFW
69.2 (54.9–81.3) 72.2 (66.6–77.2) 30.8 (22.6–40.0) 92.9 (88.8–95.9)

10. Results: Prediction of SGA <10 centile
PlGF to predict SGA
Griffin et al., UOG 2015
Biomarker/Test Sensitivity
(% (95% CI))
Specificity
(% (95% CI))
PPV
(% (95% CI))
NPV
(% (95% CI))
EFW <10th centile 47.1 (39.7–54.5) 84.0 (80.0–87.4) 57.9 (49.6–65.8) 77.2 (72.9–81.1)
AFI <5 cm 3.4 (0.9–8.5) 99.6 (97.6–100) 80.0 (28.4–99.5) 66.6 (61.3–71.6)
UA-PI >95th centile 8.2 (4.3–13.8) 95.5 (92.6–97.5) 46.2 (26.6–66.6) 68.8 (64.1–73.1)
PlGF <5th centile 24.5 (18.6–31.2) 90.0 (86.6–92.8) 54.0 (43.0–64.8) 71.3 (67.1–75.2)
Abnormal AFI or
EFW
48.7 (39.3–58.2) 84.6 (79.3–89.1) 61.5 (50.8– 71.6) 76.6 (70.9–81.7)
Abnormal PlGF or
AFI or EFW
57.4 (47.8–66.6) 77.6 (71.7–82.9) 56.4 (46.9–65.6) 78.3 (72.4–83.5)

11. Results: Perinatal outcomes
• 94% (555/592) of women recruited had no maternal complications in
pregnancy and only 4% (24/592) had a new hypertensive disorder.
• Adverse perinatal outcome in 2.2% (13 cases)
– one stillbirth (not SGA and normal PlGF)
– four cases of respiratory distress syndrome
– nine infants admitted to neonatal intensive care unit for >48 hours
• Adverse maternal outcome in 3.2%
• Maternal and perinatal complications were higher in pregnancies with
SGA infants (4.7% and 3.1% compared with 2.5% and 1.8%, respectively)
PlGF to predict SGA
Griffin et al., UOG 2015

12. • Ultrasound parameters utilized currently, including EFW <10th centile, had
modest test performance for predicting delivery of an SGA infant.
• Maternal PlGF measurement performed no better than the ultrasound
parameters and provided only minimal increment in overall test performance
when used in combination.
• PlGF appears to have limited clinical utility in women presenting with reduced
SFH late in pregnancy and delivering near term. Findings from this study do
not support the use of PlGF to screen for SGA infants in women with reduced
SFH.
Discussion
PlGF to predict SGA
Griffin et al., UOG 2015

13. • Strengths
– Largest reported prospective study evaluating ability of third-trimester PlGF to predict
delivery of an SGA infant in women presenting with reduced SFH
– Diverse ethnic and geographical population
– Blinding of clinicians to PlGF results
– Clinically relevant inclusion criteria of SFH difference >2 cm
– EFW <3rd centile less likely to identify constitutionally small babies
• Limitations
– Conclusions regarding ability of PlGF to determine adverse outcomes are not
possible from this study as adverse perinatal outcome occurred infrequently (2.2%).
– A single PlGF measurement was taken at study enrolment: serial measurements to
assess whether longitudinal changes correlate with evolving placental dysfunction
could be informative.
Discussion
PlGF to predict SGA
Griffin et al., UOG 2015

14. • Studies with findings similar to current study
– Conde-Agudelo 2013: systematic review of biomarkers to predict FGR found PlGF to
have a sensitivity of 49% (95% CI, 44–53%; 13 studies) for detection of SGA
– Persson 1986: large study on SFH showed sensitivity of 27% to detect SGA
– Studies of EFW <10th centile show sensitivity of 21-46% with NPV 90-94% for SGA
– Morris 2014: strong correlation between oligohydramnios and SGA<10th centile but poor
predictive accuracy of oligohydramnios for perinatal outcome
• Studies with findings different to current study
– Chappell 2013
• PlGF had high sensitivity (93%) and NPV (96%) for predicting SGA in women
presenting <35 weeks with suspected pre-eclampsia
• Differences may be due to
– different population (61% developed pre-eclampsia; 19% had adverse
perinatal outcome)
– differences in underlying etiology of SGA in current study
Discussion
PlGF to predict SGA
Griffin et al., UOG 2015

15. Discussion points
• There is a need for caution when generalizing findings from one
population to another, and a need for appropriate evaluation of novel
biomarkers before adopting them into practice.
• Should third-trimester ultrasound scan be offered to low risk women as
a screening tool for detection of SGA infants?
• Further studies are needed to explore strategies for identifying SGA
fetuses in low risk pregnancies in the third trimester.
Future perspectives
PlGF to predict SGA
Griffin et al., UOG 2015