Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Aug 31;18(1):354.
doi: 10.1186/s12884-018-1992-x.

Assessing the sensitivity of placental growth factor and soluble fms-like tyrosine kinase 1 at 36 weeks' gestation to predict small-for-gestational-age infants or late-onset preeclampsia: a prospective nested case-control study

Teresa M MacDonald  1   2   3 , Chuong Tran  4 , Tu'uhevaha J Kaitu'u-Lino  5   6 , Shaun P Brennecke  5   7 , Richard J Hiscock  5 , Lisa Hui  8   5   6 , Kirsten M Dane  8 , Anna L Middleton  8   5 , Ping Cannon  5   6 , Susan P Walker  8   5   6 , Stephen Tong  8   5   6
Affiliations

Assessing the sensitivity of placental growth factor and soluble fms-like tyrosine kinase 1 at 36 weeks' gestation to predict small-for-gestational-age infants or late-onset preeclampsia: a prospective nested case-control study

Teresa M MacDonald et al. BMC Pregnancy Childbirth. .

Abstract

Background: Fetal growth restriction is a disorder of placental dysfunction with three to four-fold increased risk of stillbirth. Fetal growth restriction has pathophysiological features in common with preeclampsia. We hypothesised that angiogenesis-related factors in maternal plasma, known to predict preeclampsia, may also detect fetal growth restriction at 36 weeks' gestation. We therefore set out to determine the diagnostic performance of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and the sFlt-1:PlGF ratio, measured at 36 weeks' gestation, in identifying women who subsequently give birth to small-for-gestational-age (SGA; birthweight <10th centile) infants. We also aimed to validate the predictive performance of the analytes for late-onset preeclampsia in a large independent, prospective cohort.

Methods: A nested 1:2 case-control study was performed including 102 cases of SGA infants and a matched group of 207 controls; and 39 cases of preeclampsia. We determined the diagnostic performance of each angiogenesis-related factor, and of their ratio, to detect SGA infants or preeclampsia, for a predetermined 10% false positive rate.

Results: Median plasma levels of PlGF at 36 weeks' gestation were significantly lower in women who subsequently had SGA newborns (178.5 pg/ml) compared to normal birthweight controls (326.7 pg/ml, p < 0.0001). sFlt-1 was also higher among SGA cases, but this was not significant after women with concurrent preeclampsia were excluded. The sensitivity of PlGF to predict SGA infants was 28.8% for a 10% false positive rate. The sFlt-1:PlGF ratio demonstrated better sensitivity for preeclampsia than either analyte alone, detecting 69.2% of cases for a 10% false positive rate.

Conclusions: Plasma PlGF at 36 weeks' gestation is significantly lower in women who subsequently deliver a SGA infant. While the sensitivity and specificity of PlGF currently limit clinical translation, our findings support a blood-based biomarker approach to detect late-onset fetal growth restriction. Thirty-six week sFlt-1:PlGF ratio predicts 69.2% of preeclampsia cases, and could be a useful screening test to triage antenatal surveillance.

Keywords: Biomarker; Fetal growth restriction; Late-onset; Placental growth factor; Preeclampsia; Small-for-gestational-age; Soluble fms-like tyrosine kinase 1.

PubMed Disclaimer

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the Mercy Health Research Ethics Committee (Ethics Approval Number R14/12) and written informed consent was obtained from all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Study profile. AGA = appropriate-for-gestational-age (customised birthweight ≥10th centile), n = number, PlGF=Placental growth Factor, sFlt-1 = soluble fms-like tyrosine kinase 1, SGA = small-for-gestational-age (customised birthweight <10th centile)
Fig. 2
Fig. 2
Levels of angiogenesis-related factors in cases of small-for-gestational-age (SGA) fetuses compared to controls. a. soluble fms-like tyrosine kinase-1 (sFlt-1) levels in ‘All SGA’ cases and controls; b. sFlt-1 levels in ‘SGA only’ (excluding concurrent preeclampsia) cases and controls; c. Placental growth factor (PlGF) levels in ‘All SGA’ cases and controls; d. PlGF levels in ‘SGA only’ cases and controls; e. sFlt-1:PlGF ratios in ‘All SGA’ cases and controls; f. sFlt-1:PlGF ratios in ‘SGA only’ cases and controls. Medians and interquartile ranges shown. * = P < 0.05, *** = P < 0.001, **** = P < 0.0001
Fig. 3
Fig. 3
Levels of angiogenesis-related factors in cases of preeclampsia compared to controls. a. soluble fms-like tyrosine kinase-1 (sFlt-1) levels in preeclampsia cases and controls; b. Placental growth factor (PlGF) levels in preeclampsia cases and controls; c. sFlt-1:PlGF ratios in preeclampsia cases and controls. Medians and interquartile ranges shown. **** = P < 0.0001
Fig. 4
Fig. 4
Receiver operating characteristic curves for most sensitive analytes to detect small-for-gestational-age (SGA) infants, or preeclampsia. a. ROC curve for the performance of placental growth factor (PlGF) in detecting ‘All SGA’ – including cases of concurrent preeclampsia; b. ROC curve for the performance of PlGF in detecting ‘SGA only’ – excluding cases of concurrent preeclampsia; c. ROC curve for the performance of the soluble fms-like tyrosine kinase 1:PlGF ratio in detecting preeclampsia
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Flenady V, Koopmans L, Middleton P, Froen JF, Smith GC, Gibbons K, Coory M, Gordon A, Ellwood D, McIntyre HD, et al. Major risk factors for stillbirth in high-income countries: a systematic review and meta-analysis. Lancet. 2011;377:1331–1340. doi: 10.1016/S0140-6736(10)62233-7. - DOI - PubMed
    1. Gardosi J, Madurasinghe V, Williams M, Malik A, Francis A. Maternal and fetal risk factors for stillbirth: population based study. BMJ. 2013;346:f108. doi: 10.1136/bmj.f108. - DOI - PMC - PubMed
    1. Vashevnik S, Walker S, Permezel M. Stillbirths and neonatal deaths in appropriate, small and large birthweight for gestational age fetuses. Aust N Z J Obstet Gynaecol. 2007;47:302–306. doi: 10.1111/j.1479-828X.2007.00742.x. - DOI - PubMed
    1. Mendez-Figueroa H, Truong VT, Pedroza C, Khan AM, Chauhan SP. Small-for-gestational-age infants among uncomplicated pregnancies at term: a secondary analysis of 9 maternal-fetal medicine units network studies. Am J Obstet Gynecol. 2016;215:628.e621–628.e627. doi: 10.1016/j.ajog.2016.06.043. - DOI - PubMed
    1. Pattinson R, Kerber K, Buchmann E, Friberg IK, Belizan M, Lansky S, Weissman E, Mathai M, Rudan I, Walker N, Lawn JE. Stillbirths: how can health systems deliver for mothers and babies? Lancet. 2011;377:1610–1623. doi: 10.1016/S0140-6736(10)62306-9. - DOI - PubMed

Substances