Diagnostic utility of serial circulating placental growth factor levels and uterine artery Doppler waveforms in diagnosing underlying placental diseases in pregnancies at high risk of placental dysfunction


      Placental pathology assessment following delivery in pregnancies complicated by preeclampsia, fetal growth restriction, abruption, and stillbirth reveals a range of underlying diseases. The most common pathology is maternal vascular malperfusion, characterized by high-resistance uterine artery Doppler waveforms and abnormal expression of circulating maternal angiogenic growth factors. Rare placental diseases (massive perivillous fibrinoid deposition and chronic histiocytic intervillositis) are reported to have high recurrence risks, but their associations with uterine artery Doppler waveforms and angiogenic growth factors are presently ill-defined.


      To characterize the patterns of serial placental growth factor measurements and uterine artery Doppler waveform assessments in pregnancies that develop specific types of placental pathology to gain insight into their relationships with the timing of disease onset and pregnancy outcomes.

      Study Design

      A retrospective cohort study conducted between January 2017 and November 2021 included all singleton pregnancies with at least 1 measurement of maternal circulating placental growth factor between 16 and 36 weeks’ gestation, delivery at our institution, and placental pathology analysis demonstrating diagnostic features of maternal vascular malperfusion, fetal vascular malperfusion, villitis of unknown etiology, chronic histiocytic intervillositis, or massive perivillous fibrinoid deposition. Profiles of circulating placental growth factor as gestational age advanced were compared between these placental pathologies. Maternal and perinatal outcomes were recorded.


      A total of 337 pregnancies from 329 individuals met our inclusion criteria. These comprised placental pathology diagnoses of maternal vascular malperfusion (n=109), fetal vascular malperfusion (n=87), villitis of unknown etiology (n=96), chronic histiocytic intervillositis (n=16), and massive perivillous fibrinoid deposition (n=29). Among patients who developed maternal vascular malperfusion, placental growth factor levels gradually declined as pregnancy progressed (placental growth factor <10th percentile at 16–20 weeks’ gestation in 42.9%; 20–24 weeks in 61.9%; 24–28 weeks in 77%; and 28–32 weeks in 81.4%) accompanied by mean uterine artery Doppler pulsatility index >95th percentile in 71.6% cases. Patients who developed either fetal vascular malperfusion or villitis of unknown etiology mostly exhibited normal circulating placental growth factor values in association with normal uterine artery Doppler waveforms (mean [standard deviation] pulsatility index values: fetal vascular malperfusion, 1.14 [0.49]; villitis of unknown etiology, 1.13 [0.45]). Patients who developed either chronic histiocytic intervillositis or massive perivillous fibrinoid deposition exhibited persistently low placental growth factor levels from the early second trimester (placental growth factor <10th centile at 16–20 weeks’ gestation in 80% and 77.8%, respectively; 20–24 weeks in 88.9% and 63.6%; 24–28 weeks in 85.7% and 75%), all in combination with normal uterine artery Doppler waveforms (mean pulsatility index >95th centile: chronic histiocytic intervillositis, 25%; massive perivillous fibrinoid deposition, 37.9%). Preeclampsia developed in 83 of 337 (24.6%) patients and was most common in those developing maternal vascular malperfusion (54/109, 49.5%) followed by chronic histiocytic intervillositis (7/16, 43.8%). There were 29 stillbirths in the cohort (maternal vascular malperfusion, n=10 [9.2%]; fetal vascular malperfusion, n=5 [5.7%]; villitis of unknown etiology, n=1 [1.0%]; chronic histiocytic intervillositis, n=7 [43.8%]; massive perivillous fibrinoid deposition, n=6 [20.7%]). Most patients experiencing stillbirth exhibited normal uterine artery Doppler waveforms (21/29, 72.4%) and had nonmaternal vascular malperfusion pathologies (19/29, 65.5%). By contrast, 28 of 29 (96.5%) patients experiencing stillbirth had ≥1 low placental growth factor values before fetal death.


      Serial circulating maternal placental growth factor tests, in combination with uterine artery Doppler waveform assessments in the second trimester, may indicate the likely underlying type of placental pathology mediating severe adverse perinatal events. This approach has the potential to test disease-specific therapeutic strategies to improve clinical outcomes. Serial placental growth factor testing, compared with uterine artery Doppler studies, identifies a greater proportion of patients destined to have a poor perinatal outcome because diseases other than maternal vascular malperfusion are characterized by normal uteroplacental circulation.

      Key words

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        • Brosens I.
        • Pijnenborg R.
        • Vercruysse L.
        • Romero R.
        The “Great Obstetrical Syndromes” are associated with disorders of deep placentation.
        Am J Obstet Gynecol. 2011; 204: 193-201
        • Robson S.C.
        • Simpson H.
        • Ball E.
        • Lyall F.
        • Bulmer J.N.
        Punch biopsy of the human placental bed.
        Am J Obstet Gynecol. 2002; 187: 1349-1355
        • Zur R.L.
        • Kingdom J.C.
        • Parks W.T.
        • Hobson S.R.
        The placental basis of fetal growth restriction.
        Obstet Gynecol Clin North Am. 2020; 47: 81-98
        • Ho A.E.P.
        • Hutter J.
        • Jackson L.H.
        • et al.
        T2∗ placental magnetic resonance imaging in preterm preeclampsia: an observational cohort study.
        Hypertension. 2020; 75: 1523-1531
        • McLaughlin K.
        • Hobson S.R.
        • Chandran A.R.
        • et al.
        Circulating maternal placental growth factor responses to low-molecular-weight heparin in pregnant patients at risk of placental dysfunction.
        Am J Obstet Gynecol. 2022; 226: S1145-S1156.e1
        • Chappell L.C.
        • Duckworth S.
        • Seed P.T.
        • et al.
        Diagnostic accuracy of placental growth factor in women with suspected preeclampsia: a prospective multicenter study.
        Circulation. 2013; 128: 2121-2131
        • Agrawal S.
        • Shinar S.
        • Cerdeira A.S.
        • Redman C.
        • Vatish M.
        Predictive performance of PlGF (placental growth factor) for screening preeclampsia in asymptomatic women: a systematic review and meta-analysis.
        Hypertension. 2019; 74: 1124-1135
        • Korzeniewski S.J.
        • Romero R.
        • Chaiworapongsa T.
        • et al.
        Maternal plasma angiogenic index-1 (placental growth factor/soluble vascular endothelial growth factor receptor-1) is a biomarker for the burden of placental lesions consistent with uteroplacental underperfusion: a longitudinal case-cohort study.
        Am J Obstet Gynecol. 2016; 214: 629.e1-629.e17
        • McLaughlin K.
        • Snelgrove J.W.
        • Audette M.C.
        • et al.
        PlGF (placental growth factor) testing in clinical practice: evidence from a Canadian tertiary maternity referral center.
        Hypertension. 2021; 77: 2057-2065
        • Benton S.J.
        • McCowan L.M.
        • Heazell A.E.
        • et al.
        Placental growth factor as a marker of fetal growth restriction caused by placental dysfunction.
        Placenta. 2016; 42: 1-8
        • Levytska K.
        • Higgins M.
        • Keating S.
        • et al.
        Placental pathology in relation to uterine artery Doppler findings in pregnancies with severe intrauterine growth restriction and abnormal umbilical artery Doppler changes.
        Am J Perinatol. 2017; 34: 451-457
        • Kingdom J.C.
        • Audette M.C.
        • Hobson S.R.
        • Windrim R.C.
        • Morgen E.
        A placenta clinic approach to the diagnosis and management of fetal growth restriction.
        Am J Obstet Gynecol. 2018; 218: S803-S817
        • Espinoza J.
        • Romero R.
        • Nien J.K.
        • et al.
        Identification of patients at risk for early onset and/or severe preeclampsia with the use of uterine artery Doppler velocimetry and placental growth factor.
        Am J Obstet Gynecol. 2007; 196: 326.e1-326.e13
        • Myers J.E.
        • Kenny L.C.
        • McCowan L.M.
        • et al.
        Angiogenic factors combined with clinical risk factors to predict preterm pre-eclampsia in nulliparous women: a predictive test accuracy study.
        BJOG. 2013; 120: 1215-1223
        • Rolnik D.L.
        • Wright D.
        • Poon L.C.
        • et al.
        Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia.
        N Engl J Med. 2017; 377: 613-622
        • Falco M.L.
        • Sivanathan J.
        • Laoreti A.
        • Thilaganathan B.
        • Khalil A.
        Placental histopathology associated with pre-eclampsia: systematic review and meta-analysis.
        Ultrasound Obstet Gynecol. 2017; 50: 295-301
        • Aviram A.
        • Giltvedt M.K.
        • Sherman C.
        • et al.
        The role of placental malperfusion in the pathogenesis of preeclampsia in dichorionic twin and singleton pregnancies.
        Placenta. 2018; 70: 41-49
        • Khong T.Y.
        • Sebire N.J.
        • Heazell A.E.P.
        • et al.
        Research priority setting partnership for placental pathology.
        Placenta. 2022; 117: 154-155
        • Redline R.W.
        Classification of placental lesions.
        Am J Obstet Gynecol. 2015; 213: S21-S28
        • Marchaudon V.
        • Devisme L.
        • Petit S.
        • Ansart-Franquet H.
        • Vaast P.
        • Subtil D.
        Chronic histiocytic intervillositis of unknown etiology: clinical features in a consecutive series of 69 cases.
        Placenta. 2011; 32: 140-145
        • Homatter C.
        • Stichelbout M.
        • Devisme L.
        • et al.
        Is chronic histiocytic intervillositis a severe placental disease? A case-control study.
        Placenta. 2020; 91: 31-36
        • Koby L.
        • Keating S.
        • Malinowski A.K.
        • D’Souza R.
        Chronic histiocytic intervillositis – clinical, biochemical and radiological findings: an observational study.
        Placenta. 2018; 64: 1-6
        • Chaiworapongsa T.
        • Romero R.
        • Korzeniewski S.J.
        • et al.
        Pravastatin to prevent recurrent fetal death in massive perivillous fibrin deposition of the placenta (MPFD).
        J Matern Fetal Neonatal Med. 2016; 29: 855-862
        • Brady C.A.
        • Williams C.
        • Batra G.
        • et al.
        Immunomodulatory therapy reduces the severity of placental lesions in chronic histiocytic intervillositis.
        Front Med (Lausanne). 2021; 8753220
        • Bhide A.
        • Acharya G.
        • Baschat A.
        • et al.
        ISUOG Practice Guidelines (updated): use of Doppler velocimetry in obstetrics.
        Ultrasound Obstet Gynecol. 2021; 58: 331-339
        • Lees C.C.
        • Romero R.
        • Stampalija T.
        • et al.
        Clinical Opinion: the diagnosis and management of suspected fetal growth restriction: an evidence-based approach.
        Am J Obstet Gynecol. 2022; 226: 366-378
        • Gómez O.
        • Figueras F.
        • Fernández S.
        • et al.
        Reference ranges for uterine artery mean pulsatility index at 11-41 weeks of gestation.
        Ultrasound Obstet Gynecol. 2008; 32: 128-132
      1. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy.
        Obstet Gynecol. 2013; 122: 1122-1131
        • Kramer M.S.
        • Platt R.W.
        • Wen S.W.
        • et al.
        A new and improved population-based Canadian reference for birth weight for gestational age.
        Pediatrics. 2001; 108: E35
        • Khong T.Y.
        • Mooney E.E.
        • Ariel I.
        • et al.
        Sampling and definitions of placental lesions: Amsterdam placental workshop group consensus statement.
        Arch Pathol Lab Med. 2016; 140: 698-713
        • Redline R.W.
        • Vik T.
        • Heerema-McKenney A.
        • et al.
        Interobserver reliability for identifying specific patterns of placental injury as defined by the Amsterdam classification.
        Arch Pathol Lab Med. 2022; 146: 372-378
        • Levy M.
        • Alberti D.
        • Kovo M.
        • et al.
        Placental pathology in pregnancies complicated by fetal growth restriction: recurrence vs. new onset.
        Arch Gynecol Obstet. 2020; 301: 1397-1404
        • Levy M.
        • Kovo M.
        • Schreiber L.
        • et al.
        Pregnancy outcomes in correlation with placental histopathology in subsequent pregnancies complicated by preeclampsia.
        Preg Hypertens. 2019; 18: 163-168
        • Adam-Darque A.
        • Grouiller F.
        • Vasung L.
        • et al.
        fMRI-based neuronal response to new odorants in the newborn brain.
        Cereb Cortex. 2018; 28: 2901-2907
        • Society for Maternal-Fetal Medicine (SMFM)
        Electronic address: [email protected], Martins JG, Biggio JR, Abuhamad A. Society for Maternal-Fetal Medicine Consult Series #52: diagnosis and management of fetal growth restriction: (replaces Clinical Guideline Number 3, April 2012).
        Am J Obstet Gynecol. 2020; 223: B2-B17
        • Parry S.
        • Sciscione A.
        • Haas D.M.
        • et al.
        Role of early second-trimester uterine artery Doppler screening to predict small-for-gestational-age babies in nulliparous women.
        Am J Obstet Gynecol. 2017; 217: 594.e1-594.e10
        • Lees C.C.
        • Stampalija T.
        • Baschat A.
        • et al.
        ISUOG Practice Guidelines: diagnosis and management of small-for-gestational-age fetus and fetal growth restriction.
        Ultrasound Obstet Gynecol. 2020; 56: 298-312
        • Erez O.
        • Romero R.
        • Jung E.
        • et al.
        Preeclampsia and eclampsia: the conceptual evolution of a syndrome.
        Am J Obstet Gynecol. 2022; 226: S786-S803
        • Zeisler H.
        • Llurba E.
        • Chantraine F.
        • et al.
        Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia.
        N Engl J Med. 2016; 374: 13-22
        • Rana S.
        • Powe C.E.
        • Salahuddin S.
        • et al.
        Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia.
        Circulation. 2012; 125: 911-919
        • Lim S.
        • Li W.
        • Kemper J.
        • Nguyen A.
        • Mol B.W.
        • Reddy M.
        Biomarkers and the prediction of adverse outcomes in preeclampsia: a systematic review and meta-analysis.
        Obstet Gynecol. 2021; 137: 72-81
        • Agrawal S.
        • Cerdeira A.S.
        • Redman C.
        • Vatish M.
        Meta-analysis and systematic review to assess the role of soluble FMS-like tyrosine kinase-1 and placenta growth factor ratio in prediction of preeclampsia: the SaPPPhirE study.
        Hypertension. 2018; 71: 306-316
        • Sovio U.
        • Goulding N.
        • McBride N.
        • et al.
        A maternal serum metabolite ratio predicts fetal growth restriction at term.
        Nat Med. 2020; 26: 348-353
        • Benton S.J.
        • Hu Y.
        • Xie F.
        • et al.
        Can placental growth factor in maternal circulation identify fetuses with placental intrauterine growth restriction?.
        Am J Obstet Gynecol. 2012; 206: 163.e1-163.e7
        • Anderson N.
        • De Laat M.
        • Benton S.
        • von Dadelszen P.
        • McCowan L.
        Placental growth factor as an indicator of fetal growth restriction in late-onset small-for-gestational age pregnancies.
        Aust N Z J Obstet Gynaecol. 2019; 59: 89-95
        • Stepan H.
        • Hund M.
        • Andraczek T.
        Combining biomarkers to predict pregnancy complications and redefine preeclampsia: the angiogenic-placental syndrome.
        Hypertension. 2020; 75: 918-926
        • Whitten A.E.
        • Romero R.
        • Korzeniewski S.J.
        • et al.
        Evidence of an imbalance of angiogenic/antiangiogenic factors in massive perivillous fibrin deposition (maternal floor infarction): a placental lesion associated with recurrent miscarriage and fetal death.
        Am J Obstet Gynecol. 2013; 208: 310.e1-310.e11
        • Audette M.C.
        • McLaughlin K.
        • Kingdom J.C.
        Second trimester placental growth factor levels and placental histopathology in low-risk nulliparous pregnancies.
        J Obstet Gynaecol Can. 2021; 43: 1145-1152.e1
        • O’Brien M.
        • Baczyk D.
        • Kingdom J.C.
        Endothelial dysfunction in severe preeclampsia is mediated by soluble factors, rather than extracellular vesicles.
        Sci Rep. 2017; 7: 5887
        • Taché V.
        • LaCoursiere D.Y.
        • Saleemuddin A.
        • Parast M.M.
        Placental expression of vascular endothelial growth factor receptor-1/soluble vascular endothelial growth factor receptor-1 correlates with severity of clinical preeclampsia and villous hypermaturity.
        Hum Pathol. 2011; 42: 1283-1288
        • Levine R.J.
        • Maynard S.E.
        • Qian C.
        • et al.
        Circulating angiogenic factors and the risk of preeclampsia.
        N Engl J Med. 2004; 350: 672-683
        • Chen A.
        • Roberts D.J.
        Placental pathologic lesions with a significant recurrence risk – what not to miss!.
        APMIS. 2018; 126: 589-601
        • Cluver C.A.
        • Hiscock R.
        • Decloedt E.H.
        • et al.
        Use of metformin to prolong gestation in preterm pre-eclampsia: randomised, double blind, placebo controlled trial.
        BMJ. 2021; 374: n2103
        • Lampi K.
        • Papadogiannakis N.
        • Sirotkina M.
        • Pettersson K.
        • Ajne G.
        Massive perivillous fibrin deposition of the placenta and pregnancy outcome: a retrospective observational study.
        Placenta. 2022; 117: 213-218