Background
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.
Objective
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.
Results
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.
Conclusion
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
- chronic histiocytic intervillositis
- fetal growth restriction
- fetal vascular malperfusion
- massive perivillous fibrinoid deposition
- maternal vascular malperfusion
- placenta growth factor
- placental pathology
- prediction
- preeclampsia
- pregnancy outcomes
- stillbirth
- uterine artery Doppler
- villitis of unknown etiology
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Article Info
Publication History
Published online: May 26, 2022
Accepted:
May 19,
2022
Received in revised form:
May 18,
2022
Received:
March 9,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
J.K. reports receiving research funding from Canadian Institutes of Health Research (CIHR) grant # 64302.
The authors report no conflict of interest.
No financial support was received for this study.
Cite this article as: Agrawal S, Parks WT, Zeng HD, et al. 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. Am J Obstet Gynecol 2022;XX:x.ex–x.ex.
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