Placental lesions in small for gestational age fetuses with and without clinical features of fetal growth restriction: a secondary analysis of the Doppler Ratio In fetal Growth restriction Intervention Trial At (near) Term (DRIGITAT) study

Abstract

Objective: The primary pathophysiological mechanism underlying fetal growth restriction is placental insufficiency, which can be attributed to various placental lesions. It is unknown if ultrasound markers can antenatally detect and distinguish between different placental lesions and their grading. This study aimed to investigate the association between placental lesions, clinical markers, including Doppler velocimetry, and birth outcome.

Study design: This study was a secondary analysis of the DRIGITAT study, a multicenter prospective cohort with nested randomized controlled trial of late preterm small for gestational age pregnancies. Placental slides were independently revised, scored, and classified using a digital synoptic reporting tool, according to the Amsterdam Consensus criteria and the Freedman-Ernst subclassification, by 2 perinatal pathologists blinded to clinical data, except for gestational age. Pregnancy characteristics and birth outcomes of cases with placental pathology available were compared to those without. Within the group with pathology available, participants were classified as fetal growth restriction (2 consecutive abnormal Doppler measurements: umbilicocerebral ratio>0.8 or umbilical artery pulsatility index>p90 or both abnormal), potential fetal growth restriction (once or intermittent abnormal umbilicocerebral ratio or umbilical artery pulsatility index or both abnormal), or small for gestational age not otherwise specified (never-abnormal umbilicocerebral ratio or umbilical artery pulsatility index). Placental lesion prevalence and grading were analyzed in relation to Doppler ultrasound findings (umbilicocerebral ratio>0.8 or umbilical artery pulsatility index>p90), biomarkers (placental growth factor, and the soluble fms-like tyrosine kinase-1 placental growth factor ratio), birthweight percentiles, and composite adverse perinatal outcome. The potential relation between grading of maternal vascular malperfusion, fetal vascular malperfusion, and chronic inflammation (CI) and Doppler ultrasound and composite adverse perinatal outcome were calculated by performing a multinomial logistic regression analysis yielding a likelihood in terms of an odds ratio and 95% confidence intervals (95% CI). We used inverse probability weighting to account for selection bias in the pathology sample and adjusted odds ratios were calculated.

Results: Of the 690 participants, 294 placentas (42.6%) were available for this analysis, while placental pathology was unavailable for 396 participants (57.4%). Prelabor caesarean for suspected fetal distress was significantly more frequent in the group with pathology available (37.2%) compared to the group without pathology available (11.4%). In the fetal growth restriction group, 37.8% of placentas showed high-grade maternal vascular malperfusion, vs 18.2% in the small for gestational age not otherwise specified group; high-grade fetal vascular malperfusion was found in 28.9% and 15.1%, respectively. High-grade maternal vascular malperfusion was associated with the greatest odds of fetal growth restriction, with an adjusted odds ratio of 2.6 (95% CI, 1.7-4.2; p<.001). The adjusted odds ratio for high-grade fetal vascular malperfusion was 1.9 (95% CI, 1.2-3.0; p .01). Both high-grade maternal vascular malperfusion and high-grade fetal vascular malperfusion were significantly associated with composite adverse perinatal outcome. High-grade maternal vascular malperfusion was significantly more frequent if maternal serum placental growth factor and soluble fms-like tyrosine kinase-1:placental growth factor ratio were abnormal.

Conclusion: Among the small for gestational age infants, clinical features of fetal growth restriction are associated with high-grade maternal vascular malperfusion and high-grade fetal vascular malperfusion and the combined presence of these lesions. Both lesions may manifest antenatally with Doppler abnormalities (umbilicocerebral ratio>0.8 or umbilical artery pulsatility index>p90).

Keywords: Doppler velocimetry; cerebroplacental ratio; fetal growth restriction; placenta pathology; small for gestational age; umbilicocerebral ratio.