Quantitative longitudinal T2* mapping for assessing placental function and association with adverse pregnancy outcomes across gestation

Abstract

Existing methods for evaluating in vivo placental function fail to reliably detect pregnancies at-risk for adverse outcomes prior to maternal and/or fetal morbidity. Here we report the results of a prospective dual-site longitudinal clinical study of quantitative placental T2* as measured by blood oxygen-level dependent magnetic resonance imaging (BOLD-MRI). The objectives of this study were: 1) to quantify placental T2* at multiple time points across gestation, and its consistency across sites, and 2) to investigate the association between placental T2* and adverse outcomes. 797 successful imaging studies, at up to three time points between 11 and 38 weeks of gestation, were completed in 316 pregnancies. Outcomes were stratified into three groups: (UN) uncomplicated/normal pregnancy, (PA) primary adverse pregnancy, which included hypertensive disorders of pregnancy, birthweight <5th percentile, and/or stillbirth or fetal death, and (SA) secondary abnormal pregnancy, which included abnormal prenatal conditions not included in the PA group such as spontaneous preterm birth or fetal anomalies. Of the 316 pregnancies, 198 (62.6%) were UN, 70 (22.2%) PA, and 48 (15.2%) SA outcomes. We found that the evolution of placental T2* across gestation was well described by a sigmoid model, with T2* decreasing continuously from a high plateau level early in gestation, through an inflection point around 30 weeks, and finally approaching a second, lower plateau in late gestation. Model regression revealed significantly lower T2* in the PA group than in UN pregnancies starting at 15 weeks and continuing through 33 weeks. T2* percentiles were computed for individual scans relative to UN group regression, and z-scores and receiver operating characteristic (ROC) curves calculated for association of T2* with pregnancy outcome. Overall, differences between UN and PA groups were statistically significant across gestation, with large effect sizes in mid- and late- pregnancy. The area under the curve (AUC) for placental T2* percentile and PA pregnancy outcome was 0.71, with the strongest predictive power (AUC of 0.76) at the mid-gestation time period (20-30 weeks). Our data demonstrate that placental T2* measurements are strongly associated with pregnancy outcomes often attributed to placental insufficiency. Trial registration: ClinicalTrials.gov: NCT02749851.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Enrollment flow chart.

Numbers detail prospective patients screened, consented, and enrolled at both study sites, along with completed MRI studies meeting quality criteria for inclusion in data analysis presented here. The majority of exclusions were due to lack of child care required to attend study visits, marijuana use and/or concomitant medical conditions.

Fig 2. Gestational dependence of placental T2* values and rates of change.

Median T2* values for each completed study, computed over the entire placenta, are plotted as a function of gestational age at time of imaging in the three panels in the left column (panels A, B, C). Rates of change in placental T2* between repeated imaging time points within the same individual, where the x value is the mean gestational age of two sequential scans and the y value is the change in T2* between the same two sequential scans, are plotted as a function of mean gestational age in the right column (panels D, E, F). The upper row plots these quantities for normal pregnancies, the middle row for abnormal (green) and adverse (red) pregnancies, and the bottom row for normal pregnancies stratified by site (OHSU in blue, Utah in red). In all graphs, model regression curves (using the functions and parameters given in Table 4) are indicated by the thick solid lines, the 95% confidence intervals by the dashed lines, and the 95% prediction intervals by the dot-dashed lines. The best fit and 95% CI curves from the UN population are superimposed in gray on the PA/SA and site-specific plots in the second and third rows for reference.

Fig 3. Comparison of anatomic magnetic resonance imaging and placental T2* mapping in uncomplicated normal and primary adverse pregnancies.

T2-weighted HASTE MRI (left column) and placental T2* maps (right column) are shown for an uncomplicated normal pregnancy at 232 days gestation (top row, panels A & B) and for a primary adverse pregnancy at 235 days gestation presenting with severe preeclampsia (bottom row, panels C & D). The placenta is indicated by the dashed blue outlines overlaid on the T2* maps.

Fig 4. Histograms of T2* percentiles.

Bar charts showing histograms of measured T2* percentiles for uncomplicated normal (UN, blue), primary adverse (PA, red), and secondary abnormal (SA, green) pregnancies for both sites (left) and for OHSU (middle) and Utah (right) separately.

Fig 5. Receiver operator characteristic (ROC) curves for T2* prediction of PA pregnancies.

The points where Youden’s J is maximized are indicated by the stars. Area under the curve (AUC), Jmax, and the corresponding optimal cutoff threshold in T2* percentile relative to UN (Copt) are given in the figure legend for each panel.