Toward a new taxonomy of obstetrical disease: improved performance of maternal blood biomarkers for the great obstetrical syndromes when classified according to placental pathology

Abstract

Background: The major challenge for obstetrics is the prediction and prevention of the great obstetrical syndromes. We propose that defining obstetrical diseases by the combination of clinical presentation and disease mechanisms as inferred by placental pathology will aid in the discovery of biomarkers and add specificity to those already known.

Objective: To describe the longitudinal profile of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PlGF/sFlt-1 ratio throughout gestation, and to determine whether the association between abnormal biomarker profiles and obstetrical syndromes is strengthened by information derived from placental examination, eg, the presence or absence of placental lesions of maternal vascular malperfusion.

Study design: This retrospective case cohort study was based on a parent cohort of 4006 pregnant women enrolled prospectively. The case cohort of 1499 pregnant women included 1000 randomly selected patients from the parent cohort and all additional patients with obstetrical syndromes from the parent cohort. Pregnant women were classified into six groups: 1) term delivery without pregnancy complications (n=540; control); 2) preterm labor and delivery (n=203); 3) preterm premature rupture of the membranes (n=112); 4) preeclampsia (n=230); 5) small-for-gestational-age neonate (n=334); and 6) other pregnancy complications (n=182). Maternal plasma concentrations of PlGF and sFlt-1 were determined by enzyme-linked immunosorbent assays in 7560 longitudinal samples. Placental pathologists, masked to clinical outcomes, diagnosed the presence or absence of placental lesions of maternal vascular malperfusion. Comparisons between mean biomarker concentrations in cases and controls were performed by utilizing longitudinal generalized additive models. Comparisons were made between controls and each obstetrical syndrome with and without subclassifying cases according to the presence or absence of placental lesions of maternal vascular malperfusion.

Results: 1) When obstetrical syndromes are classified based on the presence or absence of placental lesions of maternal vascular malperfusion, significant differences in the mean plasma concentrations of PlGF, sFlt-1, and the PlGF/sFlt-1 ratio between cases and controls emerge earlier in gestation; 2) the strength of association between an abnormal PlGF/sFlt-1 ratio and the occurrence of obstetrical syndromes increases when placental lesions of maternal vascular malperfusion are present (adjusted odds ratio [aOR], 13.6 vs 6.7 for preeclampsia; aOR, 8.1 vs 4.4 for small-for-gestational-age neonates; aOR, 5.5 vs 2.1 for preterm premature rupture of the membranes; and aOR, 3.3 vs 2.1 for preterm labor (all P<0.05); and 3) the PlGF/sFlt-1 ratio at 28 to 32 weeks of gestation is abnormal in patients who subsequently delivered due to preterm labor with intact membranes and in those with preterm premature rupture of the membranes if both groups have placental lesions of maternal vascular malperfusion. Such association is not significant in patients with these obstetrical syndromes who do not have placental lesions.

Conclusion: Classification of obstetrical syndromes according to the presence or absence of placental lesions of maternal vascular malperfusion allows biomarkers to be informative earlier in gestation and enhances the strength of association between biomarkers and clinical outcomes. We propose that a new taxonomy of obstetrical disorders informed by placental pathology will facilitate the discovery and implementation of biomarkers as well as the prediction and prevention of such disorders.

Keywords: angiogenic index-1; classification of disease; fetal death; liquid biopsy; omics; placental growth factor; placental lesions of maternal vascular malperfusion; preeclampsia; pregnancy; preterm birth; preterm labor; preterm premature rupture of the membranes; small for gestational age; soluble fms-like tyrosine kinase-1; soluble vascular endothelial growth factor receptor-1.

Figure 1:. Maternal plasma PlGF/sFlt-1 ratio in normal and complicated pregnancies with and without placental lesions of maternal vascular malperfusion.

Mean and 95% confidence intervals values were estimated by generalized additive models using splines transformations of gestational age in term delivery controls and complicated pregnancies. PE: preeclampsia; SGA: small for gestational age; PTL: preterm labor and delivery; PPROM: preterm prelabor rupture of the membranes; MVM: placental lesions of maternal vascular malperfusion. Dotted vertical lines represent the earliest gestational age when PlGF/sFlt-1 is significantly lower in cases than in controls.

Figure 2:. Maternal plasma PlGF ratio in normal and complicated pregnancies with and without placental lesions of maternal vascular malperfusion.

Mean and 95% confidence intervals values were estimated by generalized additive models using splines transformations of gestational age in term delivery controls and complicated pregnancies. PE: preeclampsia; SGA: small for gestational age; PTL: preterm labor and delivery; PPROM: preterm prelabor rupture of the membranes; MVM: placental lesions of maternal vascular malperfusion. Dotted vertical lines represent the earliest gestational age when PlGF is significantly lower in cases than in controls.

Figure 3:. Maternal plasma sFlt-1 ratio in normal and complicated pregnancies with and without placental lesions of maternal vascular malperfusion.

Mean and 95% confidence intervals values were estimated by generalized additive models using splines transformations of gestational age in term delivery controls and complicated pregnancies. PE: preeclampsia; SGA: small for gestational age; PTL: preterm labor and delivery; PPROM: preterm prelabor rupture of the membranes; MVM: placental lesions of maternal vascular malperfusion. Dotted vertical lines represent the earliest gestational age when sFlt-1 is significantly higher in cases than in controls.

Figure 4:. Adjusted odds ratios for obstetrical complications conferred by abnormal PlGF/sFlt-1 ratio at 28 to 32 weeks.

Results are presented for adverse outcomes in aggregate and disaggregated by presence of placental lesions of maternal vascular malperfusion (MVM). A positive test was defined as MoM (PlGF/sFlt-1) <20^th centiles. Significant associations (p<0.05) obtained via logistic regression are shown with (*). 95% confidence intervals are listed under estimates.

Figure 5:. Adjusted odds ratios for obstetrical complications conferred by abnormal PlGF at 28 to 32 weeks.

Results are presented for adverse outcomes in aggregate and disaggregated by presence of placental lesions of maternal vascular malperfusion (MVM). A positive test was defined as MoM PlGF <20^th centiles. Significant associations (p<0.05) obtained via logistic regression are shown with (*). 95% confidence intervals are listed under estimates.

Figure 6:. Adjusted odds ratios for obstetrical complications conferred by abnormal sFlt-1 at 28 to 32 weeks.

Results are presented for adverse outcomes in aggregate and disaggregated by presence of placental lesions of maternal vascular malperfusion (MVM). A positive test was defined as MoM sFlt-1 >20^th centiles. Significant associations (p<0.05) obtained via logistic regression are shown with (*). 95% confidence intervals are listed under estimates.

Figure 7:. Maternal plasma PlGF/sFlt-1 ratio in normal pregnancies and complicated pregnancies with placental lesions of maternal vascular malperfusion.

Mean values were estimated by generalized additive models using splines transformations of gestational age. PE: preeclampsia; SGA: small for gestational age; PTL: preterm labor and delivery; PPROM: preterm prelabor rupture of the membranes; MVM: maternal vascular underperfusion.

Figure 8:. Maternal plasma sFlt-1/PlGF ratio in normal pregnancies and complicated pregnancies with placental lesions of maternal vascular malperfusion.

Mean values were estimated by generalized additive models using splines transformations of gestational age. PE: preeclampsia; SGA: small for gestational age; PTL: preterm labor and delivery; PPROM: preterm prelabor rupture of the membranes; MVM: maternal vascular underperfusion. A logarithmic axis was used to enhance visualization of differences between groups.