Placental Growth Factor and Soluble, Fms-Like Tyrosine Kinase-1 in Preeclampsia: A Case-Cohort (PEARL) Study.

OBJECTIVE: Preeclampsia is associated with a higher maternal blood levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and lower levels of placental growth factor (PlGF) that appear before clinical onset. We aimed to estimate the normal progression of these biomarkers in normal pregnancies and in those affected by preeclampsia. METHODS: We conducted a case-cohort study including low-risk nulliparous women recruited at 11-13 weeks gestation (cohort) and women with preeclampsia (cases). Maternal blood was collected at different points during pregnancy including at the time of diagnosis of preeclampsia for cases. Maternal serum PlGF and sFlt-1 concentrations and the sFlt-1/PlGF ratio were measured using B•R•A•H•M•S plus KRYPTOR automated assays and were compared between patients in both groups matched for gestational age. Cases were stratified as early- (≤34 weeks), intermediate- (35-37 weeks) and late-onset (>37 weeks) preeclampsia. RESULTS: The cohort consisted of 45 women whose results were compared with those of 31 women who developed preeclampsia, diagnosed at a median gestational age of 32 weeks (range 25-38 weeks). We observed that sFlt-1, PlGF and their ratio fluctuated during pregnancy in both groups, with a significant correlation with gestational age after 28 weeks (P < 0.05). We observed a significant difference between cases and controls, with a median ratio 100 times higher in early preeclampsia (P < 0.001), 13 times higher in intermediate preeclampsia (P < 0.001), but no significant difference between groups in late-onset preeclampsia with matched controls. CONCLUSION: PlGF, sFlt-1, and their ratio may be useful in the prediction and diagnosis of early- and intermediate-onset preeclampsia but are not useful for late-onset preeclampsia.

The association between maternal placental growth factor and placental maternal vascular malperfusion lesions.

INTRODUCTION: Placental Growth Factor (PlGF) is used for the prediction of preeclampsia (PE), a syndrome associated with maternal vascular malperfusion (MVM). Our goal is to determine the correlation between PlGF and MVM. MATERIAL AND METHODS: We performed a secondary analysis of the PEARL study that included nulliparous women with PE (cases), and low-risk nulliparous women recruited in early pregnancy (controls). All participants provided blood samples at diagnosis of PE (cases), or between 26 and 34 weeks (controls) for measurement of PlGF (B·R·A·H·M·S plus KRYPTOR automated assays), that was transformed into multiple of median (MoM). Placental examination was performed for the diagnosis of MVM based on the Amsterdam Placental Workshop Group Consensus Statement. Nonparametric tests and receiver operating characteristic (ROC) curves were used to compare PlGF in pregnancies with, and without PE, stratified by the presence of MVM. RESULTS: Third trimester PlGF was lower in PE cases with MVM (N = 20; median: 0.04 MoM; interquartile: 0.03-0.09; p<0.0001), and in controls with MVM (N = 4; 0.30MoM; 0.07-0.52; p = 0.002) compared to controls without MVM (N = 29; 0.99 MoM; 0.67-1.52). PlGF in PE cases without MVM (N = 5; 0.18 MoM; 0.17-1.64) was not significantly different than in controls without MVM but the sample size was small. ROC curve demonstrated a greater predictability of PlGF for PE with MVM than PE without MVM (AUC: 0.99 vs. 0.38; p<0.0001). DISCUSSION: Third trimester PlGF is a better predictor of PE associated with MVM than a predictor of PE without MVM. We hypothesize that PlGF is a stronger marker of MVM than PE.

Pathological investigation of placentas in preeclampsia (the PEARL study).

INTRODUCTION: Preeclampsia (PE), but mainly preterm PE, is associated with deep placentation disorders. We aimed to compare placental pathologies in pregnancies affected by term and preterm PE compared to normal pregnancies. METHODS: We performed a prospective case-cohort study. Low-risk nulliparous women were recruited in the first trimester and women who developed PE were recruited at diagnosis. Placental pathologies were reported according to the Amsterdam Placental Workshop Group Consensus Statement and were compared between cases and controls. PE cases stratified as term (≥37 weeks) and preterm PE (<37 weeks). Our primary outcome was maternal vascular malperfusion (MVM). RESULTS: Twenty-four women who developed preterm PE were compared to 10 women who developed term PE and 41 women without PE. Preterm PE (92%) was associated with more MVM than term PE (10%, p < 0.01) and controls (4%, p < 0.01), but the rate of MVM was similar between term PE and controls (p = 0.56). Preterm PE was also associated with more placental infarcts (65% vs. 20% vs. 15%); advanced villous maturation (91% vs. 30% vs. 1%); and hypoplastic villous maturation (70% vs. 10% vs. 3%); and moderate to severe decidual vasculopathy (56% vs. 10% vs. 3%) than term PE and controls (all p < 0.05). CONCLUSION: Most cases of preterm PE are associated with MVM, placental infarcts, advanced and/or hypoplastic villous maturation, and moderate to severe decidual vasculopathy, while it is infrequent in term PE and pregnancies without PE. Preterm and term preeclampsia have a different pathologic process that should be considered for their prevention and clinical management.

Pandemic stress and SARS-CoV-2 infection are associated with pathological changes at the maternal-fetal interface.

INTRODUCTION: The reported effects of SARS-CoV-2 on pregnancy outcomes are conflicting; studies frequently overlook the placenta, which is critical for the health of the mother and infant(s). This study aimed to determine the effect of pandemic stress ± SARS CoV-2 infection on placental histopathology. METHODS: Women were recruited in Canada (n = 69); France (n = 21) or in the UK (n = 25), between March and October 2020. Historic controls (N = 20) were also included. Placenta and fetal membrane samples were collected rapidly after delivery and were fixed and stained for histopathological analysis. Maternal demographical data and obstetric outcomes were recorded. RESULTS: Over 80% of the placentas from SARS-CoV-2+ pregnancies had histopathological abnormalities: predominantly structural (71-86%) or inflammatory (9-22%), depending on geographical location. Excessive fibrin was seen in all sites, whereas deciduitis (Canada), calcifications (UK), agglutinations and chorangiosis (France) predominated in different locations. The frequency of abnormalities was significantly higher than in SARS-CoV-2 negative women (50%, p < 0.05). Demographic and obstetric data were similar in the SARS-CoV-2+ women across all sites - characterised by predominantly Black/Middle Eastern women, and women with elevated body mass index. DISCUSSION: Overall, the frequency of placental abnormalities is increased in SARS-CoV-2+ women, but the incidence of placental abnormalities is also higher in SARS-CoV-2- women that gave birth during the pandemic, which highlights the importance of appropriate control groups to ascertain the roles of pandemic stress and SARS-CoV-2 infection on the placenta and pregnancy outcomes.

Variable phenotypic expression of Apert syndrome in monozygotic twins.

Apert syndrome in monozygotic twins can lead to different phenotypic expression of the disease in the two fetuses. Apert syndrome can be associated with congenital left diaphragmatic hernia and cleft palate.