Placental Pathology in Pregnancies with Maternally Perceived Decreased Fetal Movement - A Population-Based Nested Case-Cohort Study

<div><h3>Background</h3><p>Decreased fetal movements (DFM) are associated with fetal growth restriction and stillbirth, presumably linked through an underlying placental dysfunction. Yet, the role of placental pathology has received limited attention in DFM studies. Our main objective was to explore whether maternal perceptions of DFM were associated with placental pathology in pregnancies recruited from a low-risk total population.</p> <h3>Methods/Principal Findings</h3><p>Placentas from 129 DFM and 191 non-DFM pregnancies were examined according to standardized macro- and microscopic protocols. DFM was defined as any maternal complaint of DFM leading to a hospital examination. Morphological findings were timed and graded according to their estimated onset and clinical importance, and classified in line with a newly constructed Norwegian classification system for reporting placental pathology. With our population-based approach we were unable to link DFM to an overall measure of all forms of placental pathology (OR 1.3, 95% CI 0.8–2.2, p = 0.249). However, placental pathology leading to imminent delivery could be a competing risk for DFM, making separate subgroup analyses more appropriate. Our study suggests a link between DFM and macroscopic placental pathology related to maternal, uteroplacental vessels, i.e. infarctions, placental lesions (intraplacental hematomas) and abruptions. Although not statistically significant separately, a compound measure showed a significant association with DFM (OR 2.4, 95%CI 1.1–5.0, p = 0.023). This association was strengthened when we accounted for relevant temporal aspects. More subtle microscopic materno-placental ischemic changes outside the areas of localized pathology showed no association with DFM (OR 0.5, 95%CI 0.2–1.4, p = 0.203). There was a strong association between placental pathology and neonatal complications (OR 2.9, 95% CI 1.6–5.1, p<0.001).</p> <h3>Conclusions</h3><p>In our population-based study we were generally unable to link maternally perceived DFM to placental pathology. Some associations were seen for subgroups.</p> </div

Placental pathology by birth outcome (n = 320).

¶<p>p-values refer to odds ratio for categorical data and t-test for continuous variables for comparisons between pregnancies with or without placental pathology.</p>a<p>Includes all cases with pathology with assumed moderate to important clinical impact from macroscopic or microscopic examination.</p>l<p>Neonatal complications: preterm birth, SGA, infections, Apgar scores <7_5min or transfer to NCU for conditions relevant to fetal growth restriction or fetal distress (respiratory syndrome or cerebral irritation).</p>ii<p>Small for gestational age: birth weight for gestational below 10^th percentile adjusted for maternal height and pre pregnancy weight and infant sex.</p>§<p>Includes the cord anomalies; true umbilical cord knots (n = 7), velamentous (n = 5) and marginal cord (n = 9) insertion.</p

Maternal and fetal characteristics and birth outcome for DFM versus non-DFM pregnancies, from pregnancy week 24⁰ (n = 320).

¶<p>p-values refer to odds ratios for categorical data and t-test for continuous variables for comparisons between DFM vs non-DFM pregnancies.</p>a<p>Maternal general health risk factors include: diabetes type I and II, chronic renal, hypertensive or coronary disease, inflammatory and collagen disease, epilepsy or coagulopathy. Obstetric risk factors include: previous pregnancy with FGR, stillbirth>21 weeks, fetal malformations, serious pre eclampsia, preterm delivery or spontaneous abortions >3.</p>b<p>Non-reassuring fetal state: pathological CTG or Doppler or other signs of fetal distress.</p>l<p>Neonatal complications: preterm birth, SGA, infections, Apgar scores <7_5min or transfer to NCU for conditions relevant to fetal growth restriction or fetal distress (respiratory syndrome or cerebral irritation).</p>ll<p>Small for gestational age (SGA): birth weight for gestational age below 10^th percentile adjusted for maternal height and pre pregnancy weight and infant sex.</p

Flowchart for data collection.

<p>Flowchart for data collection.</p

A systematic and standardized classification of placental pathology [34].

<p>A systematic and standardized classification of placental pathology <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039259#pone.0039259-Roald1" target="_blank">[34]</a>.</p

Characteristics of consultations for DFM from 129 pregnancies.

<p>Characteristics of consultations for DFM from 129 pregnancies.</p

Placental pathology in DFM pregnancies versus non-DFM pregnancies (n = 320).

¶<p>p-values refer to odds ratio for categorical data and t-test for continuous variables for comparisons between DFM vs non-DFM pregnancies.</p>a<p>Include all cases with pathology with assumed moderate to important clinical impact from macroscopic or microscopic examination.</p>b<p>Maturation disorders, pathology was not timed.</p>c<p>Cord pathology includes cases with uncoiled umbilical cord (n = 8), single umbilical artery (n = 3), thrombosis (n = 2), severe edema (n = 1), cord pathology was not timed.</p

Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI) : a phase 3, placebo-controlled, randomised trial

Background: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor. Methods: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population). Findings: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8–3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74–0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, p interaction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78–1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75–1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48–2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36–3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74–1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75–0·95, p=0·005, in contrast to patients without PCI where it did not, p interaction=0·012. Benefit was present irrespective of time from most recent PCI. Interpretation: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk