Prediction of preterm birth in women with fetal growth restriction - Is the weekly change in sFlt-1/PlGF ratio or PlGF levels useful?

INTRODUCTION: To assess the rate of change in soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio and PlGF levels per week compared to a single sFlt-1/PlGF ratio or PlGF level to predict preterm birth for pregnancies complicated by fetal growth restriction. MATERIAL AND METHODS: A prospective cohort study of pregnancies complicated by isolated fetal growth restriction. Maternal serum PlGF levels and the sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. We investigated the utility of PlGF levels, sFlt-1/PlGF ratio, change in PlGF levels per week or sFlt-1/PlGF ratio per week. Cox-proportional hazard models and Harrell's C concordance statistic were used to evaluate the effect of biomarkers on time to preterm birth. RESULTS: The total study cohort was 158 pregnancies comprising 91 (57.6%) with fetal growth restriction and 67 (42.4%) with appropriate for gestational age controls. In the fetal growth restriction cohort, sFlt-1/PlGF ratio and PlGF levels significantly affected time to preterm birth (Harrell's C: 0.85-0.76). The rate of increase per week of the sFlt-1/PlGF ratio (hazard ratio [HR] 3.91, 95% confidence interval [CI]: 1.39-10.99, p = 0.01, Harrell's C: 0.74) was positively associated with preterm birth but change in PlGF levels per week was not (HR 0.65, 95% CI: 0.25-1.67, p = 0.37, Harrell's C: 0.68). CONCLUSIONS: Both a high sFlt-1/PlGF ratio and low PlGF levels are predictive of preterm birth in women with fetal growth restriction. Although the rate of increase of the sFlt-1/PlGF ratio predicts preterm birth, it is not superior to either a single elevated sFlt-1/PlGF ratio or low PlGF level.

Maternal physical activity and sitting time and its association with placental morphology and blood flow during gestation: Findings from the Queensland Family Cohort study.

OBJECTIVES: Antenatal exercise is associated with placental morphological alterations, however research in this area is limited. Given the emphasis on the beneficial effects of antenatal exercise, it is important to understand its effect on placental function and the relationship to foetal development. The aim of this study was to investigate the association between physical activity, sitting time, and placental outcomes measured during gestation. DESIGN: Prospective cohort study. METHODS: Pregnant women in the Queensland Family Cohort study self-reported physical activity at 24 and 36 weeks of gestation (n = 203) and were categorised into physical activity volume groups of nil-low (0-<500 metabolic equivalent of task·minutes/week), moderate (500-<1000 metabolic equivalent of task·minutes/week), or high-volume activity (≥1000 metabolic equivalent of task·minutes/week). Participants reported average daily sitting time, whereby excessive sitting time was considered as ≥8h/day. Placental stiffness, thickness, and uteroplacental blood flow resistance were measured by ultrasound imaging at each timepoint. RESULTS: Physical activity volume was not associated with changes to placental morphometrics or uteroplacental blood flow resistance at 24 or 36 weeks of gestation. Excessive sitting time at 36 weeks was associated with greater placental stiffness (p = 0.046), and a lower umbilical artery pulsatility index (p = 0.001). CONCLUSIONS: Placental tissue stiffness and umbilical artery resistance were altered in late gestation with higher maternal sitting time but not with physical activity volume. Overall, excessive sitting time may be a risk for suboptimal placental function and could be an important focus for antenatal care.

Prediction of preterm birth in growth-restricted and appropriate-for-gestational-age infants using maternal PlGF and the sFlt-1/PlGF ratio-A prospective study.

OBJECTIVE: To assess the utility of placental growth factor (PlGF) levels and the soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio to predict preterm birth (PTB) for infants with fetal growth restriction (FGR) and those appropriate for gestational age (AGA). DESIGN: Prospective, observational cohort study. SETTING: Tertiary maternity hospital in Australia. POPULATION: There were 320 singleton pregnancies: 141 (44.1%) AGA, 83 (25.9%) early FGR (<32+0 weeks) and 109 (30.0%) late FGR (≥32+0 weeks). METHODS: Maternal serum PlGF and sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. Low maternal PlGF levels and elevated sFlt-1/PlGF ratio were defined as <100 ng/L and >5.78 if <28 weeks and >38 if ≥28 weeks respectively. Cox proportional hazards models were used. The analysis period was defined as the time from the first measurement of PlGF and sFlt-1/PlGF ratio to the time of birth or censoring. MAIN OUTCOME MEASURES: The primary study outcome was overall PTB. The relative risks (RR) of birth within 1, 2 and 3 weeks and for medically indicated and spontaneous PTB were also ascertained. RESULTS: The early FGR cohort had lower median PlGF levels (54 versus 229 ng/L, p < 0.001) and higher median sFlt-1 levels (2774 ng/L versus 2096 ng/L, p < 0.001) and sFlt-1/PlGF ratio higher (35 versus 10, p < 0.001). Both PlGF <100 ng/L and elevated sFlt-1/PlGF ratio were strongly predictive for PTB as well as PTB within 1, 2 and 3 weeks of diagnosis. For both FGR and AGA groups, PlGF <100 ng/L or raised sFlt-1/PlGF ratio were strongly associated with increased risk for medically indicated PTB. The highest RR was seen in the FGR cohort when PlGF was <100 ng/L (RR 35.20, 95% CI 11.48-175.46). CONCLUSIONS: Low maternal PlGF levels and elevated sFlt-1/PlGF ratio are potentially useful to predict PTB in both FGR and AGA pregnancies.

Shear wave velocity measurement of the placenta is not limited by placental location.

INTRODUCTION: Ultrasound elastography shows diagnostic promise via the non-invasive determination of placental elastic properties. A limitation is a potential for inadequate measurements from posterior placentae. This study aimed to analyse placental position's influence on measures of shear wave elastography (SWV). METHODS: SWV elastography measurements were obtained via ultrasound at 24, 28 and 36 weeks gestation from 238 pregnancies. . The placental position was labelled as either anterior, posterior or fundal/lateral. Average SWV measurements (m/s) and the corresponding standard deviations (SD) were used for data analysis. RESULTS: There was a statistically significant difference between SWV recorded from anterior (1.33 ± 0.19)m/s and posterior (1.39 ± 0.18)m/s placentae (p < 0.001). However, the average sampling depth between these groups was significantly different (3.98 cm vs. 5.38 cm, p < 0.001). There was no statistically significant difference between SWV when measurements were compared at similar depths, regardless of placental location. The addition of placental position to a previously developed mixed-effects model confirmed placental position did not result in improved SWV measurements. In this model, sampling depth remained the best predictor for SWV. CONCLUSIONS: This study showed that placental position does not influence the accuracy or reliability of SWV.

Relationship between placental elastography, maternal pre-pregnancy body mass index and gestational weight gain.

INTRODUCTION: Maternal obesity is a significant risk factor for poor pregnancy outcomes. Obesity is linked to abnormalities in placental tissue at term. The purpose of this study was to correlate changes in placental stiffness, measured via ultrasound elastography, with maternal pre-pregnancy body mass index and gestational weight gain. METHODS: Body Mass Index and gestation weight gain data was collected from 238 women. Elastography measurements were obtained via ultrasound at 24-, 28- and 36-weeks' gestation. An analysis using a linear mixed regression model assessed for the statistical significance of pre-pregnancy BMI, pregnancy weight gain and placental SWV (Shear Wave Velocity). RESULTS: Pre-pregnancy weight status has a significant impact on placental tissue stiffness detectable via ultrasound elastography. Placental tissue stiffness was highest in obese women, followed by overweight women. Obese women, on average, had a MeanSWV 0.11 m/s (95% CI (0.061-0.15) m/s, p < 0.001) above the healthy group throughout the 3rd trimester. Weight gain during pregnancy had a small impact on placental stiffness at the end of pregnancy. MeanSWV was 0.06 m/s (95% CI (0.03-0.10) m/s, p < 0.001) higher in the excessive weight gain group. DISCUSSION: Structural changes of the placenta detected via ultrasound elastography techniques are not exclusive to placental dysfunction conditions (pre-eclampsia and growth restriction) but are also associated with maternal obesity.

Changes in placental elastography in the third trimester - Analysis using a linear mixed effect model.

INTRODUCTION: Research into the role of ultrasound elastography to assess compromised placental tissue is ongoing. There is particular interest in evaluating its potential in the investigation of changes associated with uteroplacental dysfunction. To date, there is limited data on how different maternal and fetal considerations, such as advancing gestational age, amniotic fluid Index (AFI) and maternal body mass index (BMI) may influence shear wave velocity (SWV) measurements. This study aimed to evaluate longitudinal changes in SWV throughout gestation and model these changes with other developing fetal and maternal physiological and biological characteristics. METHODS: The study utilised 238 singleton pregnancies and collected longitudinal data at repeated intervals in the 3rd trimester representing 629 individual data points. Linear mixed model regression analysis was used to identify significant predictors for SWV. RESULTS: From a total of ten variables selected for modelling, only gestational age, AFI, BMI, and sample depth were found to be significant predictors of placental SWV, and gestational age and AFI were found to have only a minimal impact on SWV. DISCUSSION: Sophisticated statistical modelling demonstrates that many of the expected maternal and fetal changes in the 3rd trimester have no or minimal impact on placental SWV. Understanding which factors influence placental SWV is essential to ascertain the technique's utility in managing pregnancies complicated by placental dysfunction in the future.

Queensland Family Cohort: a study protocol.

INTRODUCTION: The perinatal-postnatal family environment is associated with childhood outcomes including impacts on physical and mental health and educational attainment. Family longitudinal cohort studies collect in-depth data that can capture the influence of an era on family lifestyle, mental health, chronic disease, education and financial stability to enable identification of gaps in society and provide the evidence for changes in government in policy and practice. METHODS AND ANALYSIS: The Queensland Family Cohort (QFC) is a prospective, observational, longitudinal study that will recruit 12 500 pregnant families across the state of Queensland (QLD), Australia and intends to follow-up families and children for three decades. To identify the immediate and future health requirements of the QLD population; pregnant participants and their partners will be enrolled by 24 weeks of gestation and followed up at 24, 28 and 36 weeks of gestation, during delivery, on-ward, 6 weeks postpartum and then every 12 months where questionnaires, biological samples and physical measures will be collected from parents and children. To examine the impact of environmental exposures on families, data related to environmental pollution, household pollution and employment exposures will be linked to pregnancy and health outcomes. Where feasible, data linkage of state and federal government databases will be used to follow the participants long term. Biological samples will be stored long term for future discoveries of biomarkers of health and disease. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Mater Research Ethics (HREC/16/MHS/113). Findings will be reported to (1) QFC participating families; (2) funding bodies, institutes and hospitals supporting the QFC; (3) federal, state and local governments to inform policy; (4) presented at local, national and international conferences and (5) disseminated by peer-review publications.

The use of elastography in placental research - A literature review.

INTRODUCTION: Ultrasound elastography is a technique used to quantify biomechanical changes that occur in parenchymal tissue with disease. Recent research has applied the technique to the placenta in order to investigate changes associated with uteroplacental dysfunction. We performed a literature review to summarise the current available information regarding this novel technique. METHODS: Pubmed, CINAHL and Embase were searched using the terms "placenta", "ultrasound" and "elastography". Only full text studies written in English and limited to placental sonoelastography were included. RESULTS: Twenty-eight studies met the inclusion criteria and were included in this review. Publications were divided into in vivo and ex vivo groups, and further categorised into four subgroups: normal pregnancy, pregnancy-induced hypertension and pre-eclampsia, fetal growth restriction and other pregnancy complications. CONCLUSION: Ultrasound elastography can quantitatively assess biomechanical properties of the placenta in conditions where placental function is compromised.

Circulating dipeptidyl peptidase-4 activity correlates with measures of hepatocyte apoptosis and fibrosis in non-alcoholic fatty liver disease in type 2 diabetes mellitus and obesity: A dual cohort cross-sectional study.

BACKGROUND: Intrahepatic expression of dipeptidyl peptidase-4 (DPP4), and circulating DPP4 (cDPP4) levels and its enzymatic activity, are increased in non-alcoholic fatty liver disease (NAFLD) and in type 2 diabetes mellitus and/or obesity. DPP4 has been implicated as a causative factor in NAFLD progression but few studies have examined associations between cDPP4 activity and NAFLD severity in humans. This study aimed to examine the relationship of cDPP4 activity with measures of liver disease severity in NAFLD in subjects with diabetes and/or obesity. METHODS: cDPP4 was measured in 106 individuals with type 2 diabetes who had transient elastography (Cohort 1) and 145 individuals with morbid obesity who had liver biopsy (Cohort 2). Both cohorts had caspase-cleaved keratin-18 (ccK18) measured as a marker of apoptosis. RESULTS: Natural log increases in cDPP4 activity were associated with increasing quartiles of ccK18 (Cohorts 1 and 2) and with median liver stiffness ≥10.3 kPa (Cohort 1) and significant fibrosis (F ≥ 2) on liver biopsy (Cohort 2). CONCLUSIONS: In diabetes and/or obesity, cDPP4 activity is associated with current apoptosis and liver fibrosis. Given the pathogenic mechanisms by which DPP4 may progress NAFLD, measurement of cDPP4 activity may have utility to predict disease progression and DPP4 inhibition may improve liver histology over time.