Prospective Validation of First-Trimester Screening for Preterm Preeclampsia in Nulliparous Women (PREDICTION Study).

BACKGROUND: Fetal Medicine Foundation (FMF) studies suggest that preterm preeclampsia can be predicted in the first trimester by combining biophysical, biochemical, and ultrasound markers and prevented using aspirin. We aimed to evaluate the FMF preterm preeclampsia screening test in nulliparous women. METHODS: We conducted a prospective multicenter cohort study of nulliparous women recruited at 11 to 14 weeks. Maternal characteristics, mean arterial blood pressure, PAPP-A (pregnancy-associated plasma protein A), PlGF (placental growth factor) in maternal blood, and uterine artery pulsatility index were collected at recruitment. The risk of preterm preeclampsia was calculated by a third party blinded to pregnancy outcomes. Receiver operating characteristic curves were used to estimate the detection rate (sensitivity) and the false-positive rate (1-specificity) for preterm (<37 weeks) and for early-onset (<34 weeks) preeclampsia according to the FMF screening test and according to the American College of Obstetricians and Gynecologists criteria. RESULTS: We recruited 7554 participants including 7325 (97%) who remained eligible after 20 weeks of which 65 (0.9%) developed preterm preeclampsia, and 22 (0.3%) developed early-onset preeclampsia. Using the FMF algorithm (cutoff of ≥1 in 110 for preterm preeclampsia), the detection rate was 63.1% for preterm preeclampsia and 77.3% for early-onset preeclampsia at a false-positive rate of 15.8%. Using the American College of Obstetricians and Gynecologists criteria, the equivalent detection rates would have been 61.5% and 59.1%, respectively, for a false-positive rate of 34.3%. CONCLUSIONS: The first-trimester FMF preeclampsia screening test predicts two-thirds of preterm preeclampsia and three-quarters of early-onset preeclampsia in nulliparous women, with a false-positive rate of ≈16%. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02189148.

CX3CL1/Fractalkine as a biomarker for early pregnancy prediction of preterm premature rupture of membranes.

OBJECTIVES: The objective of our study was to evaluate serum CX3CL1/Fractalkine, a monocyte/macrophage chemoattractant expressed in cytotrophoblasts and decidual cells, as a predictive biomarker for the occurrence of preterm premature rupture of membranes (PPROM). METHODS: A case-control study of 438 pregnancies including 82 PPROM cases and 64 preterm labor with intact membranes cases with blood samples collected at first trimester, second trimester and delivery was conducted. The predictive ability of CX3CL1 and maternal risk factors for the occurrence of PPROM was assessed by receiver operating characteristic curve analysis. A second, independent cohort was prospectively constituted to confirm the case-control study results. RESULTS: First trimester CX3CL1 was significantly increased in PPROM cases when compared to matched controls. Multivariate regression analysis highlighted a significant difference for CX3CL1 measured during the first trimester (p<0.001). Alone, CX3CL1 predicts PPROM with a 90 % sensitivity and a specificity around 40 %. The area under the receiver operating characteristic curve for PPROM prediction were 0.64 (95% confidence interval: 0.57-0.71) for first trimester CX3CL1, and 0.61 (95% confidence interval: 0.54-0.68) for maternal risk factors (body mass index<18.5 kg/m2, nulliparity, tobacco use and the absence of high school diploma). The combination of CX3CL1 and maternal risk factors significantly improved the area under the curve: 0.72 (95% confidence interval: 0.66-0.79) (p<0.001). The results were confirmed on a second independent cohort. CONCLUSIONS: CX3CL1 is a promising blood biomarker in the early (first trimester) prediction of PPROM.

Impact of COVID-19 and Vaccination During Pregnancy on Placenta-Mediated Complications (COVIGRO Study).

OBJECTIVES: COVID-19 has been associated with preterm birth (PTB) and placental-mediated complications, including fetal growth restriction and preeclampsia (PE). This study aimed to estimate the impact of COVID-19 and vaccination on adverse pregnancy outcomes and markers of placental function. METHODS: We performed a study on a prospective cohort of women recruited in the first trimester of pregnancy during the early COVID-19 pandemic period (December 2020 to December 2021). At each trimester of pregnancy, the assessment included a questionnaire on COVID-19 and vaccination status; serological tests for COVID-19 (for asymptomatic infection); measurement of placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) in maternal blood; measurement of mean uterine artery pulsatility index (UtA-PI); and pregnancy outcomes (PTB, PE, birth weight below the fifth and the tenth percentile). RESULTS: Among 788 patients with complete data, we observed 101 (13%) cases of symptomatic infection and 74 (9%) cases of asymptomatic infection with SARS-CoV-2. Most cases (73%) of infection were among women with previous vaccination or COVID-19 infection before pregnancy. COVID-19 infection was not associated with adverse pregnancy outcomes, abnormal fetal growth, sFlt-1/PlGF ratio, or mean UtA-PI. Vaccination during pregnancy did not influence these outcomes either. We observed no case of severe COVID-19 infection requiring respiratory support. CONCLUSION: Mild symptomatic or asymptomatic COVID-19 during pregnancy did not influence the risk of adverse pregnancy outcomes and the markers of placental function in predominantly vaccinated women. Fetal growth monitoring is unlikely to be mandatory in women with mild symptoms of COVID-19.

Methods and Software to Analyze Gene-Environment Interactions under a Case-Mother-Control-Mother Design with Partially Missing Child Genotype.

INTRODUCTION: The case-mother-control-mother design allows to study fetal and maternal genetic factors together with environmental exposures on early life outcomes. Mendelian constraints and conditional independence between child genotype and environmental factors enabled semiparametric likelihood methods to estimate logistic models with greater efficiency than standard logistic regression. Difficulties in child genotype collection require methods handling missing child genotype. METHODS: We review a stratified retrospective likelihood and two semiparametric likelihood approaches: a prospective one and a modified retrospective one, the latter either modeling the maternal genotype as a function of covariates or leaving their joint distribution unspecified (robust version). We also review software implementing these modeling alternatives, compare their statistical properties in a simulation study, and illustrate their application, focusing on gene-environment interactions and partially missing child genotype. RESULTS: The robust retrospective likelihood provides generally unbiased estimates, with standard errors only slightly larger than when modeling maternal genotype based on exposure. The prospective likelihood encounters maximization problems. In the application to the association of small-for-gestational-age babies with CYP2E1 and drinking water disinfection by-products, the retrospective likelihood allowed a full array of covariates, while the prospective likelihood was limited to few covariates. CONCLUSION: We recommend the robust version of the modified retrospective likelihood.

Canadian SARS-CoV-2 serological survey using antenatal serum samples: a retrospective seroprevalence study.

BACKGROUND: Insufficient data on the rate and distribution of SARS-CoV-2 infection in Canada has presented a substantial challenge to the public health response to the COVID-19 pandemic. Our objective was to assess SARS-CoV-2 seroprevalence in a representative sample of pregnant people throughout Canada, across multiple time points over 2 years of the pandemic, to describe the seroprevalence and show the ability of this process to provide prevalence estimates. METHODS: This Canadian retrospective serological surveillance study used existing serological prenatal samples across 10 provinces over multiple time periods: Feb. 3-21, 2020; Aug. 24-Sept. 11, 2020; Nov. 16-Dec. 4, 2020; Nov. 15-Dec. 3, 2021; and results from the province of British Columbia during a period in which the SARS-CoV-2 B.1.1.529 (Omicron) variant was predominant, from Nov. 15, 2021, to June 11, 2022. Age and postal code administrative data allowed for comparison with concurrent polymerase chain reactivity (PCR)-positive results collected by Statistics Canada and the Canadian Surveillance of COVID-19 in Pregnancy (CANCOVID-Preg) project. RESULTS: Seropositivity in antenatal serum as early as February 2020 indicates SARS-CoV-2 transmission before the World Health Organization's declaration of the pandemic. Seroprevalence in our sample of pregnant people was 1.84 to 8.90 times higher than the recorded concurrent PCR-positive prevalence recorded among females aged 20-49 years in November-December 2020. Overall seropositivity in our sample of pregnant people was low at the end of 2020, increasing to 15% in 1 province by the end of 2021. Seroprevalence among pregnant people in BC during the Omicron period increased from 5.8% to 43% from November 2021 to June 2022. INTERPRETATION: These results indicate widespread vulnerability to SARS-CoV-2 infection before vaccine availability in Canada. During the time periods sampled, public health tracking systems were under-reporting infections, and seroprevalence results during the Omicron period indicate extensive community spread of SARS-CoV-2 infection.

Work-Related Psychosocial Factors and Global Cognitive Function: Are Telomere Length and Low-Grade Inflammation Potential Mediators of This Association?

The identification of modifiable factors that could maintain cognitive function is a public health priority. It is thought that some work-related psychosocial factors help developing cognitive reserve through high intellectual complexity. However, they also have well-known adverse health effects and are considered to be chronic psychosocial stressors. Indeed, these stressors could increase low-grade inflammation and promote oxidative stress associated with accelerated telomere shortening. Both low-grade inflammation and shorter telomeres have been associated with a cognitive decline. This study aimed to evaluate the total, direct, and indirect effects of work-related psychosocial factors on global cognitive function overall and by sex, through telomere length and an inflammatory index. A random sample of 2219 participants followed over 17 years was included in this study, with blood samples and data with cognitive function drawn from a longitudinal study of 9188 white-collar workers (51% female). Work-related psychosocial factors were evaluated according to the Demand-Control-Support and the Effort-Reward Imbalance (ERI) models. Global cognitive function was evaluated with the validated Montreal Cognitive Assessment (MoCA). Telomere length and inflammatory biomarkers were measured using standardised protocols. The direct and indirect effects were estimated using a novel mediation analysis method developed for multiple correlated mediators. Associations were observed between passive work or low job control, and shorter telomeres among females, and between low social support at work, ERI or iso-strain, and a higher inflammatory index among males. An association was observed with higher cognitive performance for longer telomeres, but not for the inflammatory index. Passive work overall, and low reward were associated with lower cognitive performance in males; whereas, high psychological demand in both males and females and high job strain in females were associated with a higher cognitive performance. However, none of these associations were mediated by telomere length or the inflammatory index. This study suggests that some work-related psychosocial factors could be associated with shorter telomeres and low-grade inflammation, but these associations do not explain the relationship between work-related psychosocial factors and global cognitive function. A better understanding of the biological pathways, by which these factors affect cognitive function, could guide future preventive strategies to maintain cognitive function and promote healthy aging.

First-trimester screening for Down syndrome using quadruple maternal biochemical markers.

OBJECTIVES: Placental growth factor (PlGF) is used for first-trimester preeclampsia screening and could be combined with other biochemical markers for Down syndrome screening. We aim to estimate the predictive value of the combination of pregnancy-associated plasma protein (PAPP-A), free ß-human chorionic gonadotropin (free ß-hCG), placental growth factor (PlGF) and α-fetoprotein (AFP) with and without nuchal translucency. METHODS: Singleton pregnancies recruited at 11-14 weeks and followed until delivery. The four maternal markers were measured using Kryptor (ThermoFisher-BRAHMS) and adjusted for gestational age and maternal characteristics. The risk of Down syndrome was calculated using the Fetal Medicine Foundation algorithm and multivariate linear regression analyses in all cases and in 2,200 controls. Receiver-operator characteristic (ROC) curves were used to calculate the detection and false-positive rates. RESULTS: Twenty-six (0.2%) cases of Down syndrome were diagnosed among 13,386 participants. The combination of the four biomarkers could have detected 88% (95% CI: 72-97%) of the cases at a false-positive rate of 13% (95% CI: 12-15%). The addition of nuchal translucency would have increased the detection rate to 96% (95% CI: 82-99%) at a false-positive rate of 4% (95% CI: 4-5%) using a 1:300 cut-off and to 100% (95% CI: 89-100%) at a false-positive rate of 6% (95% CI: 5-8%) using a 1:500 cut-off. CONCLUSIONS: First-trimester screening using biochemical markers allows the identification of approximately 88% of Down syndrome cases for a false-positive rate of 13%. The addition of nuchal translucency raises the detection rate above 95% with a false-positive rate below 5%.

Expected Benefits and Challenges of Using Economic Evaluations to Make Decisions About the Content of Newborn Screening Programs in Vietnam: A Scoping Review of the Literature

Abstract Screening newborns for genetic and other diseases is one of the most effective ways to improve health and reduce disease in a population. In developed countries, newborn screening has been a cornerstone of public health for decades. In many developing countries, however, newborn screening is still in its infancy. Many countries still lack screening programs. When a program is available, it generally lacks well-defined criteria on which decision-makers can justify the choice of diseases screened for and the methods used. One of the reasons put forward to understand this observation is the fact that little consideration is given by decision-makers to economic evaluations as a pillar of decision-making, as is the case in industrialized countries. This article provides a brief description of the challenges of using economic evaluation of newborn screening in developing countries. This will be illustrated by the example of the national newborn screening program in Vietnam.

User Experience of a Computer-Based Decision Aid for Prenatal Trisomy Screening: Mixed Methods Explanatory Study.

BACKGROUND: Mobile health tools can support shared decision-making. We developed a computer-based decision aid (DA) to help pregnant women and their partners make informed, value-congruent decisions regarding prenatal screening for trisomy. OBJECTIVE: This study aims to assess the usability and usefulness of computer-based DA among pregnant women, clinicians, and policy makers. METHODS: For this mixed methods sequential explanatory study, we planned to recruit a convenience sample of 45 pregnant women, 45 clinicians from 3 clinical sites, and 15 policy makers. Eligible women were aged >18 years and >16 weeks pregnant or had recently given birth. Eligible clinicians and policy makers were involved in prenatal care. We asked the participants to navigate a computer-based DA. We asked the women about the usefulness of the DA and their self-confidence in decision-making. We asked all participants about usability, quality, acceptability, satisfaction with the content of the DA, and collected sociodemographic data. We explored participants' reactions to the computer-based DA and solicited suggestions. Our interview guide was based on the Mobile App Rating Scale. We performed descriptive analyses of the quantitative data and thematic deductive and inductive analyses of the qualitative data for each participant category. RESULTS: A total of 45 pregnant women, 14 clinicians, and 8 policy makers participated. Most pregnant women were aged between 25 and 34 years (34/45, 75%) and White (42/45, 94%). Most clinicians were aged between 35 and 44 years (5/14, 36%) and women (11/14, 79%), and all were White (14/14, 100%); the largest proportion of policy makers was aged between 45 and 54 years (4/8, 50%), women (5/8, 62%), and White (8/8, 100%). The mean usefulness score for preparing for decision-making for women was 80/100 (SD 13), and the mean self-efficacy score was 88/100 (SD 11). The mean usability score was 84/100 (SD 14) for pregnant women, 77/100 (SD 14) for clinicians, and 79/100 (SD 23) for policy makers. The mean global score for quality was 80/100 (SD 9) for pregnant women, 72/100 (SD 12) for clinicians, and 80/100 (SD 9) for policy makers. Regarding acceptability, participants found the amount of information just right (52/66, 79%), balanced (58/66, 88%), useful (38/66, 58%), and sufficient (50/66, 76%). The mean satisfaction score with the content was 84/100 (SD 13) for pregnant women, 73/100 (SD 16) for clinicians, and 73/100 (SD 20) for policy makers. Participants thought the DA could be more engaging (eg, more customizable) and suggested strategies for implementation, such as incorporating it into clinical guidelines. CONCLUSIONS: Pregnant women, clinicians, and policy makers found the DA usable and useful. The next steps are to incorporate user suggestions for improving engagement and implementing the computer-based DA in clinical practice.

Sex-specific association of high maternal psychological stress during pregnancy on newborn birthweight.

Birthweight is an important predictor of newborn health and has been linked to maternal psychological stress during pregnancy. However, it is unclear whether prenatal stress affects birthweight similarly for both male and female infants. We used a well-established pregnancy cohort to investigate the impact of high maternal psychological stress during pregnancy on birthweight as a function of infant sex. Overall, 5702 mother-newborn pairs were analysed. Of these, 198 mothers reported high levels of stress using the Psychological Stress Measure (nine-items version; PSM-9). Maternal psychological stress was assessed between the 24th and 28th week of gestation and analyses were performed jointly and independently as a function of neonatal sex (separate analyses for male and female infants). Newborns exposed to high maternal psychological stress during pregnancy (a score above 26 measured using the PSM-9 questionnaire, corresponding to >97.5th percentile) were compared to newborns of mothers who reported lower stress. ANCOVAs revealed that high levels of maternal stress during pregnancy were linked to infant birthweight as a function of infant sex. Male infants of mothers who reported high levels of stress had a greater birthweight whereas female infants had a lower birthweight under the same conditions, in comparison to mothers who did not report greater levels of stress. Although the effect size is small, these results underline the possibility that male and female fetuses may use different strategies when adapting to maternal adversity and highlight the need to consider infant sex as a moderator of the association between maternal psychological stress during pregnancy and infant birthweight.

Proteomic Analysis of Maternal Urine for the Early Detection of Preeclampsia and Fetal Growth Restriction.

BACKGROUND: To explore the use of maternal urine proteome for the identification of preeclampsia biomarkers. METHODS: Maternal urine samples from women with and without preeclampsia were used for protein discovery followed by a validation study. The targeted proteins of interest were then measured in urine samples collected at 20-24 and 30-34 weeks among nine women who developed preeclampsia, one woman with fetal growth restriction, and 20 women with uncomplicated pregnancies from a longitudinal study. Protein identification and quantification was obtained using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Among the 1108 urine proteins quantified in the discovery study, 21 were upregulated in preeclampsia and selected for validation. Nineteen (90%) proteins were confirmed as upregulated in preeclampsia cases. Among them, two proteins, ceruloplasmin and serpin A7, were upregulated at 20-24 weeks and 30-34 weeks of gestation (p < 0.05) in cases of preeclampsia, and could have served to identify 60% of women who subsequently developed preeclampsia and/or fetal growth restriction at 20-24 weeks of gestation, and 78% at 30-34 weeks, for a false-positive rate of 10%. CONCLUSIONS: Proteomic profiling of maternal urine can differentiate women with and without preeclampsia. Several proteins including ceruloplasmin and serpin A7 are upregulated in maternal urine before the diagnosis of preeclampsia and potentially fetal growth restriction.

Psychosocial stressors at work and inflammatory biomarkers: PROspective Quebec Study on Work and Health.

BACKGROUND: Chronic low-grade inflammation has been associated with high risk of several chronic diseases such as cardiovascular diseases, diabetes, depression, and dementia. As low-grade inflammation could be present long before the apparition of the disease, identifying modifiable risk factors could allow to act upstream. Psychosocial stressors at work have been suggested as modifiable risk factors of low-grade inflammation, but few longitudinal studies have evaluated the association between these stressors and inflammatory biomarkers, such as C-reactive protein (CRP) and interleukin-6 (IL-6). OBJECTIVE: This longitudinal study evaluate the associations between exposure to psychosocial stressors at work and CRP and IL-6, separately and combined into an inflammatory index. METHODS: Data came from a cohort of 9188 white-collar workers recruited in 1991-1993 (T1) and followed-up after 8 (T2, 1999-2000) and 24 (T3, 2015-2018) years. Participants included in this study were randomly selected at T3 for serum biomarkers studies (n = 2557). CRP and IL-6 were measured using standardized protocols. Psychosocial stressors at work were assessed at T2 according to recognized models: Karasek's Demand-Control-Support model and Siegrist's Effort-Reward Imbalance (ERI) model, using validated questionnaires. High job strain was defined by an exposure to high psychological demand combined with low job control, and iso-strain was defined by an exposure to high job strain combined with low social support at work. ERI was defined by an imbalance between psychological demand and social, economic, and organizational reward. Several covariates were considered including sociodemographic, anthropometric, and lifestyle characteristics, and comorbidities. Prevalence ratios (PRs) and 95% confidence interval (CI) for the highest quartile of CRP, IL-6 and inflammatory index at T3 according to psychosocial stressors at work measured at T2 were calculated using generalized estimating equations. Multiple imputation and inverse probability of censoring weighting were done. RESULTS: In men, an association was observed between exposure to iso-strain and the inflammatory index (PR of 1.42 (95% CI: 1.06;1.90)), mainly among men aged less than 65 years (PR of 2.00 (95% CI: 1.37;2.92)). In this same age group, associations with inflammatory biomarkers were also observed among men with exposure to ERI, and among women with exposure to low reward at work or moderate social support at work. CONCLUSION: These results suggest that psychosocial stressors at work may increase low-grade inflammation. However, further studies are needed to corroborate these results and to clarify the potential differences between men and women. As these stressors are frequent and modifiable, their reduction is important for public health and could play a role in the primary prevention of chronic diseases.

Cumulative exposure to psychosocial stressors at work and global cognitive function: the PROspective Quebec Study on Work and Health.

OBJECTIVES: Psychosocial stressors at work have been proposed as modifiable risk factors for mild cognitive impairment (MCI). This study aimed to evaluate the effect of cumulative exposure to psychosocial stressors at work on cognitive function. METHODS: This study was conducted among 9188 white-collar workers recruited in 1991-1993 (T1), with follow-ups 8 (T2) and 24 years later (T3). After excluding death, losses to follow-up and retirees at T2, 5728 participants were included. Psychosocial stressors at work were measured according to the Karasek's questionnaire. Global cognitive function was measured with the Montreal Cognitive Assessment. Cumulative exposures to low psychological demand, low job control, passive job and high strain job were evaluated using marginal structural models including multiple imputation and inverse probability of censoring weighting. RESULTS: In men, cumulative exposures (T1 and T2) to low psychological demand, low job control or passive job were associated with higher prevalences of more severe presentation of MCI (MSMCI) at T3 (Prevalence ratios (PRs) and 95% CIs of 1.50 (1.16 to 1.94); 1.38 (1.07 to 1.79) and 1.55 (1.20 to 2.00), respectively), but not with milder presentation of MCI. In women, only exposure to low psychological demand or passive job at T2 was associated with higher prevalences of MSMCI at T3 (PRs and 95% CI of 1.39 (0.97 to 1.99) and 1.29 (0.94 to 1.76), respectively). CONCLUSIONS: These results support the deleterious effect of a low stimulating job on cognitive function and the cognitive reserve theory. Psychosocial stressors at work could be part of the effort for the primary prevention of cognitive decline.

Frequency, timing and risk factors for primary maternal cytomegalovirus infection during pregnancy in Quebec.

INTRODUCTION: Maternal Cytomegalovirus (CMV) infection in the first trimester (T1) of pregnancy is a public health concern, as it increases the risk of severe neurodevelopmental outcomes associated with congenital infection compared to infections occurring later during pregnancy. OBJECTIVES: To determine CMV seroprevalence in T1 of pregnancy, its trend, risk factors and the incidence rate of primary infection during pregnancy. METHODS: Using the biobank of the prospective cohort "Grossesse en Santé de Québec" collected between April 2005 and March 2010 at the Québec-Laval Hospital, Québec, Canada, maternal CMV serology was determined using Abbott Architect Chemiluminescence microparticle immunoassays for immunoglobulin G(IgG), immunoglobulin M(IgM) titration and IgG avidity testing. Changepoint detection analysis was used to assess temporal trends. Risk factors associated with seropositivity were determined by multivariable logistic regression. RESULTS: CMV seroprevalence in T1 of pregnancy was 23.4% (965/4111, 95% CI, 22.1-24.7%). The incidence rate for CMV primary infection during pregnancy was 1.8 (95% CI, 1.2-2.6) per 100 person-years. No changepoint was identified in the maternal CMV-seroprevalence trend. Multivariable analyses showed that T1 maternal CMV seropositivity was associated with having one child OR 1.3 (95% CI, 1.10-1.73) or two or more children OR 1.5 (95%CI, 1.1-2.1), ethnicity other than Caucasian OR 2.1 (95% CI, 1.1-3.8) and country of birth other than Canada and the USA OR 2.8 (95% CI, 1.5-4.9). CONCLUSIONS: In this cohort, maternal seroprevalence in T1 of pregnancy and seroconversion rate were low. This information and identified risk factors could help guide the development and implementation of preventive actions and evidence-based health policies to prevent CMV infection during pregnancy.

First-Trimester Preterm Preeclampsia Screening in Nulliparous Women: The Great Obstetrical Syndrome (GOS) Study.

OBJECTIVES: To estimate the ability of a combination of first-trimester markers to predict preterm preeclampsia in nulliparous women. METHODS: We conducted a prospective cohort study of nulliparous women with singleton gestations, recruited between 110 and 136 weeks gestation. Data on the following were collected: maternal age; ethnicity; chronic diseases; use of fertility treatment; body mass index; mean arterial blood pressure (MAP); serum levels of pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), alpha fetoprotein (AFP), free beta human chorionic gonadotropin (ß-hCG); and mean uterine artery pulsatility index (UtA-PI). We constructed a proportional hazard model for the prediction of preterm preeclampsia selected based on the Akaike information criterion. A receiver operating characteristic curve was created with the predicted risk from the final model. Our primary outcome was preterm preeclampsia and our secondary outcome was a composite of preeclampsia, small for gestational age, intrauterine death, and preterm birth. RESULTS: Among 4659 nulliparous women with singleton gestations, our final model included 4 variables: MAP MoM, log10PlGF MoM, log10AFP MoM and log10UtA-PI MoM. We obtained an area under the curve of 0.84 (95% CI 0.75-0.93) with a detection rate of preterm preeclampsia of 55% (95% CI 37%-73%) and a false-positive rate of 10%. Using a risk cut-off with a false-positive rate of 10%, the positive predictive value for our composite outcome was 33% (95% CI 29%-37%). CONCLUSIONS: The combination of MAP, maternal serum PlGF and AFP, and UtA-PI are useful to identify nulliparous women at high risk of preterm preeclampsia but also at high risk of other great obstetrical syndromes.

Impact of maternal prenatal psychological stress on birth weight.

OBJECTIVE: The study aimed to evaluate the impact of prenatal maternal stress on birth weight using a large cohort of predominantly White women living in an urban area. METHOD: Women were recruited between 2005 and 2010. Data collection took place between the 24th and the 28th week of gestation. The Measure of Psychological Stress (MSP-9), a validated tool to assess stress symptoms, was used to collect data on prenatal maternal stress (independent variable). Birth weight (dependent variable) was classified as low birth weight (<2,500 g), normal birth weight (2,500-4,000 g), and macrosomia (>4,000 g). Adjusted odds ratios (aOR) were obtained after performing multivariate logistic regressions adjusted for potential cofounders. At the final stage, 5,721 women were included in analysis. RESULTS: When compared with women experiencing low stress, participants with high stress scores were at increased risk of delivering a newborn with low birth weight before adjustment (OR = 2.06, 95% CI [1.04, 4.09]), but after adjustment, only a nonsignificant trend remained. However, women experiencing intermediate and high levels of stress were at increased risk of delivering a newborn with macrosomia, even after adjustment (aOR = 1.23, [1.02, 1.49]) and (aOR = 1.76, [1.11, 2.77]) compared to those who scored low on the psychological stress scale. CONCLUSION: Women exposed to high psychological stress during the second trimester (24th to 28th weeks) of pregnancy have a 1.8-fold increased risk for delivering a newborn with macrosomia when compared to women exposed to low psychological stress. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Specific inflammatory profile in each pregnancy complication: A comparative study.

PROBLEM: Pre-eclampsia (PE), preterm birth (PTB) and intra-uterine growth restriction (IUGR) affect 5%-12% of pregnancies. They have been associated with placental inflammation, although the detection of inflammatory mediators in the maternal circulation is still controversial. Our goal was to determine the inflammatory changes occurring in the second part of pregnancy to identify profiles distinguishing pathological pregnancies from each other. METHOD OF STUDY: We performed a nested case-control study of 200 women randomly selected from a cohort recruited at the CHU de Quebec-Universite Laval, Quebec, Canada. Women with uncomplicated term pregnancy (CTRL); PE (severe or not); PTB or IUGR (N = 50/each) were included. Plasma samples, obtained from the late second trimester and at delivery, were analysed for over 30 selected mediators (including cytokines/alarmins), by multiplex, ELISA or specific assays. Demographic and obstetrical information were obtained for classification. RESULTS: In CTRL, we observed significant differences between 2nd trimester and delivery, with increased levels of inflammatory mediators (ex. MCP-1, IL-6), supporting an inflammatory profile towards term. Increased levels of IL-6, CXCL10 and CRP were observed in PE as compared to CTRL. In PTB, we observed increased CXCL9 in 2nd trimester and decreased progesterone at delivery. In IUGR, increased HMGB1 and IL-1α were observed only in the 2nd trimester. CONCLUSIONS: Our work showed significant inflammatory changes in uncomplicated pregnancies towards delivery, supporting that normal delivery is pro-inflammatory, although not to the same extent as in pathological pregnancies. Inflammatory profiles are specific to each pregnancy complication which may help to understand the contribution of inflammation to the clinical presentation of these conditions.

Study of sRAGE, HMGB1, AGE, and S100A8/A9 Concentrations in Plasma and in Serum-Extracted Extracellular Vesicles of Pregnant Women With Preterm Premature Rupture of Membranes.

Preterm premature rupture of membranes (PPROM), defined as rupture of fetal membranes prior to 37 weeks of gestation, complicates approximately 2-4% of pregnancies and is responsible for 40% of all spontaneous preterm births. PPROM arises from complex pathophysiological pathways with a key actor: inflammation. Sterile inflammation is a feature of senescence-associated fetal membrane maturity. During specific steps of sterile inflammation, cells also release highly inflammatory damage-associated molecular pattern markers (DAMPs), such as high-mobility group box 1 (HMGB1) or S100A8/A9, known to link and activate the receptor for advanced glycation end products (RAGE). The objective of this study was to measure longitudinally during pregnancy concentrations of the soluble form of RAGE (sRAGE) and its main ligands (AGE, HMGB1, S100A8/A9) in blood specimens. We studied 246 pregnant women (82 with PPROM and 164 matched control pregnant women without complications) from a cohort of 7,866 pregnant women recruited in the first trimester and followed during pregnancy until delivery. sRAGE, AGE, HMGB1, and S100A8/A9 concentrations were measured in plasma and in serum-extracted extracellular vesicles from first trimester (T1), second trimester (T2), and delivery (D). In plasma, we observed, in both PPROM and control groups, (i) a significant increase of HMGB1 concentrations between T1 vs. T2, T1 vs. D, but not between T2 vs. D; (ii) a significant decrease of sRAGE concentrations between T1 and T2 and a significant increase between T2 and D; (iii) a significant decrease of AGE from T1 to D; (iv) no significant variation of S100A8/A9 between trimesters. In intergroup comparisons (PPROM vs. control group), there were no significant differences in time variation taking into account the matching effects. There was a correlation between plasma and serum-extracted extracellular vesicle concentrations of sRAGE, AGE, HMGB1, and S100A8/A9. Our results suggest that the rupture of fetal membranes (physiological or premature) is accompanied by a variation in plasma concentrations of sRAGE, HMGB1, and AGE. The study of RAGE and its main ligands in extracellular vesicles did not give additional insight into the pathophysiological process conducting to PPROM.

Vitamin D status, cognitive decline and incident dementia: the Canadian Study of Health and Aging.

OBJECTIVE: Vitamin D could prevent cognitive decline because of its neuroprotective, anti-inflammatory and antioxidant properties. This study aimed to evaluate the associations of plasma 25-hydroxyvitamin D (25(OH)D) concentrations with global cognitive function and incident dementia, including Alzheimer's disease (AD). METHODS: The Canadian Study of Health and Aging is a 10-year cohort study of a representative sample of individuals aged 65 years or older. A total of 661 subjects initially without dementia with frozen blood samples and follow-up data were included. Global cognitive function was measured using the validated Modified Mini-Mental State (3MS) examination. A consensus diagnosis of all-cause dementia and AD was made between the physician and the neuropsychologist according to published criteria. Cognitive decline for a 5-year increase in age at specific 25(OH)D concentrations was obtained using linear mixed models with repeated measures. Hazard ratios of incident dementia and AD were obtained using semi-parametric proportional hazards models with age as time scale. RESULTS: Over a mean follow-up of 5.4 years, 141 subjects developed dementia of which 100 were AD. Overall, no significant association was found between 25(OH)D and cognitive decline, dementia or AD. Higher 25(OH)D concentrations were associated with an increased risk of dementia and AD in women, but not in men. CONCLUSION: This study does not support a protective effect of vitamin D status on cognitive function. Further research is needed to clarify the relation by sex.

Cord blood S100B: reference ranges and interest for early identification of newborns with brain injury.

Background Neurological complications are common in the premature and full-term neonates admitted to the intensive care unit, but the diagnosis of these complications is often difficult to make. S100B protein, measured in cord blood, may represent a valuable tool to better identify patients at risk of brain injury. Methods As a first step, we established S100B cord blood serum reference intervals from 183 preterm and 200 full-term neonates. We then measured cord blood serum S100B to identify neurological complications in 272 neonates hospitalized at the neonatal intensive care unit (NICU). Diagnosis of brain injury relied on imaging examination. Results The 95th percentiles of S100B concentration in cord blood were established as 1.21 µg/L for the 383 neonates, 0.96 µg/L for full-term neonates and 1.36 µg/L for premature neonates. Among the 272 neonates hospitalized at the NICU, 11 presented neurological complications. Using 1.27 µg/L as the optimal sensitivity/specificity threshold, S100B differentiate neonates with and without neurological complications with a sensitivity of 45.5% (95% confidence intervals [CI]: 16.7-76.6) and a specificity of 88.9% (95% CI: 84.4-92.4) (p = 0.006). In combination with arterial pH (<7.25), sensitivity increased to 90.9% (95% CI: 58.7-99.8), while specificity was 51.2% (95% CI: 44.8-57.7). The sensitivity is significantly (p = 0.03) increased in comparison to S100B alone. The specificity is significantly higher with S100B only than with pH + S100B (p < 0.001). Conclusions Cord blood S100B protein, in combination with arterial cord blood pH, has the potential to help clinicians to detect at birth neurological complications in neonates hospitalized in an NCIU.