Screening For Pregnancy Endpoints Study Research Articles

Early pregnancy cardio metabolic risk factors and the prevalence of metabolic syndrome 10 years after the first pregnancy.

We aimed to compare risk factors for CVD 10 years postpartum among women who had ≥ 1 compared to no cardio metabolic risk factor in early first pregnancy. Women of the SCOPE (Screening fOr Pregnancy Endpoints) study from Adelaide, South Australia were invited to participate in a cardiovascular risk assessment 10 years after the delivery of the first child. Data from 141 women who completed all the assessments are included in the analyses. Compared to women who did not have any cardio metabolic risk factor at 15 ± 1 weeks' gestation during the first pregnancy, those who had ≥ 1 risk factor were 5.5 times more likely to have metabolic syndrome 10 years postpartum (aOR = 5.5, 95% CI 1.8-17.3, p = 0.004). Women who had ≥ 1cardio metabolic risk factor during the first pregnancy were more likely to be obese (p = 0.001), have high total cholesterol levels (p <0.001) or have increased insulin resistance (p <0.001) 10 years later compared to women who had no risk factor during the first pregnancy. 63.5% of the women with no cardio metabolic risk factor compared to 39% of women who had ≥ 1 risk factor in first pregnancy, had neither a complicated first pregnancy nor was diagnosed with MetS 10 years postpartum (p = 0.023). Cardio metabolic risk factors at the booking visit in the first pregnancy may be useful in identifying young women at risk of future CVD.

A screening test proposal for congenital defects based on maternal serum metabolomics profile

Historically, noninvasive techniques are only able to identify chromosomal anomalies that accounted for <50% of all congenital defects; the other congenital defects are diagnosed via ultrasound evaluations in the later stages of pregnancy. Metabolomic analysis may provide an important improvement, potentially addressing the need for novel noninvasive and multicomprehensive early prenatal screening tools. A growing body of evidence outlines notable metabolic alterations in different biofluids derived from pregnant women carrying fetuses with malformations, suggesting that such an approach may allow the discovery of biomarkers common to most fetal malformations. In addition, metabolomic investigations are inexpensive, fast, and risk-free and often generate high performance screening tests that may allow early detection of a given pathology. This study aimed to evaluate the diagnostic accuracy of an ensemble machine learning model based on maternal serum metabolomic signatures for detecting fetal malformations, including both chromosomal anomalies and structural defects. This was a multicenter observational retrospective study that included 2 different arms. In the first arm, a total of 654 Italian pregnant women (334 cases with fetuses with malformations and 320 controls with normal developing fetuses) were enrolled and used to train an ensemble machine learning classification model based on serum metabolomics profiles. In the second arm, serum samples obtained from 1935 participants of the New Zealand Screening for Pregnancy Endpoints study were blindly analyzed and used as a validation cohort. Untargeted metabolomics analysis was performed via gas chromatography-mass spectrometry. Of note, 9 individual machine learning classification models were built and optimized via cross-validation (partial least squares-discriminant analysis, linear discriminant analysis, naïve Bayes, decision tree, random forest, k-nearest neighbor, artificial neural network, support vector machine, and logistic regression). An ensemble of the models was developed according to a voting scheme statistically weighted by the cross-validation accuracy and classification confidence of the individual models. This ensemble machine learning system was used to screen the validation cohort. Significant metabolic differences were detected in women carrying fetuses with malformations, who exhibited lower amounts of palmitic, myristic, and stearic acids; N-α-acetyllysine; glucose; L-acetylcarnitine; fructose; para-cresol; and xylose and higher levels of serine, alanine, urea, progesterone, and valine (P<.05), compared with controls. When applied to the validation cohort, the screening test showed a 99.4%±0.6% accuracy (specificity of 99.9%±0.1% [1892 of 1894 controls correctly identified] with a sensitivity of 78%±6% [32 of 41 fetal malformations correctly identified]). This study provided clinical validation of a metabolomics-based prenatal screening test to detect the presence of congenital defects. Further investigations are needed to enable the identification of the type of malformation and to confirm these findings on even larger study populations.

Relative importance of metabolic syndrome components for developing gestational diabetes.

To assess the independent and joint contribution of the individual components of metabolic syndrome, and known risk factors for gestational diabetes (GDM), on risk of GDM. Two thousand nine hundred and fifteen women from Australia and New Zealand, who participated in The Screening for Pregnancy Endpoints Study (SCOPE), were included. Using the SCOPE clinical data set and biomarkers obtained at 14-16weeks' gestation, a logistic regression model was fitted to the binary outcome GDM, with individual metabolic syndrome components (waist circumference, blood pressure, glucose, HDL-C, triglycerides), recruitment site, and other established factors associated with GDM. Hierarchical partitioning was used to assess the relative contribution of each variable. Of the 2915 women, 103 women (3.5%) developed GDM. The deviance explained by the logistic regression model containing all variables was 18.65% and the AUC was 0.809. Seventy percent of the independent effect was accounted for by metabolic syndrome components. The highest independent relative contribution to GDM was circulating triglycerides (17 ± 3%), followed by waist circumference (13 ± 3%). Glucose and maternal BMI contributed 12 ± 2% and 12 ± 3%, respectively. The remaining factors had an independent relative contribution of < 10%. Triglyceride concentrations had the highest independent relative importance for risk of GDM. Increased focus for lowering triglycerides as an important risk factor for GDM is warranted.

The metabolic syndrome in pregnancy and its association with child telomere length.

The aim of this study was to determine whether presence of the metabolic syndrome in pregnancy associates with child telomere length or child anthropometry (weight, BMI) and BP, measured at 10years of age. The Screening for Pregnancy Endpoints study (SCOPE) was a multicentre, international prospective cohort of nulliparous pregnant women recruited from Australia, New Zealand, Ireland and the UK (N = 5628). The current analysis is a 10year follow-up of SCOPE pregnant women and their children, from the Australian cohort. Clinical data collected at 14-16weeks' gestation during the SCOPE study were used to diagnose the metabolic syndrome using IDF criteria. Telomere length, a biomarker of ageing, was assessed by quantitative PCR from children's saliva collected at 10years of age. In women who completed follow-up (n = 255), 20% had the metabolic syndrome in pregnancy. After adjusting for a range of confounders, children of mothers who had the metabolic syndrome in pregnancy had 14% shorter telomeres than children of mothers without the metabolic syndrome in pregnancy (mean difference -0.36 [95% CI -0.74, 0.01]). Height- and weight-for-age, and BMI z scores were similar in children of mothers who did and did not have the metabolic syndrome during pregnancy. Children of mothers who had the metabolic syndrome in pregnancy have shorter telomeres, a biomarker of accelerated ageing. These findings warrant further studies in larger cohorts of children, as well as investigations into whether telomere length measured in cord blood associates with telomere length in childhood.

Maternal Selenium, Copper and Zinc Concentrations in Early Pregnancy, and the Association with Fertility.

Trace elements such as zinc, copper, and selenium are essential for reproductive health, but there is limited work examining how circulating trace elements may associate with fertility in humans. The aim of this study was to determine the association between maternal plasma concentrations of zinc, copper, and selenium, and time to pregnancy and subfertility. Australian women (n = 1060) who participated in the multi-centre prospective Screening for Pregnancy Endpoints study were included. Maternal plasma concentrations of copper, zinc and selenium were assessed at 15 ± 1 weeks’ gestation. Estimates of retrospectively reported time to pregnancy were documented as number of months to conceive; subfertility was defined as taking more than 12 months to conceive. A range of maternal and paternal adjustments were included. Women who had lower zinc (time ratio, 1.20 (0.99–1.44)) or who had lower selenium concentrations (1.19 (1.01–1.40)) had a longer time to pregnancy, equivalent to a median difference in time to pregnancy of around 0.6 months. Women with low selenium concentrations were also at a 1.46 (1.06–2.03) greater relative risk for subfertility compared to women with higher selenium concentrations. There were no associations between copper and time to pregnancy or subfertility. Lower selenium and zinc trace element concentrations, which likely reflect lower dietary intakes, associate with a longer time to pregnancy. Further research supporting our work is required, which may inform recommendations to increase maternal trace element intake in women planning a pregnancy.

Relationships of maternal body mass index and plasma biomarkers with childhood body mass index and adiposity at 6years: The Children of SCOPE study.

Maternal obesity has been implicated in the origins of childhood obesity through a suboptimal environment in-utero. We examined relationships of maternal early pregnancy body mass index (BMI), overweight/obesity, and plasma biomarkers of obesity, inflammation, insulin resistance, and placental function with measures of childhood BMI and adiposity. BMI z-score, sum of skinfold thicknesses (SST), body fat percentage (BFP, by bioelectrical impedance), and waist, arm, and hip circumferences were measured in 1173 6-year-old children of nulliparous pregnant women in the Screening for Pregnancy Endpoints (SCOPE) study, New Zealand. Relationships of maternal early pregnancy (15weeks' gestation) BMI and biomarkers with these childhood anthropometric measures were assessed by linear regression, with appropriate adjustment. 28.1% of mothers were classified as overweight and 10.1% with obesity; compared with normal weight mothers, the BFP of their children were 5.3% higher (0.16 SD [95% CI, 0.04-0.29] p=.01) and 7.8% higher (0.27 [0.08-0.47] p=.006) with comparable values for BMI z-score and arm, waist, and hip circumferences. Early pregnancy maternal BMI and plasma placental growth factor (PlGF) were associated with higher child's SST, BMI z-score, hip circumference, and BFP. None of the metabolic or inflammatory maternal biomarkers were associated with childhood obesity. In this contemporary large prospective cohort study with extensive maternal/childhood phenotyping and a high prevalence of maternal overweight/obesity, we found independent relationships of maternal early pregnancy BMI with childhood BMI and adiposity; similar associations were observed with PlGF, which may imply a role for placenta function in the developmental programming of childhood obesity risk.

Lifestyle and pregnancy complications in polycystic ovary syndrome: The SCOPE cohort study.

To investigate the risk of pregnancy complications in women with and without polycystic ovary syndrome after consideration of lifestyle factors. Prospective cohort. Participants (n=5628) were apparently healthy nulliparous women with singleton pregnancies from the Screening for Pregnancy Endpoints study in New Zealand, Australia, United Kingdom and Ireland. Multivariable regression models were performed assessing the association of self-reported polycystic ovary syndrome status with pregnancy complications with consideration of lifestyle factors at the 15th week of gestation. Women with polycystic ovary syndrome (n=354) were older, had a higher socio-economic index and body mass index and were less likely to consume alcohol and smoke but more likely to do vigorous exercise and take multivitamins. In univariable analysis, polycystic ovary syndrome was associated with increased risk of gestational diabetes (OR: 2.2, 95% CI: 1.2, 4.0). In multivariable models, polycystic ovary syndrome was only significantly associated with decreased risk of large for gestational age (OR: 0.62, 95% CI: 0.40, 0.98) with a population attributable risk of 0.22%. None of the other outcomes were attributable to polycystic ovary syndrome status. Polycystic ovary syndrome is associated with a lower risk of large for gestational age infants. In this low-risk population, the risk of pregnancy complications was not increased in women with polycystic ovary syndrome who were following a healthy lifestyle. Further studies are warranted assessing the contribution of lifestyle factors to the risk of pregnancy complications in higher risk groups of women with and without polycystic ovary syndrome.

Association between caesarean section delivery and obesity in childhood: a longitudinal cohort study in Ireland

ObjectivesTo investigate the association between caesarean section (CS) birth and body fat percentage (BF%), body mass index (BMI) and being overweight or obese in early childhood.DesignProspective longitudinal cohort study.SettingBabies After...

Pre-pregnancy fast food and fruit intake is associated with time to pregnancy.

STUDY QUESTION Is preconception dietary intake associated with reduced fecundity as measured by a longer time to pregnancy (TTP)? SUMMARY ANSWER Lower intake of fruit and higher intake of fast food in the preconception period were both associated with a longer TTP. WHAT IS KNOWN ALREADY Several lifestyle factors, such as smoking and obesity, have consistently been associated with a longer TTP or infertility, but the role of preconception diet in women remains poorly studied. Healthier foods or dietary patterns have been associated with improved fertility, however, these studies focused on women already diagnosed with or receiving treatments for infertility, rather than in the general population. STUDY DESIGN, SIZE, DURATION This was a multi-center pregnancy-based cohort study of 5628 nulliparous women with low-risk singleton pregnancies who participated in the Screening for Pregnancy Endpoints (SCOPE) study. PARTICIPANTS/MATERIALS, SETTING, METHODS A total of 5598 women were included. Data on retrospectively reported TTP and preconception dietary intake were collected during the first antenatal study visit (14-16 weeks' gestation). Dietary information for the 1 month prior to conception was obtained from food frequency questions for fruit, green leafy vegetables, fish and fast foods, by a research midwife. Use of any fertility treatments associated with the current pregnancy was documented (yes, n = 340, no, n = 5258). Accelerated failure time models with log normal distribution were conducted to estimate time ratios (TR) and 95% CIs. The impact of differences in dietary intake on infertility (TTP >12 months) was compared using a generalized linear model (Poisson distribution) with robust variance estimates, with resulting relative risks (RR) and 95% CIs. All analyses were controlled for a range of maternal and paternal confounders. Sensitivity analyses were conducted to explore potential biases common to TTP studies. MAIN RESULTS AND THE ROLE OF CHANCE Lower intakes of fruit and higher intakes of fast food were both associated with modest increases in TTP and infertility. Absolute differences between the lowest and highest categories of intake for fruit and fast food were in the order of 0.6-0.9 months for TTP and 4-8% for infertility. Compared with women who consumed fruit ≥3 times/day, the adjusted effects of consuming fruit ≥1- 0- 0-<2 times/week, or no fast food, corresponded to an 18, 34 and 41% reduced risk of infertility (Ptrend <0.001). Pre-pregnancy intake of green leafy vegetables or fish were not associated with TTP or infertility. Estimates remained stable across a range of sensitivity analyses. LIMITATIONS, REASONS FOR CAUTION Collection of dietary data relied on retrospective recall and evaluated a limited range of foods. Paternal dietary data was not collected and the potential for residual confounding cannot be eliminated. Compared to prospective TTP studies, retrospective TTP studies are prone to a number of potential sources of bias. WIDER IMPLICATIONS OF THE FINDINGS These findings underscore the importance of considering preconception diet for fecundity outcomes and preconception guidance. Further research is needed assessing a broader range of foods and food groups in the preconception period. STUDY FUNDING/COMPETING INTEREST(S) The SCOPE database is provided and maintained by MedSciNet AB (http://medscinet.com). The Australian SCOPE study was funded by the Premier's Science and Research Fund, South Australian Government (http://www.dfeest.sa.gov.au/science-research/premiers-research-and-industry-fund). The New Zealand SCOPE study was funded by the New Enterprise Research Fund, Foundation for Research Science and Technology; Health Research Council (04/198); Evelyn Bond Fund, Auckland District Health Board Charitable Trust. The Irish SCOPE study was funded by the Health Research Board of Ireland (CSA/2007/2; http://www.hrb.ie). The UK SCOPE study was funded by National Health Service NEAT Grant (Neat Grant FSD025), Biotechnology and Biological Sciences Research council (www.bbsrc.ac.uk/funding; GT084) and University of Manchester Proof of Concept Funding (University of Manchester); Guy's and St. Thomas' Charity (King's College London) and Tommy's charity (http://www.tommys.org/; King's College London and University of Manchester); and Cerebra UK (www.cerebra.org.uk; University of Leeds). L.E.G. is supported by an Australian National Health and Medical Research Council (NHMRC) Early Career Fellowship (ID 1070421). L.J.M. is supported by a SACVRDP Fellowship; a program collaboratively funded by the National Heart Foundation, the South Australian Department of Health and the South Australian Health and Medical Research Institute. L.C.K. is supported by a Science Foundation Ireland Program Grant for INFANT (12/RC/2272). C.T.R. was supported by a National Health and Medical Research Council (NHMRC) Senior Research Fellowship (GNT1020749). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER Not applicable.

Gene-by-Activity Interactions on Obesity Traits of 6-Year-Old New Zealand European Children: A Children of SCOPE Study.

The decline of physical activity in children is considered an important determinant to explain the rising rates of obesity. However, this risk may be augmented in children who are genetically susceptible to increased weight gain. We hypothesized that a sedentary lifestyle and moderate activity will interact with genetic loci, resulting in differential effects in relation to obesity risk. We recruited 643 European children born to participants in the New Zealand-based Screening for Pregnancy Endpoints (SCOPE) study. Seventy gene variants were evaluated by the Sequenom assay. Interaction analyses were performed between the genetic variants and the activity type derived from actigraphy, in relation to percentage body fat. We found a statistically significant association between increased proportions of sedentary activity with increased percentage body fat scores (P = .012). The OLFM4-9568856 (P = .01) and GNPDA2-rs10938397 (P = .044) gene variants showed genotype differences with proportions of sedentary activity. Similarly, the OLFM4-9568856 (P = .021), CLOCK-rs4864548 (P = .029), and LEPR-1045895 (P = .047) showed genotype differences with proportions of moderate activity. We found evidence for unadjusted gene-by-activity interactions of SPACA3/SPRASA-rs16967845, PFKP-rs6602024, and SH2B1-rs7498665 on percentage body fat scores. These findings indicate a differential effect of physical activity in relation to obesity risk, suggesting that children genetically predisposed to increased weight gain may benefit from higher levels of moderate activity.

Risk Factors and Birth Outcomes of Anaemia in Early Pregnancy in a Nulliparous Cohort

BackgroundAnaemia in pregnancy is a major public health and economic problem worldwide, that contributes to both maternal and fetal morbidity and mortality.ObjectiveThe aim of the study was to calculate the prevalence of anaemia in early pregnancy in a cohort of ‘low risk’ women participating in a large international multicentre prospective study (n = 5 609), to identify the modifiable risk factors for anaemia in pregnancy in this cohort, and to compare the birth outcomes between pregnancies with and without anaemia in early gestation.MethodsThe study is an analysis of data that were collected prospectively during the Screening for Pregnancy Endpoints study. Anaemia was defined according to the World Health Organization’s definition of anaemia in pregnancy (haemoglobin < 11g/dL). Binary logistic regression with adjustment for potential confounders (country, maternal age, having a marital partner, ethnic origin, years of schooling, and having paid work) was the main method of analysis.ResultsThe hallmark findings were the low prevalence of anaemia (2.2%), that having no marital partner was an independent risk factor for having anaemia (OR 1.34, 95% CI 1.01-1.78), and that there was no statistically significant effect of anaemia on adverse pregnancy outcomes (small for gestational age, pre-tem birth, mode of delivery, low birth weight, APGAR score < 7 at one and five minutes). Adverse pregnancy outcomes were however more common in those with anaemia than in those without.ConclusionIn this low risk healthy pregnant population we found a low anaemia rate. The absence of a marital partner was a non-modifiable factor, albeit one which may reflect a variety of confounding factors, that should be considered for addition to anaemia’s conceptual framework of determinants. Although not statistically significant, clinically, a trend towards a higher risk of adverse pregnancy outcomes was observed in women that were anaemic in early pregnancy.

Assessment of glycogen phosphorylase isoenzyme BB as a biomarker for pre-eclampsia and small for gestational age

BackgroundGlycogen phosphorylase is a key enzyme in the regulation of glycogen metabolism and consists of three isoenzymes, including glycogen phosphorylase isoenzyme BB (GPBB). Pre-eclampsia, gestational hypertension, and small-for-gestational-age (SGA) infants are complications in about 15% of all nulliparous pregnancies. Biomarkers for these adverse pregnancy outcomes remain elusive. GPBB has been proposed as a potential biomarker for the detection of these adverse outcomes. We aimed to investigate this hypothesis. MethodsBlood samples from women with pre-eclampsia or SGA were analysed from the time of disease presentation and from samples collected at 15 and 20 weeks' gestation. They were compared with control samples obtained from women recruited to the Screening for Pregnancy Endpoints (SCOPE) study. These control samples were from healthy women with uncomplicated pregnancies matched for age, ethnicity, parity, body-mass index, and gestational age. GPBB concentrations were measured with ELISA (Diacordon, Diagenics, Essen, Germany). FindingsSignificant differences in GPBB were observed between all three gestations (p=0·03). GPBB concentrations were higher in women with pre-eclampsia than in controls at the time of disease presentation (term pre-eclampsia n=14, median 22·2 ng/mL [IQR 15·1–39·8] vs 16·9 [10·4–19·1], p=0·04; preterm pre-eclampsia n=11, 23·1 [11·2–30·9] vs 17·2 [9·8–19·1], p=0·04) and at 20 weeks' gestation (n=39, 23·0 [15·6–31·4] vs 17·0 [13·4–23·6]; p=0·04). GPBB concentrations were also significantly higher in women with SGA than in controls at the time of disease detection (n=23, 22·7 [12·6–25·5] vs 17·0 [9·8–18·0]; p=0·03) but significantly less than in controls at 15 weeks' gestation before disease detection (n=25, 16·0 [12·1–23·2] vs 22·2 [17·0–28·9]; p=0·02). InterpretationWe have shown that significant variation of GPBB concentrations occurs in normal pregnancy, pre-eclampsia, and SGA pregnancies. GPBB in healthy pregnancy lowers as pregnancy progresses from the first to the third trimester. GPBB might, therefore, be useful as a biomarker in early pregnancy and at the time of disease in the prediction of both preterm and term pre-eclampsia and SGA. FundingNational Institute for Health Research, SCOPE Study was funded by the Health Research Board. This work was performed in the Irish Centre for Fetal and Neonatal Translational Research and partly supported by Science Foundation Ireland.

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Objectives Venous thromboembolism (VTE) remains a leading cause of maternal mortality. An effective predictive test would be very clinically important. Measurements of Calibrated Automated Thrombogram (CAT) parameters in the presence and absence of thrombomodulin have been correlated with risk of recurrent VTE. D-Dimers and soluble P-selectin are markers of thrombosis. We aimed to evaluate the CAT assay, D-Dimers and P-selectin as potential predictive tools for thrombosis in pregnancy. Methods The SCOPE (Screening for Pregnancy Endpoints) study is a prospective, multicentre cohort study of nulliparous women with the primary aim of developing screening tests to predict pre-eclampsia, small for gestational age infants and spontaneous preterm birth. Twenty patients with documented VTE in pregnancy or postpartum and 61 controls were identified from the SCOPE cohort (total of 5000 pregnant women). The control group was matched for age, gestation, BMI and ethnicity. CAT assay with and without presence of thrombomodulin was performed on citrated plasma collected at 15 weeks gestation, prior to any thrombotic event. Normalised thrombomodulin sensitivity ratios (n-TMsr) were calculated. D-dimers and P-selectin were also measured by ELISA. Results There were no significant difference in ETP, peak thrombin, lagtime , time to peak, n-TMsr, D-dimer or P-selectin levels between patients who subsequently developed VTE compared with those who remained thrombosis free. Standardisation of CAT assay is needed to ensure it is a clinically effective predictive tool. Conclusions CAT assay, D-dimer and P-selectin levels are not useful as predictors of VTE in a low risk population of primigravida screened at 15 weeks. Disclosures S.K. Ismail: None. L. Norris: None. A. Khashan: None. N. Simpson: None. G. Dekker: None. J. Myers: None. L. McCowan: None. L. Kenny: None. J.R. Higgins: None.

The role of prepregnancy pelvic floor dysfunction in postnatal pelvic morbidity in primiparous women.

Little is known about the natural history of pelvic floor dysfunction (PFD). We investigated the association between prepregnancy and postnatal PFD in premenopausal primiparous women and the associated effect of mode of delivery. A prospective cohort study, nested within the parent Screening for Pregnancy Endpoints (SCOPE) study, was performed in a tertiary referral teaching hospital with approximately 9,000 deliveries per annum. The validated Australian pelvic floor questionnaire was completed by 872 nulliparous women at 15 weeks' gestation, at the time of recruitment to the SCOPE study and 1 year postnatally. The questionnaire contained four sections with questions about urinary, faecal, prolapse and sexual dysfunction. One year postnatally urinary dysfunction was present in 73%, faecal in 49%, prolapse in 14% and sexual in 58% of participants. Prepregnancy PFD persistent postnatally constituted more than half of total PFD. The majority of affected (71%) had multicompartment involvement. Participants with persistent PFD had higher prevalence of severe symptoms and bothersome symptoms within the group. Severity of prepregnancy PFD worsened in <15% cases postnatally. The main damage to the pelvic floor seems to occur in the majority of patients before first pregnancy, where first childbearing does not worsen prepregnancy PFD in the majority of cases. Pregnancy appears to affect more pre-existing symptoms of urgency and urge incontinence comparing to stress incontinence. Caesarean section seems to be more protective against postnatal worsening of prepregnancy PFD comparing to de novo onset pathology. However, larger studies are needed to confirm these findings.

A Label-free Selected Reaction Monitoring Workflow Identifies a Subset of Pregnancy Specific Glycoproteins as Potential Predictive Markers of Early-onset Pre-eclampsia

Pre-eclampsia (PE) is a serious complication of pregnancy with potentially life threatening consequences for both mother and baby. Presently there is no test with the required performance to predict which healthy first-time mothers will go on to develop PE. The high specificity, sensitivity, and multiplexed nature of selected reaction monitoring holds great potential as a tool for the verification and validation of putative candidate biomarkersfor disease states. Realization of this potential involves establishing a high throughput, cost effective, reproducible sample preparation workflow. We have developed a semi-automated HPLC-based sample preparation workflow before a label-free selected reaction monitoring approach. This workflow has been applied to the search for novel predictive biomarkers for PE. To discover novel candidate biomarkers for PE, we used isobaric tagging to identify several potential biomarker proteins in plasma obtained at 15 weeks gestation from nulliparous women who later developed PE compared with pregnant women who remained healthy. Such a study generates a number of "candidate" biomarkers that require further testing in larger patient cohorts. As proof-of-principle, two of these proteins were taken forward for verification in a 100 women (58 PE, 42 controls) using label-free SRM. We obtained reproducible protein quantitation across the 100 samples and demonstrated significant changes in protein levels, even with as little as 20% change in protein concentration. The SRM data correlated with a commercial ELISA, suggesting that this is a robust workflow suitable for rapid, affordable, label-free verification of which candidate biomarkers should be taken forward for thorough investigation. A subset of pregnancy-specific glycoproteins (PSGs) had value as novel predictive markers for PE.

Integrated Proteomics Pipeline Yields Novel Biomarkers for Predicting Preeclampsia

Preeclampsia, a hypertensive pregnancy complication, is largely unpredictable in healthy nulliparous pregnant women. Accurate preeclampsia prediction in this population would transform antenatal care. To identify novel protein markers relevant to the prediction of preeclampsia, a 3-step mass spectrometric work flow was applied. On selection of candidate biomarkers, mostly from an unbiased discovery experiment (19 women), targeted quantitation was used to verify and validate candidate biomarkers in 2 independent cohorts from the SCOPE (SCreening fOr Pregnancy Endpoints) study. Candidate proteins were measured in plasma specimens collected at 19 to 21 weeks' gestation from 100 women who later developed preeclampsia and 200 women without preeclampsia recruited from Australia and New Zealand. Protein levels (n=25), age, and blood pressure were then analyzed using logistic regression to identify multimarker models (maximum 6 markers) that met predefined criteria: sensitivity ≥50% at 20% positive predictive value. These 44 algorithms were then tested in an independent European cohort (n=300) yielding 8 validated models. These 8 models detected 50% to 56% of preeclampsia cases in the training and validation sets; the detection rate for preterm preeclampsia cases was 80%. Validated models combine insulin-like growth factor acid labile subunit and soluble endoglin, supplemented with maximally 4 markers of placental growth factor, serine peptidase inhibitor Kunitz type 1, melanoma cell adhesion molecule, selenoprotein P, and blood pressure. Predictive performances were maintained when exchanging mass spectrometry measurements with ELISA measurements for insulin-like growth factor acid labile subunit. In conclusion, we demonstrated that biomarker combinations centered on insulin-like growth factor acid labile subunit have the potential to predict preeclampsia in healthy nulliparous women.

Patterns of vaginal bleeding during the first 20 weeks of pregnancy and risk of pre‐eclampsia in nulliparous women: results from the SCOPE study

To describe patterns of vaginal bleeding in the first 20 weeks of pregnancy and evaluate the association between patterns of bleeding and risk of subsequent pre-eclampsia in nulliparous women. Cohort study. Participating centres of the Screening for Pregnancy Endpoints (SCOPE) study in Auckland (New Zealand), Adelaide (Australia), Manchester and London (UK) and Cork (Ireland). Healthy nulliparous women (n= 3431). Logistic regression was used to assess the association between bleeding characteristics and pre-eclampsia while controlling for known determinants of pre-eclampsia. Preeclampsia, defined as gestational hypertension with proteinuria or any multi-system complication of preeclampsia. Four bleeding variables were evaluated: any bleeding during the first 20 weeks; maximal bleeding intensity; duration of bleeding; and number of bleeding episodes. Of the 3431 women enrolled, 780 (23%) experienced vaginal bleeding during the first 20 weeks of pregnancy. Risk of pre-eclampsia was not associated with the presence or absence of bleeding (adjusted odds ratio (ORa) 0.96, 95% confidence interval (95% CI) 0.67-1.38). Analyses confined to women with vaginal bleeding showed that any bleeding episode of five or more consecutive days, compared with shorter episodes, increased risk of pre-eclampsia approximately twofold (ORa 2.15, 95% CI 1.01-4.57), as did multiple compared with single episodes of bleeding (ORa 2.33, 95% CI 1.16-4.67). Bleeding is a common complication during the first 20 weeks of nulliparous pregnancy, and the presence or absence of vaginal bleeding is not a determinant of subsequent pre-eclampsia. Among women with vaginal bleeding, consideration of the bleeding pattern, in terms of intensity, duration and frequency, appears to be informative with respect to pre-eclampsia risk.

Prospective cohort study to examine the association between maternal anxiety and depression and subsequent pregnancy outcomes

ObjectiveMaternal stress has been linked with higher risks of adverse pregnancy outcome. The authors investigated the association between maternal anxiety and depression scores in early pregnancy to birthweight and spontaneous...

Patterns of Change in Uterine Artery Doppler Studies Between 20 and 24 Weeks of Gestation and Pregnancy Outcomes

OBJECTIVES: To describe changes in mean uterine artery resistance index and bilateral notches between 20 and 24 weeks of gestation in healthy nulliparous women and to relate these changes to pregnancy outcome. METHODS: A total of 2,189 nulliparous participants in the Screening for Pregnancy Endpoints study had pregnancy outcomes compared between four uterine artery Doppler groups: normal at 20 and 24 weeks of gestation (group 1), normal at 20 weeks and abnormal at 24 weeks (group 2), abnormal at 20 weeks and normal at 24 weeks (group 3), and abnormal at both 20 and 24 weeks (group 4). Abnormal uterine Doppler was defined as 1) mean resistance index greater than the 90th centile; 2) bilateral notches; and 3) a combination of 1, 2, or both. The main outcomes were preeclampsia and small for gestational age (SGA) neonates (less than the 10th customized centile). RESULTS: Preeclampsia developed in 116 (5.3%) women, and 223 (10.2%) delivered SGA neonates. With abnormal Doppler defined as mean resistance index greater than the 90th centile, the rate of SGA increased across Doppler groups: group 1, 156 (8.4%); group 2, 13 (11%); group 3, 25 (19.5%); and group 4, 29 (35.4%) (P<.001). The rate of SGA was higher in group 3 compared with group 1. Preeclampsia differed among groups 1 (85 [4.6%]), 2 (9 [7.6%], 3 (7 [5.5%]), and 4 (15 [18.3%]) (P<.001). CONCLUSION: Pregnancy outcomes in women with abnormal uterine artery Doppler results at either 20 or 24 weeks were intermediate between those with normal or abnormal results at both time points. If overall test performance could be enhanced by the addition of clinical data, biomarkers, or both, we would recommend that 20 weeks is the most appropriate gestation in the second trimester to perform uterine artery Doppler studies.

Patterns of Change in Uterine Artery Doppler Studies Between 20 and 24 Weeks of Gestation and Pregnancy Outcomes

To describe changes in mean uterine artery resistance index and bilateral notches between 20 and 24 weeks of gestation in healthy nulliparous women and to relate these changes to pregnancy outcome. A total of 2,189 nulliparous participants in the Screening for Pregnancy Endpoints study had pregnancy outcomes compared between four uterine artery Doppler groups: normal at 20 and 24 weeks of gestation (group 1), normal at 20 weeks and abnormal at 24 weeks (group 2), abnormal at 20 weeks and normal at 24 weeks (group 3), and abnormal at both 20 and 24 weeks (group 4). Abnormal uterine Doppler was defined as 1) mean resistance index greater than the 90th centile; 2) bilateral notches; and 3) a combination of 1, 2, or both. The main outcomes were preeclampsia and small for gestational age (SGA) neonates (less than the 10th customized centile). Preeclampsia developed in 116 (5.3%) women, and 223 (10.2%) delivered SGA neonates. With abnormal Doppler defined as mean resistance index greater than the 90th centile, the rate of SGA increased across Doppler groups: group 1, 156 (8.4%); group 2, 13 (11%); group 3, 25 (19.5%); and group 4, 29 (35.4%) (P<.001). The rate of SGA was higher in group 3 compared with group 1. Preeclampsia differed among groups 1 (85 [4.6%]), 2 (9 [7.6%], 3 (7 [5.5%]), and 4 (15 [18.3%]) (P<.001). Pregnancy outcomes in women with abnormal uterine artery Doppler results at either 20 or 24 weeks were intermediate between those with normal or abnormal results at both time points. If overall test performance could be enhanced by the addition of clinical data, biomarkers, or both, we would recommend that 20 weeks is the most appropriate gestation in the second trimester to perform uterine artery Doppler studies. II.