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Objective To compare morbidity, as measured by length of stay in the neonatal intensive care unit (NICU), in twin and singleton gestations classified as small-for-gestational age (SGA) according to estimated fetal weight < 10th percentile on twin or singleton growth charts. Methods NICU length of stay was compared in 1150 twins and 29 035 singletons that underwent ultrasound assessment between 35 + 0 and 36 + 6 weeks' gestation. Estimated fetal weight was obtained from measurements of head circumference, abdominal circumference and femur length using the Hadlock formula. Gestational age was derived from the first-trimester crown–rump length measurement, using the larger of the two twins. Singletons and twins were compared in terms of NICU admission rate and length of stay according to classification as SGA by the Fetal Medicine Foundation singleton and twin reference distributions. Results The overall proportions of twins and singletons admitted to NICU were similar (7.3% vs 7.4%), but twins tended to have longer lengths of stay in NICU (≥ 7 days: 2.4% vs 0.8%; relative risk (RR), 3.0 (95% CI, 1.6–4.4)). Using the singleton chart, a higher proportion of twins were classified as SGA compared with singletons (37.6% vs 7.0%). However, the proportion of SGA neonates entering NICU was similar (10.2% for twins and 10.1% for singletons) and the proportion of SGA neonates spending ≥ 7 days in NICU was substantially higher for twins compared with singletons (3.7% vs 1.4%; RR, 2.6 (95% CI, 1.4–4.7)). Conclusions When singleton charts are used to define SGA in twins and in singletons, there is a greater degree of growth-related neonatal morbidity amongst SGA twins compared with SGA singletons. Consequently, singleton charts do not inappropriately overdiagnose fetal growth restriction in twins and they should be used for monitoring fetal growth in both twins and singletons. © 2023 International Society of Ultrasound in Obstetrics an, Objective: To compare morbidity, as measured by length of stay in the neonatal intensive care unit (NICU), in twin and singleton gestations classified as small-for-gestational age (SGA) according to estimated fetal weight < 10th percentile on twin or singleton growth charts. Methods: NICU length of stay was compared in 1150 twins and 29 035 singletons that underwent ultrasound assessment between 35 + 0 and 36 + 6 weeks' gestation. Estimated fetal weight was obtained from measurements of head circumference, abdominal circumference and femur length using the Hadlock formula. Gestational age was derived from the first-trimester crown–rump length measurement, using the larger of the two twins. Singletons and twins were compared in terms of NICU admission rate and length of stay according to classification as SGA by the Fetal Medicine Foundation singleton and twin reference distributions. Results: The overall proportions of twins and singletons admitted to NICU were similar (7.3% vs 7.4%), but twins tended to have longer lengths of stay in NICU (≥ 7 days: 2.4% vs 0.8%; relative risk (RR), 3.0 (95% CI, 1.6–4.4)). Using the singleton chart, a higher proportion of twins were classified as SGA compared with singletons (37.6% vs 7.0%). However, the proportion of SGA neonates entering NICU was similar (10.2% for twins and 10.1% for singletons) and the proportion of SGA neonates spending ≥ 7 days in NICU was substantially higher for twins compared with singletons (3.7% vs 1.4%; RR, 2.6 (95% CI, 1.4–4.7)). Conclusions: When singleton charts are used to define SGA in twins and in singletons, there is a greater degree of growth-related neonatal morbidity amongst SGA twins compared with SGA singletons. Consequently, singleton charts do not inappropriately overdiagnose fetal growth restriction in twins and they should be used for monitoring fetal growth in both twins and singletons.

Objective To derive reference distributions of estimated fetal weight (EFW) in twins relative to singletons. Methods Gestational-age- and chorionicity-specific reference distributions for singleton percentiles and EFW were fitted to data on 4391 twin pregnancies with two liveborn fetuses from four European centers, including 3323 dichorionic (DC) and 1068 monochorionic diamniotic (MCDA) twin pregnancies. Gestational age was derived using the larger of the two crown–rump length measurements obtained during the first trimester of pregnancy. EFW was obtained from ultrasound measurements of head circumference, abdominal circumference and femur length using the Hadlock formula. Singleton percentiles were obtained using the Fetal Medicine Foundation population weight charts for singleton pregnancies. Hierarchical models were fitted to singleton Z-scores with autoregressive terms for serial correlations within the same fetus and between twins from the same pregnancy. Separate models were fitted for DC and MCDA twins. Results Fetuses from twin pregnancies tended to be smaller than singletons at the earliest gestational ages (16 weeks for MCDA and 20 weeks for DC twins). This was followed by a period of catch-up growth until around 24 weeks. After that, both DC and MCDA twins showed reduced growth. In DC twins, the EFW corresponding to the 50th percentile was at the 50th percentile of singleton pregnancies at 23 weeks, the 43rd percentile at 28 weeks, the 32nd percentile at 32 weeks and the 22nd percentile at 36 weeks. In MCDA twins, the EFW corresponding to the 50th percentile was at the 36th percentile of singleton pregnancies at 24 weeks, the 29th percentile at 28 weeks, the 19th percentile at 32 weeks and the 12th percentile at 36 weeks. Conclusions In DC and, to a greater extent, MCDA twin pregnancies, fetal growth is reduced compared with that observed in singleton pregnancies. Furthermore, after 24 weeks, the divergence in gr, OBJECTIVE: To derive reference distributions of estimated fetal weight (EFW) in twins relative to singletons.METHODS: Gestational-age- and chorionicity-specific reference distributions for singleton percentiles and EFW were fitted to data on 4391 twin pregnancies with two liveborn fetuses from four European centers, including 3323 dichorionic (DC) and 1068 monochorionic diamniotic (MCDA) twin pregnancies. Gestational age was derived using the larger of the two crown-rump length measurements obtained during the first trimester of pregnancy. EFW was obtained from ultrasound measurements of head circumference, abdominal circumference and femur length using the Hadlock formula. Singleton percentiles were obtained using the Fetal Medicine Foundation population weight charts for singleton pregnancies. Hierarchical models were fitted to singleton Z-scores with autoregressive terms for serial correlations within the same fetus and between twins from the same pregnancy. Separate models were fitted for DC and MCDA twins.RESULTS: Fetuses from twin pregnancies tended to be smaller than singletons at the earliest gestational ages (16 weeks for MCDA and 20 weeks for DC twins). This was followed by a period of catch-up growth until around 24 weeks. After that, both DC and MCDA twins showed reduced growth. In DC twins, the EFW corresponding to the 50th percentile was at the 50th percentile of singleton pregnancies at 23 weeks, the 43rd percentile at 28 weeks, the 32nd percentile at 32 weeks and the 22nd percentile at 36 weeks. In MCDA twins, the EFW corresponding to the 50th percentile was at the 36th percentile of singleton pregnancies at 24 weeks, the 29th percentile at 28 weeks, the 19th percentile at 32 weeks and the 12th percentile at 36 weeks.CONCLUSIONS: In DC and, to a greater extent, MCDA twin pregnancies, fetal growth is reduced compared with that observed in singleton pregnancies. Furthermore, after 24 weeks, the divergence in growth trajectories

Introduction: Gestational diabetes mellitus (GDM) is a common disorder of pregnancy and contributes to adverse pregnancy outcomes. Metformin is often used for the prevention and management of GDM; however, its use in pregnancy continues to be debated. The Metformin in Pregnancy Study aims to use individual patient data (IPD) meta-analysis to clarify the efficacy and safety of metformin use in pregnancy and to identify relevant knowledge gaps. Methods and analysis: MEDLINE, EMBASE and all Evidence-Based Medicine will be systematically searched for randomised controlled trials (RCT) testing the efficacy of metformin compared with placebo, usual care or other interventions in pregnant women. Two independent reviewers will assess eligibility using prespecified criteria and will conduct data extraction and quality appraisal of eligible studies. Authors of included trials will be contacted and asked to contribute IPD. Primary outcomes include maternal glycaemic parameters and GDM, as well as neonatal hypoglycaemia, anthropometry and gestational age at delivery. Other adverse maternal, birth and neonatal outcomes will be assessed as secondary outcomes. IPD from these RCTs will be harmonised and a two-step meta-analytic approach will be used to determine the efficacy and safety of metformin in pregnancy, with a priori adjustment for covariates and subgroups to examine effect moderators of treatment outcomes. Sensitivity analyses will assess heterogeneity, risk of bias and the impact of trials which have not provided IPD. Ethics and dissemination: All IPD will be deidentified and studies contributing IPD will have ethical approval from their respective local ethics committees. This study will provide robust evidence regarding the efficacy and safety of metformin use in pregnancy, and may identify subgroups of patients who may benefit most from this treatment modality. Findings will be published in peer-reviewed journals and disseminated at scientific meetings, provi

Objectives: To determine if concentrations of placental glycans and glycan components are altered in pre-eclamspia and to determine if serum levels can predict pre-eclampsia. Methods: Serum samples were collected from women in the third trimester of singleton pregnancy but before the onset of pre-eclampsia (n=10) and also from women during unaffected pregnancies at the same gestational age. Tissues were collected from the basal plate of placentas collected at delivery following uncomplicated singleton pregnancy (term and preterm) and from pregnancies complicated by preeclampsia (n=8). Pre-eclampsia was diagnosed according to International Society for the Study of Hypertension in Pregnancy criteria. Glycan components were isolated using a combination of enzyme digestion, molecular weight filtration and ion exchange chromatography, and then derivatised prior to separation using hydrophilic interaction liquid chromatography. Components were detected using electrospray ionisation operated in positive ion mode with single ion monitoring. Results: Specific glycan components (designated glycan 1, 2 and 3) were significantly altered in the serum from women who went on to have pre-eclampsia compared to those who had an unaffected pregnancy. Interestingly levels of the same biomarkers were also elevated in nulliparous versus multiparous pregnancy. Biomarkers were also significantly altered in placental tissues from pregnancies complicated by preeclampsia. Conclusion: This study suggests that altered glycan levels may contribute to impaired placental development and that the glycome is a potential diagnostic target for pre-eclampsia, and possibly other disorders of pregnancy.

Objectives: To determine if concentrations of placental glycans and glycan components are altered in pre-eclamspia and to determine if serum levels can predict pre-eclampsia. Methods: Serum samples were collected from women in the third trimester of singleton pregnancy but before the onset of pre-eclampsia (n=10) and also from women during unaffected pregnancies at the same gestational age. Tissues were collected from the basal plate of placentas collected at delivery following uncomplicated singleton pregnancy (term and preterm) and from pregnancies complicated by preeclampsia (n=8). Pre-eclampsia was diagnosed according to International Society for the Study of Hypertension in Pregnancy criteria. Glycan components were isolated using a combination of enzyme digestion, molecular weight filtration and ion exchange chromatography, and then derivatised prior to separation using hydrophilic interaction liquid chromatography. Components were detected using electrospray ionisation operated in positive ion mode with single ion monitoring. Results: Specific glycan components (designated glycan 1, 2 and 3) were significantly altered in the serum from women who went on to have pre-eclampsia compared to those who had an unaffected pregnancy. Interestingly levels of the same biomarkers were also elevated in nulliparous versus multiparous pregnancy. Biomarkers were also significantly altered in placental tissues from pregnancies complicated by preeclampsia. Conclusion: This study suggests that altered glycan levels may contribute to impaired placental development and that the glycome is a potential diagnostic target for pre-eclampsia, and possibly other disorders of pregnancy.

Objectives: To determine if concentrations of placental glycans and glycan components are altered in pre-eclamspia and to determine if serum levels can predict pre-eclampsia. Methods: Serum samples were collected from women in the third trimester of singleton pregnancy but before the onset of pre-eclampsia (n=10) and also from women during unaffected pregnancies at the same gestational age. Tissues were collected from the basal plate of placentas collected at delivery following uncomplicated singleton pregnancy (term and preterm) and from pregnancies complicated by preeclampsia (n=8). Pre-eclampsia was diagnosed according to International Society for the Study of Hypertension in Pregnancy criteria. Glycan components were isolated using a combination of enzyme digestion, molecular weight filtration and ion exchange chromatography, and then derivatised prior to separation using hydrophilic interaction liquid chromatography. Components were detected using electrospray ionisation operated in positive ion mode with single ion monitoring. Results: Specific glycan components (designated glycan 1, 2 and 3) were significantly altered in the serum from women who went on to have pre-eclampsia compared to those who had an unaffected pregnancy. Interestingly levels of the same biomarkers were also elevated in nulliparous versus multiparous pregnancy. Biomarkers were also significantly altered in placental tissues from pregnancies complicated by preeclampsia. Conclusion: This study suggests that altered glycan levels may contribute to impaired placental development and that the glycome is a potential diagnostic target for pre-eclampsia, and possibly other disorders of pregnancy.

Objectives: To determine if concentrations of placental glycans and glycan components are altered in pre-eclamspia and to determine if serum levels can predict pre-eclampsia. Methods: Serum samples were collected from women in the third trimester of singleton pregnancy but before the onset of pre-eclampsia (n=10) and also from women during unaffected pregnancies at the same gestational age. Tissues were collected from the basal plate of placentas collected at delivery following uncomplicated singleton pregnancy (term and preterm) and from pregnancies complicated by preeclampsia (n=8). Pre-eclampsia was diagnosed according to International Society for the Study of Hypertension in Pregnancy criteria. Glycan components were isolated using a combination of enzyme digestion, molecular weight filtration and ion exchange chromatography, and then derivatised prior to separation using hydrophilic interaction liquid chromatography. Components were detected using electrospray ionisation operated in positive ion mode with single ion monitoring. Results: Specific glycan components (designated glycan 1, 2 and 3) were significantly altered in the serum from women who went on to have pre-eclampsia compared to those who had an unaffected pregnancy. Interestingly levels of the same biomarkers were also elevated in nulliparous versus multiparous pregnancy. Biomarkers were also significantly altered in placental tissues from pregnancies complicated by preeclampsia. Conclusion: This study suggests that altered glycan levels may contribute to impaired placental development and that the glycome is a potential diagnostic target for pre-eclampsia, and possibly other disorders of pregnancy.

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Objectives: To examine the effect of first-trimester screening for pre-eclampsia (PE) on the prediction of delivering a small-for-gestational-age (SGA) neonate and the effect of prophylactic use of aspirin on the prevention of SGA. Methods: The data for this study were derived from two multicenter studies. In SPREE, we investigated the performance of screening for PE by a combination of maternal characteristics and biomarkers at 11–13 weeks' gestation. In ASPRE, women with a singleton pregnancy identified by combined screening as being at high risk for preterm PE (> 1 in 100) participated in a trial of aspirin (150 mg/day from 11–14 until 36 weeks' gestation) compared to placebo. In this study, we used the data from the ASPRE trial to estimate the effect of aspirin on the incidence of SGA with birth weight < 10th, < 5th and < 3rd percentile for gestational age. We also used the data from SPREE to estimate the proportion of SGA in the pregnancies with a risk for preterm PE of > 1 in 100. Results: In SPREE, screening for preterm PE by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index and serum placental growth factor identified a high-risk group that contained about 46% of SGA neonates < 10th percentile born at < 37 weeks' gestation (preterm) and 56% of those born at < 32 weeks (early); the overall screen-positive rate was 12.2% (2014 of 16 451 pregnancies). In the ASPRE trial, use of aspirin reduced the overall incidence of SGA < 10th percentile by about 40% in babies born at < 37 weeks' gestation and by about 70% in babies born at < 32 weeks; in babies born at ≥ 37 weeks, aspirin did not have a significant effect on incidence of SGA. The aspirin-related decrease in incidence of SGA was mainly due to its incidence decreasing in pregnancies with PE, for which the decrease was about 70% in babies born at < 37 weeks' gestation and about 90% in babies born at < 32 weeks. On the basis of these results, it was estimated that first, SCOPUS: ar.j, info:eu-repo/semantics/published

Objective: To examine the performance of screening for early, preterm and term pre-eclampsia (PE) at 11–13 weeks' gestation by maternal factors and combinations of mean arterial pressure (MAP), uterine artery (UtA) pulsatility index (PI), serum placental growth factor (PlGF) and serum pregnancy-associated plasma protein-A (PAPP-A). Methods: The data for this study were derived from three previously reported prospective non-intervention screening studies at 11 + 0 to 13 + 6 weeks' gestation in a combined total of 61 174 singleton pregnancies, including 1770 (2.9%) that developed PE. Bayes' theorem was used to combine the prior distribution of gestational age at delivery with PE, obtained from maternal characteristics, with various combinations of biomarker multiples of the median (MoM) values to derive patient-specific risks of delivery with PE at < 37 weeks' gestation. The performance of such screening was estimated. Results: In pregnancies that developed PE, compared to those without PE, the MoM values of UtA-PI and MAP were increased and those of PAPP-A and PlGF were decreased, and the deviation from normal was greater for early than late PE for all four biomarkers. Combined screening by maternal factors, UtA-PI, MAP and PlGF predicted 90% of early PE, 75% of preterm PE and 41% of term PE, at a screen-positive rate of 10%; inclusion of PAPP-A did not improve the performance of screening. The performance of screening depended on the racial origin of the women; on screening by a combination of maternal factors, MAP, UtA-PI and PlGF and using a risk cut-off of 1 in 100 for PE at < 37 weeks in Caucasian women, the screen-positive rate was 10% and detection rates for early, preterm and term PE were 88%, 69% and 40%, respectively. With the same method of screening and risk cut-off in women of Afro-Caribbean racial origin, the screen-positive rate was 34% and detection rates for early, preterm and term PE were 100%, 92% and 75%, respectively. Conclusion: Screening by mat, SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Preeclampsia is a major pregnancy complication with adverse short- and long-term implications for both the mother and baby. Screening for preeclampsia at 11–13 weeks’ gestation by a combination of maternal demographic characteristics and medical history with measurements of biomarkers can identify about 75% of women who develop preterm preeclampsia with delivery at <37 weeks’ gestation and 90% of those with early preeclampsia at <32 weeks, at a screen-positive rate of 10%. A recent trial (Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention) has reported that in women identified by first-trimester screening as being at high risk for preeclampsia, use of aspirin (150 mg/d from the first to the third trimester), compared to placebo, reduced the incidence of preterm preeclampsia, which was the primary outcome, by 62% (95% confidence interval, 26–80%) and the incidence of early preeclampsia by 89% (95% confidence interval, 53–97%). The surprising finding of the trial was that despite the reduction in preeclampsia the incidence of admission to the neonatal intensive care unit, which was one of the secondary outcomes, was not significantly affected (odds ratio, 0.93; 95% confidence interval, 0.62–1.40). Objective: We sought to examine the effect of prophylactic use of aspirin during pregnancy in women at high risk of preeclampsia on length of stay in the neonatal intensive care unit. Study Design: This was a secondary analysis of data from the Aspirin for Evidence-Based Preeclampsia Prevention trial to assess evidence of differences in the effect of aspirin on length of stay in neonatal intensive care. Bootstrapping was used for the comparison of mean length of stay between the aspirin and placebo groups. Logistic regression was used to assess treatment effects on stay in the neonatal intensive care unit. Results: In the trial there were 1620 participants and 1571 neonates were liveborn. The to, SCOPUS: ar.j, info:eu-repo/semantics/published

Objective: To examine the diagnostic accuracy of a previously developed model for prediction of pre-eclampsia (PE) by a combination of maternal factors and biomarkers at 11–13 weeks' gestation. Methods: This was a prospective first-trimester multicenter study of screening for PE in 8775 singleton pregnancies. A previously published algorithm was used for the calculation of patient-specific risk of PE in each individual. The detection rates (DRs) and false-positive rates (FPRs) for delivery with PE < 32, < 37 and ≥ 37 weeks were estimated and compared with those for the dataset used for development of the algorithm. Results: In the study population, 239 (2.7%) cases developed PE, of which 17 (0.2%), 59 (0.7%) and 180 (2.1%) developed PE < 32, < 37 and ≥ 37 weeks, respectively. With combined screening by maternal factors, mean arterial pressure, uterine artery pulsatility index and serum placental growth factor, the DR was 100% (95% CI, 80–100%) for PE < 32 weeks, 75% (95% CI, 62–85%) for PE < 37 weeks and 43% (95% CI, 35–50%) for PE ≥ 37 weeks, at a 10% FPR. These DRs were similar to the estimated rates for the dataset used for development of the model: 89% (95% CI, 79–96%) for PE < 32 weeks, 75% (95% CI, 70–80%) for PE < 37 weeks and 47% (95% CI, 44–51%) for PE ≥ 37 weeks. Conclusion: Assessment of a combination of maternal factors and biomarkers at 11–13 weeks provides effective first-trimester screening for preterm PE. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd., SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND: Preterm preeclampsia is an important cause of maternal and perinatal death and complications. It is uncertain whether the intake of low-dose aspirin during pregnancy reduces the risk of preterm preeclampsia. METHODS: In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1776 women with singleton pregnancies who were at high risk for preterm preeclampsia to receive aspirin, at a dose of 150 mg per day, or placebo from 11 to 14 weeks of gestation until 36 weeks of gestation. The primary outcome was delivery with preeclampsia before 37 weeks of gestation. The analysis was performed according to the intention-to-treat principle. RESULTS: A total of 152 women withdrew consent during the trial, and 4 were lost to follow up, which left 798 participants in the aspirin group and 822 in the placebo group. Preterm preeclampsia occurred in 13 participants (1.6%) in the aspirin group, as compared with 35 (4.3%) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004). Results were materially unchanged in a sensitivity analysis that took into account participants who had withdrawn or were lost to follow-up. Adherence was good, with a reported intake of 85% or more of the required number of tablets in 79.9% of the participants. There were no significant between-group differences in the incidence of neonatal adverse outcomes or other adverse events. CONCLUSIONS: Treatment with low-dose aspirin in women at high risk for preterm preeclampsia resulted in a lower incidence of this diagnosis than placebo., SCOPUS: ar.j, info:eu-repo/semantics/published

Objective: To examine the performance of screening for preterm and term pre-eclampsia (PE) in the study population participating in the ASPRE (Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention) trial. Methods: This was a prospective first-trimester multicenter study on screening for preterm PE in 26 941 singleton pregnancies by means of an algorithm that combines maternal factors, mean arterial pressure, uterine artery pulsatility index and maternal serum pregnancy-associated plasma protein-A and placental growth factor at 11–13 weeks' gestation. Eligible women with an estimated risk for preterm PE of > 1 in 100 were invited to participate in a double-blind trial of aspirin (150 mg per day) vs placebo from 11–14 until 36 weeks' gestation, which showed that, in the aspirin group, the incidence of preterm PE was reduced by 62%. In the screened population, the detection rates (DRs) and false-positive rates (FPRs) for delivery with PE < 37 and ≥ 37 weeks were estimated after adjustment for the effect of aspirin in those receiving this treatment. We excluded 1144 (4.2%) pregnancies because of loss to follow-up or study withdrawal (n = 716), miscarriage (n = 243) or termination (n = 185). Results: The study population of 25 797 pregnancies included 180 (0.7%) cases of preterm PE, 450 (1.7%) of term PE and 25 167 (97.6%) without PE. In combined first-trimester screening for preterm PE with a risk cut-off of 1 in 100, the DR was 76.7% (138/180) for preterm PE and 43.1% (194/450) for term PE, at screen-positive rate of 10.5% (2707/25 797) and FPR of 9.2% (2375/25 797). Conclusion: The performance of screening in the ASPRE study was comparable with that of a study of approximately 60 000 singleton pregnancies used for development of the algorithm; in that study, combined screening detected 76.6% of cases of preterm PE and 38.3% of term PE at a FPR of 10%. Copyright © 2017 ISUOG. Published by John Wiley & So, SCOPUS: ar.j, info:eu-repo/semantics/published

Background The Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention trial demonstrated that in women who were at high risk for preterm preeclampsia with delivery at <37 weeks’ gestation identified by screening by means of an algorithm that combines maternal factors and biomarkers at 11-13 weeks’ gestation, aspirin administration from 11 to 14 until 36 weeks’ gestation was associated with a significant reduction in the incidence of preterm preeclampsia (odds ratio 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004). Objective We sought to examine whether there are differences in the effect of aspirin on the incidence of preterm preeclampsia in the Aspirin for Evidence-Based Preeclampsia Prevention trial in subgroups defined according to maternal characteristics and medical and obstetrical history. Study Design This was a secondary analysis of data from the Aspirin for Evidence-Based Preeclampsia Prevention trial. Subgroup analysis was performed to assess evidence of differences in the effect of aspirin on incidence of preterm preeclampsia in subgroups defined by maternal age (<30 and ≥30 years), body mass index (<25 and ≥25 kg/m2), racial origin (Afro-Caribbean, Caucasian and other), method of conception (natural and assisted), cigarette smoking (smoker and non-smoker), family history of preterm preeclampsia (present and absent), obstetrical history (nulliparous, multiparous with previous preterm preeclampsia and multiparous without previous preterm preeclampsia), history of chronic hypertension (present and absent). Interaction tests were performed on the full data set of patients in the intention to treat population and on the data set of patients who took ≥ 90% of the prescribed medication. Results are presented as forest plot with P values for the interaction effects, group sizes, event counts and estimated odds ratios. We examined whether the test of interaction was significant at the 5% level, SCOPUS: ar.j, info:eu-repo/semantics/published

UNLABELLED: A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP) or due to benign pruritus gravidarum. ICP is characterized by raised serum bile acids and complicated by spontaneous preterm labor and stillbirth. A biomarker for ICP would be invaluable for early diagnosis and treatment and to enable its differentiation from other maternal diseases. Three progesterone sulfate compounds, whose concentrations have not previously been studied, were newly synthesized and assayed in the serum of three groups of ICP patients and found to be significantly higher in ICP at 9-15 weeks of gestation and prior to symptom onset (group 1 cases/samples: ICP n = 35/80, uncomplicated pregnancy = 29/100), demonstrating that all three progesterone sulfates are prognostic for ICP. Concentrations of progesterone sulfates were associated with itch severity and, in combination with autotaxin, distinguished pregnant women with itch that would subsequently develop ICP from pruritus gravidarum (group 2: ICP n = 41, pruritus gravidarum n = 14). In a third group of first-trimester samples all progesterone sulfates were significantly elevated in serum from low-risk asymptomatic women who subsequently developed ICP (ICP/uncomplicated pregnancy n = 54/51). Finally, we show mechanistically that progesterone sulfates mediate itch by evoking a Tgr5-dependent scratch response in mice. CONCLUSION: Our discovery that sulfated progesterone metabolites are a prognostic indicator for ICP will help predict onset of ICP and distinguish it from benign pruritus gravidarum, enabling targeted obstetric care to a high-risk population. Delineation of a progesterone sulfate-TGR5 pruritus axis identifies a therapeutic target for itch management in ICP.

Background: The current approach to prenatal care, which was established more than 80 years ago, is characterised by a high concentration of visits in the third-trimester of pregnancy which implies that firstly, most complications occur at this late stage of pregnancy and secondly, most adverse outcomes are unpredictable during the first or even the second trimester. Objectives: The objective of this thesis is to provide evidence that most pregnancy complications are predictable as early as 12 weeks’ gestation. The pregnancy complications examined include fetal aneuploidies, fetal structural defects, preeclampsia, preterm birth, gestational diabetes mellitus and fetal macrosomia. Methods: I have critically examined fourteen articles reporting on screening for pregnancy complications at 11-13 weeks’ gestation, where more than 90,000 singleton pregnancies were prospectively assessed at 11-13 weeks’ gestation as part of a routine prenatal visit for screening for trisomy 21. We recorded a series of maternal characteristics and history, measured maternal weight and height, performed a detailed ultrasound examination of the fetus, measured maternal uterine artery Doppler pulsatility index and maternal mean arterial pressure and collected blood for analysis of biomarkers for prospective or retrospective analysis. All data were prospectively entered into our data base as well as the pregnancy outcomes as soon as they became available. Ethical approval was obtained for these studies. Multivariate regression analysis was used to define the contribution of each maternal characteristic and history in predicting each adverse outcome and those with a significant contribution formed an algorithm to estimate the background risk (a priori risk) for each one of these complications. The potential value of biophysical and biochemical markers in improving the performance of the a priori risk in predicting adverse pregnancy outcomes, was evaluated. Results: First trimester effective scre

Background: The current approach to prenatal care, which was established more than 80 years ago, is characterised by a high concentration of visits in the third-trimester of pregnancy which implies that firstly, most complications occur at this late stage of pregnancy and secondly, most adverse outcomes are unpredictable during the first or even the second trimester. Objectives: The objective of this thesis is to provide evidence that most pregnancy complications are predictable as early as 12 weeks’ gestation. The pregnancy complications examined include fetal aneuploidies, fetal structural defects, preeclampsia, preterm birth, gestational diabetes mellitus and fetal macrosomia. Methods: I have critically examined fourteen articles reporting on screening for pregnancy complications at 11-13 weeks’ gestation, where more than 90,000 singleton pregnancies were prospectively assessed at 11-13 weeks’ gestation as part of a routine prenatal visit for screening for trisomy 21. We recorded a series of maternal characteristics and history, measured maternal weight and height, performed a detailed ultrasound examination of the fetus, measured maternal uterine artery Doppler pulsatility index and maternal mean arterial pressure and collected blood for analysis of biomarkers for prospective or retrospective analysis. All data were prospectively entered into our data base as well as the pregnancy outcomes as soon as they became available. Ethical approval was obtained for these studies. Multivariate regression analysis was used to define the contribution of each maternal characteristic and history in predicting each adverse outcome and those with a significant contribution formed an algorithm to estimate the background risk (a priori risk) for each one of these complications. The potential value of biophysical and biochemical markers in improving the performance of the a priori risk in predicting adverse pregnancy outcomes, was evaluated. Results: First trimester effective scre

This paper investigates the causal linkages between monetary and equity market integration of the new member states (NMS) as well as of the non economic monetary union (Non- EMU) member states with the euro zone, after the official launch of the euro. Granger causality in mean and in variance tests are utilized. Our results reveal a number of interesting facts that can be summarized as follows. Firstly, there is little evidence of causality in mean effects for all countries. Secondly, there are significant spill over effects for the NMS. Thirdly, the excess currency return is the chief variable which leads the excess stock market return volatility of the NMS. Our findings have obvious implications for both investors and policy makers.

This paper investigates the causal linkages between monetary and equity market integration of the new member states (NMS) as well as of the non economic monetary union (Non- EMU) member states with the euro zone, after the official launch of the euro. Granger causality in mean and in variance tests are utilized. Our results reveal a number of interesting facts that can be summarized as follows. Firstly, there is little evidence of causality in mean effects for all countries. Secondly, there are significant spill over effects for the NMS. Thirdly, the excess currency return is the chief variable which leads the excess stock market return volatility of the NMS. Our findings have obvious implications for both investors and policy makers.

This paper investigates the causal linkages between monetary and equity market integration of the new member states (NMS) as well as of the non economic monetary union (Non- EMU) member states with the euro zone, after the official launch of the euro. Granger causality in mean and in variance tests are utilized. Our results reveal a number of interesting facts that can be summarized as follows. Firstly, there is little evidence of causality in mean effects for all countries. Secondly, there are significant spill over effects for the NMS. Thirdly, the excess currency return is the chief variable which leads the excess stock market return volatility of the NMS. Our findings have obvious implications for both investors and policy makers.

This thesis investigates three cutting edge issues in empirical finance. The first, examined in Chapter 2, is an investigation of the hypothesis that macroeconomic uncertainty is a significant risk factor in explaining deviations from the uncovered interest parity (UIP) condition (or time-varying risk premium) using data from the G7 countries. To analyze the relationship between the risk premium and macroeconomic risk factors, we employ VAR-GARCH-in-mean models. The results show that the currency risk premium may be due to macroeconomic volatility. The second issue (Chapter 3) concerns the causal linkages between monetary and financial market returns of the New Member States (NMS) with the euro zone following the introduction of the euro. To measure monetary convergence we employ UIP deviations and stock market integration is proxied by the differential of the risk-adjusted returns of the NMS countries versus a euro zone stock index. We look for a causal relationship between excess currency and excess stock market returns of the aforementioned countries. We employ Granger causality in mean and variance tests to assess this relationship. The main finding is that the excess currency return is a significant leading indicator of the excess stock market return, with stronger evidence of causality in the variance of the process. Finally, the third issue (Chapter 4) examines the time-varying co-movements of equity returns within major sectors, for a number of developed and developing countries. In particular, we ask the question if the conditional return correlations have increased excessively by historical standards during the recent financial crisis. We utilize asymmetric multivariate GARCH models. The main finding is that correlations have increased over the recent period, but the levels of co-movements are not excessive by historical standards. There is little difference between the co-movements of financial and non-financial stocks across countries, implying that this

This thesis investigates three cutting edge issues in empirical finance. The first, examined in Chapter 2, is an investigation of the hypothesis that macroeconomic uncertainty is a significant risk factor in explaining deviations from the uncovered interest parity (UIP) condition (or time-varying risk premium) using data from the G7 countries. To analyze the relationship between the risk premium and macroeconomic risk factors, we employ VAR-GARCH-in-mean models. The results show that the currency risk premium may be due to macroeconomic volatility. The second issue (Chapter 3) concerns the causal linkages between monetary and financial market returns of the New Member States (NMS) with the euro zone following the introduction of the euro. To measure monetary convergence we employ UIP deviations and stock market integration is proxied by the differential of the risk-adjusted returns of the NMS countries versus a euro zone stock index. We look for a causal relationship between excess currency and excess stock market returns of the aforementioned countries. We employ Granger causality in mean and variance tests to assess this relationship. The main finding is that the excess currency return is a significant leading indicator of the excess stock market return, with stronger evidence of causality in the variance of the process. Finally, the third issue (Chapter 4) examines the time-varying co-movements of equity returns within major sectors, for a number of developed and developing countries. In particular, we ask the question if the conditional return correlations have increased excessively by historical standards during the recent financial crisis. We utilize asymmetric multivariate GARCH models. The main finding is that correlations have increased over the recent period, but the levels of co-movements are not excessive by historical standards. There is little difference between the co-movements of financial and non-financial stocks across countries, implying that this

The aim of this thesis was to examine the role of biobehavioural and social variables in explaining adolescent antisocial behaviour. One study examined neuropsychological functioning in 115 young offenders. A more extensive second study was carried out on a sub-sample of the original young offender group, consisting of 48 participants. This second study used more detailed neuropsychological assessments and assessed participants' responses to emotional stimuli. Emotional functioning was assessed in 3 ways: by recording electrodermal responses during a fear conditioning task, by recording the eye-blink startle reflex while participants passively viewed different types of affective pictures, and by examining facial affect recognition. It was expected, first, that antisocial teenagers would be characterised by a sensation-seeking personality, neuropsychological impairments as evidenced by executive functioning tasks, low IQ, poor electrodermal fear conditioning, and reduced startle amplitudes, compared to age and sex matched controls. Second, it was expected that biobehavioural risk factors would interact with social risk factors in explaining ASB, and that social factors would moderate the biobehavioural - ASB relationship. We found that young offenders differed from matched controls in terms of personality traits, and neuropsychological and emotional functioning. With respect to the second hypothesis, it was found that biobehavioural risk factors did not interact with social variables in explaining different types of offending behaviour, contrary to previous studies. Specifically, the research findings indicated that young offenders were characterised by lower IQ and specific neuropsychological deficits in terms of working memory, planning and decision-making. Additionally, they had problems with the learning, processing, and recognition of emotions. Finally, we showed that different risk factors were associated with different types of offending, with both social and

The aim of this thesis was to examine the role of biobehavioural and social variables in explaining adolescent antisocial behaviour. One study examined neuropsychological functioning in 115 young offenders. A more extensive second study was carried out on a sub-sample of the original young offender group, consisting of 48 participants. This second study used more detailed neuropsychological assessments and assessed participants' responses to emotional stimuli. Emotional functioning was assessed in 3 ways: by recording electrodermal responses during a fear conditioning task, by recording the eye-blink startle reflex while participants passively viewed different types of affective pictures, and by examining facial affect recognition. It was expected, first, that antisocial teenagers would be characterised by a sensation-seeking personality, neuropsychological impairments as evidenced by executive functioning tasks, low IQ, poor electrodermal fear conditioning, and reduced startle amplitudes, compared to age and sex matched controls. Second, it was expected that biobehavioural risk factors would interact with social risk factors in explaining ASB, and that social factors would moderate the biobehavioural - ASB relationship. We found that young offenders differed from matched controls in terms of personality traits, and neuropsychological and emotional functioning. With respect to the second hypothesis, it was found that biobehavioural risk factors did not interact with social variables in explaining different types of offending behaviour, contrary to previous studies. Specifically, the research findings indicated that young offenders were characterised by lower IQ and specific neuropsychological deficits in terms of working memory, planning and decision-making. Additionally, they had problems with the learning, processing, and recognition of emotions. Finally, we showed that different risk factors were associated with different types of offending, with both social and