Objective: To investigate the effects of aspirin on the distribution of birthweight and its impact on the rates of large-for-gestational age (LGA) neonates. Design: Secondary analysis of the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-based Preeclampsia Prevention (ASPRE) trial. Setting: Thirteen hospitals in England, Spain, Belgium, Greece, Italy, and Israel. Population: Participants of the ASPRE trial at increased risk of preterm pre-eclampsia (PE) who had a live birth. Methods: We compared the birthweight distributions and the rates of LGA neonates between the trial groups. Analyses were stratified according to the presence of pre-existing diabetes mellitus and the development of pre-eclampsia, and logistic regression was used to investigate independent predictors of LGA neonates. Main Outcome Measures: Birthweight distribution and rate of LGA neonates. Results: Among 1,571 singleton, live neonates (777 from the aspirin group and 794 from the placebo group), aspirin was associated with a shift in birthweight from below 2,500 to between 2,500 and 4,000 grams, and birthweight percentile from below the 25 th to between the 25 th and 75 th percentiles, with no significant increase in LGA neonates (5.5% vs. 6.2%, p=0.667). Logistic regression demonstrated a significant interaction between treatment and pre-existing diabetes (p-value 0.034), and a positive association between maternal weight and LGA neonates (adjusted odds ratio 1.040, 95% confidence interval 1.030 – 1.051, p<0.001). Conclusions: Aspirin use is associated with increased birthweight without increasing the rate of LGA neonates. Among women with pre-existing diabetes, however, aspirin may lead to a higher rate of LGA neonates.

Objectives: To examine the association between racial origin and preeclampsia(PE) and gestational hypertension(GH) after adjustment for factors in maternal characteristics and medical history in screening study from the Fetal Medicine Foundation (FMF) in England, and to perform a systematic review and meta-analysis of studies on PE. Methods: In the FMF data regression analysis was performed to examine the association between racial origin and PE or GH. Literature search to December 2021 was carried out to identify peer-reviewed publications on race and PE. Main outcome measure: Relative risk of PE and GH in women of black, South Asian and East Asian racial origin by comparison to white women. Results: In the FMF study there were 168,966 singleton pregnancies without major abnormalities delivering at ≥24 weeks’ gestation. In black women the respective risk of total-PE and preterm-PE was 2-fold and 2.5-fold higher and risk of GH was 25% higher, in South Asian women there was a 1.5-fold higher risk of preterm-PE but not total-PE, and in East Asian women there was no significant difference in risk of hypertensive disorders. The literature search identified 19 studies that provided data on several million of pregnancies, but 17 were at moderate or high-risk of bias and only three provided risks adjusted for some maternal characteristics; consequently, these studies did not provide accurate contribution of different racial groups to the prediction of PE. Conclusion: In women of black and South Asian origin the risk of PE, after adjustment for confounders, is higher than in white women

Objectives: First, to examine the predictive performance for placental dysfunction related stillbirths of the competing risks model for small for gestational age (SGA) fetuses based on a combination of maternal risk factors, estimated fetal weight (EFW) and uterine artery pulsatility index (UtA-PI); and second, to compare the performance of this model to that of stillbirth-specific model utilizing the same biomarkers and to the Royal College of Obstetricians and Gynecologists (RCOG) guideline for the investigation and management of the SGA fetus. Design: Prospective observational study. Setting: Two UK maternity hospitals. Population: 131,514 women with singleton pregnancies attending for routine ultrasound examination at 19-24 weeks’ gestation. Methods: The predictive performance for stillbirth achieved by three models was compared. Main outcome measures: Placental dysfunction related stillbirth. Results: At 10% false positive rate, the competing risks model predicted 59%, 66% and 71% of placental dysfunction related stillbirths, at any gestation, at <37 weeks and at <32 weeks, respectively, which were similar to the respective figures of 62%, 70% and 73% for the stillbirth-specific model. At a screen positive rate of 21.8 %, as defined by the RCOG guideline, the new model predicted 71%, 76% and 79% of placental dysfunction related stillbirths at any gestation, at <37 weeks and at <32 weeks, respectively, and the respective figures for the RCOG guideline were 42%, 44% and 40%. Conclusion: The predictive performance for placental dysfunction related stillbirths by the competing risks model for SGA was similar to the stillbirth-specific model and superior to the RCOG guideline.

Objectives: Assess first trimester serum placental growth factor (PLGF), soluble fms-like tyrosine kinase-1 (sFLT-1), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), endothelin and vascular cell adhesion molecule (VCAM) in women with chronic hypertension (CH) stratified according to blood pressure (BP) control. Design: Case-control. Setting: Tertiary referral centre. Population: 650 women with CH, 142 normotensive controls. Methods: In the first trimester, patients with CH were subdivided into 4 groups. Group 1 included women without pre-pregnancy CH presenting with BP ≥140/90mmHg. Groups 2-4 had pre-pregnancy CH; in group 2 the BP was <140/90mmHg without antihypertensive medication, in group 3 the BP was <140/90mmHg with antihypertensive medication and in group 4 the BP was ≥ 140/90 mmHg despite antihypertensive medication. PLGF, sFLT-1, IL-6, TNF-α, endothelin and VCAM were measured at 11+0-13+6 weeks’ and converted into multiples of the expected median (MoM) using multivariate regression analysis in the controls. Main outcome measure: Comparisons of MoM values of PLGF, sFLT-1, IL-6, TNF-α, endothelin and VCAM between the 4 CH groups and the controls were made using analysis of variance or Kruskal-Wallis tests. Results: In the CH groups, compared to controls, PLGF was reduced in groups 2-4, sFLT-1 was reduced in groups 2 and 3, endothelin was increased in groups 1 and 4 but IL-6 was reduced in group 4. Conclusion: In women with CH, differences exist in first trimester angiogenic and inflammatory profiles according to BP control. Further evaluation is needed to determine if these differences are useful in the stratification of care.

Dear Sir We congratulate Dr Guy and colleagues on their paper1which demonstrates that implementation of combined screening using the FMF algorithm2 is feasible in practice and is better than the existing NICE guidelines in prevention of preeclampsia, especially preterm preeclampsia with delivery before 34 weeks. We hope that this will lead to wider application of combined screening for prediction and prevention of preeclampsia.The authors acknowledge that treatment with aspirin will have led to underestimation of screening performance. We would like to highlight this and emphasise the importance of accounting for the effect of aspirin when assessing predictive performance. To make the point, consider the most extreme case with 100% compliance with a treatment that prevents 100% of cases. In the screen positive group, all cases would be prevented by the treatment and classified as false positives. Adopting the same analysis presented in this paper would result in a detection rate and positive predictive value of zero regardless of performance without treatment.In the data presented in this study, for the FMF algorithm with 99% compliance to aspirin at a dose of 150 mg / day and assuming 62% reduction in risk,3 99%×62% = 61.4% of cases of preterm preeclampsia would be prevented and classed as false positives. The remaining 100-61.4% = 38.6% would be classed as true positives so the 15 cases of preterm preeclampsia which led to the detection rate of 15/27 = 55.6% represent just 38.6% of the cases of preterm preeclampsia detected. An estimate of the number detected, including those prevented by aspirin is, 15/0.386 = 39. The estimated number of cases in total is therefore 39 + 12 = 51, obtained by adding the false negatives 27-15 = 12 to the estimated true positives. This gives a detection rate of 39/51 = 76% compared to the figure of 55.6% given in Table 2. Applying similar calculations to the positive predictive value (i.e. proportion of women in the screen positive group who would, without aspirin, have developed preterm preeclampsia) of 9.8%. This should be compared with the 3.8% presented in the paper. Applying the same arithmetic to the NICE group gives a detection rate of 41.6% and a positive predictive value of 2.4%. These are much closer to the figures in Table 2 of the paper because of the relatively low compliance in the NICE group. Other measures of screening performance presented on this paper including the likelihood ratios, negative predictive value the receiver operating characteristic (ROC) curve analysis are also affected by this problem.The arithmetic presented above is intended for illustration; for the SPREE study4 we applied Markov chain monte carlo (MCMC) methods for inferences about screening performance. These or similar methods should be applied in future studies of screening performance.Dave Wright,1 Kypros Nicolaides2Institute of Health Research, University of Exeter, Exeter, UKHarris Birthright Research Centre for Fetal Medicine, King’s College Hospital, London, UK.

Objective: To determine whether cardiac functional and structural changes in fetuses of mothers with gestational diabetes mellitus (GDM) persist in the offspring beyond the neonatal period. Design: Longitudinal study Setting: Fetal Medicine Unit in a UK teaching hospital Population: 73 women with GDM and 73 women with uncomplicated pregnancy were recruited and fetal cardiac scans were performed at 35-36 weeks’ gestation. Repeat echocardiogram was performed in their offspring during infancy. Main outcome measures: Fetal and infant cardiac functional and structural changes Results: Fetuses of mothers with GDM, compared to controls, had more globular right ventricles (sphericity index 0.7, IQR 0.6/0.7 vs 0.6, IQR 0.5/ 0.6, p<0.001) and reduced right global longitudinal systolic strain (-16.4, IQR -18.9/-15.3 vs -18.5, IQR -20.6/-16.8, p=0.001) and left global longitudinal systolic strain (-20.1, IQR -22.5/-16.9 vs -21.3, IQR -23.5/-19.5), p=0.021). In the GDM group, compared to controls, in infancy there was higher left ventricular E/e’ (8.7, IQR 7.3/9.7 vs 7.9 IQR, 6.8/8.9 p=0.011) and lower left ventricular global longitudinal systolic strain (-21.0, IQR -22.5/-19.4 vs -22.3, IQR -23.5/-20.7, p=0.001) and tricuspid annular plane systolic excursion (13.8, IQR 12.7/16.1 vs 15.2, IQR 13.8/16.8, p=0.003). These differences remained following multivariable analysis. Conclusion: GDM is associated with alterations in fetal cardiac function and structure compared to controls and persistent cardiac changes in infancy.