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Objective Stillbirth is a potentially preventable complication of pregnancy. Identifying women at high risk of stillbirth can guide decisions on the need for closer surveillance and timing of delivery in order to prevent fetal death. Prognostic models have been developed to predict the risk of stillbirth, but none has yet been validated externally. In this study, we externally validated published prediction models for stillbirth using individual participant data (IPD) meta-analysis to assess their predictive performance. Methods MEDLINE, EMBASE, DH-DATA and AMED databases were searched from inception to December 2020 to identify studies reporting stillbirth prediction models. Studies that developed or updated prediction models for stillbirth for use at any time during pregnancy were included. IPD from cohorts within the International Prediction of Pregnancy Complications (IPPIC) Network were used to validate externally the identified prediction models whose individual variables were available in the IPD. The risk of bias of the models and cohorts was assessed using the Prediction study Risk Of Bias ASsessment Tool (PROBAST). The discriminative performance of the models was evaluated using the C-statistic, and calibration was assessed using calibration plots, calibration slope and calibration-in-the-large. Performance measures were estimated separately in each cohort, as well as summarized across cohorts using random-effects meta-analysis. Clinical utility was assessed using net benefit. Results Seventeen studies reporting the development of 40 prognostic models for stillbirth were identified. None of the models had been previously validated externally, and the full model equation was reported for only one-fifth (20%, 8/40) of the models. External validation was possible for three of these models, using IPD from 19 cohorts (491 201 pregnant women) within the IPPIC Network database. Based on evaluation of the model development studies, all three models had an overall high risk of bias, according to PROBAST. In the IPD meta-analysis, the models had summary C-statistics ranging from 0.53 to 0.65 and summary calibration slopes ranging from 0.40 to 0.88, with risk predictions that were generally too extreme compared with the observed risks. The models had little to no clinical utility, as assessed by net benefit. However, there remained uncertainty in the performance of some models due to small available sample sizes. Conclusions The three validated stillbirth prediction models showed generally poor and uncertain predictive performance in new data, with limited evidence to support their clinical application. The findings suggest methodological shortcomings in their development, including overfitting. Further research is needed to further validate these and other models, identify stronger prognostic factors and develop more robust prediction models. (c) 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Objective: Stillbirth is a potentially preventable complication of pregnancy. Identifying women at risk can guide decisions on closer surveillance or timing of birth to prevent fetal death.Prognostic models have been developed to predict the risk of stillbirth, but none have yet been externally validated. We externally validated published prediction models for stillbirth using individual participant data (IPD) meta-analysis to assess their predictive performance. Methods: We searched Medline, EMBASE, DH-DATA and AMED databases from inception to December 2020 to identify stillbirth prediction models. We included studies that developed or updated prediction models for stillbirth for use at any time during pregnancy. IPD from cohorts within the International Prediction of Pregnancy Complication (IPPIC) Network were used to externally validate the identified prediction models whose individual variables were available in the IPD. We assessed the risk of bias of the models and IPD using PROBAST, and reported discriminative performance using the C-statistic, and calibration performance using calibration plots, calibration slopeand calibration-in-the-large. We estimated performance measures separately in each study, and then summarised across studies using random-effects meta-analysis. Clinical utility was assessed using net benefit. Results: We identified 17 studies reporting the development of 40 prognostic models for stillbirth. None of the models were previously externally validated, and only a fifth (20%, 8/40) reported the full model equation. We were able to validate three of these models using the IPD from 19 cohort studies (491,201 pregnant women) within the IPPIC Network database. Based on evaluating their development studies, all three models had an overall high risk of bias according to PROBAST. In our IPD meta-analysis, the models had summary C-statistics ranging from 0.53 to 0.65; summary calibration slopes of 0.40to 0.88, and generally with observed risks predictions that were too extreme compared to observed risks; and little to no clinical utility as assessed by net benefit. However, there remained uncertainty in performance for some models due to small available sample sizes. Conclusion: The three validated models generally showed poor and uncertain predictive performancein new data, with limited evidence to support their clinical application. Findings suggest methodological shortcomings in their development including overfitting of models. Further research is needed to further validate these and other models, identify stronger prognostic factors, and to develop more robust prediction models

Objective: Establish reference ranges for the Elecsys (R) soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) immunoassay ratio in twin pregnancies. Methods: Data analyzed were from 3 prospective studies: Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia (PE) (PROGNOSIS), Study of Early-onset PE in Spain (STEPS), and a multicenter case-control study. Median, 5th, and 95th percentiles for sFlt-1, PlGF, and the sFlt-1/PlGF ratios were determined for normal twin pregnancies for 7 gestational windows and compared with the previous data for singleton pregnancies. Results: The reference range analysis included 269 women with normal twin pregnancies. Before 29 weeks' gestation, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios did not differ between twin and singleton pregnancies. From 29 weeks' gestation to delivery, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios were substantially higher in twin versus singleton pregnancies. sFlt-1 values were higher in women with twin pregnancies across all gestational windows. PlGF values were similar or higher in twin versus singleton pregnancies; PlGF concentrations increased from 10 weeks + 0 days to 28 weeks + 6 days' gestation. Conclusions: Reference ranges for the sFlt-1/PlGF ratio are similar in women with twin and singleton pregnancies until 29 weeks' gestation but appear higher in twin pregnancies thereafter.

Preeclampsia is associated with increased cardiovascular long-term risk; however, the underlying functional and structural mechanisms are unknown. We investigated maternal cardiac alterations after preeclampsia. Female rats harboring the human angiotensinogen gene [TGR(hAogen)L1623] develop a preeclamptic phenotype with hypertension and albuminuria during pregnancy when mated with male rats bearing the human renin gene [TGR(hRen)L10J] but behave physiologically normal before and after pregnancy. Furthermore, rats were treated with pravastatin. We tested the hypothesis that statins are a potential therapeutic intervention to reduce cardiovascular alterations due to simulated preeclamptic pregnancy. Although hypertension persists for only 8 days in pregnancy, former preeclampsia rats exhibit significant cardiac hypertrophy 28 days after pregnancy observed in both speckle tracking echocardiography and histological staining. In addition, fibrosis and capillary rarefaction was evident. Pravastatin treatment ameliorated the remodeling and improved cardiac output postpartum. Preeclamptic pregnancy induces irreversible structural changes of cardiac hypertrophy and fibrosis, which can be moderated by pravastatin treatment. This pathological cardiac remodeling might be involved in increased cardiovascular risk in later life.

Objectives: The soluble fms‐like tyrosine kinase‐1 (sFlt‐1) to placental growth factor (PlGF) ratio is generally elevated some time before and at the clinical onset of pre‐eclampsia. The PROGNOSIS study validated a sFlt‐1/PlGF ratio cut‐off of ≤ 38 to rule out the onset of pre‐eclampsia within 1 week of testing in women with suspected disease. The aim of this study was to assess the predictive value of the sFlt‐1/PlGF ratio to rule out the onset of pre‐eclampsia for up to 4 weeks, and to assess the value of repeat measurements.Methods: This was an exploratory post‐hoc analysis of data from the PROGNOSIS study performed in pregnant women aged ≥ 18 years with suspected pre‐eclampsia, who were at 24 + 0 to 36 + 6 weeks' gestation at their first clinic visit. Serum samples were collected at the first visit and weekly thereafter. sFlt‐1 and PlGF levels were measured using Elecsys® sFlt‐1 and PlGF immunoassays. Whether the sFlt‐1/PlGF ratio cut‐off of ≤ 38 used to rule out the onset of pre‐eclampsia within 1 week could predict the absence of pre‐eclampsia 2, 3, and 4 weeks post‐baseline was assessed. The value of repeat sFlt‐1/PlGF testing was assessed by examining the difference in sFlt‐1/PlGF ratio 2 and 3 weeks after the first measurement in women with, and those without, pre‐eclampsia or adverse fetal outcome.Results: On analysis of 550 women, sFlt‐1/PlGF ratio ≤ 38 ruled out the onset of pre‐eclampsia 2 and 3 weeks post‐baseline with high negative predictive values (NPV) of 97.9% and 95.7%, respectively. The onset of pre‐eclampsia within 4 weeks was ruled out with a high NPV (94.3%) and high sensitivity and specificity (66.2% and 83.1%, respectively). Compared with women who did not develop pre‐eclampsia, those who developed pre‐eclampsia had significantly larger median increases in sFlt‐1/PlGF ratio at 2 weeks (∆, 31.22 vs 1.45; P < 0.001) and at 3 weeks (∆, 48.97 vs 2.39; P < 0.001) after their initial visit. Women who developed pre‐eclampsia and/or adverse fetal outcome compared with those who did not had a significantly greater median increase in sFlt‐1/PlGF ratio over the same period (∆, 21.22 vs 1.40; P < 0.001 at 2 weeks; ∆, 34.95 vs 2.30; P < 0.001 at 3 weeks).Conclusion: The Elecsys® immunoassay sFlt‐1/PlGF ratio can help to rule out the onset of pre‐eclampsia for 4 weeks in women with suspected pre‐eclampsia. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Objectives: The soluble fm--s-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio is generally elevated some time before and at the clinical onset of pre-eclampsia. The PROGNOSIS study validated a sFlt-1/PlGF ratio cut-off of ≤ 38 to rule out the onset of pre-eclampsia within 1 week of testing in women with suspected disease. The aim of this study was to assess the predictive value of the sFlt-1/PlGF ratio to rule out the onset of pre-eclampsia for up to 4 weeks, and to assess the value of repeat measurements. Methods: This was an exploratory post-hoc analysis of data from the PROGNOSIS study performed in pregnant women aged ≥ 18 years with suspected pre-eclampsia, who were at 24 + 0 to 36 + 6 weeks' gestation at their first clinic visit. Serum samples were collected at the first visit and weekly thereafter. sFlt-1 and PlGF levels were measured using Elecsys® sFlt-1 and PlGF immunoassays. Whether the sFlt-1/PlGF ratio cut-off of ≤ 38 used to rule out the onset of pre-eclampsia within 1 week could predict the absence of pre-eclampsia 2, 3, and 4 weeks post-baseline was assessed. The value of repeat sFlt-1/PlGF testing was assessed by examining the difference in sFlt-1/PlGF ratio 2 and 3 weeks after the first measurement in women with, and those without, pre-eclampsia or adverse fetal outcome. Results: On analysis of 550 women, sFlt-1/PlGF ratio ≤ 38 ruled out the onset of pre-eclampsia 2 and 3 weeks post-baseline with high negative predictive values (NPV) of 97.9% and 95.7%, respectively. The onset of pre-eclampsia within 4 weeks was ruled out with a high NPV (94.3%) and high sensitivity and specificity (66.2% and 83.1%, respectively). Compared with women who did not develop pre-eclampsia, those who developed pre-eclampsia had significantly larger median increases in sFlt-1/PlGF ratio at 2 weeks (∆, 31.22 vs 1.45; P < 0.001) and at 3 weeks (∆, 48.97 vs 2.39; P < 0.001) after their initial visit. Women who developed pre-eclampsia and/or adverse fetal outcome compared with those who did not had a significantly greater median increase in sFlt-1/PlGF ratio over the same period (∆, 21.22 vs 1.40; P < 0.001 at 2 weeks; ∆, 34.95 vs 2.30; P < 0.001 at 3 weeks). Conclusion: The Elecsys® immunoassay sFlt-1/PlGF ratio can help to rule out the onset of pre-eclampsia for 4 weeks in women with suspected pre-eclampsia. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.