Validation of ultrasound criteria for prediction of severe preeclampsia in a Peruvian population

To discover the value of combined maternal first and second-trimester serum β-hCG, pregnancy associated plasma protein A (PAPP-A), alpha-fetoprotein(AFP)and unconjugated estriol (uE3) in the prediction of preeclampsia. A total of 1 805 pregnant women who had antenatal care at International Peace Maternal and Child Health Hospital Affiliated to Shanghai Jiaotong University between April 2012 and June 2013 were selected prospectively by random method. According to the outcome, they were defined as the control group and the preeclampsia group (including mild and severe cases). PAPP-A and β-hCG level were measured at 10-14 gestational weeks. AFP, β-hCG and uE3 were measured at 15-20 gestational weeks. The relevance between the serological indicators and outcomes was analyzed. The value of the indicators was judged by receiver operating characteristic (ROC) and Youden index, and the relevant predictive boundary values were identified. (1) Among the 1 805 cases, 1 739 women did not have hypertension(the control group), while 66 women had preeclampsia (the preeclampsia group). The incidence of preeclampsia was 3.66% (66/1 805), including 43 mild cases and 23 severe cases. (2) At 10-14 gestational weeks, the mean value of PAPP-A in the control group was (3 972 ± 2 311) mU/L, while in the preeclampsia group it was (2 837 ± 1 849)mU/L. The difference between the two groups had statistical significance (P < 0.01). The mean value of β-hCG of the control group was 55(37∼83) U/L, while in the preeclampsia group it was (57 ± 35)U/L. There was no statistical significance (P > 0.05). PAPP-A, β-hCG and AFP of mild preeclampsia cases were (3 249 ± 1 877) mU/L, (61 ± 38) U/L and (35 ± 11) µg/L respectively, and in severe cases they were(1 758 ± 1 297)mU/L, (47 ± 23)U/L and (47 ± 22)µg/L, respectively. There was statistically significant difference in PAPP-A (P < 0.05). (3) At 15-20 gestational weeks, β-hCG, AFP and uE3 in the preeclampsia group were (47 909 ± 31 396 )U/L, (38 ± 15)µg/L and (0.98 ± 0.31)µg/L respectively, and in the control group they were (39 267 ± 25 054 )U/L, (47 ± 18)µg/L and (1.17 ± 0.39) µg/L, respectively. AFP and uE3 of the preeclampsia group were lower than those in the control group and the difference was statistically significant (P < 0.05). However, β-hCG and uE3 of the mild preeclampsia cases and the severe cases had no statistical difference (P > 0.05). (4)At 10-14 gestational weeks, PAPP-A demonstrated positive relevance to the newborn weight (r = 0.068, P = 0.011) and gestational weeks at delivery (r = 0.057, P = 0.048). At 15-20 weeks, positive relevance was found between AFP and the newborn weight (r = 0.149, P = 0.000), while negative relevance was found between β-hCG and Apgar scores (r = -0.085, P = 0.024), and positive relevance was found between uE3 and gestational weeks at delivery (r = 0.086, P = 0.036). (5) PAPP-A, AFP and uE3 data were used as testing parameters to obtain the boundary values of preeclampsia prediction as follows: PAPP-A 1 831 mU/L, AFP 41 µg/L and uE3 1.04 µg/L. The specificity was 97.82% , 98.54% and 98.80% , respectively. (6) ROC was drawn and Youden index was calculated based on the joint predicative factor of PAPP-A, AFP and uE3. Youden index reached its peak (0.41) when the joint predictive factor was 0.032, meaning that the factor had the highest prediction value. The prediction value of the PAPP-A, AFP and uE3 was 0.032, with the specificity and sensitivity of 98.93% and 70.59%, respectively. The odds ratio was 2.37. Both the individual parameter (PAPP-A, AFP and uE3) and the combined data have prediction value for preeclampsia, but the latter is more effective than any of the single parameter.

Objective To observe the levels of serum complement C1q, C3, C4 and factor B in different phases during normal pregnancy; To evaluate the diagnostic value and the predictive value of serum complement C1q, C3, C4 and factor B in preeclampsia (PE). Methods Three groups of subjectes were enrolled from January 2017 to March 2018 in Department of Obstetrics and Gynecology, Peking University Third Hospital. (1) 30 pregnant women in each group at 8-14 weeks, 20-26 weeks and 28-36 weeks were retrospectively selected, and the serum levels of complement C1q, C3, C4 and B factors were measured and compared. (2)Selecting 17 cases of early-onset mild PE, 47 cases of early-onset severe PE, 24 cases of late-onset mild PE, 27 cases of late-onset severe PE, and 30 normal pregnant cases of the same gestational stage as early-onset / late-onset controls, through ANOVA analysis and comparison between two groups, this study evaluated the diagnostic value of serum complement C1q, C3, C4 and factor B in PE. (3)To evaluate the predictive effect in PE, it analyzed serum C1q and factor B levels of pregnant women at 20-26 gestation weeks through prospective nested case-control study of 214 cases. Results The levels of serum C1q remained stable in the whole pregnancy. The levels of C3 and factor B increased at the early stage of pregnancy and remained stable after the middle stage. C4 increased early in pregnancy and then remained stable. Compared with the control group, the levels of serum C1q in all four types of PE patients were significantly decreased (median: 169 mg/L, 161 mg/L, 165 mg/L, 163 mg/L; early-onset, late-onset control group: 187 mg/L, 194 mg/L; U=130.500, 426.500, 159.500, 130.500, all P 0.05). 33 (15.4%) cases developed PE out of 214 pregnant women with PE risk factors. Compared to those who didn′t develop PE, it showed no statistical difference of serum C1q, C3, C4, and factor B levels at 20-26 gestational weeks of the women who subsequently developed PE (C1q: 175 mg/L vs. 184 mg/L; C3: 1 523 mg/L vs. 1 467 mg/L; C4: 230 mg/L vs. 229 mg/L; FB: 344 mg/L vs. 320 mg/L; U=2 090.000, 1 575.000, 2 058.500, 1 362.000, all P>0.05). Compared to those of the healthy pregnant controls, it showed no statistical difference of serum C1q, C3 and C4 levels of 20-26 gestational weeks of the women who subsequently developed PE (C1q: 175 mg/L vs. 190 mg/L; C3: 1 523 mg/L vs. 1 428 mg/L; C4: 230 mg/L vs. 227 mg/L; U=353.000, 395.000, 493.500, all P>0.05), while it showed statistical difference (344 mg/L vs. 306 mg/L; U= 233.500, P=0.007) for factor B. Conclusions Serum C1q level of PE patients significantly decreased, which can be used as potential indicators of PE diagnosis, but serum C1q, C3, C4 level of 20-26 gestational weeks cannot predict risk of PE. Factor B cannot serve as serum index of PE diagnosis, but its serum levels at 20-26 gestational weeks werer higher than those of normal pregnant controls, factor B may be a potential predictor, but need further verification. (Chin J Lab Med, 2018, 41: 934-942) Key words: Preeclampsia; Complement; C1q; C3; C4; factor B

Background: Preeclampsia is a multisystem disorder of pregnancy, which complicates 3%-5% of pregnancies in the western world. It is a major cause of maternal morbidity and mortality worldwide. The cardinal clinical features of the condition are hypertension and proteinuria occurring after 20 weeks gestation in women who were not previously known to be hypertensive. Objective: This study was aimed to assess the efficacy of C3 estimation and measurement of bilateral uterine artery Doppler before 20 weeks of pregnancy for prediction of preeclampsia in primigravida. Methods: The study was performed at the Antenatal Care Unit, Obstetrics and Gynecology Department, Sayed Galal Hospital, Al Azhar University on 131 pregnant women at 14-20 gestational weeks during period from July 2017 to December 2017 gestation attending. Results: On follow up the population of the study 131 pregnant women had completed the study that were classified to 119 (90.8%) with no pre-eclampsia and 12 (9.2%) developed preeclampsia, As regards the Patients characteristics there was no statistical significant difference between the two groups as regard age, height, weight, gestational age, SBP and DPB at enrollment (p-value>0.05). There was a significant difference regarding BMI as (p value < 0.05), with more increasing BMI and decreasing gestational age at delivery in preeclampsia group in comparison with the no preeclampsia group. As regards the C3, there was statistically highly significant difference between the two groups regarding serum C3 level as p value <0.05, with lower levels of C3 serum levels in preeclampsia group. Receiver operator characteristics (ROC) curves were constructed for estimating the association between pre-eclampsia and serum C3 level. A significant association was found with serum C3 level being a significant predictor with lower values in cases with pre-eclampsia than in normal cases [area under the curve (AUC) = 0.935, 95% CI (0.878 to 0.9711.35), best cut off (≤53.1), sensitivity of 83.3%, specificity of 100% positive predictive value (PPV) of 100% and negative predictive value (NPV) of 98.3%. Conclusion: This study demonstrates that lower level of maternal serum C3 in the early second trimester (14-20 weeks gestation) and abnormal increasing in uterine artery indices (PI and RI) are associated with developing pre-eclampsia several months later in pregnancy.

To study the value of second trimester maternal serum soluble Fms-like tyrosine kinase 1 (sFlt-1), placenta grouth factor (PlGF) and their ratio in the prediction of preeclampsia. In this nested case-control study, we collected second trimester maternal serum samples at 15-20 weeks and 24-28 weeks of gestation from those who developed gestational hypertensive disorders. Maternal serum sFlt-1 and PlGF were measured by electrochemiluminescence immunoassay on an automated platform. The value of sFlt-1, PlGF and their ratio were compared between gestational hypertensive group and the control group. Totally 41 patients with preeclampsia, 44 patients with gestational hypertension and 88 women with normal pregnancy outcomes were included in this study. There was no difference of age, gravidity, parity and preconception body mass index (BMI) between these three groups (P > 0.05) .Gestational week at delivery and neonatal birth weight were different between preeclampsia group and the control group (P < 0.01). The mean value of sFlt-1, PlGF and sFlt-1/PlGF ratio was (1 658 ± 488) µg/L, (141 ± 80) µg/L and 17 ± 9 in preeclampsia group, (1 945 ± 575) µg/L, (143 ± 52) µg/L and 15 ± 6 in gestational hypertension group, and (2 084 ± 741) µg/L, (65 ± 58) µg/L and 16 ± 9 in the control group at 15-20 weeks of gestation. There was no difference of sFlt-1, PlGF value and their ratio among the three groups at 15-20 weeks of gestation (P > 0.05) . The median value of sFlt-1, PlGF and sFlt-1/PlGF ratio were 8 525 µg/L, 35 µg/L and 398.0 in preeclampsia group, 905 µg/L, 336 µg/L and 2.7 in gestational hypertension group, 1 028 µg/L, 477 µg/L and 2.3 in the control group at 24-28 weeks of gestation. The value of sFlt-1, PlGF and their ratio was significantly different between preeclampsia group and the control group at 24-28 weeks of gestation (P < 0.01) . PlGF value was different between gestational hypertension group and the control group (P < 0.01) . The sensitivity and specificity of serum sFlt-1, PlGF and sFlt-1/PlGF ratio at 24-28 weeks of gestation to predict preeclampsia were 93% and 99% for sFlt-1 (cut off value 2 500 µg/L), 92% and 77% for PlGF (cut off value 270 µg/L) , 89% and 99% for sFlt-1/PlGF ratio (cut off value 11) . The value of sFlt-1, PlGF and their ratio at 24-28 weeks of gestation was significantly changed before clinical onset of preeclampsia.Use these serum indicators to predict preeclampsia will hopefully provide objective evidence for the management of patients who will develop preeclampsia later.

Objective To evaluate the characteristics and performance of various prediction models for early-onset preeclampsia, and to provide a reference for further study of preeclampsia prediction methods. Methods (1) Databases of PubMed, Medline, Embase, China National Knowledge Infrastructure (CNKI) and Wanfang Database were searched since their inception to October 2016. Studies in models for predicting early-onset preeclampsia during the first trimester were included. (2) Two reviewers independently checked potentially eligible articles, assessed risk of bias and extracted data. (3) Subtotals for the performance of different models were created and their properties were analyzed. Differences between simple models (based upon high risk factors such as demographic figures, medical history and family history, etc) and complex models (based upon blood pressure, uterine artery Doppler and biomarkers) were compared by analyzing forest plot created by SAS 9.4. Results (1) Seventeen studies met the inclusion criteria were screened out, including nine prospective cohort studies, two case-control studies and six nested case-control studies. A total of 76 436 gravidas from tendifferent populations were assessed by the established models in these studies. (2) The area under the curve (AUC) of 13 simple models ranged from 0.64 to 0.81 with the sensitivity of 21%-60% when the false positive rate (FPR) was 10%. The AUC of 17 complex models ranged from 0.77 to 0.98 and the sensitivity was between 48.0% and 95.2% at a fixed FPR of 10%. (3) Compared with the simple models, the best complex models could ensure a promotion of 0.171 (range from 0.060 to 0.245) in median AUC, and a promotion of 40.8% (16.0% to 52.2%) in sensitivity at a FPR of 10%. Based on the simple models, additional mean arterial pressure (MAP) would increase the AUC and sensitivity by 0.092 (0.079 to 0.104) and 28.7% (16.2% to 55.0%), respectively, while additional uterine artery pulsatility index (UtA-PI) would bring an increase of 0.106 (0 to 0.137) and 31.8% (-1.0% to 41.9%), respectively. Moreover, when both MAP and UtA-PI were included into the simple models, the AUC and sensitivity would increase by 0.157 (0.094 to 0.218) and 31.6% (12.0% to 52.2%). Conclusions Complex prediction models perform better than simple models in prediction of early-onset preeclampsia. However, further confirmation is required in different population. Key words: Pregnancy trimester, first; Preeclampsia; Risk factors; Forecasting; Logistic models

Background Pre-eclampsia is a pregnancy-associated disease occurring in 5–8% of pregnancies and is a major cause of maternal and fetal morbidity and mortality. A potentially important process in the pathogenesis of pre-eclampsia is an imbalance between placenta-derived proangiogenic and antiangiogenic proteins. The proangiogenic proteins vascular endothelial growth factor (VEGF) and placental growth factor (PLGF) are involved in the regulation of placental vascular development and maternal endothelial function during pregnancy. Aim of the study The aim of this study is to assess the PLGF and soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) in the prediction of pre-eclampsia. Materials and methods This study included 88 pregnant women: 68 pregnant women with pre-eclampsia divided into two subgroups (mild and severe pre-eclampsia) and 20 healthy pregnant women matched for age and sex, who served as the control group. Laboratory investigations such as determination of complete blood count, blood urea, serum creatinine, aspartate aminotransferase, alanine transaminase, serum albumin, quantitative determination of total protein in urine, estimation of prothrombin time and concentration, serum PLGF concentration, and serum sVEGFR-1 concentrations were carried out by ELISA. BMI was estimated in this study. Results The results showed that serum PLGF was highly significant decreased in women with pre-eclampsia when compared with the control group. There was a highly statistically significant difference between mild and severe cases, where the PLGF decreased with increased severity of pre-eclampsia (P Conclusion Finally, it is concluded that high concentrations of sVEGFR-1 combined with low concentrations of PLGF may be used to predict the development of pre-eclampsia.

Objective To investigate the clinical value of acoustic radiation forcs impulse (ARFI) in quantitative evaluating placental elasticity. Methods The study population included 487 normal pregnant women, and ARFI generated shear wave velocity (SWV) was measured. On the basis of gestational ages, placental sites and sampling depths in region of interest (ROI), the normal population was divided into different groups.One-way analysis of variance was used to compare the discrepancy on the SWV values amomg the nomal placental sites or the sampling depths in ROI. Pearson correlation coefficient were used to assess the possible relationships between the normal placental SWV values and the different gestational ages or the placental grades. A total of 51 cases were diagnosed with severe preeclampsia, among them 25 cases were categorized as severe preeclampsia with fetal growth restriction (FGR). The placental SWV values were measured and compared with those of the normal population. The pathological examinations were performed on 50 normal and 51 abnormal placentas. Results Basing on the placental sites, the normal population were divided into three groups: anterior wall, lateral wall and posterior wall groups. Compared with the posterior wall group, the placental SWV values in the anterior wall or lateral wall group significantly decreased (P<0.05). No statistical significant difference was found between the anterior wall group and the lateral wall group. Basing on the distance from the sampling depths to the probe (range from 2 to 7.99 cm, and each additional 1 cm corresponding a group), the normal population were divided into six groups. There was statistical significant difference for the placental SWV values between the two groups of distance in the range of 2.0 to 5.99 cm and 6.0 to 7.99 cm (P<0.05). There was no statistical significant difference between the other two groups. The mean SWV value was (0.78±0.08 m/s) in the normal group. No significant relationships were found between the placental SWV values and the gestational ages of the normal population. However the placental SWV values were significantly related to the placental grades. For the placental SWV values, there was statistical significant difference between the normal group and the abnormal group (P<0.05). No statistical significant difference was found between the severe preeclampsia group and the severe preeclampsia with FGR group. The pathological examinations also showed significant changes in the abnormal group. Conclusions ARFI may quantitatively analyze the placental elasticity and make a difference between nomal and abnormal placenta. Key words: Ultrasonography, prenatal; Placenta; Severe preeclampsia; Acoustic radiation force impulse

Objectives: To explore the association of uterine arteries (UA) waveform analysis with brachial artery flow-mediated dilation (BAFMD) in the prediction of preeclampsia in high-risk pregnancies. Methods: UA waveforms were recorded using Pulsed Doppler ultrasonography in 33 women at 22–24 weeks of gestation with high risk factors for preeclampsia (PE). Mean Pulsatility Index (PI) of both UA were registered. At the same time, brachial artery diameter was evaluated in basal and after stress conditions using Color Doppler; BAFMD was expressed as percent change in diameter from baseline. The onset of PE was divided in early (before 34 weeks of gestation) or late (after 34 weeks). Logistic regression models were developed, and their predictive ability assessed using ROC curves. Results: The prevalence of PE in the studied group was 24% (8/33), 5 early and 3 late-onset. Mean UA-PI and BAFMD values of cases without PE were lower, but not significant, than those developing PE (mean difference (MD): −0.39 (95% CI: −0.90–0.13) and −4.41% (95% CI: −16.1–7.3) respectively). Area under ROC curve for mean UA-PI was of 0.70 (95% CI: 0.41–0.99%), and for BAFMD of 0.59 (95% CI: 0.37–0.80). Logistic regression analysis was only significant for mean UA-PI (P = 0.034), and adding BAFMD did not improve the prediction. For early-onset PE, there were significant higher values in mean UA-PI (MD: 0.56 (95% CI: 0.19–0.94)), and higher BAFMD results but not significant (MD: 8.8% (95% CI: −4.6–22.2%)). Area under ROC curve for mean UA-PI was of 0.79 (95% CI: 0.44–1), and for BAFMD of 0.69 (95% CI: 0.46–0.91). Logistic regression analysis was only significant for mean UA-PI (P = 0.02), multivariate regression analysis combining UA-PI and BAFMD did not get better the prediction of early-onset PE. Conclusions: Although there is a trend of higher BAFMD in pregnancies with PE, the test in the second trimester did not improve the capacity for prediction of PE that provides the UA by itself.

Objective: To examine whether plasma levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) during the first 20 weeks of pregnancy can predict preeclampsia in the second half of pregnancy. Methods: The study population included 150,10 registered births. Receiver operating characteristic (ROC) curve analysis was used to describe the relationship between different values of AST and ALT during the first 20 weeks of pregnancy in the prediction of preeclampsia. Results: Using ROC curve analyses, elevated ALT levels were significantly associated with both mild preeclampsia (p < 0.001) and severe preeclampsia (p = 0.032). However, an ALT level of 50 IU/L had a sensitivity of only 3.3% (despite a specificity of 97%) in the prediction of severe preeclampsia. While no significant association was noted between AST levels and mild preeclampsia (p = 0.669), elevated levels of AST during this period were significantly associated with severe preeclampsia (p = 0.027). However, AST of 50I U/L had a sensitivity of only 2.0% (despite a specificity of 98%) in the prediction of severe preeclampsia. Conclusions: Higher levels of the liver enzymes AST and ALT during the first 20 weeks of pregnancy are associated with higher risk for the development of severe preeclampsia in the second half of the pregnancy. Nevertheless, there is no clinical cutoff value that can be practically used for the prediction of preeclampsia.

O21. First trimester serum placental growth factor and hyperglycosylated human chorionic gonadotropin are associated with later pre-eclampsia

Maternal vascular indices at 36 weeks’ gestation in the prediction of preeclampsia

Objective To investigate the changes of fatty acid oxidase in the placenta of preeclampsia cases with different clinical features, and the relationship with oxidative stress and inflammatory response. To study the correlation of serum free fatty acid (FFA) and triglycerides (TG) level in early second trimester with the molecular changes of the long-chain fatty acid oxidase in the third trimester. Methods This was prospective cohort study, in which cases with singleton pregnancies who archived in Haidian Maternal and Children's Hospital, Beijing, from January 1st 2012 to May 31st, with regular prenatal care were included. Doppler ultrasound was used for screening for the presence of early diastolic notch of uterine artery at 22-24 weeks of gestation. All the 101 cases with the early diastolic notch of uterine artery were included as the notch group, and 377 cases without the early diastolic notch of uterine artery were included as the non-notch group. The perinatal outcomes and the incidence of hypertensive disorders in pregnancy of the two groups were observed. The serum level of FFA and TG was tested, and the mRNA and protein expression of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), P47-phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, p38 mitogen-activated protein kinase α(p38MAPK-α) and cyclooxygenase-2 (COX-2) were detected using real-time quantitative PCR and western blot. The relationship between serum level of FFA and TG and the mRNA and protein expression of LCHAD, NADPH P47-phox,p38MAPK-α and COX-2 of the placental tissue specimens were analyzed. Results (1) In the notch group, there were 9 cases of early-onset preeclampsia, 15 cases of late-onset preeclampsia and 10 cases of gestational hypertension; and there were 8 cases of late-onset preeclampsia and 18 cases of gestational hypertension in the non-notch group. 15 cases with normal blood pressure in each group were randomly selected as the control group.(2)The serum level of TG of cases of early-onset preeclampsia, late-onset preeclampsia and gestational hypertension in the notch group were(2.0 ± 0.8),(1.8 ± 0.6) and(1.9±0.7)mmol/L, and that of FFA were(0.68±0.26), (0.52±0.10) and (0.52±0.17) mmol/L, respectively. The serum level of TG of cases of late-onset preeclampsia and gestational hypertension in the non-notch group were(1.6±0.6) and (1.4±0.4) mmol/L, and that of FFA were (0.49±0.11) and (0.48±0.05) mmol/L, respectively. The serum level of TG and FFA in the control group were (1.4±0.5) and (0.52±0.06) mmol/L, respectively. The TG level of the notch group was higher than that of the control group, and the difference was statistically significant (P 0.05) . (6) The mRNA expression of placental LCHAD in the early-onset preeclampsia in the notch group was significantly negatively correlated with the mRNA expression of placental NADPH P47-phox and COX-2 (r=- 0.877,-0.762,P<0.05). The mRNA expression of placental LCHAD in the control group was significantly negatively correlated with the mRNA expression of placental COX-2 (r=-0.565,P<0.01). The protein expression of placental LCHAD in the early-onset preeclampsia in the notch group was significantly negatively correlated with the protein expression of NADPH P47-phox (r=-0.818,P<0.01). The protein expression of placental LCHAD in the control group was significantly negatively correlated with the protein expression of COX-2 (r=-0.502,P<0.01). Conclusions The placental mRNA and protein expression of long-chain fatty acid oxidation enzymes were different in different clinical features of preeclampsia, which were reduced more obviously in the early-onset preeclampsia in the notch group than that of the late-onset preeclampsia in the notch group, and were negatively correlated with the elevated serum FFA level, significantly enhanced oxidative stress and inflammatory response, but with no correlation with serum TG level. Key words: Pre-eclampsia; 3-Hydroxyacyl CoA dehydrogenases; NADPH oxidase; Fatty acids, nonesterified; Triglycerides; Oxidative stress

Preeclampsia (PE) is one of the main causes of maternal and infant death, but its pathogenesis has not been fully clarified. Recent studies have indicated that hypoxia inducible factor(HIF)-1α and soluble fms-like tyrosine kinase receptor (sFlt)-1 are the two important factors leading to and aggravating the symptoms of PE. With the expression of HIF-1α in peripheral blood and placenta tissue of PE patients increased, it would prompted the increased expression of target gene sFlt-1, which led to maternal vascular injury and organ dysfunction, and maternal and neonatal complications occur. According to the biological function of HIF-1α and sFlt-1, and their expression levels in peripheral blood and placenta tissue of PE patients, it can be one of the prediction indicators of the occurrence of PE, maternal complications and prognosis of perineonate for early prevention and treatment, and provide a theoretical basis and a new way to reduce maternal and neonatal complications and mortality. Key words: Pre-eclampsia; Hypoxia-inducible factor 1, alpha subunit; Vascular endothelial growth factor receptor-1; Female

The meta-analysis of previous meta-analyses by Townsend et al.1 does not benefit but rather hinders research and clinical implementation of strategies for the prediction and prevention of pre-eclampsia (PE). It is inevitable that there is limited value in performing such umbrella meta-analyses and that misleading conclusions can be drawn when combining data from a series of heterogeneous studies in terms of size and type of populations examined, methodology used, timing of biomarker measurement, adjustment or not for confounders, use of different models combining risk factors from maternal demographic characteristics and medical history with biomarkers, as well as use of a plethora of PE definitions resulting in delivery at different gestational ages. Whilst we agree with the conclusion of Townsend et al.1 that well-designed prospective studies of predictive markers and randomized intervention studies are necessary to develop and validate new prediction models before their introduction into clinical practice, we strongly disagree that these have yet to be performed. In the last three decades, many well-designed prospective studies involving tens of thousands of patients have established all the necessary requirements for effective clinical implementation of routine screening for PE2. We present here some of the evidence generated by our group; however, many other researchers have contributed through their data to the following conclusions. First, it is now established that the best approach for estimation of individual patient-specific risk of delivery with PE before any specified gestational age is by a combination of maternal factors and biomarkers, obtained either individually or in combination at any stage in pregnancy, using the competing-risks model. This model for estimation of risk based on maternal factors was originally derived from a prospective study of 58 884 singleton pregnancies3 and was subsequently updated based on the study of 120 492 pregnancies4. Second, many potential biomarkers have been extensively investigated and it has been established that, at present, useful biomarkers for the prediction of PE are: uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP) and serum placental growth factor (PlGF) measured at 11–13 and 19–24 weeks' gestation; UtA-PI, MAP, PlGF and serum soluble fms-like tyrosine kinase-1 (sFlt-1) measured in the early third trimester; and MAP, PlGF and sFlt-1 evaluated in the late third trimester5-28. The methodology for obtaining appropriate measurements of biomarkers and auditing of results has also been established. Third, it is established that biomarker levels depend on gestational age, maternal weight and race, method of conception, medical conditions and elements of obstetric history, and they are also affected by the instrument used for their measurement. Consequently, appropriate evaluation and application of biomarkers in screening requires prior standardization by expressing the measured values as multiples of the median (MoM)28-31. In pregnancies that develop PE, MoM values of MAP, UtA-PI and sFlt-1 tend to be higher and PlGF tends to be lower than in normal pregnancies; the effect size increases with increasing severity of the disease, quantified by the gestational age at delivery5-8. Fourth, the competing-risks model has been successfully applied for assessment of risk for PE and stratification of pregnancy care by a combination of maternal factors and biomarkers in the first, second and third trimesters of pregnancy32-44. In the first trimester, the competing-risks approach utilizing maternal factors, MAP, UtA-PI and PlGF was used to identify women at high risk of developing preterm PE; at a 10% screen-positive rate, 90% of early-PE cases and 75% of those with preterm PE were predicted in both a training dataset of 35 948 singleton pregnancies and in two independent, non-intervention, multicenter studies involving 8775 and 16 451 singleton pregnancies, respectively32, 45-48. We have also shown, in a study involving 66 964 pregnancies, that the predictive performance of this approach is similar irrespective of whether PE is defined by the traditional criteria of the International Society for the Study of Hypertension in Pregnancy (ISSHP), which requires the presence of both hypertension and proteinuria, or the new criteria of ISSHP and the American College of Obstetricians and Gynecologists which include cases without proteinuria but with evidence of renal, hepatic or hematological dysfunction49-52. Fifth, a randomized controlled trial found that aspirin administration after 23 weeks' gestation in a high-risk group identified by second-trimester screening was not effective in preventing PE53. In contrast, a more recent randomized trial demonstrated that, in women at high risk of PE, administration of aspirin (150 mg/day) from 11–14 until 36 weeks' gestation reduces the risk of early PE and preterm PE by about 90% and 60%, respectively, and the length of stay in the neonatal intensive care unit by about 70%54, 55. There is no justification for further delay in the implementation of strategies for prediction and prevention of PE in routine clinical practice.

Objective To investigate the practical value of monitoring uterine hemodynamics with ultrasound during second trimester in clinical diagnosis and treatment on early-onset preeclampsia.Methods Doppler ultrasound was given to observe PI,RI and S/D of uterine arteries in 20-23+6 weeks and 24-28 weeks for all pregnant women,follow up observation was conducted to pregnant women during pregnancy and childbirth,then we compared the group uterine artery blood flow parameters of early-onset preeclampsia with normal pregnancy.Results According to pregnancy outcomes,access to 21 cases of early-onset preeclampsia and 40 cases of normal control group,patients with early-onset preeclampsia had higher uterine arterie PI,RI and S/D than the those of normal control group in 20-23+6 weeks and 24-28 weeks,the difference has statistical significance,P ＜ 0.05.Conclusion The early-onset preeclampsia compared with normal,uterine artery blood flow velocity of pregnant women is quite different,uterine artery blood flow parameters can be used as a secondary indicator to assist clinicians of screening risk populations with early-onset preeclampsia during second trimester. Key words: Early-onset preeclampsia; Uterine artery; Color Doppler ultrasound