Accuracy of placental growth factor alone or in combination with soluble fms-like tyrosine kinase-1 or maternal factors in detecting preeclampsia in asymptomatic women in the second and third trimesters: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to: (1) identify all relevant studies reporting on the diagnostic accuracy of maternal circulating placental growth factor) alone or as a ratio with soluble fms-like tyrosine kinase-1), and of placental growth factor-based models (placental growth factor combined with maternal factors±other biomarkers) in the second or third trimester to predict subsequent development of preeclampsia in asymptomatic women; (2) estimate a hierarchical summary receiver-operating characteristic curve for studies reporting on the same test but different thresholds, gestational ages, and populations; and (3) select the best method to screen for preeclampsia in asymptomatic women during the second and third trimester of pregnancy by comparing the diagnostic accuracy of each method. DATA SOURCES: A systematic search was performed through MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform databases from January 1, 1985 to April 15, 2021. STUDY ELIGIBILITY CRITERIA: Studies including asymptomatic singleton pregnant women at >18 weeks' gestation with risk of developing preeclampsia were evaluated. We included only cohort or cross-sectional test accuracy studies reporting on preeclampsia outcome, allowing tabulation of 2×2 tables, with follow-up available for >85%, and evaluating performance of placental growth factor alone, soluble fms-like tyrosine kinase-1- placental growth factor ratio, or placental growth factor-based models. The study protocol was registered on the International Prospective Register Of Systematic Reviews (CRD 42020162460). METHODS: Because of considerable intra- and interstudy heterogeneity, we computed the hierarchical summary receiver-operating characteristic plots and derived diagnostic odds ratios, ß, θi, and Λ for each method to compare performances. The quality of the included studies was evaluated by the QUADAS-2 tool. RESULTS: The search identified 2028 citations, from which we selected 474 studies for detailed assessment of the full texts. Finally, 100 published studies met the eligibility criteria for qualitative and 32 for quantitative syntheses. Twenty-three studies reported on performance of placental growth factor testing for the prediction of preeclampsia in the second trimester, including 16 (with 27 entries) that reported on placental growth factor test alone, 9 (with 19 entries) that reported on the soluble fms-like tyrosine kinase-1-placental growth factor ratio, and 6 (16 entries) that reported on placental growth factor-based models. Fourteen studies reported on performance of placental growth factor testing for the prediction of preeclampsia in the third trimester, including 10 (with 18 entries) that reported on placental growth factor test alone, 8 (with 12 entries) that reported on soluble fms-like tyrosine kinase-1-placental growth factor ratio, and 7 (with 12 entries) that reported on placental growth factor-based models. For the second trimester, Placental growth factor-based models achieved the highest diagnostic odds ratio for the prediction of early preeclampsia in the total population compared with placental growth factor alone and soluble fms-like tyrosine kinase-1-placental growth factor ratio (placental growth factor-based models, 63.20; 95% confidence interval, 37.62-106.16 vs soluble fms-like tyrosine kinase-1-placental growth factor ratio, 6.96; 95% confidence interval, 1.76-27.61 vs placental growth factor alone, 5.62; 95% confidence interval, 3.04-10.38); placental growth factor-based models had higher diagnostic odds ratio than placental growth factor alone for the identification of any-onset preeclampsia in the unselected population (28.45; 95% confidence interval, 13.52-59.85 vs 7.09; 95% confidence interval, 3.74-13.41). For the third trimester, Placental growth factor-based models achieved prediction for any-onset preeclampsia that was significantly better than that of placental growth factor alone but similar to that of soluble fms-like tyrosine kinase-1-placental growth factor ratio (placental growth factor-based models, 27.12; 95% confidence interval, 21.67-33.94 vs placental growth factor alone, 10.31; 95% confidence interval, 7.41-14.35 vs soluble fms-like tyrosine kinase-1-placental growth factor ratio, 14.94; 95% confidence interval, 9.42-23.70). CONCLUSION: Placental growth factor with maternal factors ± other biomarkers determined in the second trimester achieved the best predictive performance for early preeclampsia in the total population. However, in the third trimester, placental growth factor-based models had predictive performance for any-onset preeclampsia that was better than that of placental growth factor alone but similar to that of soluble fms-like tyrosine kinase-1-placental growth factor ratio. Through this meta-analysis, we have identified a large number of very heterogeneous studies. Therefore, there is an urgent need to develop standardized research using the same models that combine serum placental growth factor with maternal factors ± other biomarkers to accurately predict preeclampsia. Identification of patients at risk might be beneficial for intensive monitoring and timing delivery.

Does low-dose aspirin initiated before 11 weeks' gestation reduce the rate of preeclampsia?

OBJECTIVE DATA: Preconception or early administration of low-dose aspirin might improve endometrial growth, placental vascularization, and organogenesis. Most studies have evaluated the potential benefit of preconception or early administration of low-dose aspirin in women with a history of recurrent pregnancy loss, women who have undergone in vitro fertilization, or women with thrombophilia or antiphospholipid syndrome. These women are at an increased risk of placenta-associated complications of pregnancy, including preeclampsia, preterm delivery, and fetal growth restriction. STUDY OUTCOMES: We performed a systematic review and meta-analysis to evaluate the effect of low-dose aspirin initiated at <11 weeks' gestation on the risk of preeclampsia, gestational hypertension, or any hypertensive disorder of pregnancy. Secondary outcomes included preterm delivery at <37 weeks' gestation and fetal growth restriction. STUDY APPRAISAL AND SYNTHESIS METHODS: We searched in MEDLINE via PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform from 1985 to November 2018. Entry criteria were randomized controlled trials evaluating the effect of aspirin administered at <11 weeks' gestation in preventing preeclampsia and/or hypertensive disorders in pregnancy or improving pregnancy outcomes in women with recurrent miscarriage as compared with placebo or no treatment and outcome data available or provided by authors for >85% of the study population. Relative risks with 95% confidence intervals were calculated for each study and pooled for global analysis as the effect measure. We assessed statistical heterogeneity in each meta-analysis using the χ2 statistics, I2, and Tau2. Heterogeneity was considered substantial if an I2 was greater than 50% and either the Tau2 was greater than zero or there was a low P value (<0.10) in the χ2 test for heterogeneity. Random-effects meta-analysis, weighted by the size of the studies, was performed to produce an overall summary on aspirin effect for each outcome. Sensitivity analysis by sequential omission of each individual study and by fixed-effects model was performed. Publication bias was not assessed because of the small number of included studies. Statistical analysis was performed using Stata release 14.0 (StataCorp). RESULTS: The entry criteria were fulfilled by 8 randomized controlled trials on a combined total of 1426 participants. Low-dose aspirin initiated at <11 weeks' gestation was associated with a nonsignificant reduction in the risk of preeclampsia (relative risk, 0.52; 95% confidence interval, 0.23-1.17, P = .115), gestational hypertension (relative risk, 0.49; 95% confidence interval, 0.20-1.21; P = .121), and any hypertensive disorder of pregnancy (relative risk, 0.59; 95% confidence interval, 0.33-1.04, P = .067). Early administration of low-dose aspirin reduced the risk of preterm delivery (relative risk, 0.52; 95% confidence interval, 0.27-0.97, P = .040) but had no impact on the risk of fetal growth restriction (relative risk, 1.10; 95% confidence interval, 0.58-2.07, P = .775). Except for preterm delivery and any hypertensive disorder of pregnancy, sensitivity analysis demonstrated similar observations, therefore confirming the robustness of the analysis. CONCLUSION: The administration of low-dose aspirin at <11 weeks' gestation in women at high risk does not decrease the risk of preeclampsia, gestational hypertension, any hypertensive disorder of pregnancy, and fetal growth restriction. However, it might reduce the risk of preterm delivery. Larger randomized controlled trials will be required to substantiate the findings.