Early pregnancy biomarker discovery study for spontaneous preterm birth.

(1) OBJECTIVE: discover new candidate biomarkers for spontaneous preterm birth in early pregnancy samples. When fully clinically validated, early pregnancy biomarkers for sPTB give the possibility to intervene or monitor high-risk pregnancies more intensively through, as example, pelvic exams, ultrasound or sonographic cervical length surveillance. (2) STUDY DESIGN: Early pregnancy serum samples of eight spontaneous extreme and very preterm birth cases (<32 weeks of gestational age) without any symptoms of preeclampsia and fetal growth restriction and eight uncomplicated pregnancies were analyzed by liquid chromatography mass spectrometry (LC-MS). Thirteen proteins, which were differentially expressed according to the LC-MS data, were subsequently selected for confirmation by enzyme-linked immunosorbent assay (ELISA). (3) RESULTS: Differential expression of four candidate biomarkers was confirmed by ELISA with decreased early pregnancy levels of gelsolin and fibulin-1 and increased levels of c-reactive protein and complement C5 in the preterm birth group. (4) CONCLUSIONS: The confirmed candidate biomarkers are all to some extent related to inflammatory pathways and/or the complement system. This supports the hypothesis that both play a role in extreme and very preterm birth without any symptoms of preeclampsia and fetal growth restriction. The predictive value of complement C5, c-reactive protein, fibulin-1 and gelsolin should, therefore, be validated in another cohort with early pregnancy samples.

First trimester serum biomarker discovery study for early onset, preterm onset and preeclampsia at term.

INTRODUCTION: Preeclampsia (PE) is a heterogeneous syndrome during pregnancy and postpartum and it is subdivided in this study into early onset (<34 weeks), preterm onset (34-37 weeks) and PE at term (>37 weeks). First trimester models currently lack a sufficient power to predict PE, but inclusion of biochemical markers shows an improvement of their predictive power. The aim of this study was to perform a biomarker discovery study in order to find possible novel first trimester biomarkers for each PE subtype. Further, our findings were related to available literature and the possible role of the proteins in the development of preeclampsia was discussed. METHODS: In this study, 9 early onset (<34 weeks), 8 preterm onset (34-37 weeks), 6 PE at term (>37 weeks) and 23 control samples were drawn between 11 and 14 weeks gestational age. Serum samples were prepared for liquid chromatography mass spectrometry analysis and protein data were exported for statistical analyses. All differentially expressed proteins were further evaluated by searching literature in MEDLINE, Embase and Web of science and differential expression of two proteins, which were not yet associated with PE, was verified through enzyme-linked immunosorbent assay (ELISA). RESULTS: After statistical analysis, six, four and eight proteins were differently expressed in early onset, preterm onset and PE at term, respectively. After exclusion of antibody fragments, only nine proteins remained. Seven out of these nine proteins were already in literature associated with preeclampsia and only three of them were described as differentially expressed in the first trimester or early second trimester of preeclamptic pregnancies. Differential expression of Apolipoprotein D (ApoD), which was not yet associated with PE, was confirmed by ELISA in both early and preterm onset PE in the first trimester. DISCUSSION: In this study, two main observations were made. First, some of the differentially expressed proteins have a role in the same biological pathway, such as the acute phase response or endometrium receptivity, and their differential expression was observed in all three PE subtypes. This observation supports the hypothesis that classification of PE could be more accurate when subtyping is based on the etiology and/or phenotype instead of the arbitrary parameter gestational age at onset or delivery. Second, seven differential expressed proteins were already associated in literature with preeclampsia, but this association was for only three of them observed in the first trimester. In addition, ApoD was not yet associated with PE in other studies and, moreover, its differential expression was confirmed by ELISA. Therefore the predictive power of these proteins in the first trimester is worth evaluating in a larger and more heterogeneous cohort.

Performance of the FMF First-Trimester Preeclampsia-Screening Algorithm in a High-Risk Population in The Netherlands.

OBJECTIVE: The aim of the study was to evaluate the performance of the first-trimester Fetal Medicine Foundation (FMF) screening algorithm, including maternal characteristics and medical history, blood pressure, pregnancy-associated plasma protein A and placenta growth factor, crown rump length, and uterine artery pulsatility index, for the prediction of preeclampsia in a high-risk population in the Netherlands. METHODS: This is a prospective cohort including nulliparous women and women with preeclampsia or intrauterine growth restriction in previous pregnancy. We screened patients at 11-14 weeks of gestation to calculate the risk for preeclampsia. The primary outcome was preeclampsia and gestational age at delivery. Performance of the model was evaluated by area under the receiver operating characteristic (ROC) curves (AUCs) and calibration graphs; based on the ROC curves, optimal predicted risk cutoff values for our study population were defined. RESULTS: We analyzed 362 women, of whom 22 (6%) developed preeclampsia. The algorithm showed fair discriminative performance for preeclampsia <34 weeks (AUC 0.81; 95% CI 0.65-0.96) and moderate discriminative performance for both preeclampsia <37 weeks (AUC 0.71; 95% CI 0.51-0.90) and <42 weeks (AUC 0.71; 95% CI 0.61-0.81). Optimal cutoffs based on our study population for preeclampsia <34, <37, and <42 weeks were 1:250, 1:64, and 1:22, respectively. Calibration was poor. CONCLUSIONS: Performance of the FMF preeclampsia algorithm was satisfactory to predict early and preterm preeclampsia and less satisfactory for term preeclampsia in a high-risk population. However, by addressing some of the limitations of the present study, the performance can potentially improve. This is essential before implementation is considered.

Neonatal developmental and behavioral outcomes of immediate delivery versus expectant monitoring in mild hypertensive disorders of pregnancy: 5-year outcomes of the HYPITAT II trial.

OBJECTIVE: To compare effects of immediate delivery vs expectant monitoring on neurodevelopmental and behavioral outcomes at 5 years of age in offspring of women with mild late preterm hypertensive disorders. STUDY DESIGN: We studied children born during the HYPITAT-II trial, in which 704 women with a hypertensive disorder between 34 and 37 weeks of gestation were randomized to immediate delivery or expectant monitoring. Participating women were asked to complete the Ages and Stages Questionnaire (ASQ) for developmental outcome and the Child Behavior Checklist (CBCL) for behavioral problems when their child was 5 years old. Outcomes were dichotomized and analyzed by logistic regression analysis. We also assessed factors influencing development and behavior at both 2 and 5 years after a hypertensive pregnancy. RESULTS: Five years after the original study 322(46%) women were contacted for follow-up, of whom 148 (46%) responded. In the delivery group 22%(n = 14/65) of the children had an abnormal ASQ score compared to 21% (n = 13/62) in the expectant monitoring group (p = 0.9). Abnormal CBCL-scores were found in 19% (n = 14/72) of the children in the delivery group versus in 27% (n = 20/75) in the expectant monitoring group (p = 0.3). The main predictor of development and behavior at 2 and 5 years was fetal growth restriction (for abnormal development OR 2.1, CI 1.0-4.4; for behavior problems OR 2.2, CI 1.1-5.5). Higher maternal education decreased abnormal behavior outcomes (OR 0.5, CI 0.2-0.9) and a similar tendency was observed for developmental problems (OR 0.6, CI 0.3 - 1.1). CONCLUSION: We did not find different developmental and behavior outcomes at 5 years of age between a management policy of immediate delivery and expectant management in preterm hypertensive disorders. The increased risk of developmental delay at 2 years of age after immediate delivery, we found in the 2 year follow up study, did not persist at 5 years of age.

Neonatal developmental and behavioral outcomes of immediate delivery versus expectant monitoring in mild hypertensive disorders of pregnancy: 2-year outcomes of the HYPITAT-II trial.

BACKGROUND: Management of preterm hypertensive disorders remains a clinical dilemma. The maternal benefits of delivery need to be weighed against the adverse neonatal consequences of preterm birth. Long-term consequences of obstetric management in offspring of women with hypertensive disorders in preterm pregnancy are largely unknown. We report child neurodevelopmental and behavioral outcomes at 2 years after the Hypertension and Preeclampsia Intervention Trial at near Term (HYPITAT-II) trial, which compared immediate delivery versus expectant monitoring in mild late preterm hypertensive disorders of pregnancy. OBJECTIVE: To compare effects of immediate delivery vs expectant monitoring on neurodevelopmental and behavioral outcomes at 2 years of age in offspring of women with mild late preterm hypertensive disorders. MATERIALS AND METHODS: We studied children born in the HYPITAT-II trial, a study in which women (n = 704) with hypertensive disorders of pregnancy who were between 34 and 37 weeks' gestation were randomized to immediate delivery or expectant monitoring. Participating women were asked to complete the Ages and Stages Questionnaire for developmental outcome and the Child Behavior Checklist for behavioral problems when their toddlers were 2 years old. RESULTS: We approached 545 of 704 randomized women (77%); 330 of 545 (61%) returned the questionnaires. In the immediate delivery group, 45 of 162 infants (28%) had an abnormal Ages and Stages Questionnaire score compared to 27 of 148 (18%) in the expectant monitoring group (risk difference, 9.6%; 95% CI, 0.3-18.0%); P = .045. In the pregnancies (n = 94) that delivered before reaching 36 weeks, 27% (n = 25) had an abnormal Ages and Stages Questionnaire score compared to 22% (n = 47) when delivered after 36 weeks (odds ratio, 0.77; confidence interval, 0.44-1.34). An abnormal Child Behavior Checklist outcome was found in 31 of 175 (18%) in the delivery group vs 24 of 166 (15%) in the expectant monitoring group (risk difference, 3.2%; 95% CI, -4.6% to 11.0%). After correction for maternal education, management strategy remained an independent predictor of abnormal Ages and Stages Questionnaire score (odds ratio, 0.48; confidence interval, 0.24 to -0.96, P = .03). In multivariable analyses, low birth weight, low maternal education, and immediate delivery policy were all significantly associated with an abnormal Ages and Stages Questionnaire score. CONCLUSION: In this study, we found that early delivery in women with late preterm hypertensive disorders is associated with poorer neurodevelopmental outcomes in their children at 2 years of age. These findings indicate an increased risk of developmental delay after early delivery compared to expectant monitoring. This follow-up study underlines the conclusion of the original HYPITAT-II study that, until the clinical situation deteriorates, expectant monitoring remains the most appropriate management strategy in the light of short- and long-term neonatal outcomes in women with preterm hypertensive disorders.

Prediction of progression to severe disease in women with late preterm hypertensive disorders of pregnancy.

INTRODUCTION: If hypertensive disorders of pregnancy are diagnosed before term, the benefits of immediate delivery need to be weighed against the neonatal consequences of preterm delivery. If we are able to predict which women are at high risk of progression to severe disease, they could be targeted for delivery and maternal complications might be reduced. In addition, this may prevent unnecessary preterm births in women at low risk. MATERIAL AND METHODS: We developed a prediction model using data from the HYPITAT-II trail, which evaluated immediate delivery vs. expectant monitoring in women with non-severe hypertensive disorders of pregnancy between 34 and 37 weeks of gestation. Univariate and multivariate logistic regression analysis were used to identify relevant variables from clinical and laboratory parameters. The performance of the resulting prediction model was assessed by receiver operating characteristic analysis, calibration and bootstrapping, using the average predicted probabilities. RESULTS: We included 519 women, 115 (22.2%) of whom developed severe hypertensive disorders of pregnancy. The prediction model included: maternal age (odds ratio 0.92 per year), gestational age (odds ratio 0.87 per week), systolic blood pressure (odds ratio 1.05 per mmHg), the presence of chronic hypertension (odds ratio 2.4), platelet count (odds ratio 0.996), creatinine (odds ratio 1.02) and lactate dehydrogenase (odds ratio 1.003). The model showed good fit (p = 0.64), fair discrimination (area under the curve 0.76, 95% confidence interval 0.73-0.81, p < 0.001) and could stratify women in three risk groups of average, intermediate and high risk (predicted probabilities <0.22, <0.44 and >0.45, respectively). CONCLUSION: In women with non-severe hypertension in pregnancy near term, progression to severe disease can be predicted. This model requires external validation before it can be applied in practice.