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Objective: To estimate the association between maternal metformin use for the treatment of early gestational or pre-existing type 2 diabetes and preterm preeclampsia., Methods: This is a planned secondary analysis of the MOMPOD study (Medical Optimization of Management of Overt Type 2 Diabetes in Pregnancy), a randomized trial comparing the effect of adding metformin with insulin treatment on composite neonatal outcome in singleton pregnancies with early gestational or type 2 diabetes. Participants were randomized at 11-23 weeks of gestation to 1,000 mg metformin twice daily or placebo until delivery. A subset of participants had maternal blood collected at 24-30 weeks of gestation, and serum soluble endoglin, apolipoprotein B, vascular cell adhesion molecule-1, soluble fms-like tyrosine kinase 1, placental growth factor, high-sensitivity C-reactive protein, adiponectin, and vascular endothelial growth factor levels were measured. Our primary outcome was preterm preeclampsia , defined as preeclampsia requiring delivery before 37 weeks of gestation. Secondary outcomes included preterm preeclampsia requiring delivery before 34 weeks of gestation and differences in serum biomarkers. Multivariable regression analysis was used to estimate the associations between metformin use and primary or secondary study outcomes., Results: Of 831 participants, 119 (14.3%) developed preeclampsia requiring delivery before 37 weeks of gestation: 57 of 416 (13.7%) in the placebo group and 62 of 415 (14.9%) in the metformin group. Thirty-seven (4.4%) developed preeclampsia requiring delivery before 34 weeks of gestation: 15 (3.6%) receiving placebo and 22 (5.3%) receiving metformin. Compared with placebo, metformin was not associated with a significant difference in the occurrence of preeclampsia before 37 weeks of gestation (adjusted odds ratio [aOR] 1.04, 95% CI, 0.70-1.56) or before 34 weeks (aOR 1.43, 95% CI, 0.73-2.81). Similarly, there was no association between maternal metformin use and serum biomarker levels., Conclusion: Among parturients with early gestational or pre-existing type 2 diabetes, the addition of metformin to insulin was not associated with lower odds of preterm preeclampsia or with serum biomarkers associated with cardiovascular disease risk., Competing Interests: Financial Disclosure Maya Patel reports money paid to her by National Institute of Diabetes and Digestive and Kidney Diseases. Gayle Olson discloses she is the chair of ACOG District XI, sits on the Board of Directors, and receives support from ACOG. Celeste Durnwald reports that money was paid to her institution from DexCom. Christina Scifres reports money paid to her by Visterra/Otsuka Pharmaceuticals. Amy Valent reports that money was paid to her institution from Dexcom and Mannkind. The other authors did not report any potential conflicts of interest., (Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Angiogenic imbalances, characterized by an excess of antiangiogenic factors (soluble fms-like tyrosine kinase 1) and reduced angiogenic factors (vascular endothelial growth factor and placental growth factor), contribute to the mechanisms of disease in preeclampsia. The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor has been used as a biomarker for preeclampsia, but the cutoff values may vary with gestational age and assay platform., Objective: This study aimed to compare multiples of the median of the maternal plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio, soluble fms-like tyrosine kinase 1, placental growth factor, and conventional clinical and laboratory values in their ability to predict preeclampsia with severe features., Study Design: We conducted a cohort study across 18 United States centers involving hospitalized individuals with hypertension between 23 and 35 weeks' gestation. Receiver operating characteristic curve analyses of maternal plasma biomarkers, highest systolic or diastolic blood pressures, and laboratory values at enrollment were performed for the prediction of preeclampsia with severe features. The areas under the curve were compared, and quasi-Poisson regression models were fitted to estimate relative risks. The primary outcome was preeclampsia with severe features within 2 weeks of enrollment. Secondary outcomes were a composite of severe adverse maternal outcomes (elevated liver enzymes, low platelets count, placental abruption, eclampsia, disseminated intravascular coagulation, and pulmonary edema) and a composite of severe adverse perinatal outcomes (birth weight below the third percentile, very preterm birth [<32 weeks' gestation], and fetal or neonatal death)., Results: Of the 543 individuals included in the study, preeclampsia with severe features within 2 weeks was observed in 33.1% (n=180) of them. A receiver operating characteristic curve-derived cutoff of 11.5 multiples of the median for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio provided good sensitivity (90.6%), specificity (76.9%), positive predictive value (66.0%), negative predictive value (94.3%), positive likelihood ratio (3.91), negative likelihood ratio (0.12), and accuracy (81.4%) for preeclampsia with severe features within 2 weeks. This cutoff was used to compare test positive cases (≥ cutoff) and test negative cases (< cutoff). Preeclampsia with severe features (66.0% vs 5.7%; P<.001) and composites of severe adverse maternal (8.11% vs 2.7%; P=.006) or perinatal (41.3% vs 10.14%; P=.001) outcomes within 2 weeks were more frequent in test positive cases than in test negative cases. A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the median was independently associated with preeclampsia with severe features (adjusted incidence rate ratio, 9.08; 95% confidence interval, 6.11-14.06; P<.001) and a composite of severe adverse perinatal outcomes (adjusted incidence rate ratio, 9.42; 95% confidence interval, 6.36-14.53; P<.001) but not with a composite of severe adverse maternal outcomes (adjusted incidence rate ratio, 2.20; 95% confidence interval, 0.95-5.54; P=.08). The area under the curve for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio in multiples of the median (0.91; 95% confidence interval, 0.89-0.94) for preeclampsia with severe features within 2 weeks was significantly higher (P<.001 for all comparisons) than either plasma biomarker alone or any other parameter with the exception of absolute soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio values., Conclusion: A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the mean among hospitalized patients with hypertension between 23 and 35 week's gestation predicts progression to preeclampsia with severe features and severe adverse perinatal outcomes within 2 weeks., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In pre-eclampsia models, nicotinamide (NAM) has protective effects in pre-eclampsia and is being evaluated as a therapeutic nutraceutical in clinical studies. NAM undergoes extensive hepatic metabolism by NAM N-methyltransferase to methylnicotinamide (MNA), which is subsequently metabolized to methyl-2-pyridone-5-carboxamide (M2PY) by aldehyde oxidase. However, the pharmacokinetics of NAM and its major metabolites has never been studied in pregnant individuals. Blood samples were collected before and 1, 2, 4, 8, and 24 hours after single 1 g oral NAM dose in healthy pregnant (gestational age 24-33 weeks) and nonpregnant female volunteers (n = 6/group). Pooled urine was collected from 0 to 8 hours. NAM, MNA, and M2PY area under the concentration-time curve (AUC) data were analyzed by noncompartmental analysis. No difference in the plasma AUC 0→24 of NAM (median (25%-75%): 463 (436-576) vs. 510 (423, 725) μM*hour, P = 0.430) and its intermediate metabolite MNA (89.1 (60.4, 124.4) vs. 83.8 (62.7, 93.7) μM*hour, P = 0.515) was observed in pregnant and nonpregnant volunteers, respectively; however, the terminal metabolite M2PY AUC 0 → 24 was significantly lower in pregnant individuals (218 (188, 254) vs. 597 (460, 653) μM*hour, P < 0.001). NAM renal clearance (CL R ; P = 0.184), MNA CL R (P = 0.180), and total metabolite formation clearance (P = 0.405) did not differ across groups; however, M2PY CL R was significantly higher in pregnant individuals (10.5 (9.3-11.3) vs. 7.5 (6.4-8.5) L/h, P = 0.002). These findings demonstrate that the PK of NAM and systemic exposure to its intermediate metabolite MNA are not significantly altered during pregnancy, and systemic exposure to NAM's major metabolite M2PY was reduced during pregnancy due to increased renal elimination., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Objective: To evaluate the association between maternal blood pressure (BP) below 130/80 mm Hg compared with 130-139/80-89 mm Hg and pregnancy outcomes., Methods: We conducted a planned secondary analysis of CHAP (Chronic Hypertension and Pregnancy), an open label, multicenter, randomized controlled trial. Participants with mean BP below 140/90 mm Hg were grouped as below 130/80 mm Hg compared with 130-139/80-89 mm Hg by averaging postrandomization clinic BP throughout pregnancy. The primary composite outcome was preeclampsia with severe features, indicated preterm birth before 35 weeks of gestation, placental abruption, or fetal or neonatal death. The secondary outcome was small for gestational age (SGA)., Results: Of 2,408 patients in CHAP, 2,096 met study criteria; 1,328 had mean BP 130-139/80-89 mm Hg and 768 had mean BP below 130/80 mm Hg. Participants with mean BP below 130/80 mm Hg were more likely to be older, on antihypertensive medication, in the active treatment arm, and to have lower BP at enrollment. Mean clinic BP below 130/80 mm Hg was associated with lower frequency of the primary outcome (16.0% vs 35.8%, adjusted relative risk 0.45; 95% CI 0.38-0.54) as well as lower risk of severe preeclampsia and indicated birth before 35 weeks of gestation. There was no association with SGA., Conclusion: In pregnant patients with mild chronic hypertension, mean BP below 130/80 mm Hg was associated with improved pregnancy outcomes without increased risk of SGA., Clinical Trial Registration: ClinicalTrials.gov , NCT02299414., Competing Interests: Financial Disclosure Alan T.N. Tita reported money was paid to his institution by Pfizer for his efforts on this study. Torri D. Metz disclosed money was paid to her from UpToDate for two topics on trial of labor after cesarean, and money was paid to her institution from Gestvision as a site PI for a preeclampsia point-of-care test; her institution received money to conduct the study (ended August 2020). She has been a site PI for Pfizer on a phase III RSV vaccine trial, and her institution received money to conduct the study. She has also been a member of the Pfizer medical advisory board (1/15/21) and site PI for a COVID-19 vaccination trial in pregnancy. She has served on the SMFM Board of Directors. Lorraine Dugoff reports money was paid to her institution from Laboratory Holdings, Inc. and Natera, Inc. Brenna L. Hughes reports receiving payment from UpToDate. Mary E. Norton reports receiving payment from the American Board of Obstetrics and Gynecology and Luna Genetics. Daniel Skupski disclosed he is a consultant for Cooper Surgical, Inc, and has received payment from Organon. Namasivayam Ambalayanan reports receiving payment from Resbiotic/AlveolusBio and Shire/Oak Hill Bio. The other authors did not report any potential conflicts of interest., (Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Preeclampsia is associated with significant perinatal morbidity and mortality. Aspirin has been long purported and extensively studied for prevention of preeclampsia. For this reason, the U.S. Preventive Services Task Force, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine recommend its use in pregnancy for preeclampsia prevention in those at high risk. Yet, much controversy exists regarding optimal use in pregnancy with guidelines across global organizations varying. In this narrative review, we summarize the published literature related to the safety, optimal dose, and timing and duration of use of aspirin, as well as other indications for which aspirin has been studied in pregnancy., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To develop a model for predicting postpartum readmission for hypertension and pre-eclampsia at delivery discharge and assess external validation or model transportability across clinical sites., Design: Prediction model using data available in the electronic health record from two clinical sites., Setting: Two tertiary care health systems from the Southern (2014-2015) and Northeastern USA (2017-2019)., Population: A total of 28 201 postpartum individuals: 10 100 in the South and 18 101 in the Northeast., Methods: An internal-external cross validation (IECV) approach was used to assess external validation or model transportability across the two sites. In IECV, data from each health system were first used to develop and internally validate a prediction model; each model was then externally validated using the other health system. Models were fit using penalised logistic regression, and accuracy was estimated using discrimination (concordance index), calibration curves and decision curves. Internal validation was performed using bootstrapping with bias-corrected performance measures. Decision curve analysis was used to display potential cut points where the model provided net benefit for clinical decision-making., Main Outcome Measures: The outcome was postpartum readmission for either hypertension or pre-eclampsia <6 weeks after delivery., Results: The postpartum readmission rate for hypertension and pre-eclampsia overall was 0.9% (0.3% and 1.2% by site, respectively). The final model included six variables: age, parity, maximum postpartum diastolic blood pressure, birthweight, pre-eclampsia before discharge and delivery mode (and interaction between pre-eclampsia × delivery mode). Discrimination was adequate at both health systems on internal validation (c-statistic South: 0.88; 95% confidence interval [CI] 0.87-0.89; Northeast: 0.74; 95% CI 0.74-0.74). In IECV, discrimination was inconsistent across sites, with improved discrimination for the Northeastern model on the Southern cohort (c-statistic 0.61 and 0.86, respectively), but calibration was not adequate. Next, model updating was performed using the combined dataset to develop a new model. This final model had adequate discrimination (c-statistic: 0.80, 95% CI 0.80-0.80), moderate calibration (intercept -0.153, slope 0.960, E max 0.042) and provided superior net benefit at clinical decision-making thresholds between 1% and 7% for interventions preventing readmission. An online calculator is provided here., Conclusions: Postpartum readmission for hypertension and pre-eclampsia may be accurately predicted but further model validation is needed. Model updating using data from multiple sites will be needed before use across clinical settings., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Obesity is a risk factor for preeclampsia. We investigated how obesity influences preeclampsia in mice lacking ankyrin-repeat-and-SOCS-box-containing-protein 4 (ASB4), which promotes trophoblast differentiation via degrading the inhibitor of DNA-binding protein 2 (ID2). Asb4 -/- mice on normal chow (NC) develop mild preeclampsia-like phenotypes during pregnancy, including hypertension, proteinuria, and reduced litter size. Wild-type (WT) and Asb4 -/- females were placed on a high-fat diet (HFD) starting at weaning. At the age of 8-9 weeks, they were mated with WT or Asb4 -/- males, and preeclamptic phenotypes were assessed. HFD-WT dams had no obvious adverse outcomes of pregnancy. In contrast, HFD- Asb4 -/- dams had significantly more severe preeclampsia-like phenotypes compared to NC- Asb4 -/- dams. The HFD increased white fat weights and plasma leptin and insulin levels in Asb4 -/- females. In the HFD- Asb4 -/- placenta, ID2 amounts doubled without changing the transcript levels, indicating that insulin likely increases ID2 at a level of post-transcription. In human first-trimester trophoblast HTR8/SVneo cells, exposure to insulin, but not to leptin, led to a significant increase in ID2. HFD-induced obesity markedly worsens the preeclampsia-like phenotypes in the absence of ASB4. Our data indicate that hyperinsulinemia perturbs the timely removal of ID2 and interferes with proper trophoblast differentiation, contributing to enhanced preeclampsia.

BACKGROUND: Among women with hypertensive disorders of pregnancy, biomarkers may stratify risk for developing preeclampsia with severe features (sPE). METHODS: Across 18 U.S. centers, we prospectively measured the ratio of serum soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) in pregnant women hospitalized between 23 and 35 weeks of gestation. The primary outcome was predicting sPE, and secondary outcomes included predicting adverse outcomes within 2 weeks. The prognostic performance of the sFlt-1:PlGF ratio was assessed by using a derivation/validation design. RESULTS: A total of 1014 pregnant women were evaluated; 299 were included in the derivation cohort and 715 in the validation cohort. In the derivation cohort, the median sFlt-1:PlGF ratio was 200 (interquartile range, 53 to 458) among women who developed sPE compared with 6 (interquartile range, 3 to 26) in those who did not (P<0.001). The discriminatory ratio of ≥40 was then tested in the validation cohort and yielded a 65% positive (95% confidence interval [CI], 59 to 71) and a 96% negative (95% CI, 93 to 98) predictive value for the primary outcome. The ratio performed better than standard clinical measures (area under the receiver-operating characteristic curve, 0.92 versus <0.75 for standard-of-care tests). Compared with women with a ratio <40, women with a ratio ≥40 were at higher risk for adverse maternal outcomes (16.1% versus 2.8%; relative risk, 5.8; 95% CI, 2.8 to 12.2). CONCLUSIONS: In women with a hypertensive disorder of pregnancy presenting between 23 and 35 weeks of gestation, measurement of serum sFlt-1:PlGF provided stratification of the risk of progressing to sPE within the coming fortnight. (Funded by Cedars-Sinai Medical Center and Thermo Fisher Scientific; ClinicalTrials.gov NCT03815110.)

Background: Environmental health research has recently undergone a dramatic shift, with ongoing technological advancements allowing for broader coverage of exposure and molecular biology signatures. Approaches to integrate such measures are still needed to increase understanding between systems-level exposure and biology., Objectives: We address this gap by evaluating placental tissues to identify novel chemical-biological interactions associated with preeclampsia. This study tests the hypothesis that understudied chemicals are present in the human placenta and associated with preeclampsia-relevant disruptions, including overall case status (preeclamptic vs. normotensive patients) and underlying transcriptomic/epigenomic signatures., Methods: A non-targeted analysis based on high-resolution mass spectrometry was used to analyze placental tissues from a cohort of 35 patients with preeclampsia (n = 18) and normotensive (n = 17) pregnancies. Molecular feature data were prioritized for confirmation based on association with preeclampsia case status and confidence of chemical identification. All molecular features were evaluated for relationships to mRNA, microRNA, and CpG methylation (i.e., multi-omic) signature alterations involved in preeclampsia., Results: A total of 183 molecular features were identified with significantly differentiated abundance in placental extracts of preeclamptic patients; these features clustered into distinct chemical groupings using unsupervised methods. Of these features, 53 were identified (mapping to 40 distinct chemicals) using chemical standards, fragmentation spectra, and chemical metadata. In general, human metabolites had the largest feature intensities and strongest associations with preeclampsia-relevant multi-omic changes. Exogenous drugs were second most abundant and had fewer associations with multi-omic changes. Other exogenous chemicals (non-drugs) were least abundant and had the fewest associations with multi-omic changes., Conclusions: These global data trends suggest that human metabolites are heavily intertwined with biological processes involved in preeclampsia etiology, while exogenous chemicals may still impact select transcriptomic/epigenomic processes. This study serves as a demonstration of merging systems exposures with systems biology to better understand chemical-disease relationships., (Copyright © 2022. Published by Elsevier Ltd.)

Background: The ability to diagnose preeclampsia clinically is suboptimal. Our objective was to validate a novel multianalyte assay and characterize its performance, when intended for use as an aid to rule-out preeclampsia., Methods: Prospective, multicenter cohort study of pregnant individuals presenting between 28 0/7 and 36 6/7 weeks' with preeclampsia-associated signs and symptoms. Individuals not diagnosed with preeclampsia after baseline evaluation were enrolled in the study cohort, with those who later developed preeclampsia, classified as cases and compared with a negative control group who did not develop preeclampsia. Individuals with assay values at time of enrollment ≥0.0325, determined using a previously developed algorithm, considered at risk. The primary analysis was the time to develop preeclampsia assessed using a multivariate Cox regression model., Results: One thousand thirty-six pregnant individuals were enrolled in the study cohort with an incidence of preeclampsia of 30.3% (27.6%-33.2%). The time to develop preeclampsia was shorter for those with an at-risk compared with negative assay result (log-rank P <0.0001; adjusted hazard ratio of 4.81 [3.69-6.27, P <0.0001]). The performance metrics for the assay to rule-out preeclampsia within 7 days of enrollment showed a sensitivity 76.4% (67.5%-83.5%), negative predictive value 95.0% (92.8%-96.6%), and negative likelihood ratio 0.46 (0.32-0.65). Assay performance improved if delivery occurred <37 weeks and for individuals enrolled between 28 and 35 weeks., Conclusions: We confirmed that a novel multianalyte assay was associated with the time to develop preeclampsia and has a moderate sensitivity and negative likelihood ratio but high negative predictive value when assessed as an aid to rule out preeclampsia within 7 days of enrollment., Registration: The study was registered on Clinicaltrials.gov (Identifier NCT02780414).

Background: Postpartum hypertension or preeclampsia is one of the most frequent reasons for readmission after delivery discharge, and risk factors for readmission remain poorly characterized., Objective: This study aimed to determine risk factors of postpartum readmission for hypertension or preeclampsia among low-risk women before delivery discharge., Study Design: We conducted a nested case-control study from 2012 to 2015 at a tertiary care medical center. Cases were identified using diagnostic codes for postpartum transient hypertension, mild preeclampsia, severe preeclampsia, eclampsia, superimposed preeclampsia, and unspecified hypertension and readmission within 6 weeks of delivery. Controls not readmitted for hypertension or preeclampsia were time matched within 4 weeks of the delivery date to each case. We fit multivariable logistic regression models to identify independent risk factors for postpartum readmission for hypertension or preeclampsia and then calculated a receiver operating characteristic curve of the final model to assess model discrimination., Results: Within the source cohort resulting in 58 cases and 232 matched controls, the rate of postpartum readmission for preeclampsia or hypertension was 0.4% (n=58 of 14,503). The median time to readmission was 6 days (range, 2-15 days), and 40% of cases had an outpatient postpartum visit before readmission. In multivariable analysis, non-Hispanic black race (adjusted odds ratio, 2.14; 95% confidence interval, 0.99-4.59), gestational hypertension (adjusted odds ratio, 2.70; 95% confidence interval, 1.12-6.54), preeclampsia during delivery admission (adjusted odds ratio, 3.12; 95% confidence interval, 1.29-7.50), and maximum postpartum systolic blood pressure during delivery admission (adjusted odds ratio, 1.05; 95% confidence interval, 1.03-1.08) were risk factors for readmission. This model had a good discriminative ability to predict women who would require readmission for preeclampsia or hypertension (area under the curve, 0.83; 95% confidence interval, 0.74-0.89). Using these 4 factors to illustrate this model, the predicted risk of readmission ranged from <1% in the lowest risk scenario (eg, postpartum systolic blood pressure of 120 mm Hg + no hypertensive disorders of pregnancy + white race) to 26% in the highest risk scenario (eg, postpartum systolic blood pressure of 160 mm Hg + preeclampsia + black race)., Conclusion: Risk factors of postpartum readmission for hypertension or preeclampsia can be identified at the time of delivery discharge among low-risk women, regardless of an antenatal hypertensive disorder. A next step could be using these risk factors to develop a predictive model to guide postpartum care., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: There is a robust association between altered angiogenic factor concentrations, which includes placental growth factor and clinically recognized preeclampsia. Alterations in concentrations of angiogenic factors precede the clinical onset of preeclampsia by several weeks. The temporal relationship between the measured angiogenic factors and the time to delivery in women with suspected preeclampsia at <35 weeks gestation, however, remains to be clarified., Objective: The purposes of this study were to examine the relationship between placental growth factor and time to delivery in women at <35 weeks gestation with signs or symptoms of preeclampsia and to compare the performance of placental growth factor to other clinical markers for prediction of time to delivery in preeclampsia., Study Design: Women with signs or symptoms of preeclampsia between 20.0 and 35.0 weeks gestation were enrolled in a prospective, observational study at 24 centers. Blood was collected at presentation for placental growth factor, and subjects were evaluated and treated according to local protocols. Clinical outcomes were obtained, and all final diagnoses were adjudicated by an independent expert panel according to 2013 American College of Obstetricians and Gynecologists' Hypertension in Pregnancy criteria. Placental growth factor was measured retrospectively on the Alere, Inc, triage platform. A normal placental growth factor was defined as >100 pg/mL; the assay's limit of detection is 12 pg/mL. Two-by-2 tables were constructed for comparison of test outcomes that included negative predictive value; time-to-delivery was analyzed by survival curves and Cox regression., Results: Seven hundred fifty-three subjects were enrolled; 538 (71%) had a final diagnosis of preeclampsia; 542 (72%) delivered at <37 weeks gestation, and 358 (47%) delivered at <34 weeks gestation. Among the 279 women (37%) with a normal placental growth factor at presentation, the negative predictive value for preeclampsia delivered within 14 days or within 7 days was 90% and 93%, respectively. Compared with women with normal placental growth factor, women with placental growth factor ≤100 pg/mL have a hazard ratio of 7.17 (confidence interval, 5.08-10.13) in Cox regression for time to delivery after adjustment for both gestational age at enrollment and the final diagnosis of preeclampsia. The placental growth factor levels of normal (>100 pg/mL), low (12-100 pg/mL), and very low (<12 pg/mL) have well-separated distributions of time to delivery, with median values of 45, 10, and 2 days, respectively. Subjects with placental growth factor ≤100 pg/mL have a perinatal death rate of 5.7% and a small-for-gestational-age rate of 51.7%; subjects with placental growth factor >100 pg/mL have a perinatal death rate of 0% (no observations in this cohort) and an a small-for-gestational-age rate of 16.8%., Conclusion: In women with suspected preeclampsia at <35.0 weeks gestation, a low placental growth factor was correlated strongly with preterm delivery independent of a diagnosis of preeclampsia or gestational age at presentation, whereas a normal placental growth factor was associated with pregnancy prolongation, even in patients who ultimately had a final diagnosis of preeclampsia. This suggests that placental growth factor levels are superior to clinical markers in the prediction of adverse pregnancy in women with suspected preeclampsia., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Endothelin-1 (ET-1) is implicated in the pathophysiology of preeclampsia. An association between an EDN1 gene polymorphism with high ET-1 and preeclampsia was reported in humans, but their cause and effect relationships have not been defined. We examined the pregnancy effects in mice with a modified Edn1 allele that increases mRNA stability and thus ET-1 production. Heterozygous Edn1 H/ + females showed no obvious abnormalities before pregnancy, but when mated with wild-type (WT) males developed a full spectrum of preeclampsia-like phenotypes, including increased systolic blood pressure, proteinuria, glomerular endotheliosis, and intrauterine fetal growth restriction. At 7.5 days post-coitus, the embryos from Edn1 H/ + dams, regardless of their Edn1 genotype, lagged 12 hours in development compared with embryos from WT dams, had disoriented ectoplacental cones, and retained high E-cadherin expression. In contrast, WT females mated with Edn1 H/ + males, which also carried half of the fetuses with Edn1 H/ + genotype, showed a mild systolic blood pressure increase only. These WT dams had 2× higher plasma soluble fms-like tyrosine kinase-1 than WT dams mated with WT males. In human first trimester trophoblast cells, pharmacological doses of ET-1 increased the cellular sFlt1 transcripts and protein secretion via both type A and B ET-1 receptors. Our data demonstrate that high maternal ET-1 production causes preeclampsia-like phenotypes during pregnancy, affecting both initial stage of trophoblast differentiation/invasion and maternal peripheral vasculature during late gestation. High fetal ET-1 production, however, could cause increased soluble fms-like tyrosine kinase-1 in the maternal circulation and contribute to blood pressure elevation., (© 2018 American Heart Association, Inc.)

Preeclampsia (PE) is a pregnancy disorder characterized by high blood pressure and proteinuria that can cause adverse health effects in both mother and fetus. There is no current cure for PE other than delivery of the fetus/placenta. While the etiology is unknown, poor placentation due to aberrant signaling of growth and angiogenic factors has been postulated as a causal factor of PE. In addition, environmental contaminants, such as the metal cadmium (Cd), have been linked to placental toxicity and increased risk of developing PE. Here, we use a translational study design to investigate genomic and epigenomic alterations in both placentas and placental trophoblasts, focused on the angiogenesis-associated transforming growth factor-beta (TGF-β) pathway. Genes within the TGF-β pathway displayed increased expression in both the preeclamptic placenta and Cd-treated trophoblasts. In addition, miRNAs that target the TGF-β pathway were also significantly altered within the preeclamptic placenta and Cd-treated trophoblasts. Integrative analysis resulted in the identification of a subset of Cd-responsive miRNAs, including miR-26a and miR-155, common to preeclamptic placentas and Cd-treated trophoblasts. These miRNAs have previously been linked to PE and are predicted to regulate members of the TGF-β pathway. Results from this study provide future targets for PE treatment., Competing Interests: The authors claim no competing financial interests., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Preeclampsia is a potentially fatal pregnancy disorder affecting millions of women around the globe. Dysregulation in gene and protein expression within key biological pathways controlling angiogenesis has been implicated in the development of preeclampsia. Altered CpG methylation, a type of epimutation, may underlie this pathway dysregulation. In the present study, placental tissue from preeclamptic cases and normotensive controls was analyzed for genome-wide differential CpG methylation and concomitant changes in gene expression. A set of 123 genes, representing 19.9% of all genes with altered CpG methylation, was associated with functional changes in transcript levels. Underscoring the complex relationships between CpG methylation and gene expression, here hypermethylation was never associated with gene silencing, nor was hypomethylation always associated with gene activation. Moreover, the genomic region of the CpG mark was important in predicting the relationship between CpG methylation and gene expression. The 123 genes were enriched for their involvement in the transforming growth factor beta (TGF-β) signaling pathway, a known regulator of placental trophoblast invasion and migration. This is the first study to identify CpG hypomethylation as an activator of TGF-β-associated gene expression in the preeclamptic placenta. The results suggest functional epimutations are associated with preeclampsia disease status and the identified genes may represent novel biomarkers of disease.

Environmental exposure to heavy metals is a potentially modifiable risk factor for preeclampsia (PE). Toxicologically, there are known interactions between the toxic metal cadmium (Cd) and essential metals such as selenium (Se) and zinc (Zn), as these metals can protect against the toxicity of Cd. As they relate to preeclampsia, the interaction between Cd and these essential metals is unknown. The aims of the present study were to measure placental levels of Cd, Se, and Zn in a cohort of 172 pregnant women from across the southeast US and to examine associations of metals levels with the odds of PE in a nested case-control design. Logistic regressions were performed to assess odds ratios (OR) for PE with exposure to Cd controlling for confounders, as well as interactive models with Se or Zn. The mean placental Cd level was 3.6 ng/g, ranging from 0.52 to 14.5 ng/g. There was an increased odds ratio for PE in relationship to placental levels of Cd (OR = 1.5; 95% CI: 1.1-2.2). The Cd-associated OR for PE increased when analyzed in relationship to lower placental Se levels (OR = 2.0; 95% CI: 1.1-3.5) and decreased with higher placental Se levels (OR = 0.98; 95% CI: 0.5-1.9). Similarly, under conditions of lower placental Zn, the Cd-associated OR for PE was elevated (OR = 1.8; 95% CI: 0.8-3.9), whereas with higher placental Zn it was reduced (OR = 1.3; 95% CI: 0.8-2.0). Data from this pilot study suggest that essential metals may play an important role in reducing the odds of Cd-associated preeclampsia and that replication in a larger cohort is warranted.

Background: Maternal periodontal disease diagnosed by a detailed oral health examination is associated with preeclampsia. Our objective was to measure the association between maternal self-report of oral symptoms/problems, oral hygiene practices, and/or dental service use before or during pregnancy and severe preeclampsia., Methods: A written questionnaire was administered to pregnant females at the time of prenatal ultrasound and outcomes were ascertained by chart abstraction. The χ(2) test compared maternal oral symptoms/problems, hygiene practices, and dental service use between females with severe preeclampsia versus normotensive females. Multivariable logistic regression was used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for severe preeclampsia., Results: A total of 48 (10%) of 470 females reported ≥2 oral symptoms/problems in the 6 months before pregnancy and 77 (16%) since pregnancy. Fifty-one (11%) reported previous periodontal treatment. Twenty-eight (6%) of 470 developed severe preeclampsia. Females with a history of periodontal treatment were more likely to develop severe preeclampsia (aOR = 3.71; 95% CI = 1.40 to 9.83) than females without a history of periodontal treatment. Self-reported oral health symptoms/problems, oral hygiene practices, or dental service use before or during pregnancy were not associated with severe preeclampsia when considered in the context of other maternal risk factors., Conclusion: Maternal self-report of previous periodontal treatment before pregnancy is associated with severe preeclampsia.

Recent studies have shown that low serum 25-hydroxyvitamin D (25[OH]D) level is a risk factor for preeclampsia. The clinical significance of in vitro findings that vitamin D regulates vascular endothelial growth factor production is unclear. We sought to determine whether there is an association between midgestation serum 25(OH)D levels and angiogenic factor activity and to compare their predictive value for the development of severe preeclampsia. We conducted a nested case-control study of women with severe preeclampsia (n=41) versus women with uncomplicated term birth (n=123) who had second trimester genetic screening (15-20 weeks). Using banked frozen serum, we measured levels of 25(OH)D, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1, and placental growth factor and compared their correlations and predictive values. We found no correlation between serum 25(OH)D and angiogenic factors levels. 25(OH)D alone was comparable to vascular endothelial growth factor and soluble fms-like tyrosine kinase 1/placental growth factor ratio as a predictive marker for severe preeclampsia. A composite of both 25(OH)D level and soluble fms-like tyrosine kinase 1/placental growth factor ratio was more predictive than either alone (area under curve: 0.83 versus 0.74 and 0.67, respectively). In conclusion, combining midpregnancy 25(OH)D level with soluble fms-like tyrosine kinase 1/placental growth factor ratio provides a better prediction for the development of severe preeclampsia.

The antioxidant enzyme paraoxonase 1 is a marker of oxidative stress and has been implicated in the pathogenesis of preeclampsia. Our objective was to determine if an association exists between low paraoxonase 1 activity at midgestation and the development of preeclampsia. We conducted a case-control study of 50 women with preeclampsia and 101 women with uncomplicated term deliveries. Maternal serum collected at 15 to 20 weeks was used to measure paraoxonase 1 activity using two substrates: paraoxon and phenylacetate (arylesterase activity). The groups did not differ with respect to maternal demographics. Paraoxonase 1 activity (paraoxon) was significantly higher in women with preeclampsia compared with controls (19.4 +/- 9.4 versus 15.6 +/- 8.0 change in absorbance per minute (dA/min), P = 0.009). When stratified by disease severity, paraoxonase 1 activity (paraoxon) was highest in women with severe preeclampsia (21.6 +/- 9.1 versus 15.6 +/- 8.0 dA/min, P = 0.002). We observed a trend toward higher arylesterase activity in women with preeclampsia compared with controls (0.343 +/- 0.07 versus 0.323 +/- 0.06 dA/min, P = 0.06). Midgestational paraoxonase 1 activity is higher in women with preeclampsia before clinical signs of the disease are present. Prospective studies are needed to determine the significance of paraoxonase 1 in the pathogenesis of preeclampsia., (Thieme Medical Publishers.)

Background: Maternal periodontal infection is associated with an increased risk for preeclampsia. Periodontal infection is also associated with increased oxidative stress. Our objective was to determine the relationship among maternal periodontal disease, maternal oxidative stress, and the development of preeclampsia., Methods: A secondary analysis of prospectively collected data from the Oral Conditions and Pregnancy Study was performed. A cohort of healthy women enrolled at <26 weeks of gestation underwent an oral examination, serum sampling, and delivery follow-up. A periodontal infection was categorized by clinical parameters as healthy or mild or moderate/severe periodontal infection. Preeclampsia was defined by the American Congress of Obstetricians and Gynecologists criteria as blood pressure >140/90 mmHg and >or=1+ proteinuria on a catheterized specimen. Maternal blood was assayed for 8-isoprostane concentrations using an enzyme-linked immunosorbent assay and stratified as elevated (>or=75th percentile) or not elevated (<75th percentile). Odds ratios (ORs) for preeclampsia were calculated and stratified by periodontal disease and the level of 8-isoprostane concentration., Results: A total of 34 (4.3%) of 791 women developed preeclampsia. Women with an 8-isoprostane concentration >or=75th percentile at enrollment were more likely to develop preeclampsia compared to women with an 8-isoprostane concentration <75th percentile (38.2% versus 24.4%, respectively; P = 0.07; OR: 1.91; 95% confidence interval [CI]: 0.94 to 3.90). Among women with moderate/severe periodontal disease, an elevated 8-isoprostane concentration (>or=75th percentile) did not significantly increase the likelihood for preeclampsia (adjusted OR: 2.08; 95% CI: 0.65 to 6.60)., Conclusions: Women with oxidative stress early in pregnancy, as measured by an 8-isoprostane concentration >or=75th percentile, were at an increased risk for developing preeclampsia. The presence of periodontal disease did not appear to modify this risk.

Objective: We sought to determine whether serum lipids at midgestation differ between normotensive women and women developing mild and severe preeclampsia., Study Design: A case-control study of 50 women with preeclampsia (mild = 26; severe = 24) and 100 women with uncomplicated term deliveries was conducted. Maternal serum collected at 15-20 weeks was used to measure lipid profiles., Results: The groups were similar with respect to demographic characteristics. Women with mild preeclampsia had higher triglyceride levels and a higher total cholesterol to high-density lipoprotein ratio than control subjects (200 +/- 79.5 mg/dL vs 164 +/- 56.2 mg/dL; P = .02; and 3.31 +/- 1.06 mg/dL vs 2.91 +/- 0.59; P = .02). Women with severe preeclampsia had lower levels of low-density lipoprotein than control subjects (85.5 +/- 21.3 mg/dL vs 102 +/- 30.0 mg/dL; P = .04) and a less atherogenic lipid profile than control subjects., Conclusion: Midgestation dyslipidemia is associated with mild but not severe preeclampsia. These findings may aid in elucidating the different pathologic processes between mild and severe preeclampsia.

Objective: Maternal periodontal disease, a chronic oral infectious and inflammatory disorder, is associated with an increased risk for preeclampsia. Our objective was to determine the relationship between maternal periodontal disease, maternal systemic inflammation, and the development of preeclampsia., Study Design: A secondary analysis of data from the Oral Conditions and Pregnancy Study was performed. A cohort of healthy pregnant women enrolled at less than 26 weeks underwent an oral health examination, serum sampling, and delivery follow-up. Periodontal disease was categorized clinically as present or absent. Maternal serum was assayed for C-reactive protein by high-sensitivity enzyme-linked immunosorbent assay and stratified as elevated (> or = 75th percentile) or not elevated (< 75th percentile). Preeclampsia was defined as blood pressure > 140/90 mmHg and at least 1+ proteinuria on a catheterized urine specimen. Risk ratios (RR) for preeclampsia were calculated, stratified by periodontal disease and C-reactive protein level., Results: Thirty-one (4%) of 775 women with complete data developed preeclampsia. Women with CRP > or = 75th percentile were more likely than those with CRP < 75th percentile to develop preeclampsia (7% vs 3%, P < .03; RR, 95% CI 2.2, 1.1-4.4). Women with periodontal disease and CRP > or = 75th percentile were at increased risk for preeclampsia (adjusted RR 5.8, 1.2-26.9), compared to women without periodontal disease and either CRP < 75th or > or = 75th percentile., Conclusion: Maternal periodontal disease with systemic inflammation as measured by C-reactive protein is associated with an increased risk for preeclampsia.

Objective: The study was undertaken to exhibit and quantify the difference in modulation of CD3-zeta protein (an integral component of the T-cell receptor) in preeclamptic and normotensive women., Study Design: Serum was collected from 10 preeclamptic and 10 normotensive women at >or=37 weeks' gestation on admission. Jurkat E-61 cells were incubated with the sera (20% volume to volume) and analyzed with Western immunoblot using mouse monoclonal CD3-zeta antibody. Enhanced chemiluminescence and densitometry were used to qualitatively measure zeta expression of the cells. A de novo flow cytometry assay was developed to quantify the difference in CD3-zeta expression of these cells. Comparisons were performed by t test (P<.05 was significant)., Results: Preeclamptic patient sera produced a 2.4-fold increase in CD3-zeta expression than normotensive patients on Western blot (P<.01). Flow cytometry showed that preeclamptic sera had a 1.4-fold higher expression of CD3-zeta compared with normotensive patients (P<.0003)., Conclusion: TcR/CD3-zeta expression is normally suppressed in pregnancy. Loss of this suppression occurs in preeclamptic patients, implying increased T-cell function.

Objective: To determine if maternal periodontal disease is associated with the development of preeclampsia., Methods: A cohort of 1,115 healthy pregnant women were enrolled at less than 26 weeks' gestation and followed until delivery. Maternal demographic and medical data were collected. Periodontal examinations were performed at enrollment and within 48 hours of delivery to determine the presence of severe periodontal disease or periodontal disease progression. Preeclampsia was defined as blood pressure greater than 140/90 on two separate occasions, and at least 1+ proteinuria on catheterized urine specimen. The potential effects of maternal age, race, smoking, gestational age at delivery, and insurance status were analyzed, and adjusted odds ratios for preeclampsia were calculated using multivariable logistic regression., Results: During the study period, 763 women delivered live infants and had data available for analysis. Thirty-nine women had preeclampsia. Women were at higher risk for preeclampsia if they had severe periodontal disease at delivery (adjusted odds ratio 2.4, 95% confidence interval 1.1, 5.3), or if they had periodontal disease progression during pregnancy (adjusted odds ratio 2.1, 95% confidence interval 1.0, 4.4)., Conclusion: After adjusting for other risk factors, active maternal periodontal disease during pregnancy is associated with an increased risk for the development of preeclampsia.

Background: Preterm births are a major cause of neonatal morbidity and mortality, and represent an important public health issue. About 30% of preterm births are due to medical conditions of the mother or the fetus, among "which preeclampsia plays a major role. We have previously reported that maternal periodontal disease enhances the risk for preterm delivery and preeclampsia. Our current objective was to determine whether maternal periodontal disease increases the risk for preterm delivery among preeclamptic women., Methods: Women were enrolled prior to their twenty-sixth week of gestation. Periodontal status was assessed at baseline and defined as healthy, mild, or moderate/severe. Repeat examinations were performed at delivery to assess changes in periodontal status., Results: A cohort of 1,020 women was studied, 47 of whom had preeclampsia. A strong association between periodontal disease status at enrollment and rate of premature delivery was observed among preeclamptic women after adjusting for the major risk factors for preterm delivery, including maternal race; age; marital status; WIC (women, infants, children program) or food stamps; insurance; previous preterm delivery; and chorioamnionitis. Among preeclamptic women, 49.3% with mild periodontal disease and 82.6% with moderate to severe disease delivered preterm (hazard ratios [HR] 4.11 and 11.0, respectively). Periodontal disease worsening during pregnancy in preeclamptic women was also associated with an increased risk of preterm births (HR 8.44)., Conclusion: These results suggest that mothers with preeclampsia may be at greater risk for preterm delivery if periodontal disease is present early in pregnancy or progresses during pregnancy.

BackgroundThe benefits and safety of the treatment of mild chronic hypertension (blood pressure,

Development of effective prevention and treatment strategies for pre-eclampsia is limited by the lack of accurate methods for identification of at-risk pregnancies. We performed small RNA sequencing (RNA-seq) of maternal serum extracellular RNAs (exRNAs) to discover and verify microRNAs (miRNAs) differentially expressed in patients who later developed pre-eclampsia. Sera collected from 73 pre-eclampsia cases and 139 controls between 17 and 28 weeks gestational age (GA), divided into separate discovery and verification cohorts, are analyzed by small RNA-seq. Discovery and verification of univariate and bivariate miRNA biomarkers reveal that bivariate biomarkers verify at a markedly higher rate than univariate biomarkers. The majority of verified biomarkers contain miR-155-5p, which has been reported to mediate the pre-eclampsia-associated repression of endothelial nitric oxide synthase (eNOS) by tumor necrosis factor alpha (TNF-α). Deconvolution analysis reveals that several verified miRNA biomarkers come from the placenta and are likely carried by placenta-specific extracellular vesicles.

Objective: To develop a model for predicting postpartum readmission for hypertension and pre‐eclampsia at delivery discharge and assess external validation or model transportability across clinical sites. Design: Prediction model using data available in the electronic health record from two clinical sites. Setting: Two tertiary care health systems from the Southern (2014–2015) and Northeastern USA (2017–2019). Population: A total of 28 201 postpartum individuals: 10 100 in the South and 18 101 in the Northeast. Methods: An internal‐external cross validation (IECV) approach was used to assess external validation or model transportability across the two sites. In IECV, data from each health system were first used to develop and internally validate a prediction model; each model was then externally validated using the other health system. Models were fit using penalised logistic regression, and accuracy was estimated using discrimination (concordance index), calibration curves and decision curves. Internal validation was performed using bootstrapping with bias‐corrected performance measures. Decision curve analysis was used to display potential cut points where the model provided net benefit for clinical decision‐making. Main outcome measures: The outcome was postpartum readmission for either hypertension or pre‐eclampsia <6 weeks after delivery. Results: The postpartum readmission rate for hypertension and pre‐eclampsia overall was 0.9% (0.3% and 1.2% by site, respectively). The final model included six variables: age, parity, maximum postpartum diastolic blood pressure, birthweight, pre‐eclampsia before discharge and delivery mode (and interaction between pre‐eclampsia × delivery mode). Discrimination was adequate at both health systems on internal validation (c‐statistic South: 0.88; 95% confidence interval [CI] 0.87–0.89; Northeast: 0.74; 95% CI 0.74–0.74). In IECV, discrimination was inconsistent across sites, with improved discrimination for the Northeastern model on the Southern cohort (c‐statistic 0.61 and 0.86, respectively), but calibration was not adequate. Next, model updating was performed using the combined dataset to develop a new model. This final model had adequate discrimination (c‐statistic: 0.80, 95% CI 0.80–0.80), moderate calibration (intercept −0.153, slope 0.960, Emax 0.042) and provided superior net benefit at clinical decision‐making thresholds between 1% and 7% for interventions preventing readmission. An online calculator is provided here. Conclusions: Postpartum readmission for hypertension and pre‐eclampsia may be accurately predicted but further model validation is needed. Model updating using data from multiple sites will be needed before use across clinical settings. Linked article: This article is commented on by Jeffrey N. Bone, pp. 1541 in this issue. To view this mini commentary visit https://doi.org/10.1111/1471‐0528.17528. [ABSTRACT FROM AUTHOR]

In a 2002–2004 prospective cohort study of deliveries of infants at <28 weeks at 14 US centers, the authors sought the antecedents of white matter damage evident in newborn cranial ultrasound scans (ventriculomegaly and an echolucent lesion) and of cerebral palsy diagnoses at age 2 years. Of the 1,455 infants enrolled, those whose mothers received an antenatal steroid tended to have lower risks of ventriculomegaly and an echolucent lesion than their peers (10% vs. 23%, P < 0.001 and 7% vs. 11%, P = 0.06, respectively). Risk of ventriculomegaly was increased for infants delivered because of preterm labor (adjusted odds ratio (OR) = 2.3, 95% confidence interval (CI): 1.1, 4.9), preterm premature rupture of fetal membranes (OR = 3.6, 95% CI: 1.5, 8.7), and cervical insufficiency (OR = 2.8, 95% CI: 1.4, 5.5) when compared with infants delivered because of preeclampsia. Risk of an echolucent lesion was increased for infants delivered because of preterm labor (OR = 2.7, 95% CI: 1.2, 5.7) and intrauterine growth retardation (OR = 3.3, 95% CI: 1.2, 9.4). The doubling of diparesis risk associated with preterm labor and with preterm premature rupture of fetal membranes did not achieve statistical significance, nor did the doubling of quadriparesis risk and the tripling of diparesis risk associated with cervical insufficiency. [ABSTRACT FROM PUBLISHER]