Anna C. M. Kluivers

A model based on the soluble Fms-like tyrosine kinase-1/placental growth factor ratio, gestational age, and the urinary protein-to-creatinine ratio (PRERISK calculator) has been developed to predict preeclampsia-related maternal-fetal complications. Here, we tested whether this model can reduce hospital admissions without increasing complication rates among women with suspected or confirmed preeclampsia. In this multicenter, open-label, randomized controlled trial conducted at 5 Dutch medical centers, women with suspected or confirmed preeclampsia were randomly assigned to the intervention group, where admission was guided by the PRERISK score using a 5% cutoff, or to the control group receiving routine care with a concealed PRERISK score. Two co-primary outcomes were the incidence of maternal-fetal preeclampsia-related complications (noninferiority) and the proportion of women with a hospitalization ratio (=admission days/inclusion days) ≤0.05 (superiority). The intervention and control groups included 442 and 435 women, respectively. In the intention-to-treat analysis, complications occurred in 41.6% of the intervention group versus 39.5% of the control group (adjusted relative risk 1.06 [95% CI, 0.92–1.22]; P=0.43). The proportion of women achieving a hospitalization ratio ≤0.05 was 23.6% in the intervention group and 26.3% in the control group (adjusted relative risk, 0.89 [95% CI, 0.71–1.13]; P=0.34). The latter was comparable in the per-protocol analysis (adjusted relative risk, 0.87 [95% CI, 0.64–1.19]; P=0.38), while in this analysis, complications occurred in 47.8% of the intervention group (n=251) versus 41.7% of the control group (n=365; adjusted relative risk 1.19 [95% CI, 1.03–1.38]; P=0.02). Routine screening with the PRERISK score and a 5% cutoff in patients with suspected or confirmed preeclampsia does not decrease hospitalization and is therefore not recommended. URL: https://onderzoekmetmensen.nl/nl/trial/48687; Unique identifier: NL63386.078.17, NL-OMON48687.

Aims: To enhance understanding of betamethasone and its metabolites' pharmacokinetics in pregnancy, specifically early‐onset pre‐eclampsia, through a population pharmacokinetic model. Additionally, to investigate the placental metabolism and transfer of betamethasone and its main metabolites.Methods: A prospective, single‐centre pharmacokinetic study was conducted in pregnant women (n = 28) with imminent preterm birth treated with intramuscular betamethasone. Betamethasone serum concentrations were determined from serial venous blood samples (n = 194). Placental transfer and metabolism were studied using ex vivo human placental perfusion (healthy term; n = 3) and placental explant experiments (healthy term, n = 4; early‐onset pre‐eclampsia, n = 4). Additionally, placental mRNA expression of CYP3A4, CYP3A7, 11β‐hydroxysteroid dehydrogenase (HSD) 1 and 11β‐HSD2 were quantified in healthy and early‐onset pre‐eclampsia placentas.Results: The population pharmacokinetic model was best described by a 2‐compartment nonlinear mixed effects model. Betamethasone clearance in early‐onset pre‐eclamptic women was 60% lower of that observed in women without pre‐eclampsia (9.35 vs. 15.78 L/h), resulting in a 40% median increase in maternal betamethasone exposure (1567 vs. 1114 ng h/mL). Ex vivo experiments showed placental transfer of betamethasone to the foetal circulation (foetal‐to‐maternal ratio 0.76 ± 0.05 [in a perfused placental cotyledon]). The placenta only converted betamethasone into 11‐ketobetamethasone, with similar ratios in early‐onset pre‐eclampsia and healthy placental explants (3.0 ± 2.2 vs. 1.4 ± 0.4 per mg tissue, P = .27). The expression of 11β‐HSD1 mRNA was lower in early‐onset pre‐eclampsia placentas (P = .015), while placental CYP3A7 and 11β‐HSD2 mRNA expression were similar.Conclusion: Women with early‐onset pre‐eclampsia have elevated betamethasone exposure. Betamethasone transfers freely into the foetal circulation, with placental metabolism resulting only in 11‐ketobetamethasone. Decreased placental 11β‐HSD1 expression may play a role in increased betamethasone exposure in early‐onset pre‐eclampsia.

Background: To study whether the use of TNF (tumor necrosis factor) inhibitors (TNFi) by pregnant women with rheumatoid arthritis affects sFlt‐1 (soluble Fms‐like tyrosine kinase‐1), PlGF (placental growth factor), or their impact on birthweight. Methods and Results: sFlt‐1 and PlGF were measured in all trimesters of pregnancy in the Preconception Counseling in Active Rheumatoid Arthritis study and were compared according to the use of TNFi. The association of sFlt‐1 and PlGF with birthweight in relation to TNFi was determined. The study included 158 women, of whom 52.5% used TNFi during pregnancy. Both sFlt‐1 and PlGF increased during pregnancy, whereas their ratio declined. Taking into consideration the trimester‐related variation in levels of sFlt‐1 and PlGF, after correction for relevant confounders, the sFlt‐1/PlGF ratio was not significantly different between patients who did or did not use TNFi (sFlt‐1/PlGF ratio in the second trimester compared with the first trimester: estimated change 8.17 [95% CI, 2.54–26.29], P =0.79; sFlt‐1/PlGF ratio in the third trimester compared with the first trimester: estimated change 6.25 [95% CI, 1.73–22.50], P =0.25). In women who did not use TNFi, birthweight was significantly lower (3180 versus 3302 g; P =0.03), and sFlt‐1 displayed a negative correlation with birthweight ( r =−0.462, P r =−0.332, P =0.008). In TNFi users, these correlations were absent. Conclusions: TNF inhibitor use increases birthweight in pregnant women with rheumatoid arthritis independently of the sFlt‐1/PlGF ratio. Registration: http://clinicaltrials.gov . Unique identifier: NCT01345071.

BACKGROUND: Chemerin, an inflammatory adipokine, is upregulated in preeclampsia, and its placental overexpression results in preeclampsia-like symptoms in mice. Statins may lower chemerin. METHODS: Chemerin was determined in a prospective cohort study in women suspected of preeclampsia and evaluated as a predictor versus the sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio. Chemerin release was studied in perfused placentas and placental explants with or without the statins pravastatin and fluvastatin. We also addressed statin placental passage and the effects of chemerin in chorionic plate arteries. RESULTS: Serum chemerin was elevated in women with preeclampsia, and its addition to a predictive model yielded significant effects on top of the sFlt-1/PlGF ratio to predict preeclampsia and its fetal complications. Perfused placentas and explants of preeclamptic women released more chemerin and sFlt-1 and less PlGF than those of healthy pregnant women. Statins reversed this. Both statins entered the fetal compartment, and the fetal/maternal concentration ratio of pravastatin was twice that of fluvastatin. Chemerin constricted plate arteries, and this was blocked by a chemerin receptor antagonist and pravastatin. Chemerin did not potentiate endothelin-1 in chorionic plate arteries. In explants, statins upregulated low-density lipoprotein receptor expression, which relies on the same transcription factor as chemerin, and NO release. CONCLUSIONS: Chemerin is a biomarker for preeclampsia, and statins both prevent its placental upregulation and effects, in an NO and low-density lipoprotein receptor–dependent manner. Combined with their capacity to improve the sFlt-1/PlGF ratio, this offers an attractive mechanism by which statins may prevent or treat preeclampsia.

Objectives: To assess levels of total placental growth factor (PlGF), soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and free PlGF in women with pre‐eclampsia (PE) with or without a small‐for‐gestational‐age (SGA) neonate in order to establish whether low free PlGF levels associated with PE and SGA are due to enhanced sFlt‐1 binding or decreased PlGF production.Methods: This was a secondary analysis of a prospective multicenter cohort study involving 407 pregnancies with suspected or confirmed PE, in which total PlGF levels were calculated from measured sFlt‐1 and free PlGF levels. The control group included women who were suspected to have PE at a certain point in pregnancy but did not develop PE. The analysis was stratified according to whether PE was early‐ or late‐onset (gestational age < 34 weeks vs ≥ 34 weeks) and according to the presence of SGA at birth, which was used as a proxy of fetal growth restriction in the absence of Doppler ultrasound and biometric data.Results: In early‐onset PE, both women with and those without SGA had lower free (19 and 45 pg/mL) and total (44 and 100 pg/mL) PlGF levels compared with women without PE (free and total PlGF, 300 and 381 pg/mL, respectively). SGA alone did not affect free and total PlGF in this condition (free and total PlGF, 264 and 352 pg/mL, respectively). Observations in women with late‐onset PE were similar, although the changes were more modest. Both SGA (gestational age < 34 weeks) and PE were individually associated with increased sFlt‐1 and, in women with both PE and SGA, the upregulation of sFlt‐1 occurred in a synergistic manner, thus resulting in the highest sFlt‐1/free PlGF ratio in this group. This occurred in both early‐ and late‐onset PE.Conclusions: Particularly in pregnancies with early‐onset PE and SGA, diminished PlGF production is an important cause of low free PlGF levels. Under such conditions, sFlt‐1 lowering is unlikely to restore the angiogenic balance. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.