OBJECTIVE: The objectives of the study were first, to compare different markers of maternal vascular function in women with gestational diabetes mellitus (GDM), preeclampsia (PE), or gestational hypertension (GH) and women whose pregnancies were unaffected by these complications. Second, to assess the association between maternal vascular function and markers of placental perfusion, maternal vascular - placental axis, in these four groups of women.
METHODS: This was a prospective observational study of women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks\' gestation at King\'s College Hospital, London, UK. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, Doppler studies of the uterine arteries and ophthalmic arteries, carotid-femoral pulse-wave velocity (PWV) measurements, estimation of augmentation index (AIx) and total peripheral resistance and measurements of serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFLT-1). Linear regression was performed for the outcomes of uterine artery pulsatility index (UtA-PI) multiples of median (MoM), PLGF MoM and sFLT-1 MoM. Ophthalmic artery peak systolic velocity (PSV) ratio, PWV , AIx and total peripheral vascular resistance were assessed as potential predictors. This analysis was carried out in all women and separately in the different groups.
RESULTS: The study population of 6502 women included 614 (9.4%) with GDM, 140 (2.1%) who subsequently developed PE and 129 (2.0%) who developed GH. Women with GDM, compared to those with pregnancies unaffected by GDM, PE or GH, had increased PWV. Women with PE or GH, compared to those with unaffected pregnancies, had lower PlGF MoM and higher UtA-PI MoM, sFLT1 MoM, AIx, PWV, total peripheral resistance and ophthalmic artery PSV ratio. In unaffected pregnancies, ophthalmic artery PSV ratio was predictive of UtA-PI MoM, and ophthalmic artery PSV ratio, AIx, total peripheral resistance, and PWV were predictive of PLGF MoM and sFLT-1 MoM. In women with GDM, ophthalmic artery PSV ratio was predictive of UtA-PI MoM and ophthalmic artery PSV ratio, total peripheral resistance, and PWV were predictive of PLGF MoM, and total peripheral resistance was predictive of sFLT-1 MoM. In women with PE, ophthalmic artery PSV ratio was predictive of UtA-PI MoM, PLGF MoM and sFLT-1 MoM. In women unaffected by GDM, PE or GH, ophthalmic artery PSV ratio was predictive of UtA-PI MoM and AIx, total peripheral resistance, PWV and ophthalmic artery PSV ratio were predictive of PLGF MoM and sFLT-1 MoM.
CONCLUSIONS: In the third trimester of pregnancy, women with PE, GH, and GDM present with increased arterial stiffness. In addition, those diagnosed with hypertensive complications show increased peripheral vascular resistance. Ophthalmic artery PSV ratio provides predictive information for placental perfusion and function for all pregnant women, whereas vascular indices are more informative for placental function in women with unaffected pregnancy and those with GDM, than in those with PE or GH. These data suggest that vascular assessment in women during pregnancy may not only provide information about maternal vascular health but can be used to offer information about individual risk for development of placental insufficiency. The selection of vascular index will have to be tailored according to maternal profile and pregnancy complication.

BACKGROUND: This study aims to evaluate the safety of discontinuing aspirin treatment at 24-28 weeks in women at high risk after first-trimester combined screening for preeclampsia (PE) and normal placental growth factor (PlGF) levels at 24-28 weeks of gestation.
METHODS: This is a post hoc analysis of the StopPRE trial, conducted at nine Spanish maternity hospitals from September 2019 to September 2021. In the StopPRE trial, all high-risk single pregnancies identified during first-trimester screening for PE were treated with 150 mg of daily aspirin. Out of 1604 eligible women with a soluble fms-like tyrosine kinase-1 to PlGF ratio (sFlt-1/PlGF) ≤38 at 24-28 weeks, 968 were randomly assigned in a 1:1 ratio to either continue aspirin until 36 weeks (control group) or discontinue it (intervention group). In this secondary analysis, only women with PlGF ≥100 pg/mL at 24-28 weeks were included. As in the StopPRE trial, the non-inferiority margin was set at a 1.9% difference in preterm PE incidence between the groups.
RESULTS: Among the 13 983 screened pregnant women, 1984 (14.2%) were deemed high-risk for preterm PE, of which 397 (20.0%) were ineligible, 636 declined participation, and 32 were excluded. Ultimately, 919 women with PlGF >100 pg/mL were randomized and included in this analysis. Preterm PE occurred in 0.9% of the intervention group (4 out of 465) and 1.5% of the control group (7 out of 454), indicating non-inferiority of aspirin discontinuation. There were no significant differences between the groups in adverse pregnancy outcomes before 37 weeks, at <34 weeks, or ≥37 weeks. Minor antepartum hemorrhage incidence was significantly lower in the intervention group (absolute difference, -5.96; 95% CI, -10.10 to -1.82).
CONCLUSIONS: Discontinuation of aspirin treatment at 24-28 weeks in women with PlGF levels ≥100 pg/mL was non-inferior to continuing until 36 weeks for preventing preterm PE. However, these findings should be interpreted with caution, as they originate from a subanalysis of the StopPRE trial.

After menstruation the uterine spiral arteries are repaired through angiogenesis. This process is tightly regulated by the paracrine communication between endometrial stromal cells (EnSCs) and endothelial cells. Any molecular aberration in these processes can lead to complications in pregnancy including miscarriage or preeclampsia (PE). Placental growth factor (PlGF) is a known contributing factor for pathological angiogenesis but the mechanisms remain poorly understood. In this study, we investigated whether PlGF contributes to pathological uterine angiogenesis by disrupting EnSCs and endothelial paracrine communication. We observed that PlGF mediates a tonicity-independent activation of nuclear factor of activated T cells 5 (NFAT5) in EnSCs. NFAT5 activated downstream targets including SGK1, HIF-1α and VEGF-A. In depth characterization of PlGF - conditioned medium (CM) from EnSCs using mass spectrometry and ELISA methods revealed low VEGF-A and an abundance of extracellular matrix organization associated proteins. Secreted factors in PlGF-CM impeded normal angiogenic cues in endothelial cells (HUVECs) by downregulating Notch-VEGF signaling. Interestingly, PlGF-CM failed to support human placental (BeWo) cell invasion through HUVEC monolayer. Inhibition of SGK1 in EnSCs improved angiogenic effects in HUVECs and promoted BeWo invasion, revealing SGK1 as a key intermediate player modulating PlGF mediated anti-angiogenic signaling. Taken together, perturbed PlGF-NFAT5-SGK1 signaling in the endometrium can contribute to pathological uterine angiogenesis by negatively regulating EnSCs-endothelial crosstalk resulting in poor quality vessels in the uterine microenvironment. Taken together the signaling may impact on normal trophoblast invasion and thus placentation and, may be associated with an increased risk of complications such as PE.

UNASSIGNED: Molecular imaging is a highly effective method for diagnosing cancer and evaluating treatment. A molecular tracer often consists of two segments: A targeting segment, which can be antibodies, antibody fragments, or VHH (nanobody), and a detection segment, such as radioisotopes. The small size of VHH allows for excellent tissue penetration and fast clearance, resulting in minimal nonspecific background, which makes them appealing for use as imaging agents. 99m-technetium (99mTc), one of the well-known radioisotopes, is particularly useful in routine clinical imaging.
UNASSIGNED: This study aims to construct 99mTc-anti-placenta growth factor (PlGF) nanobody and assess its radiochemical purity (RCP).
UNASSIGNED: The mutant form of anti-PlGF nanobody was expressed in E. coli TG1 and purified using Ni-NTA column affinity chromatography. The purified nanobodies were confirmed by SDS-PAGE and western blotting. A 99mTc-tricarbonyl solution was added to phosphate-buffered saline (PBS) containing the mutant nanobody for labeling, and the mixture was purified using a PD-10 column.
UNASSIGNED: The RCP of 99mTc-tricarbonyl is > 98%. After the addition of radioisotopes to the mixture of nanobodies, purity reached 70% in 2 hours and remained constant during incubation. After purifying the labeled nanobody, activity was measured, and the highest amount of labeled nanobodies was collected in the second part. The stability of the labeled nanobody in PBS and in competition with histidine for 4 hours was checked by thin-layer chromatography (TLC).
UNASSIGNED: The findings of this study reveal that the RCP of the labeled nanobody was above 95% after 4 hours, indicating the labeled antibody\'s stability. These results are promising and could be utilized in future in vitro and in vivo studies.

Preeclampsia is characterized by impaired angiogenesis and assessment of angiogenic factors can play a crucial role in the early diagnosis of preeclampsia. The current study reports the levels of angiogenic factors longitudinally from early pregnancy in women with preeclampsia and in the subtypes of preeclampsia, to identify their role in early prediction of preeclampsia. A total of 1154 women with singleton pregnancies were recruited in early pregnancy from 2 hospitals. Blood samples were collected, plasma samples were separated and stored at four time points across gestation: V1 = 11-14 weeks, V2 = 18-22 weeks, V3 = 26-28 weeks, and V4 = at delivery. The current study includes a total of 108 women developed preeclampsia (PE), and 216 matched controls. Angiogenic factors were estimated using commercially available ELISA kits. Receiver operating characteristic (ROC) curves were used to evaluate the potential diagnostic value in the prediction of PE. Lower levels of VEGF, PlGF, and higher levels of sEng and sEng/PlGF ratio (p < 0.05 for all) predate clinical diagnosis in women with preeclampsia. sEng levels and sEng/PlGF ratio showed significant correlation with odds of preeclampsia at all the timepoints. This study identifies a cut off of 33.5 for sFlt-1/PlGF and 25.9 for sEng/PlGF for prediction of early onset preeclampsia. This study reports various angiogenic factors serially across gestation in a general population to identify women at risk of developing preeclampsia and its subtypes. The study also reports a potential biomarker and a pragmatic window for estimation of angiogenic markers to identify women at risk.

BACKGROUND: The aim of the study was to identify predictive values of the soluble fms-like tyrosine kinase/placental growth factor (sFlt-1/PlGF) ratio and interleukin (IL)-6, assessed with a clinically available method in a large-volume biochemistry laboratory, in maternal blood, amniotic fluid, and umbilical cord blood for the presence of the placental lesions consistent with maternal vascular malperfusion (MVM) and acute histological chorioamnionitis (HCA), respectively.
METHODS: This retrospective study included 92 women with preterm labor with intact membranes (PTL) delivered within 7 days of admission with gestational ages between 22+0 and 34+6 weeks. The sFlt-1/PlGF ratio and IL-6 were assessed in stored samples of maternal serum, amniotic fluid, and umbilical cord serum using Elecsys® sFlt-1, PlGF, and IL-6 immunoassays.
RESULTS: Women with MVM had a higher sFlt-1/PlGF ratio in the maternal serum, compared to those without MVM (19.9 vs. 4.6; p < 0.0001), but not in the amniotic fluid or umbilical cord blood. A cut-off value of 8 for the sFlt-1/PlGF ratio in maternal serum was identified as optimal for predicting MVM in patients with PTL. Women with HCA had higher concentrations of IL-6 in maternal serum, compared to those without HCA (11.1 pg/mL vs. 8.4 pg/mL; p = 0.03), amniotic fluid (9,216 pg/mL vs. 1,423 pg/mL; p < 0.0001), and umbilical cord blood (20.7 pg/mL vs. 10.7 pg/mL, p = 0.002). Amniotic-fluid IL-6 showed the highest predictive value. A cut-off value of IL-6 concentration in the amniotic fluid of 5,000 pg/mL was found to be optimal for predicting HCA in PTL.
CONCLUSIONS: Maternal serum sFlt-1/PlGF and amniotic fluid IL-6 concentrations can be used for liquid biopsy to predict placental lesions in women with PTL who deliver within 7 days.

UNASSIGNED: According to WHO, hypertensive disease is the leading cause of direct maternal mortality accounting for 10-25% in developing countries (James in Heart, 90(12):1499-504). This study compares the combinations of mean arterial pressure (MAP) and uterine artery doppler (UAD) versus serum-free β HCG, pregnancy-associated plasma protein-A, and placental growth factor (PlGF) versus a combination of all variables at 11 to 13+6 as long-term predictors of pregnancy-induced hypertension (PIH).
UNASSIGNED: A prospective, observational cohort study recruited 97 primigravidae at 11 to 13+6 weeks gestation at GMCH. Follow-up was done at 32-34 weeks and before delivery. Development of PIH, mode of delivery, birthweight, maternal and fetal adverse outcomes were documented, analyzed and compared among three groups. In Group A-biophysical markers, Group B-biochemical markers and in Group C all variables were used.
UNASSIGNED: The mean age, maternal weight, height and BMI of patients developing gestational hypertension were 30 ± 5 years, 64.3 ± 12.5 kg, 155.8 ± 5.5 cm and 26.4 ± 4.1, respectively. Out of the 3, Group C is the best screening test for predicting the overall chance of development of gestational hypertension with a sensitivity of 97.37% and specificity of 38.98% (p < 0.0001). A mild negative correlation is seen between PlGF levels and severity of PIH (p-0.0382).
UNASSIGNED: MAP and UAD can be easily incorporated into the infrastructure of most hospitals. If the biochemical test kits are made available at a low cost through available programs such as JSSK, it can bring down the MMR by preventing gestational hypertension.

Preeclampsia, a serious complication of pregnancy, involves intricate molecular and cellular mechanisms. Fetal microchimerism, where fetal cells persist within maternal tissues and in circulation, acts as a mechanistic link between placental dysfunction and maternal complications in the two-stage model of preeclampsia. Hormones, complements, and cytokines play pivotal roles in the pathophysiology, influencing immune responses, arterial remodeling, and endothelial function. Also, soluble HLA-G, involved in maternal-fetal immune tolerance, is reduced in preeclampsia. Hypoxia-inducible factor 1-alpha (Hif-α) dysregulation leads to placental abnormalities and preeclampsia-like symptoms. Alterations in matrix metalloproteinases (MMPs), endothelins (ETs), chemokines, and cytokines contribute to defective trophoblast invasion, endothelial dysfunction, and inflammation. Preeclampsia\'s genetic complexity includes circRNAs, miRNAs, and lncRNAs. CircRNA_06354 is linked to early-onset preeclampsia by influencing trophoblast invasion via the hsa-miR-92a-3p/VEGF-A pathway. The dysregulation of C19MC, especially miR-519d and miR-517-5p, affects trophoblast function. Additionally, lncRNAs like IGFBP1 and EGFR-AS1, along with protein-coding genes, impact trophoblast regulation and angiogenesis, influencing both preeclampsia and fetal growth. Besides aberrations in CD31+ cells, other potential biomarkers such as MMPs, soluble HLA-G, and hCG hold promise for predicting preeclampsia and its complications. Therapeutic interventions targeting factors such as peroxisome PPAR-γ and endothelin receptors show potential in mitigating preeclampsia-related complications. In conclusion, preeclampsia is a complex disorder with a multifactorial etiology and pathogenesis. Fetal microchimerism, hormones, complements, and cytokines contribute to placental and endothelial dysfunction with inflammation. Identifying novel biomarkers and therapeutic targets offers promise for early diagnosis and effective management, ultimately reducing maternal and fetal morbidity and mortality. However, further research is warranted to translate these findings into clinical practice and enhance outcomes for at-risk women.

UNASSIGNED: To observe the effect of soya yoghurt (Soyghurt), which is high in flavonoid substance, on the expression of preeclampsia biomarkers (sFLT-1 and PLGF) on preeclampsia serum-induced trophoblast primary cell culture isolated from placental tissue.
UNASSIGNED: The trophoblast primary culture was induced by preeclampsia serum (10%). The Soyghurt treatment was performed with 2.5%, 5%, and 7.5% Soyghurt supernatant concentrations in culture media. The expression of preeclampsia markers, sFLT-1 and PLGF, were evaluated using ELISA.
UNASSIGNED: Expression of sFLT-1 on preeclampsia-induced cell culture treated with Soyghurt was significantly lowered compared to the untreated group (p<0.01). However, no significant difference was observed in the PLGF levels of all groups induced by preeclampsia serum (p>0.05).
UNASSIGNED: This study demonstrates the potential effect of Soyghurt\'s in balancing preeclampsia marker expression by inhibiting the expression of sFLT-1 in preeclampsia serum -induced trophoblast cells.

BACKGROUND: To assess the rate of change in soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio and PlGF levels per week compared to a single sFlt-1/PlGF ratio or PlGF level to predict preterm birth for pregnancies complicated by fetal growth restriction.
METHODS: A prospective cohort study of pregnancies complicated by isolated fetal growth restriction. Maternal serum PlGF levels and the sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. We investigated the utility of PlGF levels, sFlt-1/PlGF ratio, change in PlGF levels per week or sFlt-1/PlGF ratio per week. Cox-proportional hazard models and Harrell\'s C concordance statistic were used to evaluate the effect of biomarkers on time to preterm birth.
RESULTS: The total study cohort was 158 pregnancies comprising 91 (57.6%) with fetal growth restriction and 67 (42.4%) with appropriate for gestational age controls. In the fetal growth restriction cohort, sFlt-1/PlGF ratio and PlGF levels significantly affected time to preterm birth (Harrell\'s C: 0.85-0.76). The rate of increase per week of the sFlt-1/PlGF ratio (hazard ratio [HR] 3.91, 95% confidence interval [CI]: 1.39-10.99, p = 0.01, Harrell\'s C: 0.74) was positively associated with preterm birth but change in PlGF levels per week was not (HR 0.65, 95% CI: 0.25-1.67, p = 0.37, Harrell\'s C: 0.68).
CONCLUSIONS: Both a high sFlt-1/PlGF ratio and low PlGF levels are predictive of preterm birth in women with fetal growth restriction. Although the rate of increase of the sFlt-1/PlGF ratio predicts preterm birth, it is not superior to either a single elevated sFlt-1/PlGF ratio or low PlGF level.