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Poor placental development and placental defects can lead to adverse pregnancy outcomes such as pre-eclampsia, fetal growth restriction, and stillbirth. This study introduces two sensors, which use a near-infrared spectroscopy (NIRS) technique to measure placental oxygen saturation transabdominally. The first one, an NIRS sensor, is a wearable device consisting of multiple NIRS channels. The second one, a Multimodal sensor, which is an upgraded version of the NIRS sensor, is a wireless and wearable device, integrating a motion sensor and multiple NIRS channels. A pilot clinical study was conducted to assess the feasibility of the two sensors in measuring transabdominal placental oxygenation in 36 pregnant women (n = 12 for the NIRS sensor and n = 24 for the Multimodal sensor). Among these subjects, 4 participants had an uncomplicated pregnancy, and 32 patients had either maternal pre-existing conditions/complications, neonatal complications, and/or placental pathologic abnormalities. The study results indicate that the patients with maternal complicated conditions (69.5 ± 5.4%), placental pathologic abnormalities (69.4 ± 4.9%), and neonatal complications (68.0 ± 5.1%) had statistically significantly lower transabdominal placental oxygenation levels than those with an uncomplicated pregnancy (76.0 ± 4.4%) ( F (3,104) = 6.6, p = 0.0004). Additionally, this study shows the capability of the Multimodal sensor in detecting the maternal heart rate and respiratory rate, fetal movements, and uterine contractions. These findings demonstrate the feasibility of the two sensors in the real-time continuous monitoring of transabdominal placental oxygenation to detect at-risk pregnancies and guide timely clinical interventions, thereby improving pregnancy outcomes.

Background: Intravascular inflammation and an antiangiogenic state have been implicated in the pathophysiology of preeclampsia. On the basis of the profiles of their angiogenic/antiangiogenic factors, women with preeclampsia at term may be classified into 2 subgroups with different characteristics and prevalence of adverse outcomes. This study was undertaken to examine whether these 2 subgroups of preeclampsia at term also show differences in their profiles of intravascular inflammation., Objective: This study aimed to determine the plasma profiles of cytokines and chemokines in women with preeclampsia at term who had a normal or an abnormal angiogenic profile., Study Design: A nested case-control study was conducted to include women classified into 3 groups: women with an uncomplicated pregnancy (n=213) and women with preeclampsia at term with a normal (n=55) or an abnormal (n=41) angiogenic profile. An abnormal angiogenic profile was defined as a plasma ratio of placental growth factor and soluble fms-like tyrosine kinase-1 multiple of the median <10th percentile for gestational age. Concentrations of cytokines were measured by multiplex immunoassays., Results: Women with preeclampsia at term and an abnormal angiogenic profile showed evidence of the greatest intravascular inflammation among the study groups. These women had higher plasma concentrations of 5 cytokines (interleukin-6, interleukin-8, interleukin-12/interleukin-23p40, interleukin-15, and interleukin-16) and 7 chemokines (eotaxin, eotaxin-3, interferon-γ inducible protein-10, monocyte chemotactic protein-4, macrophage inflammatory protein-1β, macrophage-derived chemokine, and thymus and activation-regulated chemokine compared to women with an uncomplicated pregnancy. By contrast, women with preeclampsia at term and a normal angiogenic profile, compared to women with an uncomplicated pregnancy, had only a higher plasma concentration of monocyte chemotactic protein-4. A correlation between severity of the antiangiogenic state, blood pressure, and plasma concentrations of a subset of cytokines was observed., Conclusion: Term preeclampsia can be classified into 2 clusters. One is characterized by an antiangiogenic state coupled with an excessive inflammatory process, whereas the other has neither of these features. These findings further support the heterogeneity of preeclampsia at term and may explain the distinct clinical outcomes., (Published by Elsevier Inc.)

Objective: Intra-amniotic inflammation (IAI), associated with either microbe (infection) or danger signals (sterile), plays a major role in the pathophysiology of preterm labor and delivery. Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2 (CHCHD2) [also known as Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1)], a mitochondrial protein involved in oxidative phosphorylation and cell survival, is capable of sensing tissue hypoxia and inflammatory signaling. The ability to maintain an appropriate energy balance at the cellular level while adapting to environmental stress is essential for the survival of an organism. Mitochondrial dysfunction has been observed in acute systemic inflammatory conditions, such as sepsis, and is proposed to be involved in sepsis-induced multi-organ failure. The purpose of this study was to determine the amniotic fluid concentrations of CHCHD2/MNRR1 in pregnant women, women at term in labor, and those in preterm labor (PTL) with and without IAI., Methods: This cross-sectional study comprised patients allocated to the following groups: (1) mid-trimester ( n  = 16); (2) term in labor ( n  = 37); (3) term not in labor ( n  = 22); (4) PTL without IAI who delivered at term ( n  = 25); (5) PTL without IAI who delivered preterm ( n  = 47); and (6) PTL with IAI who delivered preterm ( n  = 53). Diagnosis of IAI (amniotic fluid interleukin-6 concentration ≥2.6 ng/mL) included cases associated with microbial invasion of the amniotic cavity and those of sterile nature (absence of detectable bacteria, using culture and molecular microbiology techniques). Amniotic fluid and maternal plasma CHCHD2/MNRR1 concentrations were determined with a validated and sensitive immunoassay., Results: (1) CHCHD2/MNRR1 was detectable in all amniotic fluid samples and women at term without labor had a higher amniotic fluid CHCHD2/MNRR1 concentration than those in the mid-trimester ( p  = 0.003); (2) the amniotic fluid concentration of CHCHD2/MNRR1 in women at term in labor was higher than that in women at term without labor ( p  = 0.01); (3) women with PTL and IAI had a higher amniotic fluid CHCHD2/MNRR1 concentration than those without IAI, either with preterm ( p  < 0.001) or term delivery ( p  = 0.01); (4) women with microbial-associated IAI had a higher amniotic fluid CHCHD2/MNRR1 concentration than those with sterile IAI ( p  < 0.001); (5) among women with PTL and IAI, the amniotic fluid concentration of CHCHD2/MNRR1 correlated with that of interleukin-6 (Spearman's Rho = 0.7; p  < 0.001); and (6) no correlation was observed between amniotic fluid and maternal plasma CHCHD2/MNRR1 concentrations among women with PTL., Conclusion: CHCHD2/MNRR1 is a physiological constituent of human amniotic fluid in normal pregnancy, and the amniotic concentration of this mitochondrial protein increases during pregnancy, labor at term, and preterm labor with intra-amniotic infection. Hence, CHCHD2/MNRR1 may be released into the amniotic cavity by dysfunctional mitochondria during microbial-associated IAI.

Objectives: Fetal death is a complication of pregnancy caused by multiple etiologies rather than being the end-result of a single disease process. Many soluble analytes in the maternal circulation, such as hormones and cytokines, have been implicated in its pathophysiology. However, changes in the protein content of extracellular vesicles (EVs), which could provide additional insight into the disease pathways of this obstetrical syndrome, have not been examined. This study aimed to characterize the proteomic profile of EVs in the plasma of pregnant women who experienced fetal death and to evaluate whether such a profile reflected the pathophysiological mechanisms of this obstetrical complication. Moreover, the proteomic results were compared to and integrated with those obtained from the soluble fraction of maternal plasma., Methods: This retrospective case-control study included 47 women who experienced fetal death and 94 matched, healthy, pregnant controls. Proteomic analysis of 82 proteins in the EVs and the soluble fractions of maternal plasma samples was conducted by using a bead-based, multiplexed immunoassay platform. Quantile regression analysis and random forest models were implemented to assess differences in the concentration of proteins in the EV and soluble fractions and to evaluate their combined discriminatory power between clinical groups. Hierarchical cluster analysis was applied to identify subgroups of fetal death cases with similar proteomic profiles. A p -value of <.05 was used to infer significance, unless multiple testing was involved, with the false discovery rate controlled at the 10% level ( q  < 0.1). All statistical analyses were performed by using the R statistical language and environment-and specialized packages., Results: Nineteen proteins (placental growth factor, macrophage migration inhibitory factor, endoglin, regulated upon activation normal T cell expressed and presumably secreted (RANTES), interleukin (IL)-6, macrophage inflammatory protein 1-alpha, urokinase plasminogen activator surface receptor, tissue factor pathway inhibitor, IL-8, E-Selectin, vascular endothelial growth factor receptor 2, pentraxin 3, IL-16, galectin-1, monocyte chemotactic protein 1, disintegrin and metalloproteinase domain-containing protein 12, insulin-like growth factor-binding protein 1, matrix metalloproteinase-1(MMP1), and CD163) were found to have different plasma concentrations (of an EV or a soluble fraction) in women with fetal death compared to controls. There was a similar pattern of change for the dysregulated proteins in the EV and soluble fractions and a positive correlation between the log 2 -fold changes of proteins significant in either the EV or the soluble fraction ( ρ  = 0.89, p  < .001). The combination of EV and soluble fraction proteins resulted in a good discriminatory model (area under the ROC curve, 82%; sensitivity, 57.5% at a 10% false-positive rate). Unsupervised clustering based on the proteins differentially expressed in either the EV or the soluble fraction of patients with fetal death relative to controls revealed three major clusters of patients., Conclusion: Pregnant women with fetal death have different concentrations of 19 proteins in the EV and soluble fractions compared to controls, and the direction of changes in concentration was similar between fractions. The combination of EV and soluble protein concentrations revealed three different clusters of fetal death cases with distinct clinical and placental histopathological characteristics.

Objective: Mitochondrial dysfunction was observed in acute systemic inflammatory conditions such as sepsis and might be involved in sepsis-induced multi-organ failure. Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2 (CHCHD2), also known as Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1), a bi-organellar protein located in the mitochondria and the nucleus, is implicated in cell respiration, survival, and response to tissue hypoxia. Recently, the reduction of the cellular CHCHD2/MNRR1 protein, as part of mitochondrial dysfunction, has been shown to play a role in the amplification of inflammatory cytokines in a murine model of lipopolysaccharide-induced systemic inflammation. The aim of this study was to determine whether the plasma concentration of CHCHD2/MNRR1 changed during human normal pregnancy, spontaneous labor at term, and clinical chorioamnionitis at term., Methods: We conducted a cross-sectional study that included the following groups: 1) non-pregnant women ( n  = 17); 2) normal pregnant women at various gestational ages from the first trimester until term ( n  = 110); 3) women at term with spontaneous labor ( n  = 50); and 4) women with clinical chorioamnionitis at term in labor ( n  = 25). Plasma concentrations of CHCHD2/MNRR1 were assessed by an enzyme-linked immunosorbent assay., Results: 1) Pregnant women at term in labor with clinical chorioamnionitis had a significantly higher plasma CHCHD2/MNRR1 concentration than those in labor without chorioamnionitis ( p  = .003); 2) CHCHD2/MNRR1 is present in the plasma of healthy non-pregnant and normal pregnant women without significant differences in its plasma concentrations between the two groups; 3) there was no correlation between maternal plasma CHCHD2/MNRR1 concentration and gestational age at venipuncture; and 4) plasma CHCHD2/MNRR1 concentration was not significantly different in women at term in spontaneous labor compared to those not in labor., Conclusions: CHCHD2/MNRR1 is physiologically present in the plasma of healthy non-pregnant and normal pregnant women, and its concentration does not change with gestational age and parturition at term. However, plasma CHCHD2/MNRR1 is elevated in women at term with clinical chorioamnionitis. CHCHD2/MNRR1, a novel bi-organellar protein located in the mitochondria and the nucleus, is released into maternal plasma during systemic inflammation.

Background: Acute pyelonephritis, a risk factor for maternal sepsis, adult respiratory distress syndrome, and preterm labor, is a frequent cause of hospitalization. This condition is characterized by excessive intravascular inflammation and endothelial cell activation and dysfunction. Syndecan-1, a major component of the glycocalyx, is a gel-like layer that covers the luminal surface of healthy endothelial cells, preserving and mediating many endothelial functions. During pregnancy, there is an additional potential source of syndecan-1, the "syncytiotrophoblast glycocalyx," which lines the intervillous space. Insults that damage the glycocalyx lead to a shedding of syndecan-1 into the circulation. Hence, syndecan-1 has been proposed as a marker of endothelial injury in conditions such as sepsis, trauma, cardiovascular disease, and diabetes mellitus., Objective: The objective of this study was to determine whether the plasma syndecan-1 concentration changes in women with acute pyelonephritis in the presence or absence of bacteremia., Study Design: This cross-sectional study included three groups: (1) non-pregnant women ( n  = 25); (2) women with an uncomplicated pregnancy from whom samples were collected preterm ( n  = 61) or at term ( n  = 69); and (3) pregnant women diagnosed with acute pyelonephritis from whom samples were collected at the time of diagnosis during the second and third trimesters ( n  = 33). The diagnosis of acute pyelonephritis was based on clinical findings and a positive urine culture for bacteria. Blood culture results were available in 85% (28/33) of women with acute pyelonephritis. Plasma concentrations of syndecan-1 were determined by a validated immunoassay., Results: ( 1) Women with an uncomplicated pregnancy had a higher plasma concentration of syndecan-1 than non-pregnant women. The geometric mean (95% confidence interval [CI]) of syndecan-1 concentration was 51.0 (12.1-216.1) ng/mL in non-pregnant controls; 1280 (365-4487) ng/mL in normal preterm gestations; and 1786 (546-5834) ng/mL in normal term gestations (adjusted p  < .005 for all three between group comparisons); ( 2) plasma syndecan-1 concentrations increased with gestational age among women with a normal pregnancy ( p  < .001, R 2 = 0.27); (3) syndecan-1 multiple of the mean (MoM) values in pregnant patients with acute pyelonephritis were higher than those in normal pregnant women based on second- and third-trimester samples ( p  = .048, 1.26-fold change). The increase was driven primarily by cases with a positive blood culture ( p  = .009, 1.74-fold change); (4) when data from third-trimester samples were compared, overall differences in syndecan-1 MoM values between cases and controls were slightly larger ( p  = .03, 1.36- fold change), which were especially contributed to by cases with a positive blood culture ( p  = .023, fold change 1.79-fold change)., Conclusions: Plasma syndecan-1 concentration is higher in pregnant women and increases as a function of gestational age. Patients with acute pyelonephritis have a higher plasma concentration of syndecan-1, and this is particularly the case in the presence of bacteremia.

Objective: The identification of fetal growth disorders is an important clinical priority given that they increase the risk of perinatal morbidity and mortality as well as long-term diseases. A subset of small-for-gestational-age (SGA) infants are growth-restricted, and this condition is often attributed to placental insufficiency. Syndecan-1, a product of the degradation of the endothelial glycocalyx, has been proposed as a biomarker of endothelial damage in different pathologies. During pregnancy, a "specialized" form of the glycocalyx-the "syncytiotrophoblast glycocalyx"-covers the placental villi. The purpose of this study was to determine whether the concentration of maternal plasma syndecan-1 can be proposed as a biomarker for fetal growth restriction., Study Design: A cross-sectional study was designed to include women with normal pregnancy ( n  = 130) and pregnant women who delivered an SGA neonate ( n  = 50). Doppler velocimetry of the uterine and umbilical arteries was performed in women with an SGA fetus at the time of diagnosis. Venipuncture was performed within 48 h of Doppler velocimetry and plasma concentrations of syndecan-1 were determined by a specific and sensitive immunoassay., Results: (1) Plasma syndecan-1 concentration followed a nonlinear increase with gestational age in uncomplicated pregnancies (R 2  = 0.27, p  < .001); (2) women with a pregnancy complicated with an SGA fetus had a significantly lower mean plasma concentration of syndecan-1 than those with an appropriate-for-gestational-age fetus ( p  = .0001); (3) this difference can be attributed to fetal growth restriction, as the mean plasma syndecan-1 concentration was significantly lower only in the group of women with an SGA fetus who had abnormal umbilical and uterine artery Doppler velocimetry compared to controls ( p  = .00071; adjusted p  = .0028). A trend toward lower syndecan-1 concentrations was also noted for SGA with abnormal uterine but normal umbilical artery Doppler velocimetry ( p  = .0505; adjusted p  = .067); 4) among women with an SGA fetus, those with abnormal umbilical and uterine artery Doppler findings had a lower mean plasma syndecan-1 concentration than women with normal Doppler velocimetry ( p  = .02; adjusted p  = .04); 5) an inverse relationship was found between the maternal plasma syndecan-1 concentration and the umbilical artery pulsatility index ( r  = -0.5; p  = .003); and 6) a plasma syndecan-1 concentration ≤ 850 ng/mL had a positive likelihood ratio of 4.4 and a negative likelihood ratio of 0.24 for the identification of a mother with an SGA fetus who had abnormal umbilical artery Doppler velocimetry (area under the ROC curve 0.83; p  < .001)., Conclusion: Low maternal plasma syndecan-1 may reflect placental diseases and this protein could be a biomarker for fetal growth restriction. However, as a sole biomarker for this condition, its accuracy is low.

Objective: Preeclampsia and fetal growth disorders are pregnancy-specific conditions that share common pathophysiological mechanisms. Yet, why some patients develop preeclampsia while others experience fetal growth restriction, or a combination of both clinical presentations, is unknown. We propose that the difference in severity of the maternal inflammatory response can contribute to the clinical phenotypes of preeclampsia vs. small for gestational age (SGA). To assess this hypothesis, we measured maternal plasma concentrations of the soluble isoform of suppression of tumorigenicity-2 (sST2), a member of the interleukin-1 receptor family that buffers proinflammatory responses. Previous reports showed that serum sST2 concentrations rise in the presence of intravascular inflammation and Th1-type immune responses and are significantly higher in patients with preeclampsia compared to those with normal pregnancy. The behavior of sST2 in pregnancies complicated by SGA has not been reported. This study was conducted to compare sST2 plasma concentrations in normal pregnancies, in those with preeclampsia, and in those with an SGA fetus., Methods: This retrospective cross-sectional study included women with an SGA fetus ( n  = 52), women with preeclampsia ( n  = 106), and those with normal pregnancy ( n  = 131). Maternal plasma concentrations of sST2 were determined by enzyme-linked immunosorbent assay. Doppler velocimetry of the uterine and umbilical arteries was available in a subset of patients with SGA (42 patients and 43 patients, respectively)., Results: (1) Women with an SGA fetus had a significantly higher median plasma concentration of sST2 than normal pregnant women ( p = . 008); (2) women with preeclampsia had a significantly higher median plasma concentration of sST2 than those with normal pregnancy ( p < . 001) and those with an SGA fetus ( p < . 001); (3) patients with SGA and abnormal uterine artery Doppler velocimetry had a higher median plasma concentration of sST2 than controls ( p < . 01) and those with SGA and normal uterine artery Doppler velocimetry ( p = . 02); (4) there was no significant difference in the median plasma sST2 concentration between patients with SGA who had normal uterine artery Doppler velocimetry and controls ( p = . 4); (5) among patients with SGA, those with abnormal and those with normal umbilical artery Doppler velocimetry had higher median plasma sST2 concentrations than controls ( p = . 001 and p = . 02, respectively); and (6) there was no significant difference in the median plasma sST2 concentrations between patients with SGA who did and those who did not have abnormal umbilical artery Doppler velocimetry ( p = . 06)., Conclusions: Preeclampsia and disorders of fetal growth are conditions characterized by intravascular inflammation, as reflected by maternal plasma concentrations of sST2. The severity of intravascular inflammation is highest in patients with preeclampsia.

Objective: Sepsis is a leading cause of maternal death, and its diagnosis during the golden hour is critical to improve survival. Acute pyelonephritis in pregnancy is a risk factor for obstetrical and medical complications, and it is a major cause of sepsis, as bacteremia complicates 15-20% of pyelonephritis episodes in pregnancy. The diagnosis of bacteremia currently relies on blood cultures, whereas a rapid test could allow timely management and improved outcomes. Soluble suppression of tumorigenicity 2 (sST2) was previously proposed as a biomarker for sepsis in non-pregnant adults and children. This study was designed to determine whether maternal plasma concentrations of sST2 in pregnant patients with pyelonephritis can help to identify those at risk for bacteremia. Study design: This cross-sectional study included women with normal pregnancy ( n  = 131) and pregnant women with acute pyelonephritis ( n  = 36). Acute pyelonephritis was diagnosed based on a combination of clinical findings and a positive urine culture. Patients were further classified according to the results of blood cultures into those with and without bacteremia. Plasma concentrations of sST2 were determined by a sensitive immunoassay. Non-parametric statistics were used for analysis. Results: The maternal plasma sST2 concentration increased with gestational age in normal pregnancies. Pregnant patients with acute pyelonephritis had a higher median (interquartile range) plasma sST2 concentration than those with a normal pregnancy [85 (47-239) ng/mL vs. 31 (14-52) ng/mL, p  < .001]. Among patients with pyelonephritis, those with a positive blood culture had a median plasma concentration of sST2 higher than that of patients with a negative blood culture [258 (IQR: 75-305) ng/mL vs. 83 (IQR: 46-153) ng/mL; p  = .03]. An elevated plasma concentration of sST2 ≥ 215 ng/mL had a sensitivity of 73% and a specificity of 95% (area under the receiver operating characteristic curve, 0.74; p  = .003) with a positive likelihood ratio of 13.8 and a negative likelihood ratio of 0.3 for the identification of patients who had a positive blood culture. Conclusion: sST2 is a candidate biomarker to identify bacteremia in pregnant women with pyelonephritis. Rapid identification of these patients may optimize patient care.

Objective: To evaluate the performance of INTERGROWTH-21 st (IG-21 st ) and World Health Organization (WHO) fetal growth charts to identify small-for-gestational-age (SGA) and fetal growth restriction (FGR) neonates, as well as their specific risks for adverse neonatal outcomes., Methods: Multicenter cross-sectional study including 67 968 live births from 10 maternity units across four Latin American countries. According to each standard, neonates were classified as SGA and FGR (birth weight <10 th and less than third centiles, respectively). The relative risk (RR) and diagnostic performance for a low APGAR score and low ponderal index were calculated for each standard., Results: WHO charts identified more neonates as SGA than IG-21 st (13.9% vs 7%, respectively). Neonates classified as having FGR by both standards had the highest RR for a low APGAR (RR, 5.57 [95% confidence interval (CI), 3.99-7.78]), followed by those who were SGA by both curves (RR, 3.27 [95% CI, 2.52-4.24]), while neonates with SGA identified by WHO alone did not have an additional risk (RR, 0.87 [95% CI, 0.55-1.39]). Furthermore, the diagnostic odds ratio for a low APGAR was higher when IG-21 st was used., Conclusion: In a population from Latin America, the WHO charts seem to identify more SGA neonates, but the diagnostic performance of the IG-21 st charts for low APGAR score and low ponderal index is better., (© 2023 International Federation of Gynecology and Obstetrics.)

Background: An antiangiogenic state has emerged as a mechanism of disease in preeclampsia. Angiogenic biomarkers are used in the risk assessment of this syndrome, particularly of early disease. The role of an antiangiogenic state in late preeclampsia is unclear., Objective: This study aimed to determine the prevalence, characteristics, and clinical significance of angiogenic/antiangiogenic factor abnormalities in women with preeclampsia stratified according to gestational age at delivery., Study Design: Two studies were conducted: (1) a longitudinal nested case-control study comprising women with preeclampsia (n=151) and a control group (n=540); and (2) a case series of patients with preeclampsia (n=452). In patients with preeclampsia, blood was collected at the time of diagnosis. Plasma concentrations of placental growth factor and soluble fms-like tyrosine kinase-1 were determined by enzyme-linked immunosorbent assays. An abnormal angiogenic profile was defined as a plasma ratio of placental growth factor and soluble fms-like tyrosine kinase-1 expressed as a multiple of the median <10th percentile for gestational age based on values derived from the longitudinal study. The proportion of patients diagnosed with preeclampsia who had an abnormal angiogenic profile was determined in the case-series participants and stratified by gestational age at delivery into early (≤34 weeks), intermediate (34.1-36.9 weeks), and term (≥37 weeks) preeclampsia. The demographics, clinical characteristics, and pregnancy outcomes of women with preeclampsia with and without an abnormal angiogenic profile were compared., Results: The prevalence of an abnormal angiogenic profile was higher in preterm than in term preeclampsia (for early, intermediate, and term in the case-control study: 90%, 100%, and 39%; for the case series: 98%, 80%, and 55%, respectively). Women with preeclampsia at term who had an abnormal angiogenic profile were more frequently nulliparous (57% vs 35%), less likely to smoke (14% vs 26%), at greater risk for maternal (14% vs 5%) or neonatal (7% vs 1%) complications, and more often had placental lesions consistent with maternal vascular malperfusion (42% vs 23%; all, P<.05) than those without an abnormal profile. Women with preeclampsia at term who had a normal angiogenic profile had a higher frequency of chronic hypertension (36% vs 21%) and were more likely to have class ≥2 obesity (41% vs 23%) than those with an abnormal profile (both, P<.05)., Conclusion: Patients with early preeclampsia had an abnormal angiogenic profile in virtually all cases, whereas only 50% of women with preeclampsia at term had such abnormalities. The profile of angiogenic biomarkers can be used to classify patients with preeclampsia at term, on the basis of mechanisms of disease, into 2 clusters, which have different demographics, clinical characteristics, and risks of adverse maternal and neonatal outcomes. These findings provide a simple approach to classify preeclampsia at term and have implications for future clinical care and research., (Published by Elsevier Inc.)

Green-stained amniotic fluid, often referred to as meconium-stained amniotic fluid, is present in 5% to 20% of patients in labor and is considered an obstetric hazard. The condition has been attributed to the passage of fetal colonic content (meconium), intraamniotic bleeding with the presence of heme catabolic products, or both. The frequency of green-stained amniotic fluid increases as a function of gestational age, reaching approximately 27% in post-term gestation. Green-stained amniotic fluid during labor has been associated with fetal acidemia (umbilical artery pH <7.00), neonatal respiratory distress, and seizures as well as cerebral palsy. Hypoxia is widely considered a mechanism responsible for fetal defecation and meconium-stained amniotic fluid; however, most fetuses with meconium-stained amniotic fluid do not have fetal acidemia. Intraamniotic infection/inflammation has emerged as an important factor in meconium-stained amniotic fluid in term and preterm gestations, as patients with these conditions have a higher rate of clinical chorioamnionitis and neonatal sepsis. The precise mechanisms linking intraamniotic inflammation to green-stained amniotic fluid have not been determined, but the effects of oxidative stress in heme catabolism have been implicated. Two randomized clinical trials suggest that antibiotic administration decreases the rate of clinical chorioamnionitis in patients with meconium-stained amniotic fluid. A serious complication of meconium-stained amniotic fluid is meconium aspiration syndrome. This condition develops in 5% of cases presenting with meconium-stained amniotic fluid and is a severe complication typical of term newborns. Meconium aspiration syndrome is attributed to the mechanical and chemical effects of aspirated meconium coupled with local and systemic fetal inflammation. Routine naso/oropharyngeal suctioning and tracheal intubation in cases of meconium-stained amniotic fluid have not been shown to be beneficial and are no longer recommended in obstetrical practice. A systematic review of randomized controlled trials suggested that amnioinfusion may decrease the rate of meconium aspiration syndrome. Histologic examination of the fetal membranes for meconium has been invoked in medical legal litigation to time the occurrence of fetal injury. However, inferences have been largely based on the results of in vitro experiments, and extrapolation of such findings to the clinical setting warrants caution. Fetal defecation throughout gestation appears to be a physiologic phenomenon based on ultrasound as well as in observations in animals., (Published by Elsevier Inc.)

Background: Activation of the coagulation system and increased thrombin generation have been implicated in the pathophysiology of preeclampsia, and this rationale supports the administration of low-molecular-weight heparin to prevent this syndrome in patients at risk. Yet, randomized trials of this prophylactic measure have yielded contradictory results. A possible explanation is that only a subset of patients with preeclampsia have excessive thrombin generation and would benefit from the administration of low-molecular-weight heparin. Therefore, the key questions are whether and when patients who subsequently develop preeclampsia present evidence of abnormal thrombin generation., Objective: This study aimed to determine (1) the kinetics of thrombin generation throughout gestation in women with a normal pregnancy and in those with early and late preeclampsia, and (2) the diagnostic performance of in vivo thrombin generation parameters to predict the development of preeclampsia., Study Design: This retrospective, nested case-control study was based on a prospective longitudinal cohort of singleton gestations. Cases comprised women who developed preeclampsia (n=49), and controls consisted of patients with a normal pregnancy (n=45). Preeclampsia was classified into early-onset (n=24) and late-onset (n=25). Longitudinal changes in the parameters of the thrombin generation assay (lag time, time to peak thrombin concentration, peak thrombin concentration, endogenous thrombin generation, and velocity index) throughout gestation were compared between the study groups, and normal pregnancy percentiles were derived from the control group. We tested whether a single parameter or a combination of parameters, derived from the kinetics of thrombin generation, could identify patients who subsequently developed preeclampsia. Time-related parameters <10th percentile were considered short, and concentration-related parameters >90 th percentile were considered high., Results: (1) Patients who developed preeclampsia (early- and late-onset) had abnormal thrombin generation kinetics as early as 8 to 16 weeks of pregnancy; (2) patients with a combination of a short lag time and high peak thrombin concentration at 8 to 16 weeks of pregnancy had an odds ratio of 43.87 for the subsequent development of preeclampsia (area under the curve, 0.79; sensitivity, 56.8%; specificity, 92.7%; positive likelihood ratio, 7.76); (3) at 16 to 22 weeks of gestation, patients with a combination of a short lag time and a high velocity index had an odds ratio of 16 for the subsequent development of preeclampsia (area under the curve, 0.78; sensitivity, 62.2%; specificity, 92.5%; positive likelihood ratio, 8.29)., Conclusion: During early pregnancy, the thrombin generation assay can identify the subset of patients at a greater risk for the development of preeclampsia owing to accelerated and enhanced production of thrombin. This observation provides a rationale for testing the efficacy of low-molecular-weight heparin in this subset of patients. We propose that future research on the efficacy of low-molecular-weight heparin and other interventions targeting the coagulation system to prevent preeclampsia should be focused on patients with abnormal kinetics of thrombin generation., (Published by Elsevier Inc.)

Background: Pregnant women are at greater risk of adverse outcomes, including mortality, as well as obstetrical complications resulting from COVID-19. However, pregnancy-specific changes that underlie such worsened outcomes remain unclear., Methods: Plasma samples were collected from pregnant women and non-pregnant individuals (male and female) with (n = 72 pregnant, 52 non-pregnant) and without (n = 29 pregnant, 41 non-pregnant) COVID-19. COVID-19 patients were grouped as asymptomatic, mild, moderate, severe, or critically ill according to NIH classifications. Proteomic profiling of 7,288 analytes corresponding to 6,596 unique protein targets was performed using the SOMAmer platform., Results: Herein, we profile the plasma proteome of pregnant and non-pregnant COVID-19 patients and controls and show alterations that display a dose-response relationship with disease severity; yet, such proteomic perturbations are dampened during pregnancy. In both pregnant and non-pregnant state, the proteome response induced by COVID-19 shows enrichment of mediators implicated in cytokine storm, endothelial dysfunction, and angiogenesis. Shared and pregnancy-specific proteomic changes are identified: pregnant women display a tailored response that may protect the conceptus from heightened inflammation, while non-pregnant individuals display a stronger response to repel infection. Furthermore, the plasma proteome can accurately identify COVID-19 patients, even when asymptomatic or with mild symptoms., Conclusion: This study represents the most comprehensive characterization of the plasma proteome of pregnant and non-pregnant COVID-19 patients. Our findings emphasize the distinct immune modulation between the non-pregnant and pregnant states, providing insight into the pathogenesis of COVID-19 as well as a potential explanation for the more severe outcomes observed in pregnant women., (© 2023. The Author(s).)

Introduction: Galectins are master regulators of maternal immune responses and placentation in pregnancy. Galectin-13 (gal-13) and galectin-14 (gal-14) are expressed solely by the placenta and contribute to maternal-fetal immune tolerance by inducing the apoptosis of activated T lymphocytes and the polarization of neutrophils toward an immune-regulatory phenotype.Furthermore, their decreased placental expression is associated with pregnancy complications, such as preeclampsia and miscarriage. Yet, our knowledge of the immunoregulatory role of placental galectins is incomplete., Methods: This study aimed to investigate the effects of recombinant gal-13 and gal-14 on cell viability, apoptosis, and cytokine production of peripheral blood mononuclear cells (PBMCs) and the signaling pathways involved., Results: Herein, we show that gal-13 and gal-14 bind to the surface of non-activated PBMCs (monocytes, natural killer cells, B cells, and T cells) and increase their viability while decreasing the rate of their apoptosis without promoting cell proliferation. We also demonstrate that gal-13 and gal-14 induce the production of interleukin (IL)-8, IL-10, and interferon-gamma cytokines in a concentration-dependent manner in PBMCs. The parallel activation of Erk1/2, p38, and NF-ĸB signaling evidenced by kinase phosphorylation in PBMCs suggests the involvement of these pathways in the regulation of the galectin-affected immune cell functions., Discussion: These findings provide further evidence on how placenta-specific galectins assist in the establishment and maintenance of a proper immune environment during a healthy pregnancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Oravecz, Romero, Tóth, Kapitány, Posta, Gallo, Rossi, Tarca, Erez, Papp, Matkó, Than and Balogh.)

Objectives: An abnormal angiogenic profile is present in about one-half of women with preeclampsia at term. Few studies examined the roles of angiogenic biomarkers in eclampsia. The aims of this study were to determine (1) whether the degree of an anti-angiogenic state, reflected by a low placental growth factor (PlGF) to soluble fms-like tyrosine kinase-1 (sFlt-1) ratio, in women with eclampsia differed from that of women with severe preeclampsia; and (2) the prevalence of women who had an abnormal angiogenic profile at the diagnoses of preterm and term eclampsia., Methods: A cross-sectional study was conducted to include women in the following groups: (1) uncomplicated pregnancy (n=40); (2) severe preeclampsia (n=50); and (3) eclampsia (n=35). Maternal serum concentrations of PlGF and sFlt-1 were determined by immunoassays., Results: Women with preterm, but not term, eclampsia had a more severe anti-angiogenic state than those with severe preeclampsia ( lower PlGF and PlGF/sFlt-1 ratio, each p<0.05). However, the difference diminished in magnitude with increasing gestational age (interaction, p=0.005). An abnormal angiogenic profile was present in 95% (19/20) of women with preterm eclampsia but in only 67% (10/15) of women with eclampsia at term., Conclusions: Angiogenic biomarkers can be used for risk assessment of preterm eclampsia. By contrast, a normal profile of angiogenic biomarkers cannot reliably exclude patients at risk for eclampsia at term. This observation has major clinical implications given that angiogenic biomarkers are frequently used in the triage area as a test to rule out preeclampsia., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Infection is considered a leading cause of fetal death, responsible for approximately 20% of cases. Such estimates are derived from the frequency of acute histological chorioamnionitis and funisitis in cases of fetal death rather than direct detection of microorganisms in the fetal compartment. We report a case of clinically unexplained fetal death at 38 weeks of gestation in an uncomplicated pregnancy resulting in delivery of an appropriate-for-gestational-age fetus. The mother did not have any clinical signs of infection. Overwhelming bacterial invasion in multiple fetal organs, including the heart, liver, spleen, and kidneys, was observed despite the lack of evidence of maternal clinical infection. The bacteria were visualized by using standard histologic techniques (e.g. H&E/ tissue Gram stain) highlighting the value of autopsy in determining the cause of death.

The human plasma proteome is underexplored despite its potential value for monitoring health and disease. Herein, using a recently developed aptamer-based platform, we profiled 7288 proteins in 528 plasma samples from 91 normal pregnancies (Gene Expression Omnibus identifier GSE206454). The coefficient of variation was <20% for 93% of analytes (median 7%), and a cross-platform correlation for selected key angiogenic and anti-angiogenic proteins was significant. Gestational age was associated with changes in 953 proteins, including highly modulated placenta- and decidua-specific proteins, and they were enriched in biological processes including regulation of growth, angiogenesis, immunity, and inflammation. The abundance of proteins corresponding to RNAs specific to populations of cells previously described by single-cell RNA-Seq analysis of the placenta was highly modulated throughout gestation. Furthermore, machine learning-based prediction of gestational age and of time from sampling to term delivery compared favorably with transcriptomic models (mean absolute error of 2 weeks). These results suggested that the plasma proteome may provide a non-invasive readout of placental cellular dynamics and serve as a blueprint for investigating obstetrical disease.

Objectives: The heterogeneous nature of preeclampsia is a major obstacle to early screening and prevention, and a molecular taxonomy of disease is needed. We have previously identified four subclasses of preeclampsia based on first-trimester plasma proteomic profiles. Herein, we expanded this approach by using a more comprehensive panel of proteins profiled in longitudinal samples., Methods: Proteomic data collected longitudinally from plasma samples of women who developed preeclampsia (n=109) and of controls (n=90) were available from our previous report on 1,125 proteins. Consensus clustering was performed to identify subgroups of patients with preeclampsia based on data from five gestational-age intervals by using select interval-specific features. Demographic, clinical, and proteomic differences among clusters were determined. Differentially abundant proteins were used to identify cluster-specific perturbed KEGG pathways., Results: Four molecular clusters with different clinical phenotypes were discovered by longitudinal proteomic profiling. Cluster 1 involves metabolic and prothrombotic changes with high rates of early-onset preeclampsia and small-for-gestational-age neonates; Cluster 2 includes maternal anti-fetal rejection mechanisms and recurrent preeclampsia cases; Cluster 3 is associated with extracellular matrix regulation and comprises cases of mostly mild, late-onset preeclampsia; and Cluster 4 is characterized by angiogenic imbalance and a high prevalence of early-onset disease., Conclusions: This study is an independent validation and further refining of molecular subclasses of preeclampsia identified by a different proteomic platform and study population. The results lay the groundwork for novel diagnostic and personalized tools of prevention., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

The objective of this study was to evaluate the performance of quantitative ultrasound of fetal lung texture analysis in predicting neonatal respiratory morbidity (NRM) in twin pregnancies. This was an ambispective study involving consecutive cases. Eligible cases included twin pregnancies between 27.0 and 38.6 weeks of gestation, for which an ultrasound image of the fetal thorax was obtained within 48 h of delivery. Images were analyzed using quantusFLM ® version 3.0. The primary outcome of this study was neonatal respiratory morbidity, defined as the occurrence of either transient tachypnea of the newborn or respiratory distress syndrome. The performance of quantusFLM ® in predicting NRM was analyzed by matching quantitative ultrasound analysis and clinical outcomes. This study included 166 images. Neonatal respiratory morbidity occurred in 12.7% of cases, and it was predicted by quantusFLM ® analysis with an overall sensitivity of 42.9%, specificity of 95.9%, positive predictive value of 60%, and negative predictive value of 92.1%. The accuracy was 89.2%, with a positive likelihood ratio of 10.4, and a negative likelihood ratio of 0.6. The results of this study demonstrate the good prediction capability of NRM in twin pregnancies using a non-invasive lung texture analysis software. The test showed an overall good performance with high specificity, negative predictive value, and accuracy.

Preterm birth, the leading cause of perinatal morbidity and mortality, is associated with increased risk of short- and long-term adverse outcomes. For women identified as at risk for preterm birth attributable to a sonographic short cervix, the determination of imminent delivery is crucial for patient management. The current study aimed to identify amniotic fluid (AF) proteins that could predict imminent delivery in asymptomatic patients with a short cervix. This retrospective cohort study included women enrolled between May 2002 and September 2015 who were diagnosed with a sonographic short cervix (< 25 mm) at 16-32 weeks of gestation. Amniocenteses were performed to exclude intra-amniotic infection; none of the women included had clinical signs of infection or labor at the time of amniocentesis. An aptamer-based multiplex platform was used to profile 1310 AF proteins, and the differential protein abundance between women who delivered within two weeks from amniocentesis, and those who did not, was determined. The analysis included adjustment for quantitative cervical length and control of the false-positive rate at 10%. The area under the receiver operating characteristic curve was calculated to determine whether protein abundance in combination with cervical length improved the prediction of imminent preterm delivery as compared to cervical length alone. Of the 1,310 proteins profiled in AF, 17 were differentially abundant in women destined to deliver within two weeks of amniocentesis independently of the cervical length (adjusted p-value < 0.10). The decreased abundance of SNAP25 and the increased abundance of GPI, PTPN11, OLR1, ENO1, GAPDH, CHI3L1, RETN, CSF3, LCN2, CXCL1, CXCL8, PGLYRP1, LDHB, IL6, MMP8, and PRTN3 were associated with an increased risk of imminent delivery (odds ratio > 1.5 for each). The sensitivity at a 10% false-positive rate for the prediction of imminent delivery by a quantitative cervical length alone was 38%, yet it increased to 79% when combined with the abundance of four AF proteins (CXCL8, SNAP25, PTPN11, and MMP8). Neutrophil-mediated immunity, neutrophil activation, granulocyte activation, myeloid leukocyte activation, and myeloid leukocyte-mediated immunity were biological processes impacted by protein dysregulation in women destined to deliver within two weeks of diagnosis. The combination of AF protein abundance and quantitative cervical length improves prediction of the timing of delivery compared to cervical length alone, among women with a sonographic short cervix., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objectives: To determine whether the maternal plasma concentrations of cytokines are higher in pregnant women with postpartum hemorrhage (PPH) compared to pregnant women without PPH., Methods: A retrospective case-control study included 36 women with PPH and 72 matched controls. Cases and controls were matched for gestational age at delivery, labor status, delivery route, parity, and year of sample collection. Maternal plasma samples were collected up to 3 days prior to delivery. Comparison of the plasma concentrations of 29 cytokines was performed by using linear mixed-effects models and included adjustment for covariates and multiple testing. A false discovery rate adjusted p-value <0.1 was used to infer significance. Random forest models with evaluation by leave-one-out and 9-fold cross-validation were used to assess the combined value of the proteins in predicting PPH., Results: Concentrations of interleukin (IL)-16, IL-6, IL-12/IL-23p40, monocyte chemotactic protein 1 (MCP-1), and IL-1β were significantly higher in PPH than in the control group. This difference remained significant after adjustment for maternal age, clinical chorioamnionitis, and preeclampsia. Multi-protein random forest proteomics models had moderate cross-validated accuracy for prediction of PPH [area under the ROC curve, 0.69 (0.58-0.81) by leave-one-out cross validation and 0.73 (0.65-0.81) by 9-fold cross-validation], and the inclusion of clinical and demographic information did not increase the prediction performance., Conclusions: Pregnant women with severe PPH had higher median maternal plasma concentrations of IL-16, IL-6, IL-12/IL-23p40, MCP-1, and IL-1β than patients without PPH. These cytokines could serve as biomarkers or their pathways may be therapeutic targets., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: To determine whether placental vascular pathology and impaired placental exchange due to maturational defects are involved in the etiology of spontaneous preterm labor and delivery in cases without histologic acute chorioamnionitis., Methods: This was a retrospective, observational study. Cases included pregnancies that resulted in spontaneous preterm labor and delivery (<37 weeks), whereas uncomplicated pregnancies that delivered fetuses at term (≥37-42 weeks of gestation) were selected as controls. Placental histological diagnoses were classified into three groups: lesions of maternal vascular malperfusion, lesions of fetal vascular malperfusion, and placental microvasculopathy, and the frequency of each type of lesion in cases and controls was compared. Moreover, we specifically searched for villous maturational abnormalities in cases and controls. Doppler velocimetry of the umbilical and uterine arteries were performed in a subset of patients., Results: There were 184 cases and 2471 controls, of which 95 and 1178 had Doppler studies, respectively. The frequency of lesions of maternal vascular malperfusion was greater in the placentas of patients with preterm labor than in the control group [14.1% (26/184) vs. 8.8% (217/2471) (p=0.023)]. Disorders of villous maturation were more frequent in the group with preterm labor than in the control group: 41.1% (39/95) [delayed villous maturation in 31.6% (30/95) vs. 2.5% (13/519) in controls and accelerated villous maturation in 9.5% (9/95) vs. none in controls]., Conclusions: Maturational defects of placental villi were associated with approximately 41% of cases of unexplained spontaneous preterm labor and delivery without acute inflammatory lesions of the placenta and with delivery of appropriate-for-gestational-age fetuses., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Preeclampsia, one of the most enigmatic complications of pregnancy, is considered a pregnancy-specific disorder caused by the placenta and cured only by delivery. This article traces the condition from its origins-once thought to be a disease of the central nervous system, recognized by the occurrence of seizures (ie, eclampsia)-to the present time when preeclampsia is conceptualized primarily as a vascular disorder. We review the epidemiologic data that led to the recommendation to use diastolic hypertension and proteinuria as diagnostic criteria, as their combined presence was associated with an increased risk of fetal death and the birth of small-for-gestational-age neonates. However, preeclampsia is a multisystemic disorder with protean manifestations, and the condition can be present even in the absence of hypertension and proteinuria. Toxins gaining access to the maternal circulation have been proposed to mediate the clinical manifestations-hence, the term "toxemia of pregnancy," which was used for several decades. The search for putative toxins has challenged investigators for more than a century, and a growing body of evidence suggests that products of an ischemic or a stressed placenta are responsible for the vascular changes that characterize this syndrome. The discovery that the placenta can produce antiangiogenic factors, which regulate endothelial cell function and induce intravascular inflammation, has been a major step forward in the understanding of preeclampsia. We view the release of antiangiogenic factors by the placenta as an adaptive response to improve uterine perfusion by modulating endothelial function and maternal cardiovascular performance. However, this homeostatic response can become maladaptive and lead to damage of target organs during pregnancy or the postpartum period. Early-onset preeclampsia has many features in common with atherosclerosis, whereas late-onset preeclampsia seems to result from a mismatch of fetal demands and maternal supply, that is, a metabolic crisis. Preeclampsia, as it is understood today, is essentially vascular dysfunction unmasked or caused by pregnancy. A subset of patients diagnosed with preeclampsia are at greater risk of the subsequent development of hypertension, ischemic heart disease, heart failure, vascular dementia, and end-stage renal disease. However, these adverse events may be the result of a preexisting vascular pathologic process; it is not known if the occurrence of preeclampsia increases the baseline risk. Therefore, the understanding, prediction, prevention, and treatment of preeclampsia are healthcare priorities., (Copyright © 2021. Published by Elsevier Inc.)

Objective: Effective screening for pre-eclampsia resulting in delivery < 37 weeks' gestation (preterm PE) is provided by assessment of a combination of maternal factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF) at 11-13 or 19-24 weeks' gestation. This study explores the possibility of carrying out routine screening for preterm PE by maternal factors and MAP in all pregnancies and reserving measurements of UtA-PI and PlGF for a subgroup of the population, selected on the basis of the risk derived from screening by maternal factors and MAP alone., Methods: Study data were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit at 11-13 and/or 19-24 weeks' gestation. Bayes' theorem was used to derive the a-priori risk for preterm PE from maternal factors and MAP. The posterior risk was obtained by the addition of UtA-PI and PlGF. We estimated the detection rate (DR) of preterm PE, at an overall false-positive rate (FPR) of 10%, from a policy in which first-stage screening by a combination of maternal factors and MAP defines screen-positive, screen-negative and intermediate-risk groups, with the latter undergoing second-stage screening by UtA-PI and PlGF., Results: At 11-13 weeks' gestation, the model-based DR of preterm PE, at a 10% FPR, when screening the whole population by maternal factors, MAP, UtA-PI and PlGF was 74%. A similar DR was achieved by two-stage screening, with screening by maternal factors and MAP in the first stage and reserving measurement of UtA-PI and PlGF for the second stage and for only 50% of the population. If second-stage screening was offered to 30% of the population, there would be only a small reduction in DR from 74% to 71%. At 19-24 weeks, the model-based DR of preterm PE, at a 10% FPR, when screening the whole population by maternal factors, MAP, UtA-PI and PlGF was 84%. A similar DR was achieved by two-stage screening with measurements of UtA-PI and PlGF in only 70% of the population; if second-stage screening was offered to 40% of the population, the DR would be reduced from 84% to 81%., Conclusions: High DR of preterm PE can be achieved by two-stage screening in the first and second trimesters with maternal factors and MAP in the whole population and measurements of UtA-PI and PlGF in only some of the pregnancies. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Background: Preeclampsia (PE) affects 2-3% of all pregnancies and is a major cause of maternal and perinatal morbidity and mortality. The traditional approach to screening for PE is to use a risk-scoring system based on maternal demographic characteristics and medical history (maternal factors), but the performance of such an approach is very poor., Objective: To develop a model for PE based on a combination of maternal factors with second-trimester biomarkers., Study Design: The data for this study were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit at 19-24 weeks' gestation in 3 maternity hospitals in England between January 2006 and July 2014. We had data from maternal factors, uterine artery pulsatility index (UTPI), mean arterial pressure (MAP), serum placental growth factor (PLGF), and serum soluble fms-like tyrosine kinase-1 (SFLT) from 123,406, 67,605, 31,120, 10,828, and 8079 pregnancies, respectively. Bayes' theorem was used to combine the a priori risk from maternal factors with various combinations of biomarker multiple of the median (MoM) values. The modeled performance of screening for PE requiring delivery at <32, <37, and ≥37 weeks' gestation was estimated. The modeled performance was compared to the empirical one, which was derived from 5-fold cross validation. We also examined the performance of screening based on risk factors from the medical history, as recommended by the American Congress of Obstetricians and Gynecologists (ACOG)., Results: In pregnancies that developed PE, the values of MAP, UTPI, and SFLT were increased and PLGF was decreased. For all biomarkers the deviation from normal was greater for early than for late PE, and therefore the performance of screening was inversely related to the gestational age at which delivery became necessary for maternal and/or fetal indications. Screening by maternal factors predicted 52%, 47%, and 37% of PE at <32, <37, and ≥37 weeks' gestation, respectively, at a false-positive rate of 10%. The respective values for combined screening with maternal factors and MAP, UTPI, and PLGF were 99%, 85%, and 46%; the performance was not improved by the addition of SFLT. In our population of 123,406 pregnancies, the DR of PE at <32, <37, and ≥37 weeks with the ACOG recommendations was 91%, 90%, and 91%, respectively, but at a screen positive rate of 67%., Conclusion: The performance of screening for PE by maternal factors and biomarkers in the middle trimester is superior to taking a medical history., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To investigate the potential value of uterine artery (UtA) Doppler at 30-34 weeks' gestation in the prediction of adverse perinatal outcome., Methods: This was a screening study in 30 780 singleton pregnancies at 30-34 weeks. UtA pulsatility index (UtA-PI) was measured and the values were converted to multiples of the median (MoM) after adjustment for variables relating to maternal characteristics and medical history that affect the measurements. Multivariable logistic regression analysis was used to determine if measuring UtA-PI improved the prediction of adverse perinatal outcome provided by screening with maternal characteristics, medical history and obstetric factors. The detection rate (DR) and false-positive rate (FPR) of screening by UtA-PI were estimated for stillbirth, Cesarean section for fetal distress, umbilical arterial cord blood pH ≤ 7.0 or umbilical venous cord blood pH ≤ 7.1 and 5-min Apgar score < 7., Results: The incidence of adverse perinatal outcome was higher in small-for-gestational-age (SGA) fetuses than in non-SGA fetuses, but the majority of cases with each adverse outcome were in the non-SGA group, including about 70% of stillbirths and more than 80% with Cesarean section for fetal distress, low cord blood pH and low Apgar score. The performance of UtA-PI > 95(th) percentile in screening for each adverse outcome was poor with DR of 6-16% and a FPR of 5-6%. The DR of adverse outcome when screening by high UtA-PI was greater in pregnancies complicated by SGA than in non-SGA pregnancies; 24% vs 13% for stillbirth, 15% vs 5% for Cesarean section for fetal distress, 30% vs 9% for low cord blood pH and 20% vs 3% for low 5-min Apgar score, respectively., Conclusion: High UtA-PI at 30-34 weeks' gestation may be useful in the prediction of adverse perinatal outcome in pregnancies with a SGA fetus, however, in the absence of SGA, UtA-PI is a poor predictor of adverse outcome. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To investigate the potential value of biophysical and biochemical markers at 35-37 weeks' gestation in the prediction of adverse perinatal outcome., Methods: This was a screening study in 3953 singleton pregnancies at 35-37 weeks' gestation. Estimated fetal weight (EFW), uterine artery pulsatility index (UtA-PI), umbilical artery (UA)-PI, fetal middle cerebral artery (MCA)-PI, mean arterial pressure (MAP), serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured. The detection rate (DR) and false-positive rate (FPR) of screening by each biomarker were estimated for pre-eclampsia (PE), delivery of small-for-gestational-age (SGA) neonates, Cesarean section for fetal distress before or during labor, umbilical arterial cord blood pH ≤ 7.0 or umbilical venous cord blood pH ≤ 7.1, 5-min Apgar score < 7 and admission to the neonatal unit (NNU)., Results: Multivariable regression analysis demonstrated that significant prediction of PE was provided by PlGF, sFlt-1 and MAP, with a DR of 73% at a 10% FPR. Prediction of SGA was provided by EFW, PlGF and UtA-PI, with a DR of 63% at a 10% FPR. Prediction of Cesarean section for fetal distress before labor was provided by EFW and UA-PI with DR of 100% at 10% FPR. Prediction of fetal distress in labor was provided by EFW and sFlt-1, with a DR of 15% at a 10% FPR. There were no significant differences between those with a normal outcome and those with low cord blood pH, low Apgar score or NNU admission for any of the biomarkers assessed., Conclusion: At 35-37 weeks' gestation biomarkers of impaired placentation and fetal hypoxemia provide good prediction of PE, SGA and fetal distress before labor, but poor or no prediction of adverse events in labor or after birth., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To investigate the value of combined screening by maternal characteristics and medical history, fetal biometry and biophysical and biochemical markers at 19-24 weeks' gestation, for prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE), and examine the potential value of such assessment in deciding whether the third-trimester scan should be at 32 and/or 36 weeks' gestation., Methods: This was a screening study in 7816 singleton pregnancies, including 389 (5.0%) that delivered SGA neonates with birth weight < 5(th) percentile (SGA < 5(th) ), in the absence of PE. Multivariable logistic regression analysis was used to determine if screening by a combination of maternal factors, fetal biometry, uterine artery pulsatility index (UtA-PI) and maternal serum concentrations of placental growth factor (PlGF) and α-fetoprotein (AFP) had significant contribution in predicting SGA neonates. A model was developed for selecting the gestational age for third-trimester assessment, at 32 and/or 36 weeks, based on the results of screening at 19-24 weeks., Results: Significant independent contributions to the prediction of SGA < 5(th) were provided by maternal factors, fetal biometry, UtA-PI and serum PlGF and AFP. The detection rate (DR) of such combined screening at 19-24 weeks was 100%, 78% and 42% for SGA < 5(th) delivering < 32, at 32-36 and ≥ 37 weeks' gestation, respectively, at a false-positive rate (FPR) of 10%. In a hypothetical model, it was estimated that if the desired objective of prenatal screening is to predict about 80% of the cases of SGA < 5(th) , it would be necessary to select 11% of the population at the 19-24-week assessment to be reassessed at 32 weeks and 44% to be reassessed at 36 weeks; 57% would not require a third-trimester scan., Conclusion: Prenatal prediction of a high proportion of SGA neonates necessitates the undertaking of screening in the third trimester of pregnancy, in addition to assessment in the second trimester, and the timing of such screening, at 32 and/or 36 weeks, should be contingent on the results of the assessment at 19-24 weeks., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To investigate the potential value of uterine artery (UtA) pulsatility index (PI) and mean arterial pressure (MAP) at 19-24 weeks' gestation, in combination with maternal characteristics and medical history and fetal biometry in the prediction of delivery of small-for-gestational-age (SGA) neonates in the absence of pre-eclampsia (PE) and to examine the potential value of such assessment in deciding whether the third-trimester scan should be performed at 32 and/or 36 weeks' gestation., Methods: This was a screening study in 63 975 singleton pregnancies, including 3702 (5.8%) that delivered SGA neonates with birth weight < 5(th) percentile (SGA < 5(th) ) in the absence of PE. Multivariable logistic regression analysis was used to determine if screening by a combination of maternal factors, fetal head circumference (HC), abdominal circumference (AC), femur length (FL), UtA-PI and MAP had significant contribution in predicting SGA neonates. A model was developed to select gestational age for the third-trimester assessment, at 32 and/or 36 weeks, based on the results of screening at 19-24 weeks., Results: The detection rates (DRs) of combined screening by maternal factors, fetal biometry and UtA-PI at 19-24 weeks were 90%, 68% and 44% for SGA < 5(th) delivering < 32, 32-36 and ≥ 37 weeks' gestation, respectively, at a false-positive rate (FPR) of 10%. The performance of screening was not improved by the addition of MAP. The DR of SGA < 5(th) delivering at 32-36 weeks improved from 68% to 90% with screening at 32 rather than at 19-24 weeks. Similarly, the DR of SGA < 5(th) delivering ≥ 37 weeks improved from 44% with screening at 19-24 weeks to 59% and 76% when screening at 32 and 36 weeks, respectively. In a hypothetical model, it was estimated that if the desired objective of prenatal screening is to predict about 80% of the cases of SGA < 5(th) , it would be necessary to select 17% of the population at the 19-24-week assessment to be reassessed at 32 weeks and 38% to be reassessed at 36 weeks; 62% would not require a third-trimester scan., Conclusion: Prenatal prediction of a high proportion of SGA neonates necessitates the undertaking of screening in the third trimester of pregnancy in addition to assessment in the second trimester, and the timing of such screening, at 32 and/or 36 weeks, should be contingent on the results of the assessment at 19-24 weeks., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To investigate the value of maternal serum concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), pregnancy-associated plasma protein-A (PAPP-A), free β-human chorionic gonadotropin (β-hCG) and α-fetoprotein (AFP) at 19-24 weeks' gestation, in combination with maternal factors and fetal biometry, in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE) and examine the potential value of such assessment in deciding whether the third-trimester scan should be performed at 32 and/or 36 weeks' gestation., Methods: This was a screening study in 9715 singleton pregnancies, including 481 (5.0%) that delivered SGA neonates with birth weight < 5(th) percentile (SGA < 5(th) ), in the absence of PE. Multivariable logistic regression analysis was used to determine if screening by a combination of maternal factors, Z-scores of fetal head circumference, abdominal circumference and femur length, and log10 multiples of the median (MoM) values of PlGF, sFlt-1, PAPP-A, free β-hCG or AFP had a significant contribution to the prediction of SGA neonates. A model was developed in selecting the gestational age for third-trimester assessment, at 32 and/or 36 weeks, based on the results of screening at 19-24 weeks., Results: Compared to the normal group, the mean log10 MoM value of PlGF was lower, AFP was higher and sFlt-1, PAPP-A and free β-hCG were not significantly different in the SGA < 5(th) group that delivered < 37 weeks. The detection rate (DR) of combined screening by maternal factors, fetal biometry and serum PlGF and AFP at 19-24 weeks was 100%, 76% and 38% for SGA < 5(th) delivering < 32, 32-36 and ≥ 37 weeks' gestation, respectively, at a false-positive rate (FPR) of 10%. In a hypothetical model, it was estimated that, if the desired objective of prenatal screening is to predict about 80% of the cases of SGA < 5(th) , it would be necessary to select 11% of the population at the 19-24-week assessment to be reassessed at 32 weeks and 46% to be reassessed at 36 weeks; 54% would not require a third-trimester scan., Conclusion: Prenatal prediction of a high proportion of SGA neonates necessitates the undertaking of screening in the third trimester of pregnancy, in addition to assessment in the second trimester, and the timing of such screening, at 32 and/or 36 weeks, should be contingent on the results of the assessment at 19-24 weeks., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To investigate the potential value of serum placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), pregnancy-associated plasma protein-A (PAPP-A), free β-human chorionic gonadotropin (β-hCG) and α-fetoprotein (AFP) at 30-34 weeks' gestation in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE)., Methods: This was a screening study in singleton pregnancies at 30-34 weeks' gestation, including 490 that delivered SGA neonates and 9360 cases that were unaffected by SGA, PE or gestational hypertension (normal outcome). Multivariable logistic regression analysis was used to determine if screening by serum PlGF, sFlt-1, PAPP-A, free β-hCG and AFP, individually or in combination, improved the prediction of SGA neonates provided by screening with maternal characteristics and medical history (maternal factors), and estimated fetal weight (EFW) from fetal head circumference, abdominal circumference and femur length., Results: Compared to the normal group, the mean log10 multiples of the median (MoM) values of PlGF and AFP were significantly lower and the mean log10 MoM values of sFlt-1 and free β-hCG were significantly higher in the SGA group with a birth weight < 5(th) percentile (SGA < 5(th)) delivering < 5 weeks following assessment. The best model for prediction of SGA was provided by a combination of maternal factors, EFW and serum PlGF. Such combined screening, predicted, at a 10% false-positive rate, 85%, 93% and 92% of SGA neonates delivering < 5 weeks following assessment with birth weight < 10(th), < 5(th) and < 3(rd) percentiles, respectively; the respective detection rates of combined screening for SGA neonates delivering ≥ 5 weeks following assessment were 57%, 64% and 71%., Conclusion: Combined screening by maternal factors, EFW and serum PlGF at 30-34 weeks' gestation can identify a high proportion of pregnancies that subsequently deliver SGA neonates., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To investigate the value of fetal biometry at 19-24 weeks' gestation in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE), and examine the potential value of such assessment in deciding whether the third-trimester scan should be at 32 and/or 36 weeks' gestation., Methods: This was a screening study in 88,187 singleton pregnancies, including 5003 (5.7%) that delivered SGA neonates with birth weight < 5(th) percentile (SGA < 5(th)). Multivariable logistic regression analysis was used to determine if screening by a combination of maternal characteristics and medical history and Z-scores of fetal head circumference (HC), abdominal circumference (AC) and femur length (FL) had significant contribution in predicting SGA neonates. A model was developed for selecting the gestational age for third-trimester assessment, at 32 and/or 36 weeks, based on the results of screening at 19-24 weeks., Results: Combined screening by maternal factors and fetal biometry at 19-24 weeks, predicted 76%, 58% and 44% of SGA < 5(th) delivering < 32, 32-36 and ≥ 37 weeks' gestation, respectively, at a false-positive rate (FPR) of 10%. The detection rate (DR) of SGA < 5(th) delivering at 32-36 weeks improved from 58% to 82% with screening at 32 weeks rather than at 19-24 weeks. Similarly, the DR of SGA < 5(th) delivering ≥ 37 weeks improved from 44% with screening at 19-24 weeks to 61% and 76% with screening at 32 and 36 weeks, respectively. In a hypothetical model, it was estimated that if the desired objective of prenatal screening is to predict about 80% of the cases of SGA < 5(th), it would be necessary to select 28% of the population at the 19-24-week assessment to be reassessed at 32 weeks and 41% to be reassessed at 36 weeks; in 59% of pregnancies there would be no need for a third-trimester scan., Conclusion: Prenatal prediction of a high proportion of SGA neonates necessitates the undertaking of screening in the third trimester of pregnancy, in addition to assessment in the second trimester, and the timing of such screening, either at 32 and/or 36 weeks, should be contingent on the results of the assessment at 19-24 weeks., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To investigate the potential value of cerebroplacental ratio (CPR) at 36 weeks' gestation in the prediction of adverse perinatal outcome., Methods: This was a screening study in 6178 singleton pregnancies at 35-37 weeks' gestation. Umbilical artery (UA) and fetal middle cerebral artery (MCA) pulsatility index (PI) were measured and the values were converted to multiples of the median (MoM) after adjustment from variables in maternal characteristics and medical history that affect the measurements. CPR was calculated by dividing MCA-PI MoM by UA-PI MoM. Multivariable logistic regression analysis was used to determine if measuring CPR improved the prediction of adverse perinatal outcome provided by maternal characteristics, medical history and obstetric factors. The detection rate (DR) and false-positive rate (FPR) of screening by CPR were estimated for stillbirth, Cesarean section for fetal distress, umbilical arterial cord blood pH ≤ 7.0, umbilical venous cord blood pH ≤ 7.1, 5-min Apgar score < 7 and admission to the neonatal unit (NNU) and neonatal intensive care unit (NICU)., Results: There was a linear association between CPR and both birth-weight Z-score and arterial or venous umbilical cord blood pH, but the steepness of the regression lines was inversely related to the interval from assessment to delivery. The performance of low CPR < 5(th) percentile in screening for each adverse outcome was poor, with DRs of 6-15% and a FPR of about 6%. In the small subgroup of the population delivering within 2 weeks of assessment, the DRs improved to 14-50%, but with a simultaneous increase in FPR, to about 10%., Conclusion: The performance of CPR in routine screening for adverse perinatal outcome at 36 weeks' gestation is poor., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)

Objective: To investigate the potential value of cerebroplacental ratio (CPR) at 30-34 weeks' gestation in the prediction of adverse perinatal outcome., Methods: This was a screening study in 30 780 singleton pregnancies at 30-34 weeks' gestation. Umbilical artery (UA) and fetal middle cerebral artery (MCA) pulsatility index (PI) were measured and the values were converted to multiples of the median (MoM) after adjustment from variables in maternal characteristics and medical history that affect the measurements. CPR was calculated by dividing MCA-PI MoM by UA-PI MoM. Multivariable logistic regression analysis was used to determine if measuring CPR improved the prediction of adverse perinatal outcome provided by screening with maternal characteristics, medical history and obstetric factors. The detection rate (DR) and false-positive rate (FPR) of screening by CPR were estimated for stillbirth, Cesarean section for fetal distress, umbilical arterial cord blood pH ≤ 7.0, umbilical venous cord blood pH ≤ 7.1, 5-min Apgar score < 7 and admission to the neonatal unit (NNU) and neonatal intensive care unit (NICU)., Results: There was a significant association between CPR and birth-weight Z-score. In addition to maternal characteristics, medical history and obstetric factors, measuring CPR provided a significant contribution to the prediction of arterial cord blood pH ≤ 7.0, venous cord blood pH ≤ 7.1 and admission to NNU. The performance of CPR in screening for each adverse outcome was poor, with DR of 5-11% and a FPR of about 5%. In the small subgroup of the population delivering within 2 weeks following assessment, the DR improved to 20-50%, but with a simultaneous increase in FPR to 10-23%., Conclusion: The performance of CPR in routine screening for adverse perinatal outcome at 30-34 weeks' gestation is poor., (Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.)