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Objective: Preeclampsia (PE) has been classified into early- and late-onset disease. These two phenotypic variants of PE have been proposed to have a different pathophysiology. However, the gestational age cut-off to define 'early' vs. 'late' PE has varied among studies. The objective of this investigation was to determine the prevalence of lesions consistent with maternal underperfusion of the placenta in patients with PE as a function of gestational age. Study design: A nested case-control study of 8307 singleton pregnant women who deliver after 20 weeks of gestation was constructed based on a cohort. Cases were defined as those with PE (n=910); controls were pregnant women who did not have a hypertensive disorder in pregnancy (n=7397). The frequency of maternal underperfusion of the placenta (according to the criteria of the Society for Pediatric Pathology) was compared between the two groups. Logistic regression was used for analysis. Estimated relative risks (RRs) were calculated from odds ratios. Results: 1) The prevalence of lesions consistent with maternal underperfusion was higher in patients with PE than in the control group [43.3% vs. 15.9%, unadjusted odds ratio 4.0 (95% CI 3.5-4.7); P<0.001]; 2) the estimated RR of maternal underperfusion lesions in PE was higher than in the control group [RR=2.8 (95% CI 2.5-3.0)]; 3) the lower the gestational age at delivery, the higher the RR for these lesions; 4) early-onset PE, regardless of the gestational age used to define it (<32, 33, 34, 35 or 37 weeks) had a significantly higher frequency of placental lesions consistent with maternal underperfusion than late-onset PE (P<0.001 for all). Conclusions: 1) The earlier the gestational age of preeclampsia at delivery, the higher the frequency of placental lesions consistent with maternal underperfusion; 2) our data suggest that demonstrable placental involvement as determined by pathologic examination differs in early- and late-onset preeclampsia; and 3) this phenomenon appears to be a continuum, and we could not identify a clear and unambiguous gestational age at which lesions consistent with underperfusion would not be present. [ABSTRACT FROM AUTHOR]

Objective. Women with a fetal death at the time of diagnosis have higher maternal plasma concentrations of the anti-angiogenic factor, soluble vascular endothelial growth factor receptor (sVEGFR)-1, than women with a normal pregnancy. An important question is whether these changes are the cause or consequence of fetal death. To address this issue, we conducted a longitudinal study and measured the maternal plasma concentrations of selective angiogenic and anti-angiogenic factors before the diagnosis of a fetal death. The anti-angiogenic factors studied were sVEGFR-1 and soluble endoglin (sEng), and the angiogenic factor, placental growth factor (PlGF). Methods. This retrospective longitudinal nested case-control study included 143 singleton pregnancies in the following groups: (1) patients with uncomplicated pregnancies who delivered a term infant with an appropriate weight for gestational age ( n = 124); and (2) patients who had a fetal death ( n = 19). Blood samples were collected at each prenatal visit, scheduled at 4-week intervals from the first trimester until delivery. Plasma concentrations of sVEGFR-1, sEng, and PlGF were determined by specific and sensitive ELISA. A linear mixed-effects model was used for analysis. Results. (1) The average profiles of analyte concentrations as a function of gestational age for sVEGFR-1, sEng and PlGF were different between women destined to have a fetal death and those with a normal pregnancy after adjusting for covariates ( p < 0.05); (2) Plasma sVEGFR-1 concentrations in patients destined to have a fetal death were significantly lower between 7 and 11 weeks of gestation and became significantly higher than those of women with a normal pregnancy between 20 and 37 weeks of gestation ( p < 0.05); (3) Similarly, plasma sEng concentrations of women destined to have a fetal death were lower at 7 weeks of gestation ( p = 0.04) and became higher than those of controls between 20 and 40 weeks of gestation ( p < 0.05); (4) In contrast, plasma PlGF concentrations were higher among patients destined to develop a fetal death between 7 and 14 weeks of gestation and became significantly lower than those in the control group between 22 and 39 weeks of gestation ( p < 0.05); (5) The ratio of PlGF/(sVEGFR-1 × sEng) was significantly higher in women destined to have a fetal death between 7 and 13 weeks of gestation (94-781%) and significantly lower (44-75%) than those in normal pregnant women between 20 and 40 weeks of gestation ( p < 0.05); (6) Similar results were obtained when patients with a fetal death were stratified into those who were diagnosed before or after 37 weeks of gestation. Conclusions. Fetal death is characterised by higher maternal plasma concentrations of PlGF during the first trimester compared to normal pregnancy. This profile changes into an anti-angiogenic one during the second and third trimesters. [ABSTRACT FROM AUTHOR]

Objective. Vaginal bleeding, placental abruption, and defective placentation are frequently observed in patients with preterm prelabor rupture of membranes (PROM). Recently, a role of vascular endothelial growth factor (VEGF) and its receptor, VEGF receptor (VEGFR)- 1 has been implicated in the mechanisms of membrane rupture. The purpose of this study was to determine whether the soluble form of VEGFR-1 and -2 concentrations in amniotic fluid (AF) change with preterm PROM, intra-amniotic infection/inflammation (IAI), or parturition. Study design. This cross-sectional study included 544 patients in the following groups: (1) midtrimester (MT) ( n = 48); (2) preterm labor (PTL) leading to term delivery ( n = 143); (3) PTL resulting in preterm delivery with ( n = 72) and without IAI ( n = 100); (4) preterm PROM with ( n = 46) and without IAI ( n = 42); (5) term in labor ( n = 48); and (6) term not in labor ( n = 45). The concentrations of sVEGFR-1 and sVEGFR-2 were determined by ELISA. Non-parametric statistics and logistic regression analysis were applied. Results. (1) Preterm PROM (with and without IAI) had a lower median AF concentration of sVEGFR-1 than patients with PTL who delivered at term ( p < 0.001 for each comparison); (2) A decrease in AFsVEGFR-1 concentrations per each quartile was associated with PROM after adjusting for confounders (OR 1.8; 95%CI 1.4–2.3); (3) IAI, regardless of the membrane status, was not associated with a change in the median AF concentrations of sVEGFR-1 and sVEGFR-2 ( p > 0.05 for each comparison); and (4) Spontaneous term and PTL did not change the median sVEGFR-1 and sVEGFR-2 concentrations ( p > 0.05 for each comparison). Conclusion. (1) This is the first evidence that preterm PROM is associated with a lower AF concentration of sVEGFR-1 than patients with PTL intact membranes. These findings cannot be attributed to gestational age, labor, or IAI; and (2) AF concentrations of sVEGFR-2 did not change with preterm PROM, IAI, or labor at term and preterm. [ABSTRACT FROM AUTHOR]

Citation Vaisbuch E, Romero R, Erez O, Mazaki-Tovi S, Kusanovic JP, Soto E, Dong Z, Chaiworapongsa T, Kim SK, Ogge G, Pacora P, Yeo L, Hassan SS. Activation of the alternative pathway of complement is a feature of pre-term parturition but not of spontaneous labor at term. Am J Reprod Immunol 2010; 63: 318–330 Problem Plasma concentrations of fragment Bb (FBb) are a marker for activation of the alternative pathway of the complement system. High concentrations of FBb in maternal blood, as early as the first trimester, are associated with subsequent spontaneous pre-term delivery <34 weeks of gestation. The aim of this study was to determine whether spontaneous pre-term labor (PTL) with intact membranes, intra-amniotic infection/inflammation (IAI) or labor at term are associated with alterations in circulating maternal FBb concentrations. Method of study This cross-sectional study included women in the following groups: (i) non-pregnant ( n = 40); (ii) normal pregnancy (gestational age range 20–36, 6/7 weeks, n = 63); (iii) women at term not in labor ( n = 70); (iv) women at term in spontaneous labor ( n = 59); (v) patients with an episode of PTL who delivered at term ( n = 62); (vi) PTL without IAI who delivered pre-term ( n = 30); and (vii) PTL with IAI who delivered pre-term ( n = 67). Maternal plasma FBb concentrations were determined by ELISA. Results (i) Among patients with PTL, those who had a pre-term delivery either with IAI (1.21 μg/mL, IQR 0.77–2.16) or without IAI (1.13 μg/mL, IQR 0.92–2.08) had a higher median maternal plasma FBb concentration than those who delivered at term (0.86 μg/mL, IQR 0.64–1.57; P = 0.007 and P = 0.026, respectively); (ii) there was no difference in the median plasma FBb concentration between patients with and without IAI who delivered pre-term ( P = 0.9); (iii) in contrast, spontaneous labor at term was not associated with a significant change in the maternal plasma FBb concentration ( P = 0.8); (iv) maternal plasma concentration of FBb did not differ significantly between normal pregnant women and the non-pregnant controls ( P = 0.8) and were not correlated with advancing gestational age ( r = −0.28, P = 0.8). Conclusion (i) Pre-term parturition is associated with activation of the alternative complement pathway in maternal circulation; (ii) such activation is not detectable in spontaneous labor at term; (iii) IAI does not explain the activation of the alternative pathway of complement in PTL. Collectively, these observations suggest that pre-term and term labors have fundamental differences in the regulation of innate immunity. [ABSTRACT FROM AUTHOR]