Background. The complement system, a major component of innate immunity, has recently been implicated in the mechanisms of fetal loss and placental inflammation in the anti-phospholipid antibody syndrome. Inhibition of complement has been proposed as an absolute requirement for normal pregnancy. Yet, pregnancy is characterized by a generalized activation of the innate immune system. This study was conducted to determine whether or not normal pregnancy is associated with complement activation in the maternal circulation. Methods. Anaphylatoxins (C3a, C4a and C5a) were determined in the plasma of normal pregnant (20-42 wks; n = 134) and non-pregnant women (n = 40). These complement split products (C3a, C4a and C5a) were measured using specific immunoassays. Non-parametric statistics were used for analysis. Results. 1) The median plasma concentrations of C3a, C4a and C5a were significantly higher in normal pregnant women than in non-pregnant women (all p 5 0.001); 2) the concentration of C3a, C4a and C5a did not change with gestational age (p 4 0.05); and 3) the median plasma concentration of C3a had a positive correlation with the plasma C4a and C5a concentrations (r = 0.36, p 5 0.001 and r = 0.35, p 5 0.001, respectively). Conclusion. 1) Normal human pregnancy is associated with evidence of complement activation, as determined by higher concentrations of the anaphylatoxins C3a, C4a and C5a in the maternal circulation; and 2) we propose that physiologic activation of the complement system during pregnancy is a compensatory mechanism aimed at protecting the host against infection.

Objective To determine if maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and -2 could identify patients at risk for developing preeclampsia (PE) requiring preterm delivery. Study design Patients presenting with the diagnosis ‘rule out PE’ to the obstetrical triage area of our hospital at <37 weeks of gestation (n=87) were included in this study. Delivery outcomes were used to classify patients into 4 groups: I) patients without PE or those with gestational hypertension (GHTN) or chronic hypertension (CHTN) who subsequently developed PE at term (n=19); II): mild PE who delivered at term (n=15); III): mild disease (mild PE, GHTN, CHTN) who subsequently developed severe PE requiring preterm delivery (n=26); and IV): diagnosis of severe PE (n=27). Plasma concentrations of PlGF, sEng, sVEGFR-1 and -2 were determined at the time of presentation by ELISA. Reference ranges for analytes were constructed by quantile regression in our laboratory (n=180; 1,046 samples). Comparisons among groups were performed using multiples of the median (MoM) and parametric statistics after log transformation. Receiver operating characteristic curves, logistic regression and survival analysis were employed for analysis. Results The mean MoM plasma concentration of PlGF/sVEGFR-1, PlGF/sEng, PlGF, sVEGFR-1 and -2, and sEng in Group III was significantly different from Group II (all p<0.05). A plasma concentration of PlGF/sVEGFR-1 ≤ 0.05 MoM or PlGF/sEng ≤ 0.07 MoM had the highest likelihood ratio of a positive test (8.3, 95% CI 2.8–25 and 8.6, 95% CI 2.9–25, respectively), while that of PlGF ≤0.396 MoM had the lowest likelihood ratio of a negative test (0.08, 95% CI 0.03–0.25). The association between low plasma concentrations of PlGF/sVEGFR-1 (≤0.05 MoM) as well as that of PlGF/sEng (≤ 0.07 MoM) and the development of severe PE remained significant after adjusting for gestational age at presentation, average systolic and diastolic blood pressure, and a history of chronic hypertension [adjusted odds ratio (OR) = 27 (95% CI 6.4–109) and adjusted OR 30 (95% CI 6.9–126), respectively]. Among patients who presented <34 weeks gestation (n=59), a plasma concentration of PlGF/sVEGFR-1 <0.033 MoM identified patients who delivered within 2 weeks because of PE with a sensitivity of 93% (25/27) and a specificity of 78% (25/32). This cut-off was associated with a shorter interval-to-delivery due to PE [hazard ratio = 6 (95% CI 2.5–14.6)]. Conclusions Plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in the obstetrical triage area. These observations support the value of these biomarkers in the clinical setting for the identification of the patient at risk for disease progression requiring preterm delivery.

Objective An imbalance between maternal angiogenic/anti-angiogenic factors concentrations has been observed in preeclampsia (PE) and other obstetrical syndromes. However, the frequency of pathologic findings in the placenta and the changes in maternal plasma angiogenic/anti-angiogenic factor concentrations differ between late-and early-onset PE. The aim of this study was to determine if the maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), and soluble vascular endothelial growth factor receptor-1 and 2 (sVEGFR-1 and sVEGFR-2) are different in late-onset PE with and without placental pathologic findings consistent with maternal underperfusion. Study design A cross-sectional study was conducted including 64 uncomplicated women and 66 women with late-onset PE (>34 weeks) who had blood samples and placenta available for pathologic examination. Patients with late-onset PE were divided into those with and without placental histologic findings consistent with maternal underperfusion as proposed by the Society for Pediatric Pathology. Maternal plasma concentrations of PlGF, sEng, sVEGFR-1 and sVEGFR-2 were determined by ELISA. Non-parametric statistics were used for analysis. Results 1) the prevalence of placental histological findings consistent with maternal underperfusion among women with late-onset PE was higher than that of those with an uncomplicated pregnancy (47% (31/66) vs. 7.8% (5/64) respectively; p<0.01); 2) patients with late-onset PE and histological findings consistent with maternal underperfusion had a significantly lower median plasma concentration of PlGF, plasma PlGF/sVEGFR-1 ratio and plasma PlGF/sEng ratio than those with late-onset PE without placental underperfusion lesions (each p<0.05); 3) the most common pathological findings in the placenta of patient with PE were lesions consistent with villous changes (77%, 24/31); and 4) isolated vascular lesions in the placenta were found only in 2 cases (6.5%), and the rest had a combination of villous and vascular lesions. Conclusions Nearly half of the patients with late-onset PE have placental lesions consistent with maternal underperfusion. These lesions are associated with an imbalance in the maternal concentration of angiogenic/anti-angiogenic factors. We propose that there is a link between maternal underperfusion and an anti-angiogenic state characterized by the changes in the concentrations of angiogenic and anti-angiogenic factors in women with late onset PE.