Unexplained fetal death is associated with increased concentrations of anti-angiogenic factors in amniotic fluid

Objective.?Angiogenesis is critical for successful pregnancy. An anti-angiogenic state has been implicated in preeclampsia, fetal growth restriction and fetal death. Increased maternal plasma concentrations of the anti-angiogenic factor, soluble vascular endothelial growth factor receptor (sVEGFR)-1, have been reported in women with preeclampsia and in those with fetal death. Recent observations indicate that an excess of sVEGFR-1 and soluble endoglin (sEng) is also present in the amniotic fluid of patients with preeclampsia. The aim of this study was to determine whether fetal death is associated with changes in amniotic fluid concentrations of sVEGFR-1 and sEng, two powerful anti-angiogenic factors.

Study design.?This cross-sectional study included patients with fetal death (n?=?35) and controls (n?=?129). Fetal death was subdivided according to clinical circumstances into: (1) unexplained (n?=?25); (2) preeclampsia and/or placental abruption (n?=?5); and (3) chromosomal/congenital anomalies (n?=?5). The control group consisted of patients with preterm labor (PTL) who delivered at term (n?=?92) and women at term not in labor (n?=?37). AF concentrations of sVEGFR-1 and sEng were determined by ELISA. Non-parametric statistics and logistic regression analysis were applied.

Results.?(1) Patients with a fetal death had higher median amniotic fluid concentrations of sVEGFR-1 and sEng than women in the control group (p?<?0.001 for each); (2) these results remained significant among different subgroups of stillbirth (p?<?0.05 for each); and (3) amniotic fluid concentrations of sVEGFR-1 and those of sEng above the third quartile were associated with a significant risk of unexplained preterm fetal death (adjusted OR?=?10.8; 95%CI 1.3–89.2 and adjusted OR 87; 95% CI 2.3–3323, respectively).

Conclusion.?Patients with an unexplained fetal death at diagnosis are characterized by an increase in the amniotic fluid concentrations of sVEGFR-1 and sEng. These observations indicate that an excess of anti-angiogenic factors in the amniotic cavity is associated with unexplained fetal death especially in preterm gestations.     

Preeclampsia is associated with low concentrations of protein Z

Objective. Protein Z, a vitamin K-dependent plasma protein, has an important role in the regulation of the coagulation cascade. Protein Z deficiency has been associated with unexplained pregnancy loss and adverse pregnancy outcome in patients with thrombophilia. This study was conducted to determine if preeclampsia (PE), small for gestational age (SGA), and fetal demise are associated with changes in maternal plasma concentrations of protein Z.

Study design. This cross-sectional study included normal pregnant women (N = 71), patients with PE (N = 130), patients who delivered an SGA neonate (N = 58), and patients with fetal demise (N = 58). Maternal plasma protein Z concentrations were measured by a sensitive and specific immunoassay. Protein Z deficiency was defined as maternal plasma concentrations ≤5^th percentile of the normal pregnancy group (≤1.59 µg/mL). Non-parametric statistics were used for analysis.

Results. (1) Patients with PE had a lower median plasma concentration of protein Z than normal pregnant women (PE: median 1.6 µg/mL, range 0.2–3.3 µg/mL vs. normal pregnancy: median 2.4 µg/mL, range 1.1–3.4 µg/mL; p < 0.0001); (2) patients with an SGA neonate (median 2.3 µg/mL, range 0.2–3.8 µg/mL) and fetal demise (median 2.6 µg/mL, range 0.2–4.3 g/mL) did not have significantly different median protein Z concentrations from normal pregnant women (p > 0.05); and (3) women in the PE and fetal demise groups had significantly higher rates of protein Z deficiency than those with normal pregnancy outcome.

Conclusions. (1) PE, but not SGA or fetal demise, is associated with a significantly lower maternal median plasma concentration of protein Z than normal pregnancy, and (2) a high rate of protein Z deficiency is observed in patients with PE and fetal demise.     

孕中期血清PLGF、sFlt-1、sEng、sCD40L与子痫前期及胎儿不良结局的关系研究#br#

目的探讨孕中期血清胎盘生长因子(PLGF)、可溶性血管内皮生长因子受体1(sFlt-1)、可溶性内皮因子(s Eng)、可溶性CD40配体(sCD40L)与子痫前期及胎儿不良结局的关系。方法选取河北省唐山市妇幼保健院收治的子痫前期患者、健康孕妇各192例作为研究对象,采集两组孕妇孕20~24周的血液标本,测定血清PLGF、sFlt-1、sEng、sCD40L水平,对比检测结果。跟踪子痫前期孕妇的围产结局,对比不同围产结局孕妇的各项血清指标检测结果。结果与对照组相比,观察组孕妇的血清PLGF水平更低,sFlt-1、sEng、sCD40L水平更高(P<0.05)。轻度子痫前期、重度子痫前期与PLGF水平均呈负相关,与sFlt-1、sEng、sCD40L、Hcy水平均呈正相关(P<0.05)。相比轻度子痫前期,重度子痫前期与各血清学指标的相关性更强。胎儿妊娠结局良好162例(84.38%),结局不良30例(15.63%)。结局不良组的PLGF水平显著低于结局良好组,sFlt-1、sEng、sCD40L、Hcy水平显著高于结局良好组(P<0.05)。子痫前期患者胎儿不良结局与PLGF水平呈负相关,与sFlt-1、sEng、sCD40L、Hcy水平均呈正相关(P<0.05)。结论子痫前期的发生、进展及围产结局均与血清PLGF、s Flt-1、sEng、sCD40Ly水平密切相关,监测孕中期血清PLGF、sFlt-1、sEng、sCD40L水平变化可为临床评估子痫前期病情程度、预测胎儿不良结局提供参考依据。     

Preeclampsia is associated with low concentrations of protein Z.

OBJECTIVE: Protein Z, a vitamin K-dependent plasma protein, has an important role in the regulation of the coagulation cascade. Protein Z deficiency has been associated with unexplained pregnancy loss and adverse pregnancy outcome in patients with thrombophilia. This study was conducted to determine if preeclampsia (PE), small for gestational age (SGA), and fetal demise are associated with changes in maternal plasma concentrations of protein Z. STUDY DESIGN: This cross-sectional study included normal pregnant women (N = 71), patients with PE (N = 130), patients who delivered an SGA neonate (N = 58), and patients with fetal demise (N = 58). Maternal plasma protein Z concentrations were measured by a sensitive and specific immunoassay. Protein Z deficiency was defined as maternal plasma concentrations 0.05); and (3) women in the PE and fetal demise groups had significantly higher rates of protein Z deficiency than those with normal pregnancy outcome. CONCLUSIONS: (1) PE, but not SGA or fetal demise, is associated with a significantly lower maternal median plasma concentration of protein Z than normal pregnancy, and (2) a high rate of protein Z deficiency is observed in patients with PE and fetal demise.     

Preeclampsia and future cardiovascular risk: A point of view from the clearance of plasma vasoactive amines

Objective: To summarize the reported evidence on the relationship between vasoactive amines and preeclampsia. Methods: A literature search was conducted in MEDLINE/PubMed and EMBASE. Results: The summarized results are as follows: (1) Menstruation can effectively eliminate vasoactive amines norepinephrine, serotonin and histamine. (2) Pregnancy increases norepinephrine production due to fetal brain development and decreases vasoactive-amine elimination due to amenorrhea. (3) Preeclampsia is associated with a low renal and/or sweating capacity, or in rare cases, with increased norepinephrine production due to maternal pheochromocytoma and fetal neuroblastoma. Conclusion: Preeclampsia is mainly due to decreased excretion of norepinephrine and other vasoactive amines.     

Expectant management of severe preeclampsia with severe fetal growth restriction in the second trimester

ObjectiveWe investigated whether women with severe fetal growth restriction (FGR <5th percentile) associated with severe preeclampsia (PE) occurring in the second trimester are candidates for expectant management.Study designThis is a retrospective study involving 33 women who developed severe PE or superimposed PE in the second trimester and were expectantly managed at a tertiary center. They were divided into groups with and without severe FGR on admission (severe FGR (+) group: 17 women; severe FGR (−) group: 16 women) for comparison of the duration of pregnancy prolongation, major maternal complications, and perinatal outcomes. The data are presented as medians (range) or frequencies (percentage).ResultsThe duration of pregnancy prolongation was 10 days in both groups. Major maternal complications occurred in 5 of 17 women (29.4%) in the severe FGR (+) and 5 of 16 (31.3%) in the severe FGR (−) group, showing very similar incidence rates in the 2 groups. The perinatal survival rates were favorable at 82.4% (14/17) in the severe FGR (+) and 100% (16/16) in the severe FGR (−) group.ConclusionRegarding expectant management of severe preeclampsia occurring in the second trimester, there was no difference in the duration of pregnancy prolongation between the groups with and without severe FGR on admission. Because favorable perinatal outcomes can be expected without compromising maternal safety by prolonging pregnancy as expectant management for severe FGR, it was suggested that women with severe FGR are suitable candidates for expectant management.     

Late-onset preeclampsia is associated with an imbalance of angiogenic and anti-angiogenic factors in patients with and without placental lesions consistent with maternal underperfusion

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 sVEGRF-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.     

Urinary Excretion of Nephrin in Patients with Severe Preeclampsia

Objective. The objective of this study was to examine whether nephrin is present in the urine of patients with severe preeclampsia. Methods. A total of 45 women were recruited for this study, and 25 of these patients had severe preeclampsia. Twenty gestational age-matched normotensive women without proteinuria served as a control group. Urine samples were collected close to delivery, typically ≤24 h before delivery. Western blot analysis was performed to assess the excretion of nephrin in urine. Results. Nephrin was detected in all urine samples from all the women with severe preeclampsia but not in urine from normotensive controls. Conclusion. In pregnancy complicated by severe preeclampsia, urinary nephrin shedding, reflecting the damage in the glomerular slit diaphragm, was observed.     

Preeclampsia is an independent risk factor for spontaneous intestinal perforation in very preterm infants

Abstract

Background: Spontaneous intestinal perforation (SIP) is an important surgical emergency in preterm infants.

Aims: To evaluate the effect of maternal preeclampsia on development of SIP in premature infants.

Study design: Retrospective observational study in a large tertiary neonatal intensive care unit.

Subjects: The preterm infants of ≤32 weeks of gestational age and birthweight ≤1500?g who were hospitalized were enrolled.

Outcome measures: The primary outcome was to determine the association between preeclampsia and SIP.

Results: A total of 22 infants had SIP diagnosis. The incidence of SIP in infants born to preeclamptic mothers (6.2%) was significantly higher compared with those born to normotensive mothers (0.2%). In multinominal logistic regression model, preeclampsia was found to be an independent risk factor of SIP with an odds ratio of 13.5 (95% confidence interval 2.82–65.1).

Conclusions: Maternal preeclampsia seemed to be an independent risk factor for development of SIP in premature infants.     

Risk factors associated with presenting for abortion in the second trimester

OBJECTIVE: To determine factors associated with delay of induced abortion into the second trimester of pregnancy. METHODS: Using audio computer-assisted self-interviewing, 398 women from 5 to 23 weeks of gestation at an urban hospital described steps and reasons that could have led to a delayed abortion. Multivariable logistic regression identified independent contributors to delay. RESULTS: Half of the 70-day difference between the average gestational durations in first- and second-trimester abortions is due to later suspicion of pregnancy and administration of a pregnancy test. Delays in suspecting and testing for pregnancy cumulatively caused 58% of second-trimester patients to miss the opportunity to have a first-trimester abortion. Women presenting in the second trimester experienced more delaying factors (3.2 versus 2.0, P < .001), with logistical delays occurring more frequently for these women (63.3% versus 30.4%, P < .001). Factors associated with second-trimester abortion in logistic regression were prior second-trimester abortion, delay in obtaining state insurance, difficulty locating a provider, initial referral elsewhere, and uncertainty about last menstrual period. Factors associated with decreased likelihood of second-trimester abortion were presence of nausea or vomiting, prior abortion, and contraception use. CONCLUSION: Abortion delay results from myriad factors, many of them logistical, such as inappropriate or delayed referrals and delays in obtaining public insurance. Public health interventions could promote earlier recognition of pregnancy, more timely referrals, more easily obtainable public funding, and improved abortion access for indigent women. However, accessible second-trimester abortion services will remain necessary for the women who present late due to delayed recognition of and testing for pregnancy. LEVEL OF EVIDENCE: II-2.     

Genetic predisposition to elevated levels of C-reactive protein is associated with a decreased risk for preeclampsia

Objective: To examine the association between genetic predisposition to elevated C-reactive protein (CRP)and risk for preeclampsia using validated genetic loci for C-reactive protein. Methods: Preeclampsia cases (n = 177) and normotensive controls (n = 116) were selected from live birth certificates to nulliparous Iowa women during the period August 2002–May 2005. Disease status was verified by the medical chart review. Genetic predisposition to CRP was estimated by a genetic risk score on the basis of established loci for CRP levels. Logistic regression analyses were used to evaluate the relationships between the genotype score and preeclampsia. Replication analyses were performed in an independent, US population of preeclampsia cases (n = 516) and controls (n = 1,097) of European ancestry. Results: The genetic risk score (GRS) related to higher levels of CRP demonstrated a significantly decreased risk of preeclampsia (OR 0.89, 95% CI 0.82–0.96). When the GRS was analyzed by quartile, an inverse linear trend was observed (p = 0.0006). The results were similar after adjustments for the body mass index (BMI), smoking, and leisure-time physical activity. In the independent replication population, the association with the CRP GRS was also marginally significant (OR 0.97, 95% CI 0.92, 1.02). Meta-analysis of the two studies was statistically significant (OR 0.95, 95% CI 0.90, 0.99). Conclusion: Our data suggest an inverse, counterintuitive association between the genetic predisposition to elevated levels of CRP and a decreased risk of preeclampsia. This suggests that the blood CRP level is a marker of preeclampsia, but it does not appear to be a factor on the causal pathway.     

Urinary neutrophil gelatinase-associated lipocalin is associated with preeclampsia in a cohort of Turkish women

Purpose: We investigated the optimal cut-off level for urinary neutrophil gelatinase-associated lipocalin (NGAL) in preeclamptic patients to confirm the diagnosis.

Methods: Urinary NGAL concentrations were measured by specific enzyme-linked immunosorbent assay (ELISA).

Results: Patients with preeclampsia had significantly higher urinary NGAL concentrations than controls (mean: 387 ng/ml vs. 188 ng/ml, respectively; P< 0.001). Using a cutoff value 252 ng/ml for urinary NGAL to confirm diagnosis of preeclampsia, sensitivity, and specificity were 92% and 91%, respectively.

Conclusion: Urinary NGAL concentrations were significantly elevated in women with preeclampsia versus normotensive controls.     

先兆子痫患者母胎界面上细胞凋亡的研究

目的:研究先兆子痫患者母胎界面上细胞凋亡水平及凋亡相关分子的表达变化。方法:分别收集妊娠25、27、29、30和31周及足月分娩的正常妊娠者和先兆子痫患者的胎盘组织,采用脱氧核糖核酸末端转移酶介导的dUTP刻痕末端标记法(TUNEL)检测母胎界面上细胞凋亡情况, 并行凋亡细胞定位;RT-PCR检测正常妊娠和先兆子痫胎盘组织中P53,Bcl-2和Bax的mRNA表达水平的差异。结果:正常妊娠和先兆子痫患者胎盘中发生凋亡的细胞数目都随孕周延长而逐渐增高,但先兆子痫的胎盘中细胞凋亡率明显高于正常妊娠者;正常妊娠胎盘中凋亡细胞主要为合体滋养层细胞,足月胎盘绒毛内血管内皮细胞亦有少量细胞凋亡,而先兆子痫胎盘中细胞滋养层细胞、合体滋养层细胞和绒毛内血管内皮细胞均发生明显的凋亡;RT-PCR显示先兆子痫胎盘组织中P53和Bax的mRNA水平明显高于同期妊娠的正常胎盘,而Bcl-2水平显著降低。结论:正常妊娠过程中胎盘组织中只在有限部位出现少量细胞凋亡,而先兆子痫胎盘组织中细胞过度凋亡, 且凋亡细胞分布广泛,并伴有凋亡相关分子的表达上调。表明先兆子痫的发生与胎盘组织中滋养层细胞大量凋亡密切相关。