Fetal overgrowth in pregnancies complicated by diabetes: development of a clinical prediction index.

PURPOSE: To develop an index to predict fetal overgrowth in pregnancies complicated by diabetes. METHODS: Data were derived from a cohort of 275 women with singleton gestations in a collaborative diabetes in pregnancy program. Regression analysis incorporated clinical factors available in the first 20-30 weeks of pregnancy that were assigned beta-coefficient-based weights, the sum of which yielded a fetal overgrowth index (composite score). RESULTS: Fifty-one (18.5%) pregnancies were complicated by fetal overgrowth. The derived index included five clinical factors: age ≤ 30, history of macrosomia, excessive gestational weight gain, enlarged fetal abdominal circumference, and fasting hyperglycemia. Area under the curve (AUC) for the index is 0.88 [95% confidence interval (CI) 0.82-0.92]. Cut-points were selected to identify "high-risk" and "low-risk" ranges (≥ 8 and ≤ 3) that have positive and negative predictive values of 84% (95% CI 70-98%) and 95% (95% CI 92-98%), respectively. The majority of women in our cohort (n = 182, 66%) had a "low-risk" index while 9% (n = 25) had a "high-risk" index. Sub-analyses of nulliparous women and women with gestational and pre-gestational diabetes revealed that the overgrowth index was equally or more predictive when applied separately to each of these groups. CONCLUSION: This fetal overgrowth index that incorporates five clinical factors provides a means of predicting fetal overgrowth and thereby serves as a tool for targeting the allocation of healthcare resources and treatment individualization.

Urinary tract infection during pregnancy, angiogenic factor profiles, and risk of preeclampsia.

BACKGROUND: Despite decades of research, and much progress in discernment of biomarkers in the maternal circulation, the pathogenesis of preeclampsia (PE) remains elusive. The pathophysiology of PE is believed to involve aberrant placentation and an associated increase in systemic inflammation. In this conceptualization, PE becomes more likely when the level of systemic inflammatory burden inherent in pregnancy itself exceeds the maternal capacity to compensate for this additional stress. If this is the case, then it is possible to hypothesize that conditions, such as infectious disease, that increase systemic inflammatory burden should also increase the risk of PE. As urinary tract infection (UTI) represents a common source of inflammation during pregnancy, we tested whether presence of UTI during pregnancy increased the odds of developing PE. Prior work has documented this association. However many of these studies were limited by small cohort sizes and insufficient control for covariates. OBJECTIVE: The present study is a secondary analysis of a robust contemporary obstetrical cohort recruited to examine the ability of longitudinally sampled maternal angiogenic concentrations to predict PE. We hypothesize that the occurrence of UTI during a pregnancy is associated with the later occurrence of PE in that pregnancy. As PE is believed to be associated with aberrations in systemic angiogenic levels (placental growth factor and soluble isoform of VEGF receptor), we further hypothesize that there will be significant interactions between maternal angiogenic protein levels and the occurrence of UTI. STUDY DESIGN: Women aged ≥18 years (n = 2607) were recruited and followed up prospectively from the initiation of prenatal care through delivery at 3 regional academic centers. PE was defined by American Congress of Obstetricians and Gynecologists criteria and was independently validated by a panel of physicians. UTI was defined by the presence of clinical symptoms necessitating treatment in addition to supportive laboratory evidence. Multivariate logistic regression models were used and controlled for maternal age, race, parity, body mass index, hypertension, diabetes, in vitro fertilization, and smoking status. RESULTS: There were 129 women with diagnosed UTIs and 235 with PE. Patients with UTI in pregnancy had higher rates of PE (31.1% vs 7.8%, P < .001) compared to those without reported UTI. The mean gestational age (SD) for UTI diagnosis in PE cases and controls was 25.6 (10.4) and 21.9 (10.9) weeks, respectively (P = .08). The unadjusted odds ratio for PE in the setting of UTI was 5.29 (95% confidence interval, 3.54-7.89). After controlling for confounders, UTI was associated with an odds ratio for PE of 3.2 (95% confidence interval, 2.0-5.1). CONCLUSION: Presence of UTI in pregnancy, particularly in the third trimester, is strongly associated with PE. This association supports the hypothesis that the risk of PE is enhanced by an increased maternal inflammatory burden. Prophylaxis against UTI represents a potentially low-cost global intervention to slow or halt the development of PE.

Angiogenic markers in pregnancies conceived through in vitro fertilization.

OBJECTIVE: Pregnancies that have been conceived through in vitro fertilization (IVF) have been associated with higher rates of preeclampsia and other complications that are associated with placental dysfunction. We evaluated whether IVF pregnancies, when compared with those conceived spontaneously, would be associated with alterations in serum angiogenic markers. STUDY DESIGN: This was a retrospective cohort study from 3 US academic institutions (2006-2008). Women with singleton pregnancies who conceived via IVF or spontaneously were included. Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured at 4 time points throughout gestation. Pregnancy outcomes that included diagnosis of preeclampsia or other obstetric complications were ascertained from the medical record. The relationship among IVF status, PlGF, and sFlt-1 were modeled over gestation and stratified by clinical pregnancy outcome. RESULTS: Of the included 2392 singleton pregnancies, 4.5% (108 pregnancies) were conceived though IVF. IVF pregnancies were significantly more likely to be complicated by preeclampsia (15.7% vs 7.7%). IVF pregnancies had significantly higher levels of sFlt-1 at 18, 26, and 35 weeks of gestation (P = .04, P = .004, P < .0001, respectively) and lower levels of PlGF at 18 and 35 weeks of gestation (P = .007 and .0006, respectively). These differences persisted even after being controlled for maternal comorbidities or obstetric outcomes such as preeclampsia. CONCLUSION: Pregnancies conceived via IVF were found to have an increased antiangiogenic profile (elevated sFlt-1 and decreased PlGF) at multiple time points throughout gestation when compared with spontaneously conceived pregnancies. Alterations in the angiogenic profile persisted even after we controlled for maternal comorbidities of clinically evident disorders of abnormal placentation such as preeclampsia. The increased antiangiogenic profile suggests fundamentally aberrant placentation related to in vitro fertilization, which may warrant closer fetal surveillance in these pregnancies.

Maternal circulating angiogenic factors in twin and singleton pregnancies.

OBJECTIVE: The purpose of this study was to compare longitudinally sampled maternal angiogenic proteins between singleton and twin pregnancies. STUDY DESIGN: Placental growth factor (PlGF), soluble feline McDonough sarcoma (fms)-like tyrosine kinase (sFlt)-1, and soluble endoglin from healthy pregnant women were quantified at 10, 18, 26, and 35 weeks' gestation (n=91), and during the third trimester (31-39 weeks) and at delivery (33-41 weeks; n=41). Geometric means and 95% confidence intervals were calculated for gestational age-adjusted angiogenic protein concentrations and compared between matched twin and singleton pregnancies. RESULTS: Maternal sFlt-1 concentrations and the sFlt-1/PlGF ratio were higher in twins than singletons across pregnancy and at delivery, with the greatest differences at week 35 (sFlt-1: 36,916 vs 10,151 pg/mL; P<.0001; sFlt-1/PlGF: 168.4 vs 29.0; P<.0001). Maternal concentrations of soluble endoglin also were higher in the third trimester and delivery. Maternal PlGF concentrations were lower in twin than singleton pregnancies at week 35 only (219.2 vs 350.2 pg/mL; P<.0001). Placental weight appeared to be inversely correlated with maternal sFlt-1/PlGF ratio at the end of pregnancy in both twins and singletons. CONCLUSION: Higher maternal antiangiogenic proteins in twin than singleton pregnancies does not appear to be due to greater placental mass in the former, and may be one explanation for the increased risk of preeclampsia in women carrying multiple gestations. Determining whether women with a history of multiple gestations have an altered cardiovascular disease and breast cancer risk, like those with a history of preeclampsia, is warranted.

The association of body mass index with serum angiogenic markers in normal and abnormal pregnancies.

OBJECTIVE: Because obesity is a risk factor for placental dysfunction, we hypothesized that maternal body mass index (BMI) would be associated with alterations in serum angiogenic markers. STUDY DESIGN: We included 2399 singleton pregnancies with and without placental dysfunction in a prospective longitudinal cohort study of angiogenic markers. We modeled the relationship between categorical and continuous BMI, soluble fms-like tyrosine kinase-1 (sFlt-1), and placental growth factor (PlGF) over gestation, stratified by pregnancy outcome. RESULTS: In women with normal pregnancies, a higher BMI was associated with lower sFlt-1 values across gestation (P < .0001), lower PlGF in the second and third trimesters (P < .0001), and lower rate of change in PlGF (P < .0001). Similar relationships were seen between maternal BMI, sFlt-1 (P < .0001), and PlGF (P = .0005) in women with clinically evident placental dysfunction. CONCLUSION: The sFlt-1 value is inversely associated with maternal BMI. The pattern of change in PlGF is also dependent on maternal BMI, indicating that obese women may have abnormalities in angiogenesis near term.

Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia.

BACKGROUND: An imbalance in circulating angiogenic factors plays a central role in the pathogenesis of preeclampsia. METHODS AND RESULTS: We prospectively studied 616 women who were evaluated for suspected preeclampsia. We measured plasma levels of antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt1) and proangiogenic placental growth factor (PlGF) at presentation and examined for an association between the sFlt1/PlGF ratio and subsequent adverse maternal and perinatal outcomes within 2 weeks. The median sFlt1/PlGF ratio at presentation was elevated in participants who experienced any adverse outcome compared with those who did not (47.0 [25th-75th percentile, 15.5-112.2] versus 10.8 [25th-75th percentile, 4.1-28.6]; P<0.0001). Among those presenting at <34 weeks (n=167), the results were more striking (226.6 [25th-75th percentile, 50.4-547.3] versus 4.5 [25th-75th percentile, 2.0-13.5]; P<0.0001), and the risk was markedly elevated when the highest sFlt1/PlGF ratio tertile was compared with the lowest (odds ratio, 47.8; 95% confidence interval, 14.6-156.6). Among participants presenting at <34 weeks, the addition of sFlt1/PlGF ratio to hypertension and proteinuria significantly improved the prediction for subsequent adverse outcomes (area under the curve, 0.93 for hypertension, proteinuria, and sFlt1/PlGF versus 0.84 for hypertension and proteinuria alone; P=0.001). Delivery occurred within 2 weeks of presentation in 86.0% of women with an sFlt1/PlGF ratio ≥85 compared with 15.8% of women with an sFlt1/PlGF ratio <85 (hazard ratio, 15.2; 95% confidence interval, 8.0-28.7). CONCLUSIONS: In women with suspected preeclampsia presenting at <34 weeks, circulating sFlt1/PlGF ratio predicts adverse outcomes occurring within 2 weeks. The accuracy of this test is substantially better than that of current approaches and may be useful in risk stratification and management. Additional studies are warranted to validate these findings.

Soluble endoglin contributes to the pathogenesis of preeclampsia.

Preeclampsia is a pregnancy-specific hypertensive syndrome that causes substantial maternal and fetal morbidity and mortality. Maternal endothelial dysfunction mediated by excess placenta-derived soluble VEGF receptor 1 (sVEGFR1 or sFlt1) is emerging as a prominent component in disease pathogenesis. We report a novel placenta-derived soluble TGF-beta coreceptor, endoglin (sEng), which is elevated in the sera of preeclamptic individuals, correlates with disease severity and falls after delivery. sEng inhibits formation of capillary tubes in vitro and induces vascular permeability and hypertension in vivo. Its effects in pregnant rats are amplified by coadministration of sFlt1, leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and restriction of fetal growth. sEng impairs binding of TGF-beta1 to its receptors and downstream signaling including effects on activation of eNOS and vasodilation, suggesting that sEng leads to dysregulated TGF-beta signaling in the vasculature. Our results suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia.

Longitudinal evaluation of predictive value for preeclampsia of circulating angiogenic factors through pregnancy.

OBJECTIVE: The purpose of this study was to examine whether longitudinally sampled maternal angiogenic concentrations predict preeclampsia. STUDY DESIGN: Plasma sFlt-1 and placental growth factor (PlGF) concentrations in healthy pregnant women were quantified at 10, 17, 25, and 35 weeks' gestation. Preeclampsia was diagnosed with criteria from the American College of Obstetricians and Gynecologists. RESULTS: In the first trimester, sensitivity/specificity for PlGF and sFlt-1 were 55/43% and 57/40%, respectively, and did not improve appreciably as the pregnancy progressed. Among pregnancies that later experienced preeclampsia, median PlGF was lower beginning in the second trimester, but sFlt-1 was not higher until the third trimester. Analyte positive predictive values approached 10% in the third trimester. Negative predictive values were >90% for the entire pregnancy. CONCLUSION: Prediction of preeclampsia in early pregnancy was not possible with the use of maternal angiogenic protein concentrations. Even in late pregnancy, positive predictive values were not useful clinically. Negative predictive values are similarly unlikely to prove useful as a tool with which to a rule out suspected disease.

Sera from preeclampsia patients elicit symptoms of human disease in mice and provide a basis for an in vitro predictive assay.

Early diagnosis and treatment of preeclampsia would significantly reduce maternal and fetal morbidity and mortality. However, its etiology and prediction have remained elusive. Based on the hypothesis that sera from patients with preeclampsia could function as a "blueprint" of causative factors, we describe a serum-based pregnancy-specific mouse model that closely mirrors the human condition as well as an in vitro predictive assay. We show that a single administration of human preeclampsia serum in pregnant IL-10-/- mice induced the full spectrum of preeclampsia-like symptoms, caused hypoxic injury in uteroplacental tissues, and elevated soluble fms-like tyrosine kinase 1 and soluble endoglin, markers thought to be related to the disease. The same serum sample(s) induced a partial preeclampsia phenotype in wild-type mice. Importantly, preeclampsia serum disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity. Disruption of endovascular activity could be documented in serum samples as early as 12 to 14 weeks of gestation from patients who subsequently developed preeclampsia. These results indicate that preeclampsia patient sera can be used to understand the pregnancy-specific disease pathology in mice and can predict the disorder.

Placental expression of angiogenic factors in Trisomy 13.

OBJECTIVE: Increased levels of soluble fms-like tyrosine kinase (sFlt-1) in Trisomy 13 pregnancies are thought to be mediated by the placenta. This study aimed to compare sFlt-1 expression in Trisomy 13 (n = 7) placentas with that in control placentas (Trisomy 21, n = 11, and euploid, n = 6). STUDY DESIGN: This was a retrospective case-control study analyzing paraffin-embedded placental blocks that were stained with hematoxylin and eosin and antibodies to sFlt-1. Their staining intensity was compared using a semiquantitative technique. The Kruskal-Wallis test and Wilcox rank sum test were used for statistical analysis. RESULTS: The median staining was significantly higher in Trisomy 13 compared with control specimens (P = .008) (for Trisomy 13 vs Trisomy 21, P = .003, and Trisomy 13 vs euploid, P = .004). CONCLUSION: Our study demonstrates that Trisomy 13 placentas express more sFlt-1 than control placentas. These results strengthen the hypothesis that the increased incidence of preeclampsia in Trisomy 13 pregnancies is secondary to placental up-regulation of sFlt-1.

Early-pregnancy soluble Fas levels in idiopathic small-for-gestational-age pregnancies.

OBJECTIVE: We sought to determine first- and second-trimester serum soluble Fas (sFas) and placental growth factor (PlGF) levels in idiopathic small-for-gestational-age (SGA) pregnancies. STUDY DESIGN: We measured sFas and PlGF levels in women who delivered SGA infants uncomplicated by preeclampsia and in control subjects. For sFas there were 34 cases and 318 control subjects in the first trimester and 9 cases and 11 control subjects in the second trimester. For PlGF there were 31 cases and 281 control subjects in the first trimester and 8 cases and 11 control subjects in the second trimester. RESULTS: SGA pregnancies had lower sFas levels than control subjects in the second trimester (3703 + or - 209 pg/mL vs 4562 + or - 241 pg/mL; P = .015), but not in the first trimester (4892 + or - 191 pg/mL vs 4971 + or - 177 pg/mL; P = .68). There was no difference in PlGF levels between SGA and normal pregnancies in both trimesters. CONCLUSION: Serum sFas levels were lower in idiopathic SGA pregnancies in the second trimester, but not in the first. There was no difference in serum PlGF levels in either trimester.

Twin pregnancy and the risk of preeclampsia: bigger placenta or relative ischemia?

OBJECTIVE: Twin pregnancies are a risk factor for preeclampsia with a reported incidence of 2-3 times higher than singleton pregnancies. Soluble fms-like tyrosine kinase 1 (sFlt1), which is a circulating antiangiogenic molecule of placental origin, plays a central role in preeclampsia by antagonizing placental growth factor (PlGF) and vascular endothelial growth factor signaling in the maternal vasculature. Increased sFlt1 and the ratio sFlt1/free PlGF have been shown to antedate clinical signs in preeclampsia. Although the cause of the upregulated sFlt1 in preeclampsia still is not understood clearly, placental ischemia with accompanying hypoxia is thought to play an important role. We therefore hypothesized that the higher risk of preeclampsia in twin pregnancies results from high sFlt1 (or sFlt1/PlGF) and that the sFlt1 upregulation was due to either relative placental hypoxia and/or increased placental mass. STUDY DESIGN: Maternal serum samples and placentas from third-trimester twin and singleton pregnancies without preeclampsia were used. Serum samples were analyzed for levels of sFlt1 and free PlGF by enzyme-linked immunosorbent assay and reported as means (in nanograms per milliliter and picograms per milliliter, respectively). Placentas were weighed and examined for content of sFlt1 and PlGF messenger RNA (mRNA) by quantitative polymerase chain reaction and hypoxia inducible factor-1alpha (HIF-1alpha) protein by Western blot. RESULTS: Soluble Flt1 concentrations in twin pregnancy maternal serum were 2.2 times higher than those that were measured in singleton pregnancy maternal serum samples (30.98 +/- 9.78 ng/mL vs 14.14 +/- 9.35 ng/mL, respectively; P = .001). Free PlGF concentrations were not significantly different between twin and singleton maternal serum samples, but the mean sFlt1/PlGF ratio of twin pregnancy maternal serum samples was 2.2 times higher than the equivalent ratio in singleton pregnancy samples (197.58 +/- 126.86 ng/mL vs 89.91 +/- 70.63 ng/mL, respectively; P = .029). Quantitative polymerase chain reaction for sFlt1 and PlGF mRNA revealed no significant differences between the 2 study groups. Western blot analysis of placental samples for HIF-1alpha revealed a mean ratio HIF-1alpha/actin of 0.53 vs 0.87, for the twins vs singletons placental samples respectively (twins showed lower HIF-1alpha, not higher). The mean weights of twin and singleton placentas were 1246 vs 716 g, respectively (P < .001). Importantly, the placental weights correlated very well with the circulating sFlt1 levels (R(2) = .75). CONCLUSION: In twin pregnancies, circulating sFlt1 levels and sFlt1/PlGF ratios were twice as high as those in singleton pregnancies. The increased serum sFlt1 levels in twin pregnancies were not accompanied by any changes in the levels of sFlt1 mRNA and HIF-1alpha protein in the twin placentas but were correlated with increased placental weight. These findings suggest that the increased risk of preeclampsia in twin pregnancies may be due to increased placental mass that leads to increased circulating levels of sFlt1.

Infant size and the association between maternal circulating angiogenic factors and preeclampsia.

OBJECTIVE: To assess the effect of infant size as a marker of placental function on the association between preeclampsia and the ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF). STUDY DESIGN: The angiogenic factors sFlt-1 and PlGF were measured prospectively at 26 weeks gestation in 2322 women. Pregnancies were stratified by whether or not they were complicated by preeclampsia, the timing of delivery, and birthweight Z-score. RESULT: Independent of preeclampsia status, women with small infants (Z < -1.0) have an increased sFlt-1/PlGF ratio, and women with large infants (Z > 1.0) have a decreased ratio. Among pregnancies yielding small infants, the sFlt-1/PlGF ratio is markedly elevated in preeclamptic pregnancies requiring delivery before 37 weeks (110.0 vs. 17.9, p < 0.0001) but not in preeclamptic pregnancies delivered at term. The strength of the association between preeclampsia and the sFlt-1/PlGF ratio is increased for small infants compared to normal-sized or large infants. CONCLUSION: The sFlt-1/PlGF ratio in the late second trimester is similarly elevated in women with preeclampsia and in women with small infant size and more markedly elevated in a syndrome of placental dysfunction characterized by preeclampsia, preterm delivery, and growth restriction.

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.

Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.

Circulating angiogenic factors and the risk of preeclampsia.

BACKGROUND: The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role. METHODS: We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia. RESULTS: During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P<0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant. CONCLUSIONS: Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia.

Diagnostic utility of soluble fms-like tyrosine kinase 1 and soluble endoglin in hypertensive diseases of pregnancy.

OBJECTIVE: The objective of this pilot study was to evaluate the clinical utility of soluble fms-like tyrosine kinase 1 (sFlt 1) and soluble endoglin (sEng) in the differential diagnosis of hypertension in late pregnancy. STUDY DESIGN: We analyzed serum levels of sFlt 1 and sEng in women with gestational hypertension (GHTN; n = 17), chronic hypertension (CHTN; n = 19), preeclampsia (n = 19), and normal pregnancy (n = 20) in the third trimester. We calculated the sensitivity, specificity, and positive and negative likelihood ratio (LR) for each factor in diagnosing preeclampsia. RESULTS: The sensitivity and specificity of sFlt 1 in differentiating preeclampsia from normal pregnancy were 90% and 90%, respectively, and 90% and 95% for sEng. In women with GHTN, they were 79% and 88% for sFlt 1; 84% and 88% for sEng; 90% and 63% for uric acid. In women with CHTN, they were 84% and 95% for sFlt 1; 84% and 79% for sEng; 68%; and 78% for uric acid. The positive LR for preeclampsia was 9 for sFlt 1 and 7 for sEng in women with normal pregnancy; in women with GHTN; 6.7 for sFlt 1 and 7.2 for sEng; in CHTN, 16 for sFlt 1 and 4 for sEng. Serum uric acid had a positive LR of only 2.4 in women with GHTN and 3.1 in women with CHTN. CONCLUSION: Both sFlt 1 and sEng may prove useful in differentiating preeclampsia from other hypertensive diseases of pregnancy. A prospective cohort study should be performed determine the clinical utility of measuring these proteins.

Uric acid and preeclampsia.

Increased uric acid level is a key clinical feature of preeclampsia; higher levels correlate with significant maternal and fetal morbidity and mortality. The cause of hyperuricemia and its specific role in the pathogenesis of preeclampsia, however, remain unclear. Although uric acid has been shown to roughly parallel the severity of the maternal syndrome, it has not been useful in predicting the development of preeclampsia. Nevertheless, there have been recent data supporting a pathogenic role potentially in the hypertension and endothelial cell dysfunction of preeclampsia. This article reviews our current understanding of hyperuricemia in the setting of preeclampsia, and highlights the hypothesis that hyperuricemia may contribute to vascular damage in preeclampsia.

Urinary placental growth factor and risk of preeclampsia.

CONTEXT: Preeclampsia may be caused by an imbalance of angiogenic factors. We previously demonstrated that high serum levels of soluble fms-like tyrosine kinase 1 (sFlt1), an antiangiogenic protein, and low levels of placental growth factor (PlGF), a proangiogenic protein, predict subsequent development of preeclampsia. In the absence of glomerular disease leading to proteinuria, sFlt1 is too large a molecule to be filtered into the urine, while PlGF is readily filtered. OBJECTIVE: To test the hypothesis that urinary PlGF is reduced prior to onset of hypertension and proteinuria and that this reduction predicts preeclampsia. DESIGN, SETTING, AND PATIENTS: Nested case-control study within the Calcium for Preeclampsia Prevention trial of healthy nulliparous women enrolled at 5 US university medical centers during 1992-1995. Each woman with preeclampsia was matched to 1 normotensive control by enrollment site, gestational age at collection of the first serum specimen, and sample storage time at -70 degrees C. One hundred twenty pairs of women were randomly chosen for analysis of serum and urine specimens obtained before labor. MAIN OUTCOME MEASURE: Cross-sectional urinary PlGF concentrations, before and after normalization for urinary creatinine. RESULTS: Among normotensive controls, urinary PlGF increased during the first 2 trimesters, peaked at 29 to 32 weeks, and decreased thereafter. Among cases, before onset of preeclampsia the pattern of urinary PlGF was similar, but levels were significantly reduced beginning at 25 to 28 weeks. There were particularly large differences between controls and cases of preeclampsia with subsequent early onset of the disease or small-for-gestational-age infants. After onset of clinical disease, mean urinary PlGF in women with preeclampsia was 32 pg/mL, compared with 234 pg/mL in controls with fetuses of similar gestational age (P<.001). The adjusted odds ratio for the risk of preeclampsia to begin before 37 weeks of gestation for specimens obtained at 21 to 32 weeks, which were in the lowest quartile of control PlGF concentrations (<118 pg/mL), compared with all other quartiles, was 22.5 (95% confidence interval, 7.4-67.8). CONCLUSION: Decreased urinary PlGF at mid gestation is strongly associated with subsequent early development of preeclampsia.

Expectant management of uterine dehiscence in the second trimester of pregnancy.

BACKGROUND: Uterine dehiscence and rupture are serious complications of pregnancy after a cesarean delivery. Management of uterine dehiscence diagnosed in second trimester can be controversial. CASE: A woman with a previous cesarean delivery was diagnosed with a uterine dehiscence at 20 weeks in the area of her prior cesarean incision. Although she was counseled regarding risks to herself and the fetus, she decided to continue the pregnancy. She was, therefore, managed expectantly until 31 weeks and delivered by cesarean because of fetal heart rate decelerations. The infant did well and was discharged home at 3 weeks of age. The patient remained asymptomatic after delivery. CONCLUSION: With close monitoring, expectant management of uterine dehiscence diagnosed in the second trimester is possible.

Massive fetal ascites causing increased middle cerebral artery systolic velocity.

BACKGROUND: An elevated peak systolic velocity in the middle cerebral artery, assessed by Doppler ultrasonography, is commonly associated with fetal anemia. Other fetal abnormalities associated with a high middle cerebral artery velocity have rarely been reported. CASE: A fetus with increasing ascites was found to have an elevated middle cerebral artery peak systolic velocity. Following paracentesis, the peak systolic velocity normalized. Peak systolic velocity continued to correlate with the level of ascites, falling to normal ranges when large-volume amniocentesis and paracentesis were performed. At birth, the infant was found to have a normal hematocrit. CONCLUSION: An elevated middle cerebral artery peak systolic velocity may result from massive fetal ascites without anemia. We hypothesize that the massive ascites led to increased afterload of the heart, with relatively preserved preload, leading to an increased systolic blood pressure and an elevated middle cerebral artery peak systolic velocity.