Proteinuria during pregnancy: definition, pathophysiology, methodology, and clinical significance.

Qualitative and quantitative measurement of urine protein excretion is one of the most common tests performed during pregnancy. For more than 100 years, proteinuria was necessary for the diagnosis of preeclampsia, but recent guidelines recommend that proteinuria is sufficient but not necessary for the diagnosis. Still, in clinical practice, most patients with gestational hypertension will be diagnosed as having preeclampsia based on the presence of proteinuria. Although the reference standard for measuring urinary protein excretion is a 24-hour urine collection, spot urine protein-to-creatinine ratio is a reasonable "rule-out" test for proteinuria. Urine dipstick screening for proteinuria does not provide any clinical benefit and should not be used to diagnose proteinuria. The classic cutoff cited to define proteinuria during pregnancy is a value of >300 mg/24 hours or a urine protein-to-creatinine ratio of at least 0.3. Using this cutoff, the rate of isolated proteinuria in pregnancy may reach 8%, whereas preeclampsia occurs among 3% to 8% of pregnancies. Although this threshold is widely accepted, its origin is not based on evidence on adverse pregnancy outcomes but rather on expert opinion and results of small studies. After reviewing the available data, the most important factor that influences maternal and neonatal outcome is the severity of blood pressures and presence of end organ damage, rather than the excess protein excretion. Because the management of gestational hypertension and preeclampsia without severe features is almost identical in frequency of surveillance and timing of delivery, the separation into 2 disorders is unnecessary. If the management of women with gestational hypertension with a positive assessment of proteinuria will not change, we believe that urine assessment for proteinuria is unnecessary in women who develop new-onset blood pressure at or after 20 weeks' gestation. Furthermore, we do not recommend repeated measurement of proteinuria for women with preeclampsia, the amount of proteinuria does not seem to be related to poor maternal and neonatal outcomes, and monitoring proteinuria may lead to unindicated preterm deliveries and related neonatal complications. Our current diagnosis of preeclampsia in women with chronic kidney disease may be based on a change in protein excretion, a baseline protein excretion evaluation is critical in certain conditions such as chronic hypertension, diabetes, and autoimmune or other renal disorders. The current definition of superimposed preeclampsia possesses a diagnostic dilemma, and it is unclear whether a change in the baseline proteinuria reflects another systemic disease such as preeclampsia or whether women with chronic disease such as chronic hypertension or diabetes will experience a different "normal" pattern of protein excretion during pregnancy. Finally, limited data are available regarding angiogenic and other biomarkers in women with chronic kidney disease as a potential aid in distinguishing the worsening of baseline chronic kidney disease and chronic hypertension from superimposed preeclampsia.

Accuracy of angiogenic biomarkers at ⩽20weeks' gestation in predicting the risk of pre-eclampsia: A WHO multicentre study.

OBJECTIVE: To assess the accuracy of angiogenic biomarkers to predict pre-eclampsia. DESIGN: Prospective multicentre study. From 2006 to 2009, 5121 pregnant women with risk factors for pre-eclampsia (nulliparity, diabetes, previous pre-eclampsia, chronic hypertension) from Argentina, Colombia, Peru, India, Italy, Kenya, Switzerland and Thailand had their serum tested for sFlt-1, PlGF and sEng levels and their urine for PlGF levels at ⩽20, 23-27 and 32-35weeks' gestation (index tests, results blinded from carers). Women were monitored for signs of pre-eclampsia, diagnosed by systolic blood pressure ⩾140mmHg and/or diastolic blood pressure ⩾90mmHg, and proteinuria (protein/creatinine ratio ⩾0.3, protein ⩾1g/l, or one dipstick measurement ⩾2+) appearing after 20weeks' gestation. Early pre-eclampsia was defined when these signs appeared ⩽34weeks' gestation. MAIN OUTCOME MEASURE: Pre-eclampsia. RESULTS: Pre-eclampsia was diagnosed in 198 of 5121 women tested (3.9%) of whom 47 (0.9%) developed it early. The median maternal serum concentrations of index tests were significantly altered in women who subsequently developed pre-eclampsia than in those who did not. However, the area under receiver operating characteristics curve at ⩽20weeks' gestation were closer to 0.5 than to 1.0 for all biomarkers both for predicting any pre-eclampsia or at ⩽34weeks' gestation. The corresponding sensitivity, specificity and likelihood ratios were poor. Multivariable models combining sEng with clinical features slightly improved the prediction capability. CONCLUSIONS: Angiogenic biomarkers in first half of pregnancy do not perform well enough in predicting the later development of pre-eclampsia.

Increased protein-coding mutations in the mitochondrial genome of African American women with preeclampsia.

Preeclampsia occurs more frequently in women of African ancestry. The cause of this hypertensive complication is unclear, but placental oxidative stress may play a role. Because mitochondria are the major sites of oxidative phosphorylation, we hypothesized that placentas of preeclamptic pregnancies harbor mitochondrial DNA (mtDNA) mutations. Next-generation sequencing of placental mtDNA in African American preeclamptics (N = 30) and controls (N = 38) from Chicago revealed significant excesses in preeclamptics of nonsynonymous substitutions in protein-coding genes and mitochondrially encoded nicotinamide adenine dinucleotide dehydrogenase 5 gene and an increase in the substitution rate (P = .0001). Moreover, 88% of preeclamptics and 53% of controls carried at least one nonsynonymous substitution (P = .005; odds ratio [OR] = 6.36, 95% confidence interval [CI]: 1.5-39.1). These results were not replicated in a sample of African American preeclamptics (N = 162) and controls (N = 171) from Detroit. Differences in study design and heterogeneity may account for this lack of replication. Nonsynonymous substitutions in mtDNA may be risk factors for preeclampsia in some African American women, but additional studies are required to establish this relationship.

Pregnancy and chronic kidney disease.

This article reviews the association of chronic renal disease and pregnancy. Included are discussions of guidelines for counseling pregnant women with underlying chronic renal disease who are considering conceiving as well as management of those already pregnant. Specifically highlighted are recent studies that question the validity of using estimated glomerular filtration rate and other formulae and questions of whether we should strive to replace the classic counseling approaches based primarily on serum creatinine levels with guidelines based on chronic kidney disease classification. The article concludes with a review as well as a critique of recent research on the prevalence of preeclampsia in women with underlying chronic renal disease, as well as if women with preeclampsia and underlying kidney disease have accelerated courses toward end-stage renal disease.

Effect of smoking on circulating angiogenic factors in high risk pregnancies.

OBJECTIVE: Changes in maternal concentrations of the anti-angiogenic factors, soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng), and the pro-angiogenic placental growth factor (PlGF) precede the development of preeclampsia in healthy women. The risk of preeclampsia is reduced in women who smoke during pregnancy. The objective of this study was to investigate whether smoking affects concentrations of angiogenic factors (sFlt1, PlGF, and sEng) in women at high risk for developing preeclampsia. STUDY DESIGN: We performed a secondary analysis of serum samples from 993 high-risk women (chronic hypertension, diabetes, multifetal gestation, and previous preeclampsia) in a preeclampsia prevention trial. sFlt1, sEng and PlGF were measured in serum samples obtained at study entry, which was prior to initiation of aspirin (median 19.0 weeks' [interquartile range of 16.0-22.6 weeks']). Smoking status was determined by self-report. RESULTS: sFlt1 was not significantly different in smokers from any high-risk groups compared to their nonsmoking counterparts. PlGF was higher among smokers compared to nonsmokers among diabetic women (142.7 [77.4-337.3] vs 95.9 [48.5-180.7] pg/ml, p = 0.005) and women with a history of preeclampsia (252.2 [137.1-486.0] vs 152.2 [73.6-253.7] pg/ml, p = 0.001). sEng was lower in smokers with multifetal gestations (5.8 [4.6-6.5] vs 6.8 [5.5-8.7] ng/ml, p = 0.002) and trended lower among smokers with diabetes (4.9 [3.8-5.6] vs 5.3 [4.3-6.3] ng/ml, p = 0.05). Smoking was not associated with a lower incidence of preeclampsia in any of these groups. CONCLUSIONS: In certain high-risk groups, smoking is associated with changes in the concentrations of these factors towards a pro-angiogenic direction during early pregnancy; however, there was no apparent association between smoking and the development of preeclampsia in our cohort.

Soluble fms-Like tyrosine kinase 1 (sFlt1), endoglin and placental growth factor (PlGF) in preeclampsia among high risk pregnancies.

BACKGROUND: Differences in circulating concentrations of antiangiogenic factors sFlt1 and soluble endoglin (sEng) and the pro-angiogenic growth factor PlGF are reported to precede the onset of preeclampsia weeks to months in low-risk pregnant women. The objective of this study was to investigate whether similar changes can be detected in pregnant women at high-risk to develop the syndrome. METHODS: This study is a secondary analysis of the NICHD MFMU trial of aspirin to prevent preeclampsia in high-risk pregnancies. Serum samples were available from 194 women with pre-existing diabetes, 313 with chronic hypertension, 234 with multifetal gestation, and 252 with a history of preeclampsia in a previous pregnancy. Samples collected across pregnancy were analyzed in a blinded fashion for sFlt1, sEng and PlGF. RESULTS: The odds of developing preeclampsia were significantly increased among women with multiple fetuses for each 2-fold elevation in sFlt1, sEng and the ratio of angiogenic factors (e.g. OR 2.18, 95% CI 1.46-3.32), and significantly decreased for each 2-fold elevation in circulating PlGF (OR 0.50, 95% CI 0.30-0.82) between 7 and 26 weeks' gestation. Cross-sectional analysis of the angiogenic factors across gestation showed significant differences during the third trimester in women who develop preeclampsia compared with appropriate controls in all high-risk groups. However, when data were examined in relation to the gestational week when preeclampsia was diagnosed only sFlt1 was significantly higher 2 to 5 weeks before the clinical onset of preeclampsia and only in women with previous preeclampsia. CONCLUSIONS: The pattern of elevated concentrations of sFlt1 and sEng, and low PlGF in high-risk pregnant subjects who develop preeclampsia is similar to that reported in low-risk pregnant women. However, differences in these factors among high-risk women who do and do not develop preeclampsia are modest, and do not appear to be clinically useful predictors in these high-risk pregnant women.

Does C-reactive protein predict recurrent preeclampsia?

OBJECTIVE: Evaluate association of the inflammatory marker C-reactive protein with recurrent preeclampsia. METHODS: Serum samples collected longitudinally in women with previous preeclampsia from the Maternal-Fetal Medicine Units Network trial of aspirin to prevent preeclampsia were assayed for CRP. RESULTS: Of 255 women studied, 50 developed recurrence. Baseline C-reactive protein concentration was similar between women who did and did not recur. After adjusting for confounders, neither elevated baseline C-reactive protein nor its change over gestation was associated with recurrence. CONCLUSION: In this group of women with previous preeclampsia, neither baseline C-reactive protein concentration nor change in concentration over gestation was associated with recurrent preeclampsia.

Hypertension in pregnancy.

Hypertension complicates 5% to 7% of all pregnancies. A subset of preeclampsia, characterized by new-onset hypertension, proteinuria, and multisystem involvement, is responsible for substantial maternal and fetal morbidity and is a marker for future cardiac and metabolic disease. This American Society of Hypertension (ASH) position paper summarizes the clinical spectrum of hypertension in pregnancy, focusing on preeclampsia. Recent research breakthroughs relating to etiology are briefly reviewed. Topics include classification of the different forms of hypertension during pregnancy, and status of the tests available to predict preeclampsia, and strategies to prevent preeclampsia and to manage this serious disease. The use of antihypertensive drugs in pregnancy, and the prevention and treatment of the convulsive phase of preeclampsia, eclampsia, with intravenous MgSO(4) is also highlighted. Of special note, this guideline article, specifically requested, reviewed, and accepted by ASH, includes solicited review advice from the American College of Obstetricians and Gynecologists.

Influence of maternal asthma and asthma severity on newborn morphometry.

OBJECTIVE: To determine if maternal asthma or asthma severity affects newborn morphometry. STUDY DESIGN: A secondary analysis was performed on data collected in a multicenter prospective observational cohort study of asthma in pregnancy. Patients enrolled included women with asthma stratified by severity of disease and controls. Asthma severity was defined according to the classification proposed by the National Asthma Education Program (NAEP) Report of the Working Group on Asthma and Pregnancy, modified to include medication requirements. Newborn morphometry measurements included birth weight (BW) and multiples of the median birth weight (BW-MOM), head circumference (HC), length (L), HC:BW ratio, and ponderal index (PI). RESULTS: Of 2480 patients there were 828 nonasthmatic controls, 828 with mild, 775 with moderate, and 49 with severe disease. Comparing all groups, there were statistically significant differences in maternal age (p < .001), race (p = .005), parity (p = .006), prepregnancy weight (p = .028), and medical care source (p = .001), with the severe asthma group having the highest mean maternal age (25.7 years), and proportion of African Americans (71.4%), proportion of multiparous patients (63.3%), and proportion of patients receiving government assistance (85.7%). When the control group was excluded from the comparisons, differences in prepregnancy weight and medical care source were no longer significant. BW-MOM and L did not differ between groups. The HC:BW ratio increased with asthma severity (p = .029) and was increased compared to controls (p = .010). This remained significant after controlling for confounding variables (both p <.001). HC was statistically significantly different between all groups (p = .032), as well as among women with varying degrees of asthma severity (p = .013), which was not clinically significant. After covariates adjustment, HC was not significantly different among all groups (p = .228), nor the asthma groups (p = .144). CONCLUSION: Asthma severity is associated with an increased HC:BW ratio. Severity was not found to impact HC, BW-MOM, L, or PI independently. However, the magnitudes of the effects were too small to suggest a clinically significant effect of asthma on neonatal morphometry in this large prospectively studied sample.

Interpreting abnormal proteinuria in pregnancy: the need for a more pathophysiological approach.

This review and opinion article focuses on the definitions and meanings of abnormal protein excretion in pregnancy, asking the following questions: Are our tests to determine abnormal proteinuria adequately performed? Are current guidelines for diagnosis of excessive proteinuria, especially when used to identify preeclampsia, supported by adequate data? Can the magnitude of proteinuria be used as a reliable clinical biomarker of the gravity of preeclampsia? Should timed urine collections, primarily 24-hour excretions, be supplanted by the urine protein/creatinine ratio in clinical practice? The answers to most of these questions are: We are not sure, or some guidelines are poorly supported by data and may prove erroneous. We suggest a more physiologic approach to assessment of proteinuria and believe that if clinicians and investigators looked at proteinuria in terms of how the kidney handles protein in health and disease it would lead to a more rational and evidence-based approach to proteinuria in pregnancy. Finally, we recommend that current cutoff for abnormal proteinuria be used to diagnose preeclampsia, but the level of proteinuria should not guide management. Other variables, such as status of blood pressure control, evidence of increasing organ damage in the liver and hematological systems, evidence of falling glomerular filtration rate, and signs of neurological involvement, are more reliable indicators of severity of preeclampsia.

Angiogenic dysfunction in molar pregnancy.

OBJECTIVE: Molar pregnancy is associated with very early-onset preeclampsia. Since excessive circulating antiangiogenic factors may play a pathogenic role in preeclampsia, we hypothesized that molar placentas produce more antiangiogenic proteins than normal placentas. STUDY DESIGN: This retrospective case-control study used a semiquantitative immunohistochemical technique to compare histologic sections of molar placentas to normal controls. Tissue slides were treated with 2 antisera: one recognized the antiangiogenic markers fms-like tyrosine kinase receptor 1 (Flt1) and its soluble form (sFlt1), while the other recognized vascular endothelial marker CD31. Stain intensity was graded from 1+ (strong focal staining) to 4+ (91-100% staining). RESULTS: Molar placentas (n = 19) showed significantly more staining than controls (n = 16) for Flt/sFlt1 (P < .0001). CONCLUSION: There was a significant difference in Flt1/sFlt1 immunostaining intensity when molar placentas were compared to controls. This supports a hypothesis that the phenotype of preeclampsia in molar pregnancy may result from trophoblasts overproducing at least 1 antiangiogenic protein.

ASH position paper: hypertension in pregnancy.

The American Society of Hypertension is publishing a series of Position Papers in their official journals throughout the 2008-2009 years. The following Position Paper originally appeared: JASH. 2008;2(6):484-494. Hypertension complicates 5% to 7% of all pregnancies. A subset of preeclampsia, characterized by new-onset hypertension, proteinuria, and multisystem involvement, is responsible for substantial maternal and fetal morbidity and is a marker for future cardiac and metabolic disease. This American Society of Hypertension, Inc (ASH) position paper summarizes the clinical spectrum of hypertension in pregnancy, focusing on preeclampsia. Recent research breakthroughs relating to etiology are briefly reviewed. Topics include classification of the different forms of hypertension during pregnancy, status of the tests available to predict preeclampsia, and strategies to prevent preeclampsia and to manage this serious disease. The use of antihypertensive drugs in pregnancy, and the prevention and treatment of the convulsive phase of preeclampsia, eclampsia, with intravenous magnesium sulfate is also highlighted. Of special note, this guideline article, specifically requested, reviewed, and accepted by ASH, includes solicited review advice from the American College of Obstetricians and Gynecologists.

Maternal plasma concentrations of the soluble tumor necrosis factor receptor 2 are increased prior to the diagnosis of preeclampsia.

OBJECTIVE: Soluble receptor levels of tumor necrosis factor (sTNF-R)-1 and -2 are increased during preeclampsia. We postulated the increase preceded overt disease. STUDY DESIGN: Archived plasma from the Eunice Kennedy Shriver National Institute of Child Health and Human Development aspirin to prevent preeclampsia in high risk women trial were used to measure serial sTNF-R1 and sTNF-R2 (enrollment, 24-28 week's gestation) in 986 women (577 also sampled at 34-38 weeks). RESULTS: Preeclampsia incidence was 21.2%. sTNF-R2 levels were higher at enrollment (P = .02) and weeks 24-28 (P = .01) in women who eventually developed preeclampsia. The magnitude of increase from baseline of both receptors was significantly greater in women who developed preeclampsia in the future. Women with week 24-28 sTNF-R2 levels in the highest quartile had significantly increased odds to develop preeclampsia (P = .03 vs quartile 1). This association was observed in the placebo but not the aspirin arm (P