Urinary concentrations of phthalate metabolites in relation to preeclampsia and other hypertensive disorders of pregnancy in the environmental influences on child health outcomes (ECHO) program.

BACKGROUND: Phthalate exposure may contribute to hypertensive disorders of pregnancy (HDP), including preeclampsia/eclampsia (PE/E), but epidemiologic studies are lacking. OBJECTIVES: To evaluate associations of pregnancy phthalate exposure with development of PE/E and HDP. METHODS: Using data from 3,430 participants in eight Environmental influences on Child Health Outcomes (ECHO) Program cohorts (enrolled from 1999 to 2019), we quantified concentrations of 13 phthalate metabolites (8 measured in all cohorts, 13 in a subset of four cohorts) in urine samples collected at least once during pregnancy. We operationalized outcomes as PE/E and composite HDP (PE/E and/or gestational hypertension). After correcting phthalate metabolite concentrations for urinary dilution, we evaluated covariate-adjusted associations of individual phthalates with odds of PE/E or composite HDP via generalized estimating equations, and the phthalate mixture via quantile-based g-computation. We also explored effect measure modification by fetal sex using stratified models. Effect estimates are reported as odds ratios (OR) with 95% confidence intervals (95% CIs). RESULTS: In adjusted analyses, a doubling of mono-benzyl phthalate (MBzP) and of mono (3-carboxypropyl) phthalate (MCPP) concentrations was associated with higher odds of PE/E as well as composite HDP, with somewhat larger associations for PE/E. For example, a doubling of MCPP was associated with 1.12 times the odds of PE/E (95%CI 1.00, 1.24) and 1.02 times the odds of composite HDP (95%CI 1.00, 1.05). A quartile increase in the phthalate mixture was associated with 1.27 times the odds of PE/E (95%CI 0.94, 1.70). A doubling of mono-carboxy isononyl phthalate (MCiNP) and of mono-carboxy isooctyl phthalate (MCiOP) concentrations were associated with 1.08 (95%CI 1.00, 1.17) and 1.11 (95%CI 1.03, 1.19) times the odds of PE/E. Effect estimates for PE/E were generally larger among pregnancies carrying female fetuses. DISCUSSION: In this study, multiple phthalates were associated with higher odds of PE/E and HDP. Estimates were precise and some were low in magnitude. Interventions to reduce phthalate exposures during pregnancy may help mitigate risk of these conditions.

Pregnancy-associated changes in urinary uromodulin excretion in chronic hypertension.

BACKGROUND: Pregnancy involves major adaptations in renal haemodynamics, tubular, and endocrine functions. Hypertensive disorders of pregnancy are a leading cause of maternal mortality and morbidity. Uromodulin is a nephron-derived protein that is associated with hypertension and kidney diseases. Here we study the role of urinary uromodulin excretion in hypertensive pregnancy. METHODS: Urinary uromodulin was measured by ELISA in 146 pregnant women with treated chronic hypertension (n = 118) and controls (n = 28). We studied non-pregnant and pregnant Wistar Kyoto and Stroke Prone Spontaneously Hypertensive rats (n = 8/strain), among which a group of pregnant Stroke-Prone Spontaneously Hypertensive rats was treated with either nifedipine (n = 7) or propranolol (n = 8). RESULTS: In pregnant women, diagnosis of chronic hypertension, increased maternal body mass index, Black maternal ethnicity and elevated systolic blood pressure at the first antenatal visit were significantly associated with a lower urinary uromodulin-to-creatinine ratio. In rodents, pre-pregnancy urinary uromodulin excretion was twofold lower in Stroke-Prone Spontaneously Hypertensive rats than in Wistar Kyoto rats. During pregnancy, the urinary uromodulin excretion rate gradually decreased in Wistar Kyoto rats (a twofold decrease), whereas a 1.5-fold increase was observed in Stroke-Prone Spontaneously Hypertensive rats compared to pre-pregnancy levels. Changes in uromodulin were attributed by kidney injury in pregnant rats. Neither antihypertensive changed urinary uromodulin excretion rate in pregnant Stroke-Prone Spontaneously Hypertensive rats. CONCLUSIONS: In summary, we demonstrate pregnancy-associated differences in urinary uromodulin: creatinine ratio and uromodulin excretion rate between chronic hypertensive and normotensive pregnancies. Further research is needed to fully understand uromodulin physiology in human pregnancy and establish uromodulin's potential as a biomarker for renal adaptation and renal function in pregnancy.

Machine learning approaches to predict gestational age in normal and complicated pregnancies via urinary metabolomics analysis.

The elucidation of dynamic metabolomic changes during gestation is particularly important for the development of methods to evaluate pregnancy status or achieve earlier detection of pregnancy-related complications. Some studies have constructed models to evaluate pregnancy status and predict gestational age using omics data from blood biospecimens; however, less invasive methods are desired. Here we propose a model to predict gestational age, using urinary metabolite information. In our prospective cohort study, we collected 2741 urine samples from 187 healthy pregnant women, 23 patients with hypertensive disorders of pregnancy, and 14 patients with spontaneous preterm birth. Using gas chromatography-tandem mass spectrometry, we identified 184 urinary metabolites that showed dynamic systematic changes in healthy pregnant women according to gestational age. A model to predict gestational age during normal pregnancy progression was constructed; the correlation coefficient between actual and predicted weeks of gestation was 0.86. The predicted gestational ages of cases with hypertensive disorders of pregnancy exhibited significant progression, compared with actual gestational ages. This is the first study to predict gestational age in normal and complicated pregnancies by using urinary metabolite information. Minimally invasive urinary metabolomics might facilitate changes in the prediction of gestational age in various clinical settings.

The association between maternal urinary phthalate metabolites concentrations and pregnancy induced hypertension: Results from the EDEN Mother-Child Cohort.

BACKGROUND: Studies have suggested that exposure to endocrine disruptors such as phthalates that are widely used in our daily life (food wrapping, cosmetics, toys, medical devices, polyvinyl chloride flooring, and building materials) might be related to raised blood pressure and increased risk of cardiovascular diseases. Phthalates might induce a pro-inflammatory response and increased oxidative stress and may be a cause of pregnancy induced hypertension. METHODS: We evaluated the association between maternal exposure to phthalates during pregnancy and pregnancy induced hypertension. 604 pregnant women were included and eleven phthalate metabolites were quantified in spot maternal urine samples collected between the 23rd and 28th week of gestation in a French EDEN mother-child cohort. The associations were assessed by applying multiple logistic regression analysis. RESULTS: Twenty nine (4,8%) mothers developed pregnancy induced hypertension. Two low molecular weight phthalate metabolites: Monoethyl phthalate (MEP) and Mono-n­butyl phthalate (MBP) were positively associated with pregnancy induced hypertension in crude (Odds Ratio: 1.43, 95% Confidence Interval: 1.04-1.96, p-value = 0.02 and 1.48, 1.10-2.01, p-value =0.01) and in adjusted (1.47, 1.01-2.14, p-value = 0.04 and 1.66, 1.11-2.47, p-value = 0.01) models respectively. CONCLUSION: Our data suggest that prenatal exposure to some phthalates, including MEP and MBP, might play a role in pregnancy induced hypertension.

Association of Urinary Strontium Levels with Pregnancy-induced Hypertension.

Pregnancy-induced hypertension (PIH), including gestational hypertension and preeclampsia, accounts for the majority of maternal and perinatal morbidity and mortality. Strontium (Sr) has been recently associated with preeclampsia in a small group of women; however, the role of Sr in PIH is not fully understood and warrants further investigation. In this study, we examined the association between urinary Sr levels and PIH, and assessed the effect of maternal age on the association. Urinary Sr concentrations were measured in 5423 pregnant women before delivery by inductively coupled plasma mass spectrometry (ICP-MS). Logistic regression analysis adjusting for potential confounders was applied to explore the association between Sr and PIH, and to evaluate the Sr-PIH relationship stratified by maternal age. Among the participants, 200 (3.83%) women were diagnosed with PIH. Compared with non-PIH women, women who developed PIH had lower urinary Sr concentrations (131.26 vs. 174.98 µg/L creatinine, P<0.01). With the natural log-transformed urinary creatinine-standardized Sr concentrations increasing, the risk of PIH decreased significantly [adjusted OR=0.60 (95%CI: 0.51, 0.72)]. Furthermore, the significant association of Sr with PIH was found among women under 35 years (P<0.01). Our finding suggested that Sr may play a potential protective role in the pathogenesis of PIH, especially among young pregnant women under 35 years old.

Potential urine biomarkers for gestational hypertension and preeclampsia.

Differential proteomic technology was used to identify urine proteomic profile of gestational hypertension and preeclampsia. Urine samples were collected from 10 patients with gestational hypertension, 10 patients with mild preeclampsia, 10 patients with severe preeclampsia and 10 normal pregnancies and analyzed by 2­D difference gel electrophoresis, then matrix assisted laser desorption ionization mass spectrometry was used to identify differential proteins. Subsequently, ELISA was used to verify the content variation of the identified proteins in 200 urine samples. In total, 30 differential proteins were identified. For prostaglandin­H2 D­isomerase (L­PGDS), perlecan and other 15 proteins, the contents in patients with gestational hypertension were higher than that of normal pregnancies, but lower in mild and severe preeclampsia. By contrast, serum albumin and α­1­antitrypsin was lower in samples from patients with gestational hypertension and higher in patients with mild and severe preeclampsia compared with normal pregnancies. ELISA verified that the urinary concentration of L­PGDS and perlecan were significantly lower in patients with preeclampsia than in normal pregnancies (P<0.05). Urine proteomics is a useful tool to identify potential biomarkers to distinguish between different types of hypertensive disorders in pregnancy. L­PGDS and perlecan could potentially be used as markers to reflect the state of renal function, and may participate in the genesis and development of renal injury during preeclampsia.

Decreased Ang-(1-7) and Downregulated Intrarenal RAS May Contribute to the Direct Podocyte Injury With Proteinuria in Preeclampsia.

The mechanisms of proteinuria development in preeclampsia (PE) are still enigmatic. Renin-angiotensin system (RAS) components may play a role. Maternal serum and urinary concentrations of angiotensin-(1-7) [Ang-(1-7)], angiotensin II (Ang II), and angiotensinogen in women with PE (n = 14), gestational hypertension (n = 14), and normal pregnancy were quantified. The alteration in these concentrations was used to evaluate their relationships with podocyturia and proteinuria in PE. In addition, the podocytes cultured in vitro were interfered in serum of preeclamptic and normotensive pregnant women, with or without Ang-(1-7). The morphologic change in podocyte was observed using a microscope. The changes in podocyte-specific proteins (nephrin, CD2-associated protein [CD2AP]), the cytoskeletal protein F-actin, the tight junction protein (ZO-1), and Mas receptor (MasR) were examined by immunofluorescence. Western blot was used to examine the expression and variation of MasR. We found that the concentrations of RAS components were associated with prepartal urinary podocyte number, random urine albumin/creatinine ratio, blood pressure, and renal function. The expression of nephrin, F-actin, ZO-1, and MasR on podocytes interfered in serum of PE was significantly decreased compared to normal control and normal pregnant serum group in vitro, yet their expression was significantly increased after coculture by 10-6 mol/L Ang-(1-7) and the preeclamptic serum. The expression of CD2AP had no significant difference. We concluded that decreased Ang-(1-7) and downregulated intrarenal RAS contributed to the direct podocyte injury with proteinuria in PE.

Inverse correlation between serum adiponectin level and albuminuria in pregnancy-induced hypertension patients.

Adiponectin protects against the development of albuminuria in rodent experiments and patients with diabetic kidney disease. However, it is not clear whether higher circulating adiponectin levels have the same effect in patients with pregnancy-induced hypertension (PIH). Urine albumin excretion (UAE) is an easy to use test and a powerful index for routine management of PIH patients. This study aimed to investigate the relationship between serum total adiponectin and UAE in PIH patients. A total of 156 PIH patients were enrolled and divided into three groups according to adiponectin tertiles. UAE level was compared among three groups. Simple and multiple regression analyses were used to assess the relationship between clinical parameters and UAE. The mean UAE values tended to decrease according to adiponectin tertiles (Tertile 1, 164.8 µg/min; Tertile 2, 151.0 µg/min; and Tertile 3, 134.5 µg/min). Univariate analysis showed that body mass index, systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, uric acid, and adiponectin were significantly associated with UAE. Moreover, only body mass index, systolic blood pressure, total cholesterol, and adiponectin were correlated with UAE in the multivariate model. Adiponectin was found to be a significant determinant for decreased UAE (ß = -0.124, P< 0.01), suggesting that adiponectin might be involved in the development of albuminuria in PIH. Further studies are needed to unravel the underlying mechanisms and to identify if adiponectin would be a potential therapeutic target to decrease albuminuria in PIH.

Early pregnancy bisphenol and phthalate metabolite levels, maternal hemodynamics and gestational hypertensive disorders.

STUDY QUESTION: Are early-pregnancy urinary bisphenol and phthalate metabolite concentrations associated with placental function markers, blood pressure (BP) trajectories during pregnancy and risk of gestational hypertensive disorders? SUMMARY ANSWER: Early-pregnancy bisphenols and phthalate metabolites were not consistently associated with maternal BP changes or gestational hypertensive disorders, but subclinical, statistically significant associations with placental angiogenic markers and placental hemodynamics were identified. WHAT IS KNOWN ALREADY: In vitro studies suggest that bisphenols and phthalate metabolites may disrupt early placental development and affect the risk of gestational hypertensive disorders. Previous studies investigating effects of bisphenols and phthalate metabolites on gestational hypertensive disorders reported inconsistent results and did not examine placental function or BP throughout pregnancy. STUDY DESIGN, SIZE, DURATION: In a population-based prospective cohort study, bisphenol and phthalate metabolite concentrations were measured in a spot urine sample in early pregnancy among 1396 women whose children participated in postnatal follow-up measurements. PARTICIPANTS/MATERIALS, SETTING, METHODS: After exclusion of women without any BP measurement or with pre-existing hypertension, 1233 women were included in the analysis. Urinary bisphenol and phthalate metabolite concentrations were measured in early-pregnancy [median gestational age 13.1 weeks, inter-quartile range 12.1-14.5]. Molar sums of total bisphenols and of low molecular weight phthalate, high molecular weight (HMW) phthalate, di-2-ethylhexylphthalate, and di-n-octylphthalate metabolites were calculated. Placental angiogenic markers (placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFlt)-1), placental hemodynamic function measures (umbilical artery pulsatility index (PI), uterine artery resistance index (RI), notching and placental weight), and maternal BP were measured in different trimesters. Information on gestational hypertensive disorders was obtained from medical records. MAIN RESULTS AND THE ROLE OF CHANCE: Each log unit increase in HMW phthalate metabolites was associated with a 141.72 (95% CI: 29.13, 373.21) higher early pregnancy sFlt-1/PlGF ratio (range in total sample 9-900). This association was driven by mono-[(2-carboxymethyl)hexyl]phthalate. In the repeated measurements regression models, each log unit increase in bisphenol A was associated with a 0.15 SD (95% CI: 0.03, 0.26) higher intercept and -0.01 SD (95% CI: -0.01, -0.00) decreasing slope of the umbilical artery PI Z-score and a -1.28 SD (95% CI: -2.24, -0.33) lower intercept and 0.06 SD (95% CI: 0.02, 0.11) increasing slope of the uterine artery RI Z-score. These associations remained significant after Bonferroni correction. Early-pregnancy bisphenols or phthalate metabolites showed no consistent associations with any other outcome. LIMITATIONS, REASONS FOR CAUTION: Information on a large number of potential confounders was available but was partly self-reported. Bisphenols and phthalate metabolites, which typically have a half-life of 24-48 h, were measured via single spot urine samples in early-pregnancy. In addition, at the current sample size, the study was powered to detect an odds ratio of 1.57 for gestational hypertension and 1.78 for pre-eclampsia, but was underpowered to perform multivariable analyses for these outcomes. Further studies combining data from different cohorts may be necessary to increase power. These limitations are possible sources of non-differential misclassification leading to bias toward the null. WIDER IMPLICATIONS OF THE FINDINGS: Bisphenols and phthalate metabolites were not associated with longitudinal changes in BP in pregnancy in our low-risk population. The observed subclinical associations of phthalates with the sFlt-1/PlGF ratio and of bisphenol A with placental hemodynamics may contribute to adverse pregnancy outcomes. Our results are therefore more supportive of an association of early pregnancy bisphenols and phthalate metabolites with risk for pre-eclampsia than with gestational hypertension. STUDY FUNDING/COMPETING INTEREST(S): This analysis was supported by Grant (ES022972) from the National Institutes of Health, USA. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health. The authors report no conflicts of interest.

Urine protein-to-creatinine ratio: a point of care for the diagnosis of preeclampsia.

BACKGROUND: The aim of this study was to determine the correlation between the urine protein-creatinine ratio (UPCR) and the 24-hour urine protein excretion test (UPET), and to identify the optimal threshold values of UPCR for the diagnosis of preeclampsia and its severe form. METHODS: This prospective cohort study included 81 hypertensive pregnant patients who had a 24-h UPET and a UPCR tests. Two groups were created using a UPCR cut-off of 23.2 mg/mmol (40 negative UPCR, 41 positive UPCR). RESULTS: Forty-nine patients of were diagnosed with preeclampsia, and 23 of them had a severe disease. There was a significant correlation between UPCR and 24-h UPET. A cut-off UPCR value of 23.2 mg/mmol had an area under the curve (AUC) of 0.27, sensitivity of 89%, specificity 88%, positive predictive value 90%, a positive likelihood ratio (+LR) of 7.41 and a negative likelihood ratio (-LR) of 0.13 for the diagnosis of preeclampsia. UPCR value of 325 mg/mmol had an AUC of 0.841, and a sensitivity of 83%, specificity 81%, positive predictive value 81%, +LR of 4.4 and -LR of 0.2 for the diagnosis of severe preeclampsia. CONCLUSIONS: The UPCR test is highly correlated with the 24-h UPET. We propose a novel and sensitive cut-off for the diagnosis of preeclampsia by UPCR test. The UPCR test can be used for the identification of hypertensive patients with preeclampsia and severe disease.

[Features of the urine peptidome under the condition of hypertensive pathologies of pregnancy]. / Osobennosti peptidoma mochi pri gipertenzivnykh patologiiakh beremennykh.

In order to find a peptide panel to differentiate close hypertensive conditions a case-control study was designed for 64 women from 4 groups: preeclampsia (PE), chronic hypertension superimposed with PE, chronic hypertension, and healthy individuals. Chromatography coupled with mass-spectrometry and subsequent bioinformatic analysis showed several patterns in the changes of the urine peptidome. There were 36 peptides common for four groups. Twenty two of them 22 belonged to alpha-1-chain of collagen I, nine peptides were from alpha-1-chain of collagen III, two from alpha-2-chain of collagen I, one from alpha-1/2-chain of collagen I, one from alpha-1-chain of collagen I/XVIII and one from uromodulin. Patients with hypertensive disorders had 34 common peptides: 12 from alpha-1-chain of collagen I, 10 from fibrinogen alpha-chain, eight from alpha-1-chain of collagen III, and 4 per other types of collagen. Comparative analysis revealed 12 peptides, which could be used as a diagnostic panel for confident discrimination of pregnant women with various hypertensive disorders.

A systematic review and meta-analysis of hypocalciuria in pre-eclampsia.

BACKGROUND: Small observational studies have demonstrated that pre-eclampsia is associated with hypocalciuria. OBJECTIVES: To compare urinary calcium excretion in pre-eclampsia, gestational hypertension, and chronic hypertension with that in normotensive pregnancies. SEARCH STRATEGY: Online databases were searched through February 2016 using medical subject headings "calcium homeostasis," "calcium excretion," "hypocalciuria," and "pre-eclampsia." SELECTION CRITERIA: Observational studies were included that evaluated calcium excretion with 24-hour urine collection in patients with pre-eclampsia compared with normotensive pregnant women. DATA COLLECTION AND ANALYSIS: Data were extracted from identified studies. The primary outcome was 24-hour urinary calcium excretion. Weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated. MAIN RESULTS: Twenty-one studies were included. Urinary calcium excretion was lower among women with pre-eclampsia than among those with normotensive pregnancies (WMD -158.43, 95% CI -187.95 to -128.92) or chronic hypertension (WMD -92.92, 95% CI -100.55 to -85.29). Excretion was also reduced in severe versus mild pre-eclampsia (WMD -35.00, 95% CI -58.94 to -11.07) and gestational hypertension versus normotensive pregnancies (WMD -50.95, 95% CI -57.74 to -44.17). Calcium excretion was not significantly lower in chronic hypertension versus normotensive pregnancies (WMD -64.45, 95% CI -135.98 to 7.08). CONCLUSIONS: Urinary calcium excretion decreases with increasing severity of pregnancy-induced hypertensive disorders, but this trend is not observed in chronic hypertension.

Evaluation of maternal early obstetric warning system (MEOWS chart) as a predictor of obstetric morbidity: a prospective observational study.

OBJECTIVES: Maternal Early Obstetric Warning System (MEOWS) chart adopted from CEMACH 2003-2005 report is based on the principle that abnormalities in physiological parameters precede critical illness. The 'track and trigger' of physiological parameters on this chart can aid in recognition of maternal morbidity at an early stage, ultimately halting the cascade of severe maternal morbidity and mortality. The objectives of our study were to evaluate MEOWS chart as a bedside screening tool for predicting obstetric morbidity and to correlate each physiological parameter individually with obstetric morbidity. STUDY DESIGN: It was a prospective observational study conducted in labour wards of Guru Teg Bahadur Hospital, Delhi, India from October 2012 to April 2014. Physiological parameters of 1065 study subjects (including pregnant women in labour >28 weeks of gestation and postpartum women up to 6 weeks after delivery) were recorded on MEOWS chart. A trigger was defined as a single markedly abnormal observation (red trigger) or the combination of two simultaneously mildly abnormal observation (two yellow triggers). Based on outcome at time of discharge, Category 1 (normal and recovered without morbidity) and Category 2 (recovered with morbidity or mortality) were defined. Chi-square and Fischer's exact test were used for comparison between two groups. Performance of MEOWS chart was evaluated using Exact's method. Relative risk of morbidity (odd's ratio) and 95% confidence interval was calculated for individual parameter. p<0.05 was considered as significant. RESULTS: Two-hundred and eighty-four (26.6%) women triggered to abnormal zones on these charts. One-hundred and seventy-seven (16.61%) fulfilled the criteria for obstetric morbidity. MEOWS chart was 86.4% sensitive, 85.2% specific with a positive and negative predictive value of 53.8% and 96.9% respectively for prediction of obstetric morbidity. Individual parameters of MEOWS chart also had a significant correlation (p<0.05) with obstetric morbidity. CONCLUSIONS: MEOWS chart emerged as a useful bedside screening tool for prediction of obstetric morbidity and should be used routinely in every obstetric unit. Strict monitoring and documentation of all the vital parameters should be fundamental part of any patient's assessment to pick up acute illness at very early stage and to make a difference in final outcome.

Salt Intake, Home Blood Pressure, and Perinatal Outcome in Pregnant Women.

BACKGROUND: The relationship between salt (sodium chloride) intake and pregnancy-induced hypertension (PIH) remains unclear. The aim of this study was therefore to investigate the current status of salt intake during pregnancy and identify effective predictors for PIH. METHODS AND RESULTS: Participants were 184 pregnant women who collected 24-h home urine as well as early morning urine samples. We investigated urinary salt excretion, home blood pressure (HBP) measurements for 7 consecutive days before the 20th and after the 30th gestational week, and the development of PIH. Urinary salt excretion according to early morning urine before the 20th gestational week was 8.6±1.7 g/day, and was significantly correlated with that measured from 24-h collected urine. Early morning urine estimated urinary salt excretion was slightly but significantly increased during pregnancy. HBP was 102±10/63±8 mmHg before the 20th gestational week and 104±12/64±10 mmHg after the 30th gestational week. On multiple regression analysis, serum uric acid and body mass index, but not urinary salt excretion, contributed to HBP both before the 20th and after the 30th gestational week. Fourteen participants (7.6%) developed PIH. On multivariate analysis, higher HBP and older age, but not urinary salt excretion, were significantly associated with PIH. CONCLUSIONS: Higher HBP and older age, but not urinary salt excretion, are predictors of PIH. (Circ J 2016; 80: 2165-2172).

Urinary excretion of brush-border enzymes of the proximal renal tubules in pregnant women with hypertensive disorders.

OBJECTIVES: The aim of our study was to evaluate urinary excretion of three brush border enzymes: gamma-glutamyl transferase, alanine aminopeptidase, and leucyl aminopeptidase in pregnant women with various types of hypertensive disorders. MATERIAL AND METHODS: The study included 120 pregnant women, further subdivided into four groups: 41 women at ≥ 20 weeks gestation with gestational hypertension, 28 women > 20 weeks of pregnancy with preeclampsia, 21 women with chronic hypertension identified > 20 weeks of pregnancy and 30 healthy pregnant controls. RESULTS: No significant differences in urinary levels of all three of the brush border enzymes were found between the groups. Also, there was no correlation between enzyme concentration in the urine and blood pressure values in any of the analyzed groups of pregnant women. CONCLUSIONS: The obtained results suggest no damage to the brush border of the proximal kidney tubules in the early stages of disorders associated with increased blood pressure during pregnancy.

First Trimester Urine and Serum Metabolomics for Prediction of Preeclampsia and Gestational Hypertension: A Prospective Screening Study.

Hypertensive disorders of pregnancy, including preeclampsia, are major contributors to maternal morbidity. The goal of this study was to evaluate the potential of metabolomics to predict preeclampsia and gestational hypertension from urine and serum samples in early pregnancy, and elucidate the metabolic changes related to the diseases. Metabolic profiles were obtained by nuclear magnetic resonance spectroscopy of serum and urine samples from 599 women at medium to high risk of preeclampsia (nulliparous or previous preeclampsia/gestational hypertension). Preeclampsia developed in 26 (4.3%) and gestational hypertension in 21 (3.5%) women. Multivariate analyses of the metabolic profiles were performed to establish prediction models for the hypertensive disorders individually and combined. Urinary metabolomic profiles predicted preeclampsia and gestational hypertension at 51.3% and 40% sensitivity, respectively, at 10% false positive rate, with hippurate as the most important metabolite for the prediction. Serum metabolomic profiles predicted preeclampsia and gestational hypertension at 15% and 33% sensitivity, respectively, with increased lipid levels and an atherogenic lipid profile as most important for the prediction. Combining maternal characteristics with the urinary hippurate/creatinine level improved the prediction rates of preeclampsia in a logistic regression model. The study indicates a potential future role of clinical importance for metabolomic analysis of urine in prediction of preeclampsia.

Salt intake and the validity of a salt intake assessment system based on a 24-h dietary recall method in pregnant Japanese women.

BACKGROUND: Information regarding salt intake in pregnant women in Japan is limited. An electronic system for the assessment of salt intake using a 24-h dietary recall method has been developed in Japan. The objectives of the present study were to investigate salt intake in pregnant women and to compare the salt intake estimated by the electronic salt intake assessment system with that measured by 24-h urinary salt excretion (24-hUNaCl). METHODS: Data were collected on 24-hUNaCl and salt intake estimated by the salt intake assessment system for 35 pregnant Japanese women at approximately 20 weeks of gestation. The adjusted 24-hUNaCl (24-hUNaCl/[the number of urinations during the examination day--the number of missing urine collections] × the number of urinations during the examination day, g/day) was used as a standard. RESULTS: The mean adjusted 24-hUNaCl was 7.7 ± 2.5 g/day, and mean systolic/diastolic blood pressure values were 106.1 ± 8.6/62.8 ± 6.5 mmHg. The adjusted 24-hUNaCl was significantly correlated with the salt intake estimated by the salt intake assessment system (r = 0.47, p = 0.004). Bland-Altman analysis showed no significant mean difference (adjusted 24-hUNaCl--salt intake estimated by the assessment system = -0.36 g/day, p = 0.4) and no significant proportional bias (p = 0.1). CONCLUSION: These results suggest that pregnant women in Japan restrict their salt intake, at least when they are being examined for salt intake. They also suggest that repeated use of the described system may be useful in estimating salt intake in pregnant women.

Maternal venous Doppler characteristics are abnormal in pre-eclampsia but not in gestational hypertension.

OBJECTIVE: To compare functional characteristics of maternal thoraco-abdominal arteries and veins in proteinuric and non-proteinuric hypertension in pregnancy. METHODS: This retrospective study included women with singleton pregnancies during the third trimester, which were either uncomplicated or complicated with different clinical types of hypertension: non-proteinuric gestational hypertension (GH), early-onset pre-eclampsia (PE) diagnosed < 34 weeks or late-onset PE diagnosed ≥ 34 weeks. Demographic maternal and neonatal data were recorded, together with maternal serum and urine analytes. All women underwent standardized automated blood-pressure measurement, together with non-invasive impedance cardiography (ICG), for measurement of cardiac output (CO), aortic flow velocity index (VI) and aortic flow acceleration index (ACI). A standardized combined Doppler-electrocardiography assessment of maternal venous hemodynamics was performed to measure renal interlobar vein impedance index (RIVI), hepatic vein impedance index (HVI) and venous pulse transit time (VPTT) in liver and kidneys. Finally, resistance index (RI), pulsatility index (PI) and arterial pulse transit time (APTT) were measured in the uterine arcuate arteries. Mann-Whitney U-tests and Fisher's exact tests were used for intergroup comparisons, and linear dependence between variables was assessed using Pearson's correlation coefficient (r). RESULTS: A total of 150 pregnancies were evaluated: 22 with uncomplicated pregnancy, 41 GH, 31 early PE and 56 late PE. Aortic VI and ACI were lower in GH, early PE and late PE than in uncomplicated pregnancy. Both early PE and late PE differed from GH by having shorter APTT in the uterine arcuate arteries and higher RIVI. Hemodynamic abnormalities were most pronounced in early PE, during which uterine arcuate artery RI was higher and VPTT in kidneys was shorter than in late PE. There was a significant correlation between degree of proteinuria and RIVI for the left (r = 0.381) and right (r = 0.347) kidney in late PE, but this was not true for early PE. CONCLUSIONS: There is a gradient of worsening arterial and venous hemodynamic abnormalities from GH to late PE and then to early PE. Venous hemodynamic abnormalities are present only in PE, with a linear correlation between proteinuria and RIVI in late PE. The role of the maternal venous compartment in the pathophysiology and etiology of PE-related symptoms may be much more important than considered at present.

Alto rendimiento clínico entre albuminuria semicuantitativa y proteinuria de 24 horas en pacientes con sospecha de síndrome hipertensivo del embarazo / High clinical performance between semiquantitative albuminuria and 24-hour proteinuria in patients with suspected hypertensive syndrome of pregnancy

ANTECEDENTES: La evaluación precisa de la proteinuria constituye un pilar importante para el diagnóstico del síndrome hipertensivo del embarazo (SHE). El estándar dorado para esta medición es la recolección de orina en 24 horas, pero debido a la duración de la toma de la muestra, alternativas como la albuminuria semicuantitativa se utiliza con mayor frecuencia en los servicios de urgencia de nuestro país. OBJETIVO: Evaluar el rendimiento diagnóstico de la albuminuria semicuantitativa y su asociación con proteinuria de 24 horas en pacientes con SHE. MÉTODOS: Estudio retrospectivo de 145 pacientes con sospecha de SHE atendidas en el Hospital Padre Hurtado, Chile. A todas las pacientes se le realizó albuminuria semicuantitativa (categorizada entre 0+ y 4+) y proteinuria de 24 horas (positivo si >0,3 gramos/24 horas). Se realizó análisis por grupos compuestos de albuminuria semicuantitativa y resultado positivo en proteinuria de 24 horas. RESULTADOS: Se evidenció una sensibilidad de 50%, especificidad de 100%, VPP de 100%, VPN de 65,7%, LR+ de 50 y un LR- de 0,5. CONCLUSIÓN: La albuminuria semicuantitativa ≥2+ muestra una fuerte asociación con proteinuria ≥0,3 g/24 horas y es un método rápido para evaluar SHE.

BACKGROUND: One of the basis for the diagnosis of pregnancy induced hypertension syndrome (PIHS), includes the precise evaluation of proteinuria. The gold standard for its evaluation is the collection of a 24-hour urine specimen, but because it is a slow method, other alternatives, such as semi-quantitative albuminuria have been used more frequently on our emergency rooms. OBJECTIVE: To assess the diagnostic performance of semi-quantitative albuminuria and its association with proteinuria measured in a 24-hour urine specimen collection, in patients with PIHS. METHODS: Retrospective study of 145 patients with clinical suspicion of PIHS who assisted to Hospital Padre Hurtado, Chile. Semi-quantitative albuminuria (categorized as 0 to 4+) and proteinuria measured in a 24-hour urine specimen collection was measured on every patient. Abnormal values of proteinuria were considered when values exceeded 0.3 g/24 hours. Composite outcomes analysis was done between albuminuria groups and positive proteinuria in 24 hrs. RESULTS: Sensibility and specificity of semi-quantitative albuminuria was of 50% and 100%, respectively, with a PPV: 100%, NPV: 65.7%, LR+: 50 and a LR-: 0.5. CONCLUSION: semi-quantitative albuminuria ≥2+ shows a strong association with proteinuria ≥0.3 g/24 hours and it could be used as a fast method to assess PIHS.

Maternal proteinuria in twin compared with singleton pregnancies.

OBJECTIVE: To compare 24-hour urinary protein excretion in twin and singleton pregnancies not complicated by hypertension. METHODS: We prospectively evaluated mean 24-hour urinary protein excretion in twin and singleton pregnancies between 24 0/7 weeks and 36 0/7 weeks of gestation. Women with urinary tract infections, chronic hypertension, pregestational diabetes, and renal or autoimmune diseases were excluded. Collection adequacy was assessed by urinary creatinine excretion adjusted for maternal weight. RESULTS: Adequate samples were obtained from 50 twin and 49 singleton pregnancies at a mean gestational age of 30 weeks. At collection, the two groups were similar with regard to maternal age, gestational age, body mass index, and blood pressure. Mean urinary protein excretion was higher in twin compared with singleton pregnancies (269.3±124.1 mg compared with 204.3±92.5 mg, P=.004). Proteinuria (300 mg/day protein or greater) occurred in 38.0% (n=19) of twin and 8.2% (n=4) of singleton pregnancies (P<.001). After adjusting for confounding variables, the difference in mean total protein excretion remained significant (P=.004) and twins were more likely to have proteinuria compared with singleton pregnancies (adjusted odds ratio 9.1, 95% confidence interval 2.1-38.5). Nineteen participants developed a hypertensive disorder at a mean of 7.7 weeks after the urine collection (range 2.6-14.5 weeks). After excluding these women, proteinuria was present in 43% of twin and 7% of singleton pregnancies (P<.001). CONCLUSION: Mean 24-hour urinary protein excretion in twin pregnancies is greater than in singletons. These data suggest a reevaluation of the diagnostic criteria for preeclampsia in twin pregnancies. LEVEL OF EVIDENCE: II.