Pregnancy-associated plasma protein-A2 levels are increased in early-pregnancy gestational diabetes: a novel biomarker for early risk estimation.

AIM: To determine whether pregnancy-associated plasma protein-A2 levels are increased in early pregnancies complicated by gestational diabetes and whether gestation age influences levels. The possible use of pregnancy-associated plasma protein-A2 as a pre-screening biomarker to reduce the need for performing oral glucose tolerance tests in pregnant women was also investigated. METHODS: Pregnant women were diagnosed with gestational diabetes in early pregnancy after a 2-hour 75 g oral glucose tolerance test in the catchment area of Skåne University Hospital, Lund, Sweden during 2011-2015 (n = 99). Age- and BMI-matched pregnant women without diabetes were recruited at similar gestational ages from maternal healthcare centres in the same geographical area during 2014-2015 to act as controls (n = 100). Circulating pregnancy-associated plasma protein-A2 was analysed in participant serum using commercially available enzyme-linked immunosorbent assay kits. RESULTS: Circulating pregnancy-associated plasma protein-A2 was increased in women diagnosed with gestational diabetes [13.5 (9.58-18.8) ng/ml] compared with controls [8.11 (5.74-11.3) ng/ml; P < 0.001]. Pregnancy-associated plasma protein-A2 was associated with gestational diabetes independent of age, BMI, C-peptide and adiponectin (P < 0.001). Pregnancy-associated plasma protein-A2 as a pre-screening biomarker to identify women at a decreased risk of gestational diabetes resulted in a negative predictive value of 99.7%, with a sensitivity of 96% and a specificity of 30% at a cut-off level of 6 ng/ml. CONCLUSIONS: This is the first study to show increased pregnancy-associated plasma protein-A2 levels in gestational diabetes. Pregnancy-associated plasma protein-A2 also shows promise as a pre-screening biomarker with the potential to reduce the need for performing oral glucose tolerance tests in early pregnancy. Future prospective cohort studies in a larger group of both high- and low-risk women are, however, needed to further confirm this observation.

Serum amyloid a protein and C-reactive protein in normal pregnancy and preeclampsia.

AIMS: To study plasma levels of serum amyloid A protein and C-reactive protein in pregnant women with and without preeclampsia and non-pregnant women. Plasma levels of haptoglobin, orosomucoid and ceruloplasmin were also analyzed. METHODS: The study included 295 women with uncomplicated pregnancies, 57 women diagnosed with preeclampsia, and 58 healthy non-pregnant women. Plasma concentrations of acute phase proteins were analyzed by particle-enhanced immunoassays. Non-parametric Kruskal-Wallis and Mann-Whitney U tests were used to test differences between the groups. RESULTS: Plasma levels of C-reactive protein and ceruloplasmin were increased in pregnant women with and without preeclampsia compared to non-pregnant women. Plasma levels of serum amyloid A protein and C-reactive protein were not elevated in women with preeclampsia compared to women with normal pregnancy. CONCLUSION: The description of preeclampsia as a systemic inflammatory state was not reflected in the plasma levels of serum amyloid A protein and C-reactive protein.

Vascular mechanical properties and endothelial function in pre-eclampsia with special reference to bilateral uterine artery notch.

OBJECTIVES: To assess whether women with pre-eclampsia (PE) have different properties of the blood vessel wall compared to healthy pregnant controls. Further, to evaluate endothelial function and vascular mechanical properties in women with PE with special regard to its association with bilateral uterine artery notch and placental histopathology. PARTICIPANTS: Some 57 Caucasian pregnant women: 23 with uncomplicated pregnancies and normal uterine artery Doppler, and 34 with PE, the PE group comprising 2 subgroups according to the presence (n=20) or absence (n=14) of bilateral uterine artery notches. METHODS: Ultrasonic echo-tracking assessed the elastic properties of the common carotid artery, abdominal aorta and popliteal artery. Flow-mediated dilatation (FMD) of the brachial artery was measured by ultrasonography. Histopathological examination of the placenta was carried out in 46 pregnancies: 18 uncomplicated pregnancies, 15 with PE with bilateral notch, and 13 with PE without bilateral notch. RESULTS: There were no significant differences in carotid, aortic or popliteal vessel wall stiffness either between women with PE and controls or within the PE group. FMD was significantly lower in women with PE than in controls (p=0.03). The lowest FMD was observed in pre-eclamptic women with bilateral uterine artery notches 9.5% (SD: 5.3) compared to 11.6% (SD: 5.4) in pre-eclamptic women without bilateral uterine artery notch, and 13.4% (SD: 4.0) in controls (p=0.01). Bilateral uterine artery notching was significantly associated with a lower FMD (OR: 0.87; 95% CI: 0.77-0.98). There were significantly more placentas with high ischaemic score in the bilateral notch group than in the group with PE and normal circulation. CONCLUSIONS: There were no differences in vessel wall stiffness between women with PE and healthy controls. Women with PE showed signs of endothelial dysfunction, significantly more pronounced in women with bilateral uterine artery notch. Bilateral uterine artery notch was associated with ischaemic pathology of the placenta. Notwithstanding, a significant number of placentas in the PE group failed to show noteworthy ischaemic or other morphological changes that could explain the role of the placenta in the development of PE.

Increased plasma levels of beta2-microglobulin, cystatin C and beta-trace protein in term pregnancy are not due to utero-placental production.

OBJECTIVE: To study concentration gradients of the low molecular mass proteins, beta2-microglobulin, cystatin C and beta-trace protein, between the uterine and ante-cubital veins, the umbilical artery and vein and in the amniotic fluid compartment. MATERIALS AND METHODS: The study comprised 27 healthy women with uncomplicated pregnancies undergoing caesarean section at term. Samples were collected simultaneously and paired t-tests were used to compare mean plasma concentrations. RESULTS: There was no significant concentration gradient in the plasma levels of beta2-microglobulin, cystatin C or beta-trace protein between the uterine and antecubital veins. There were no correlations between the protein levels in the compartments. CONCLUSION: The utero-placental unit does not contribute significantly to the maternal levels of beta2-microglobulin, cystatin C and beta-trace protein in normal pregnancy, and the proteins are not likely to be transferred across the placental barrier.

Temporal changes of the plasma levels of cystatin C, beta-trace protein, beta2-microglobulin, urate and creatinine during pregnancy indicate continuous alterations in the renal filtration process.

OBJECTIVE: To determine the plasma levels of the renal functional markers creatinine, urate, cystatin C, beta2-microglobulin and beta-trace protein in samples from the first, second, early third and late third trimesters of 398 healthy women with uncomplicated singleton pregnancies. MATERIAL AND METHODS: Plasma samples from 58 healthy non-pregnant women served as controls. The creatinine levels were significantly lower at all time-points in pregnancy, whereas the urate levels were lower during the first and second trimesters but increased in the late third trimester. The cystatin C, beta2-microglobulin and beta-trace protein levels displayed similar changes with increased levels in the third trimester but unaltered levels during the first and second trimesters. RESULTS: The results indicate an increased filtration of low-molecular weight molecules during pregnancy, particularly during the first and second trimesters, whereas filtration of 10-30 kDa molecules is decreased in the third but unaltered in the first and second trimesters. The levels of albumin and alph2-macroglobulin were measured in the same samples. CONCLUSIONS: The albumin levels decreased in the second and third trimesters, whereas the levels of chi2-macroglobulin were unchanged, which is compatible with a virtually unaltered transfer of chi2-macroglobulin between the intra- and extravascular space during pregnancy and a significantly increased extravascular fraction of albumin.

Cystatin C, beta-2-microglobulin and beta-trace protein in pre-eclampsia.

BACKGROUND: An altered renal function is an essential component of the patho-physiology of pre-eclampsia. The plasma levels of low molecular mass proteins, e.g. beta-trace protein, beta-2-microglobulin and cystatin C, are increased in the third trimester of normal pregnancy. The plasma levels of cystatin C and beta-2-microglobulin are further increased in pre-eclampsia, and the cystatin C level has been reported to be a reliable marker for the disease. The aim of this investigation was to study the plasma levels of beta-trace protein, beta-2-microglobulin and cystatin C in pre-eclampsia, and to determine the diagnostic performance of these proteins compared to that of urate and creatinine. METHODS: A case-control study of 57 women diagnosed with pre-eclampsia, and 218 healthy women with uncomplicated singleton pregnancies in the third trimester. Women in the catchment area of Lund, Sweden, were included during an 18-month period from October 2003 to April 2005. Venous blood samples were drawn upon inclusion when diagnosis was made. The maternal plasma concentrations of the 3 proteins were analysed by automated particle-enhanced immunoturbidimetric assays. RESULTS: The plasma levels of the 3 proteins were significantly higher in the third trimester of pre-eclamptic patients compared to healthy pregnant women in the third trimester. The upper reference limits (parametric 97.5 percentile) were 2.57 mg/l for beta-2-microglobulin, 0.72 mg/l for beta-trace protein and 1.37 mg/l for cystatin C. ROC analysis showed similar diagnostic performance for the 3 proteins, with beta-trace protein displaying the best diagnostic performance of all the analytes. CONCLUSIONS: In this study, the maternal plasma levels of beta2-microglobulin, beta-trace protein and cystatin C were all significantly elevated in pre-eclampsia compared to those of healthy pregnant women, and displayed similar diagnostic performance for diagnosing pre-eclampsia. The results indicate that low molecular mass proteins are useful as markers of renal impairment in pre-eclampsia.

Antepartum percutaneous renal biopsy.

OBJECTIVE: To assess the value and adverse effects of an ultrasound-guided renal biopsy technique in women with normal and pathologic pregnancies. METHOD: Biopsy samples were taken from 36 women with hypertensive disease (28 with pre-eclampsia) and 18 healthy pregnant women using a thin needle and an ultrasound-guided biopsy device. RESULTS: Glomerular endotheliosis, a structural change typical of pre-eclampsia, was found in all hypertensive women, but it was more pronounced in the 28 pre-eclamptic women than in the 8 women with nonproteinuric hypertension. A similar change, however, was seen in 11 of the 18 controls. One serious adverse event occurred, retroperitoneal hematoma, in the woman with the most severe pre-eclampsia. CONCLUSION: Glomerular endotheliosis is not to be considered pathognomonic for pre-eclampsia. Few complications followed renal biopsy in this study, but complications arose in the sickest patient. It is probably not advisable to perform antepartum renal biopsies in pregnant women with a rapidly deteriorating renal function and swollen kidneys. In these women, the biopsy does not facilitate diagnosis and is hazardous.

Serum cystatin C for assessment of glomerular filtration rate in pregnant and non-pregnant women. Indications of altered filtration process in pregnancy.

Serum cystatin C is believed to reflect the glomerular filtration rate (GFR) more closely than serum creatinine in many contexts and a reference interval for serum cystatin C in term pregnancy has been defined to enable its use also in pregnant women. However, serum cystatin C levels were not found to be decreased in term pregnancy, though GFR of low molecular mass substances is known to increase by at least 40% by the third trimester. The aim of this study was therefore to determine whether serum cystatin C is a reliable GFR marker also in pregnant women. GFR was determined by measurement of plasma clearance of iohexol in 48 previously healthy women in their third trimester and in 12 healthy nonpregnant women, and was compared with their serum levels of cystatin C and creatinine. Both serum cystatin C and creatinine levels were significantly related to GFR for both pregnant and non-pregnant women. However, the correlation between cystatin C and GFR was set at different levels for pregnant and nonpregnant women. Our results indicate a physiological difference between the filtration processes in kidneys of pregnant and non-pregnant women, whether it is size-dependent, configuration-dependent or charge-dependent. Nevertheless, serum cystatin C seems to reflect GFR reliably in both non-pregnant and pregnant, healthy and hypertensive women.

Blood pressure during pregnancy in a Swedish population; impact of parity.

SUBJECT: Hypertension represents the most commonly encountered complication of pregnancy. Normal levels of blood pressure (BP) need to be established in each pregnant population in order to recognize pathology. A lack of studies from our own country and certain methodological objections to early studies motivated this study. PATIENTS AND METHODS: Six hundred pregnant women were included in a historical cohort. The maternal BP had been measured with a mercury sphygmomanometer and standardized routines at each antenatal visit. Data regarding age, baseline BMI, weight gain and smoking habits as well as parity had been recorded. RESULTS: BP values were overall somewhat higher than in international studies, the SBP increasing slightly towards term. The diastolic blood pressure (DBP) decreased slightly until 25-28 weeks of gestation. A steady increase thereafter led to values at term 7.3% above initial values. In nulliparae the increase was significantly greater, 9.9% versus 5.4% in multiparae. Primigravidae showed mean DBP levels significantly higher than all multigravidae towards term. The DBP was correlated with the baseline BMI, but not with age or weight gain. In smoking pregnant women the DBP showed a significantly greater initial decrease and failed to follow the subsequent rise to the same degree as in non-smokers. CONCLUSION: Slightly higher blood pressure levels were found in this study compared to other international studies. Multiple regression analysis showed that parity, baseline BMI and smoking all significantly influenced the DBP at term. Multiparae have significantly lower DBP levels in pregnancy compared to nulliparae. The first pregnancy seems to have the greatest impact in lowering the blood pressure in subsequent pregnancies.

Serum cystatin C is a better marker for preeclampsia than serum creatinine or serum urate.

Altered renal function is an essential component of the pathophysiological process in preeclampsia. The kidneys play a significant part in the turnover of most low molecular weight substances such as creatinine, urate and cystatin C. The present work was undertaken to investigate if the serum levels of these components are altered in characteristic ways in preeclampsia, and can be used to assist in the diagnosis of this condition. The serum levels were therefore determined in samples from 100 healthy women at term as well as in 45 samples of patients with preeclampsia (diastolic blood pressure >90 mmHg; urinary albumin excretion >300 mgL(-1)). The levels of all three components were significantly higher in samples from preeclamptic patients with the mean+SD being 1.55+/-0.29 vs. 1.05+/-0.19 mg L(-1) for cystatin C, 70+/-23 vs. 56+/-9.7 micromol L(-1) for creatinine, and 413+/-128 vs. 305+/-61 micromol L(-1) for urate. Receiver operating characteristic analysis demonstrated that the serum level of cystatin C had a superior diagnostic accuracy for preeclampsia compared to those of serum urate and creatinine and that the diagnostic accuracy of serum urate was better than that of serum creatinine.