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.

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.

Transplacental passage of isradipine in the treatment of pregnancy-induced hypertension.

The aim of this study was to assess the concentration of isradipine in maternal and fetal plasma, and in amniotic fluid under steady-state conditions. Eight women were treated with 5-mg isradipine tablets twice daily and eight women were given slow-release isradipine capsules (SRO) twice daily for hypertension in pregnancy. Blood and amniotic fluid sampling for analysis of drug concentration was performed at delivery. In the isradipine tablet group, maternal and fetal plasma levels were 788 +/- 701 pg/mL (mean +/- SD) and 270 +/- 90 pg/mL, respectively. The corresponding levels in the SRO-treated group were 463 +/- 217 pg/mL and 185 +/- 95 pg/mL, respectively. In the amniotic fluid, the concentration was 74 +/- 42 pg/mL in the tablet group and 45 +/- 14 pg/mL in the SRO group. Therefore, isradipine passes the placental barrier, but its concentration is considerably lower in the fetal compartments.

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.

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.

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.

How Swedish obstetricians manage hypertensive disorders in pregnancy. A questionnaire study.

OBJECTIVE: To study treatment of hypertension in pregnancy in Sweden and compare our results with a similar study published in 1981. METHODS: A multiple choice questionnaire was sent to 92 obstetricians throughout Sweden and 88% responded. RESULTS: Most Swedish obstetricians would treat a woman in the second trimester with blood pressure 140/95 mmHg without antihypertensive medication (83%) in the out-patient clinic (81%). The corresponding figures according to a similar study published in 1981 were 33% and 71% of obstetricians, respectively. Almost all obstetricians (95%) would give antihypertensive treatment if the blood pressure was 170/110 mmHg or more. Betablockers and hydralazine were the most commonly used drugs. Sixteen per cent of obstetricians would use calcium antagonists, drugs not available in the previous study. Treatment with diuretics, methyldopa or diazepam in hypertension was rarely used. Eight per cent of obstetricians would give low-dose aspirin to patients with mild hypertension and 20% to patients with severe hypertension. Fourteen per cent of obstetricians would stop all kind of antihypertensive medication and frequently observe patients with essential hypertension. CONCLUSION: Antihypertensive therapy and management of hypertensive disorders of pregnancy show a great disparity among Swedish obstetricians. National strategies might improve the morbidity and mortality associated with hypertensive disorders in pregnancy.

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.

Effects of isradipine, a new calcium antagonist, on maternal cardiovascular system and uterine activity in labour.

The effects of isradipine (a new calcium antagonist of the dihydropyridine type) on maternal blood pressure and heart rate, fetal heart rate, and uterine activity in labour were measured. Uterine activity was recorded by an intrauterine microtip transducer catheter connected to a fetal monitor. Isradipine was given as a slow injection in doses of 0.5 mg (10 women), 1 mg (11 women), and 1.5 mg (6 women). A reduction of systolic (6-16%) and diastolic (19-22%) blood pressure was seen, and concomitantly there was an increase in maternal (29-34%) and fetal (3-10%) heart rates. Reduction in uterine activity was not dose-related (maximum reduction 17%). Side effects (headache, palpitations) were minor and well tolerated. One women in the high-dose group had a shortlasting episode of hypotension. The results suggest that isradipine given as a bolus dose decreases blood pressure in pregnant women with little effects on uterine activity and fetal heart rate.

Respiratory distress syndrome in infants with impaired intrauterine growth.

The recently introduced intrauterine growth curve, based on ultrasonically estimated foetal weights, was retrospectively applied to an inborn population of 883 infants born before 33 gestational weeks at the University Hospital of Lund, during 1985-94. The estimation of birthweight deviation resulted in 630 (71.3%) infants with a birthweight appropriate for gestational age (AGA), 244 (27.6%) infants with a birthweight small for gestational age (SGA) and 9 (1.1%) infants with a birthweight large for gestational age. Birthweight deviation was associated with an increased mortality [odds ratio (OR) adjusted for gestational age 1.29 per SD (12%) change in birthweight for gestational age, 95% CI: 1.10-1.50; p = 0.002]. At gestational age 25-28 weeks, SGA-infants had an increased incidence of respiratory distress syndrome (RDS) as compared to AGA-infants (OR adjusted for gestational age: 1.98, 95% CI: 1.12-3.52; p = 0.019). At gestational age 29-32 weeks, SGA-infants had a lower incidence of RDS as compared to AGA-infants (OR adjusted for gestational age: OR 0.52, 95% CI: 0.34-0.80; p = 0.003). After adjustment for confounding variables, infants born at gestational age 25-28 weeks from mothers with pre-eclampsia, appeared to be a high-risk group for RDS, whereas at the age of 29-32 gestational weeks, negative birthweight deviation had a protective effect against RDS. Antenatal corticosteroid administration appeared to have a less beneficial effect on mortality, RDS and cerebral haemorrhage in infants born SGA vs in those born AGA.

Effect of methyldopa and isradipine on fetal heart rate pattern assessed by computerized cardiotocography in human pregnancy.

OBJECTIVE: The effects of two antihypertensive drugs, methyldopa and isradipine, on fetal heart rate pattern were analyzed by computerized cardiotocography. STUDY DESIGN: The first part of the study was a prospective, randomized, controlled trial of 19 women with preeclampsia in the third trimester given 2.5 mg of oral slow-release isradipine twice a day or 250 mg of methyldopa three times a day. In a second part of the study 23 women with preeclampsia in the third trimester given 5 mg of oral slow-release isradipine twice a day were compared with 23 matched controls without medication. Main outcome measures were maternal blood pressure and mean baseline fetal heart rate, fetal movements, number of accelerations, periods of high and low baseline variability, and mean baseline heart rate variability. RESULTS: Compared with the pretreatment value, the mean arterial blood pressure decreased significantly in all drug treatment groups. Fetal heart rate characteristics were not significantly changed during drug treatment or bed rest. CONCLUSION: The various features of the fetal heart rate pattern evaluated by computerized methods were not influenced by treatment with methyldopa or isradipine.

Effects of isradipine, a new calcium antagonist, on postpartum uterine activity.

The effects of a new calcium antagonist, isradipine (PN 200-110) on postpartum uterine activity and the maternal cardiovascular system were investigated. Uterine activity was recorded by a microtip transducer catheter inserted transcervically within 45 min of normal vaginal delivery. 0.5 mg of isradipine was given as a bolus injection during 5 min to 7 women with spontaneous uterine activity and 1 mg was given during a 15-min period to another 8 women with oxytocin-stimulated uterine activity. Matched controls with similar pre-injection activity (+/- 5%) but not given the drug were selected for comparison. The effects of the drug in 3 women (given 1 mg of isradipine) were compared with those in matched controls and in women given 0.25 mg of terbutalin i.v. as a bolus injection. Isradipine had a marked inhibitory effect on both spontaneous and oxytocin-stimulated uterine activity. The inhibitory effect of 1 mg of isradipine seemed comparable to that of 0.25 mg of terbutalin. The inhibition occurred within 1-2 min after the injection and was sustained throughout the study period (2 h). A transient reduction of the systolic (mean maximum decrease 10-15%) and diastolic blood pressure (mean maximum decrease 15-20%) was seen, particularly during the injection period. Hypotension (systolic blood pressure less than 80 mmHg) was not recorded. A moderate increase in pulse rate (mean maximum increase 22-27%) was seen in all cases. The results show that isradipine given as a bolus injection can inhibit early postpartum uterine activity, with minimal side effects.

Calcium channel blockade (isradipine) in treatment of hypertension in pregnancy: a randomized placebo-controlled study.

OBJECTIVE: Our purpose was to study the effects of isradipine, a dihydropyridine calcium channel blocker, on mother and fetus in the treatment of hypertensive disorders of pregnancy. STUDY DESIGN: The investigation was performed as a two-group, parallel, double-blind multicenter study of isradipine versus placebo. Fifty-four women were randomized to treatment with isradipine slow-release capsules given orally 5 mg twice a day and 57 to a placebo group. RESULTS: Isradipine lowered the maternal mean arterial blood pressure effectively in women with nonproteinuric hypertension but did not do so in women with proteinuria at recruitment or appearing during treatment. Blood flow in the umbilical artery and maternal renal and liver function were not influenced by treatment. Isradipine had few side effects and was well tolerated. CONCLUSION: Calcium channel blockade with isradipine is effective for treatment of nonproteinuric hypertension but not in preeclampsia.