PIERS proteinuria: relationship with adverse maternal and perinatal outcome.

OBJECTIVE: To examine the ability of three different proteinuria assessment methods (urinary dipstick, spot urine protein:creatinine ratio [Pr/Cr], and 24-hour urine collection) to predict adverse pregnancy outcomes. METHODS: We performed a prospective multicentre cohort study, PIERS (Preeclampsia Integrated Estimate of RiSk), in seven academic tertiary maternity centres practising expectant management of preeclampsia remote from term in Canada, New Zealand, and Australia. Eligible women were those admitted with preeclampsia who had at least one antenatal proteinuria assessment by urinary dipstick, spot urine Pr/Cr ratio, and/or 24-hour urine collection. Proteinuria assessment was done either visually at the bedside (by dipstick) or by hospital clinical laboratories for spot urine Pr/Cr and 24-hour urine collection. We calculated receiver operating characteristic area under the curve (95% CI) for each proteinuria method and each of the combined adverse maternal outcomes (within 48 hours) or adverse perinatal outcomes (at any time). Models with AUC ≥ 0.70 were considered of interest. Analyses were run for all women who had each type of proteinuria assessment and for a cohort of women ("ALL measures") who had all three proteinuria assessments. RESULTS: More women were proteinuric by urinary dipstick (≥ 2+, 61.4%) than by spot urine Pr/Cr (≥ 30 g/mol, 50.4%) or 24-hour urine collection (≥ 0.3g/d, 34.7%). Each proteinuria measure evaluated had some discriminative power, and dipstick proteinuria (categorical) performed as well as other methods. No single method was predictive of adverse perinatal outcome. CONCLUSION: The measured amount of proteinuria should not be used in isolation for decision-making in women with preeclampsia. Dipstick proteinuria performs as well as other methods of assessing proteinuria for prediction of adverse events.

Comparison of the arrhythmogenic effects of tauro- and glycoconjugates of cholic acid in an in vitro study of rat cardiomyocytes.

Obstetric cholestasis is associated with intrauterine death. In obstetric cholestasis, primary bile acids are more commonly conjugated with taurine than glycine, while glycoconjugates predominate in normal pregnancy. Using an in vitro model of rat cardiomyocytes, we compared the effect of tauro- and glycoconjugated cholate on cardiomyocyte rhythm, contraction amplitude and network integrity. We demonstrated that taurocholate had a more marked effect on all of these parameters, and the effects of the glycoconjugates were fully reversible while those of tauroconjugates were not. The increased proportion of tauroconjugated bile acids in obstetric cholestasis may contribute to the aetiology of the intrauterine death associated with the condition.

Dexamethasone and ursodeoxycholic acid protect against the arrhythmogenic effect of taurocholate in an in vitro study of rat cardiomyocytes.

OBJECTIVE: To establish whether the therapeutic agents ursodeoxycholic acid and dexamethasone protect cardiomyocytes from taurocholate-induced arrhythmias in an in vitro model. DESIGN: Laboratory study. SETTING: Imperial College London, Hammersmith Campus. SAMPLE: Neonatal rat cardiomyocytes. METHODS: Using scanning ion conductance microscopy, we measured the rate, rhythm, amplitude of contraction and calcium dynamics of ventricular myocytes from one to two day old rats. Cells were pre-incubated for 16 hours in dexamethasone (80 or 800 nM) or 0.1 mM ursodeoxycholic acid before adding taurocholate at different concentrations (0.3-4.5 mM). MAIN OUTCOME MEASURES: Changes in rate and amplitude of contraction, calcium dynamics and rhythm. RESULTS: Taurocholate at concentrations of up to 3 mM induces abnormal changes including reductions in rate, amplitude of contraction, abnormal calcium dynamics and dysrhythmias. Although dexamethasone had no immediate protective effect on these changes, pre-incubation with dexamethasone was protective. Ursodeoxycholic acid pre-incubation was protective at taurocholate concentrations up to 1 mM. CONCLUSION: The therapeutic agents dexamethasone and ursodeoxycholic acid appear protective against the arrhythmogenic effect of taurocholate on cardiomyocytes.

Management of thromboembolic disease in pregnancy.

Venous thromboembolism (VTE) is the leading cause of maternal mortality and morbidity in developed countries including Singapore. The physiological changes of pregnancy and other factors, such as maternal age, parity, obesity, operative delivery, general anaesthesia and congenital and acquired thrombophilia, further increase the risk of VTE throughout all three trimesters of pregnancy, including the puerperium. VTE has a wide spectrum of clinical presentations and a high index of clinical suspicion is vital. Clinicians should not withhold the use of chest X-rays and ventilation-perfusion (V/Q) lung scans in pregnancy as the radiation emitted is well within the safety limits to the fetus. Most treatment guidelines are based on studies in non-pregnant populations. Heparin is the preferred anticoagulant as it does not cross the placenta and therefore carries no teratogenic risk to the fetus. There is increasing experience and confidence in the use of fixed dose subcutaneous low molecular weight heparin (LMWH) which removes the need for cumbersome monitoring, thereby allowing outpatient treatment. LMWH may also have a lower risk of osteopaenic complications compared to unfractionated heparin. With the exception of acute phase treatment of pulmonary embolism, LMWH is used in all other aspects of the treatment of VTE in pregnancy, including thromboprophylaxis. Risk stratification of women into high and low risk allows judicious use of anticoagulants for thromboprophylaxis. Antenatal thromboprophylaxis with LMWH is reserved for high-risk women, while low-risk women will only require such cover in the postpartum period.

Fetal, infant, and childhood growth and adult blood pressure: a longitudinal study from birth to 22 years of age.

BACKGROUND: People who are small at birth tend to have higher blood pressure in later life. However, it is not clear whether it is fetal growth restriction or the accelerated postnatal growth that often follows it that leads to higher blood pressure. METHODS AND RESULTS: We studied blood pressure in 346 British men and women aged 22 years whose size had been measured at birth and for the first 10 years of life. Their childhood growth was characterized using a conditional method that, free from the effect of regression to the mean, estimated catch-up growth. People who had been small at birth but who gained weight rapidly during early childhood (1 to 5 years) had the highest adult blood pressures. Systolic pressure increased by 1.3 mm Hg (95% CI, 0.3 to 2.3) for every standard deviation score decrease in birth weight and, independently, increased by 1.6 mm Hg (95% CI, 0.6 to 2.7) for every standard deviation score increase in early childhood weight gain. Adjustment for adult body mass index attenuated the effect of early childhood weight gain but not of birth weight. Relationships were smaller for diastolic pressure. Weight gain in the first year of life did not influence adult blood pressure. CONCLUSIONS: Part of the risk of adult hypertension is set in fetal life. Accelerated weight gain in early childhood adds to this risk, which is partly mediated through the prediction of adult fatness. The primary prevention of hypertension may depend on strategies that promote fetal growth and reduce childhood obesity.

Association of maternal endothelial dysfunction with preeclampsia.

CONTEXT: Preeclampsia is believed to result from release of placental factors that damage maternal vascular endothelium. However, because most studies have been conducted during pregnancy, it has not been possible to separate maternal from placental mechanisms underlying endothelial dysfunction in preeclampsia. OBJECTIVE: To determine whether endothelial function is impaired in nonpregnant women with previous preeclampsia and whether endothelial dysfunction is mediated by oxidative stress. DESIGN AND SETTING: Case-control study conducted at 3 hospital maternity units in London, England, between July 1997 and June 2000. PARTICIPANTS: A total of 113 women with previous preeclampsia (n = 35 with recurrent episodes; n = 78 with a single episode) and 48 women with previous uncomplicated pregnancies, all of whom were at least 3 months (median, 3 years) postpartum. MAIN OUTCOME MEASURES: Brachial artery flow-mediated (endothelium-dependent) and glyceryl trinitrate-induced (endothelium-independent) dilatation were compared between previously preeclamptic women and controls. To investigate oxidative stress, these measurements were repeated after administration of ascorbic acid, 1 g intravenously, in 15 cases and 15 controls. RESULTS: Mean (SD) flow-mediated dilatation was lower in women with previous preeclampsia compared with controls (recurrent group, 0.9% [4.1%]; single-episode group, 2.7% [3.5%]; and control group, 4.7% [4.3%]; P<.001). In contrast, glyceryl trinitrate-induced dilatation was similar in the 3 groups (recurrent, 19.5% [5.9%]; single-episode, 21.0% [8.0%]; and control, 21.0% [8.3%]; P =.65). Impaired flow-mediated dilatation in previously preeclamptic women was not accounted for by recognized vascular risk factors. Ascorbic acid administration increased flow-mediated dilatation in previously preeclamptic women (baseline, 2.6% [3.3%]; after administration, 5.6% [3.0%]; P =.001) but not in controls (baseline, 6.2% [3.3%]; after administration, 6.7% [5.0%]; P =.72). CONCLUSIONS: Our results indicate that endothelial function is impaired in women with previous preeclampsia and is not explained by established maternal risk factors but is reversed by antioxidant ascorbic acid administration.

The bile acid taurocholate impairs rat cardiomyocyte function: a proposed mechanism for intra-uterine fetal death in obstetric cholestasis.

Obstetric cholestasis is a liver disease of pregnancy that can be complicated by sudden, hitherto unexplained, intra-uterine fetal death. Because intra-uterine death occurs suddenly, and because fetal heart rate abnormalities have been reported in obstetric cholestasis, we hypothesized that intra-uterine death is caused by impaired fetal cardiomyocyte function, resulting in fetal cardiac arrest. Obstetric cholestasis is associated with raised levels of maternal and fetal serum bile acids, and we propose that these may alter cardiomyocyte function. It was not possible to investigate the effects of bile acids on the intact human fetal heart at a cellular level. Therefore we used the closest available model of fetal myocardium at term: a primary culture of neonatal rat cardiomyocytes in which cells beat synchronously and develop pacemaker activity. The effect of the primary bile acid taurocholate (0.3 mM and 3 mM) on cultures of single cardiomyocytes, each with its own independent rate of contraction, was a reversible decrease in the rate of contraction and in the proportion of beating cells (P < 0.001). Addition of taurocholate to a network of synchronously beating cells caused a similar decrease in the rate of contraction. Furthermore, the integrity of the network was destroyed, and cells ceased to beat synchronously. Taurocholate also resulted in altered calcium dynamics and loss of synchronous beating. These data suggest that raised levels of the bile acid taurocholate in the fetal serum in obstetric cholestasis may result in the development of a fetal dysrhythmia and in sudden intra-uterine death.

Blood-pressure measurement and classification in pregnancy.

Pre-eclampsia is usually defined on the basis of new onset hypertension and albuminuria developing after 20 weeks of pregnancy. There are difficulties with measurement of these variables. Conventional sphygmomanometry remains the gold standard for blood-pressure measurement. The value of ambulatory blood-pressure measurement has yet to be established. Oedema is now omitted from all definitions of preeclampsia, although the finding of widespread severe oedema of sudden onset should not be ignored for clinical purposes. Definitions of pre-eclampsia based solely on hypertension and proteinuria ignore the wide clinical variability in this syndrome. Women with no proteinuria but who do have hypertension and other features such as severe headache or other symptoms, thrombocytopenia, hyperuricaemia, disordered liver function, and fetal compromise are likely to have pre-eclampsia. This notion is accepted in the new Australasian definition of pre-eclampsia and more than hinted at in the new American College of Obstetricians and Gynecologists' definition. Definitions used for clinical purposes should be as safe as practical; they are likely to include a considerable number of false positives. Most research studies are weakened if patients without the disease are included. Therefore, a separate stringent research definition of pre-eclampsia we also suggest.

Randomised, double-blind, placebo-controlled trial of corticosteroids for the treatment of hyperemesis gravidarum.

OBJECTIVE: To assess the efficacy of corticosteroids in the treatment of severe hyperemesis gravidarum refractory to conventional management. DESIGN: Multicentre, double-blind, randomised, placebo-controlled trial. SETTING: Inpatient gynaecology wards in eight collaborating centres. POPULATION: Twenty-five women with severe hyperemesis of which 24 completed the one- week study period. METHODS: Twenty-five women were randomised to receive either 40 mg prednisolone daily in two divided oral doses, or equivalent placebo tablets. If, after three days, a woman was still vomiting, medication was changed to the equivalent intravenous alternative (hydrocortisone 100 mg twice daily or normal saline injections) MAIN OUTCOME MEASURES: Frequency of vomiting and the dependence on intravenous fluid replacement therapy after one week of treatment. RESULTS: There was a non-significant trend towards improved nausea and vomiting and reduced dependence on intravenous fluids. However, steroid therapy led to an improved sense of wellbeing (P = 0.021), improved appetite (P = 0.039) and increased weight gain (P = 0.025) compared with placebo. There was no difference in pregnancy outcome between the treatment and placebo groups. CONCLUSIONS: This study supports a beneficial role for steroids in severe hyperemesis, but did not validate the hypothesis that they lead to rapid and complete remission of symptoms. The study was not large enough to demonstrate a significant improvement in the primary outcome measures.

Birth weight and 24-hour ambulatory blood pressure in nonproteinuric hypertensive pregnancy.

OBJECTIVE: The aim of this study was to examine the relationship between maternal ambulatory blood pressure monitor measurements during pregnancy and birth weight in a population of women considered to have hypertension according to conventional antenatal clinic measurement. STUDY DESIGN: A prospective observational study was carried out within the obstetric departments of Leicester Royal Infirmary and Queen Charlotte's Hospital. A total of 237 women were found to have hypertension (blood pressure >/=140/90 mm Hg) without significant proteinuria during examination in the antenatal assessment area. Sequential-day unit blood pressure recordings and a 24-hour automated ambulatory blood pressure recording were performed, and the results were compared with the principal outcome measure of birth weight. RESULTS: A significant inverse association (gradient, -13.5; 95% confidence interval -23.4 to -3.6) was found between daytime ambulatory diastolic blood pressure measurement and birth weight. An increase of 5 mm Hg in daytime mean diastolic blood pressure was associated with a fall in birth weight of 68.5 g. This association remained after adjustment for potential confounders that included maternal age, maternal weight, smoking status, ethnicity, and gestational age at delivery. No such association was found between obstetric day unit assessment of blood pressure and birth weight. CONCLUSION: There is a significant association between blood pressure and birth weight in nonproteinuric hypertensive pregnancies. The best predictor of this association is the daytime mean ambulatory diastolic blood pressure measurement. This is further evidence that maternal blood pressure may be an important confounding and potentially genetic variable in the association between birth weight and subsequent adult hypertension.

A comparison of hemodynamic data derived by pulmonary artery flotation catheter and the esophageal Doppler monitor in preeclampsia.

OBJECTIVE: This study was undertaken to compare hemodynamic data derived with the esophageal Doppler monitor against those obtained with a pulmonary artery flotation catheter in women with complicated preeclampsia. STUDY DESIGN: Seventeen women with severe preeclampsia who had a pulmonary artery flotation catheter placed for clinical indications also had an esophageal Doppler monitor inserted. Hemodynamic data were recorded on 2 occasions separated by several hours with both the pulmonary artery flotation catheter and the esophageal Doppler monitor simultaneously. RESULTS: The esophageal Doppler monitor underestimated cardiac output by 36% +/- 14% (mean +/- SD). The esophageal Doppler monitor accurately estimated cardiac output in 3 women >40 years old, whereas in the remaining women (all <35 years old) the esophageal Doppler monitor underestimated cardiac output by 38% +/- 11%. The esophageal Doppler monitor accurately reflected changes in cardiac output with time when compared with the pulmonary artery flotation catheter. CONCLUSION: In women with preeclampsia the esophageal Doppler monitor consistently underestimated cardiac output by approximately 40%. It is not known whether the apparent increase in accuracy among the women >40 years old arose by chance or reflected a real improvement in performance. The esophageal Doppler monitor accurately reflected the direction and magnitude of the changes in cardiac output with time.

Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy with serious consequences for the mother and fetus. Two pedigrees have been reported with ICP in the mothers of children with a subtype of autosomal recessive progressive familial intrahepatic cholestasis (PFIC) with raised serum gamma-glutamyl transpeptidase (gamma-GT). Affected children have homozygous mutations in the MDR3 gene (also called ABCB4 ), and heterozygous mothers have ICP. More frequently, however, ICP occurs in women with no known family history of PFIC and the genetic basis of this disorder is unknown. We investigated eight women with ICP and raised serum gamma-GT, but with no known family history of PFIC. DNA sequence analysis revealed a C to A transversion in codon 546 in exon 14 of MDR3 in one patient, which results in the missense substitution of the wild-type alanine with an aspartic acid. We performed functional studies of this mutation introduced into MDR1, a closely related homologue of MDR3. Fluorescence activated cell sorting (FACS) and western analysis indicated that this missense mutation causes disruption of protein trafficking with a subsequent lack of functional protein at the cell surface. The demonstration of a heterozygous missense mutation in the MDR3 gene in a patient with ICP with no known family history of PFIC, analysed by functional studies, is a novel finding. This shows that MDR3 mutations are responsible for the additional phenotype of ICP in a subgroup of women with raised gamma-GT.