Effect and mechanism of prophylactic use of tadalafil during pregnancy on l-NAME-induced preeclampsia-like rats.

INTRODUCTION: Preeclampsia (PE) is a serious maternal inflammatory disease with endothelial cell dysfunction, and there is a lack of effective treatment and prevention. Tadalafil is considered to be a promising drug for PE. This study aimed to determine whether and how tadalafil use during early pregnancy alleviates PE induced by N-nitro-l-arginine-methyl-ester (l-NAME), an antagonist of nitric oxide synthase, in rats. METHODS: Twenty-eight Sprague-Dawley (SD) rats were randomly divided into 4 equal groups on gestational day 0 (GD0): a pregnant control group, an l-NAME-treated PE group and two prophylactic low-dose and high-dose tadalafil groups. Blood pressure was measured on GD0, 5, 10, 15 and 20. Proteinuria was assessed on GD0 and 18. Femoral artery ultrasound was performed on GD19. Tissue sampling was performed on GD20. The perinatal outcomes, placenta and kidney tissue morphology, and endothelial and inflammatory markers were examined. RESULTS: Prophylactic administration of low and high doses of tadalafil improved l-NAME induced hypertension, proteinuria, maternal weight loss during pregnancy, fetal growth restriction and flow-mediated dilatation, balanced endothelial-relative factors, and alleviated inflammation activation in placenta and kidney tissue. What's more, in some results, the HT group performed better than the LT group. DISCUSSION: Our results indicate that prophylactic use of tadalafil in l-NAME-induced PE-like rat models alleviates PE symptoms, promotes fetal growth, protects endothelial function and reduces inflammation, suggesting that tadalafil may be a potential drug for the prevention of PE.

Cerebral Magnesium Levels in Preeclampsia; A Phosphorus Magnetic Resonance Spectroscopy Study.

BACKGROUND: Magnesium sulfate (MgSO4) is used as a prophylaxis for eclamptic seizures. The exact mechanism of action is not fully established. We used phosphorus magnetic resonance spectroscopy (31P-MRS) to investigate if cerebral magnesium (Mg2+) levels differ between women with preeclampsia, normal pregnant, and nonpregnant women. METHODS: This cross-sectional study comprised 28 women with preeclampsia, 30 women with normal pregnancies in corresponding gestational week (range: 23-41 weeks) and 11 nonpregnant healthy controls. All women underwent 31P-MRS from the parieto-occipital region of the brain and were interviewed about cerebral symptoms. Differences between groups were assessed by analysis of variance and Tukey's post-hoc test. Correlations between Mg2+ levels and specific neurological symptoms were estimated with Spearman's rank test. RESULTS: Mean maternal cerebral Mg2+ levels were lower in women with preeclampsia (0.12 mM ± 0.02) compared to normal pregnant controls (0.14 mM ± 0.03) (P = 0.04). Nonpregnant and normal pregnant women did not differ in Mg2+ levels. Among women with preeclampsia, lower Mg2+ levels correlated with presence of visual disturbances (P = 0.04). Plasma levels of Mg2+ did not differ between preeclampsia and normal pregnancy. CONCLUSIONS: Women with preeclampsia have reduced cerebral Mg2+ levels, which could explain the potent antiseizure prophylactic properties of MgSO4. Within the preeclampsia group, women with visual disturbances have lower levels of Mg2+ than those without such symptoms.

[Combining biochemical and ultrasonographic markers in predicting preeclampsia: a systematic review]. / Combinaison de marqueurs biochimiques et échographiques pour la prédiction de la prééclampsie : une revue systématique.

Using a series of keywords, we reviewed electronic databases (Medline, Embase, all records to May 2009) reporting the performance of biological and ultrasonographic markers to predict preeclampsia, both single markers and combinations of markers. We analyzed the data according to gestational age and risk levels of the studied populations. We evaluated the methodological quality of included publications using QUADAS (quality assessment of diagnostic accuracy studies). We identified 37 relevant studies that assessed 71 different combinations of biochemical and ultrasonographic markers. Most studies were performed during the second trimester on small-scale high-risk populations with few cases of preeclampsia. Combinations of markers generally led to an increase in sensitivity and/or specificity compared with single markers. In low-risk populations, combinations including placental protein 13 (PP13), pregnancy-associated plasma protein A (PAPP-A), a disintegrin and metalloprotease-12 (ADAM12), activin A, or inhibin Ameasured in first or early second trimester and uterine artery Doppler in second trimester appear promising (sensitivity 60%-80%, specificity > 80%). In high-risk populations, the combination of PP13 and pulsatility index in first trimester showed 90% sensitivity and 90% specificity in a single study limited to severe preeclampsia. Combinations of biochemical and ultrasonographic markers improved the performance of early prediction of preeclampsia. From a perspective of integrative medicine, large population-based studies evaluating algorithms combining multiple markers are needed, if screening approaches are to be eventually implemented.

Combining biochemical and ultrasonographic markers in predicting preeclampsia: a systematic review.

BACKGROUND: Early identification of pregnant women at risk for preeclampsia is a priority to implement preventive measures. Some biochemical and ultrasonographic parameters have shown promising predictive performance, but so far there is no clinically validated screening procedure. CONTENT: Using a series of keywords, we reviewed electronic databases (Medline, Embase, all records to May 2009) reporting the performance of biological and ultrasonographic markers to predict preeclampsia, both single markers and combinations of markers. We analyzed the data according to gestational age and risk levels of the studied populations. We evaluated the methodological quality of included publications using QUADAS (quality assessment of diagnostic accuracy studies). We identified 37 relevant studies that assessed 71 different combinations of biochemical and ultrasonographic markers. Most studies were performed during the second trimester on small-scale high-risk populations with few cases of preeclampsia. Combinations of markers generally led to an increase in sensitivity and/or specificity compared with single markers. In low-risk populations, combinations including placental protein 13 (PP13), pregnancy-associated plasma protein A (PAPP-A), a disintegrin and metalloprotease-12 (ADAM12), activin A, or inhibin A measured in first or early second trimester and uterine artery Doppler in second trimester appear promising (sensitivity 60%-80%, specificity >80%). In high-risk populations, the combination of PP13 and pulsatility index in first trimester showed 90% sensitivity and 90% specificity in a single study limited to severe preeclampsia. SUMMARY: Combinations of biochemical and ultrasonographic markers improved the performance of early prediction of preeclampsia. From a perspective of integrative medicine, large population-based studies evaluating algorithms combining multiple markers are needed, if screening approaches are to be eventually implemented.

Prediction and prevention of recurrent preeclampsia.

Women with a history of previous preeclampsia are at increased risk of preeclampsia and other adverse pregnancy outcomes in subsequent pregnancies. The magnitude of this risk is dependent on gestational age at time of disease onset, severity of disease, and presence or absence of preexisting medical disorders. The objective in the management of these patients is to reduce risk factors by optimizing maternal health before conception and to detect obstetric complications as early as possible. This objective can be achieved by formulating a rational approach that includes preconception evaluation and counseling, early antenatal care, frequent monitoring of maternal and fetal well-being, and timely delivery. First-trimester ultrasound examination is essential for accurate dating and establishing fetal number. Laboratory studies are obtained to assess the function of different organ systems that are likely to be affected by preeclampsia and to establish a baseline for future assessment. Recent studies have confirmed that there is no single biomarker that can be clinically useful for the prediction of recurrent preeclampsia. Combinations of biomarkers and biophysical parameters appear promising, but more data are needed to confirm their use in clinical practice. Supplementation with fish oil, calcium, or vitamin C and E and the use of antihypertensives have been shown to be ineffective in the prevention of recurrent preeclampsia and are not recommended. Supplementation with low-dose aspirin may be offered on an individualized basis. Because women with previous preeclampsia are at increased risk for adverse pregnancy outcomes (preterm delivery, fetal growth restriction, abruptio placentae, and fetal death) in subsequent pregnancies, we recommend more frequent monitoring for signs and symptoms of severe hypertension or preeclampsia than that recommended for normal pregnancy. This monitoring may include more frequent prenatal visits, home blood pressure monitoring, or nursing contacts. For patients with a prior pregnancy complicated by preeclampsia with fetal growth restriction, we recommend serial ultrasound evaluation of fetal growth and amniotic fluid volume. The development of severe gestational hypertension, fetal growth restriction, or recurrent preeclampsia requires maternal hospitalization.

Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial.

BACKGROUND: Oxidative stress has been implicated in the pathophysiology of pre-eclampsia. This randomised controlled trial investigated the effect of supplementation with vitamins C and E in women at increased risk of the disorder on plasma markers of vascular endothelial activation and placental insufficiency and the occurrence of pre-eclampsia. METHODS: 283 women were identified as being at increased risk of pre-eclampsia by abnormal two-stage uterine-artery doppler analysis or a previous history of the disorder and were randomly assigned vitamin C (1000 mg/day) and vitamin E (400 IU/day) or placebo at 16-22 weeks' gestation. Plasma markers of endothelial activation (plasminogen-activator inhibitor 1 [PAI-1]) and placental dysfunction (PAI-2) were measured every month until delivery. Pre-eclampsia was assessed by the development of proteinuric hypertension. Analyses were done by intention to treat, and in the cohort who completed the study. FINDINGS: Supplementation with vitamins C and E was associated with a 21% decrease in the PAI-1/PAI-2 ratio during gestation (95% CI 4-35, p=0.015). In the intention-to-treat cohort, pre-eclampsia occurred in 24 (17%) of 142 women in the placebo group and 11 (8%) of 141 in the vitamin group (adjusted odds ratio 0.39 [0.17-0.90], p=0.02). In the cohort who completed the study (81 placebo group, 79 vitamin group), the odds ratio for pre-eclampsia was 0.24 (0.08-0.70, p=0.002). INTERPRETATION: Supplementation with vitamins C and E may be beneficial in the prevention of pre-eclampsia in women at increased risk of the disease. Multicentre trials are needed to show whether vitamin supplementation affects the occurrence of pre-eclampsia in low-risk women and to confirm our results in larger groups of high-risk women from different populations.