-
1.
The bivariate NRIP1/ZEB2 RNA marker permits non-invasive presymptomatic screening of pre-eclampsia.
Manders, V, Visser, A, Keijser, R, Min, N, Poutsma, A, Mulders, J, van den Berkmortel, T, Hortensius, M, Jongejan, A, Pajkrt, E, et al
Scientific reports. 2020;(1):21857
Abstract
Using genome-wide transcriptome analysis by RNA sequencing of first trimester plasma RNA, we tested whether the identification of pregnancies at risk of developing pre-eclampsia with or without preterm birth or growth restriction is possible between weeks 9-14, prior to the appearance of clinical symptoms. We implemented a metaheuristic approach in the self-learning SVM algorithm for differential gene expression analysis of normal pregnancies (n = 108), affected pregnancies (n = 34) and non-pregnant controls (n = 19). Presymptomatic candidate markers for affected pregnancies were validated by RT-qPCR in first trimester samples (n = 34) from an independent cohort. PRKG1 was significantly downregulated in a subset of pregnancies with birth weights below the 10thpercentile as shared symptom. The NRIP1/ZEB2 ratio was found to be upregulated in pregnancies with pre-eclampsia or trisomy 21. Complementary quantitative analysis of both the linear and circular forms of NRIP1 permitted discrimination between pre-eclampsia and trisomy 21. Pre-eclamptic pregnancies showed an increase in linear NRIP1 compared to circular NRIP1, while trisomy 21 pregnancies did not.
-
2.
Adverse Maternal and Neonatal Outcomes in Indicated Compared with Spontaneous Preterm Birth in Healthy Nulliparas: A Secondary Analysis of a Randomized Trial.
Tita, AT, Doherty, L, Roberts, JM, Myatt, L, Leveno, KJ, Varner, MW, Wapner, RJ, Thorp, JM, Mercer, BM, Peaceman, A, et al
American journal of perinatology. 2018;(7):624-631
-
-
Free full text
-
Abstract
OBJECTIVE To compare the risks of adverse maternal and neonatal outcomes associated with spontaneous (SPTB) versus indicated preterm births (IPTB). METHODS A secondary analysis of a multicenter trial of vitamin C and E supplementation in healthy low-risk nulliparous women. Outcomes were compared between women with SPTB (due to spontaneous membrane rupture or labor) and those with IPTB (due to medical or obstetric complications). A primary maternal composite outcome included: death, pulmonary edema, blood transfusion, adult respiratory distress syndrome (RDS), cerebrovascular accident, acute tubular necrosis, disseminated intravascular coagulopathy, or liver rupture. A neonatal composite outcome included: neonatal death, RDS, grades III or IV intraventricular hemorrhage (IVH), sepsis, necrotizing enterocolitis (NEC), or retinopathy of prematurity. RESULTS Of 9,867 women, 10.4% (N = 1,038) were PTBs; 32.7% (n = 340) IPTBs and 67.3% (n = 698) SPTBs. Compared with SPTB, the composite maternal outcome was more frequent in IPTB-4.4% versus 0.9% (adjusted odds ratio [aOR], 4.0; 95% confidence interval [CI], 1.4-11.8), as were blood transfusion and prolonged hospital stay (3.2 and 3.7 times, respectively). The frequency of composite neonatal outcome was higher in IPTBs (aOR, 1.8; 95% CI, 1.1-3.0), as were RDS (1.7 times), small for gestational age (SGA) < 5th percentile (7.9 times), and neonatal intensive care unit (NICU) admission (1.8 times). CONCLUSION Adverse maternal and neonatal outcomes were significantly more likely with IPTB than with SPTB.
-
3.
Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial.
Wen, SW, White, RR, Rybak, N, Gaudet, LM, Robson, S, Hague, W, Simms-Stewart, D, Carroli, G, Smith, G, Fraser, WD, et al
BMJ (Clinical research ed.). 2018;:k3478
-
-
Free full text
-
Abstract
OBJECTIVE To determine the efficacy of high dose folic acid supplementation for prevention of pre-eclampsia in women with at least one risk factor: pre-existing hypertension, prepregnancy diabetes (type 1 or 2), twin pregnancy, pre-eclampsia in a previous pregnancy, or body mass index ≥35. DESIGN Randomised, phase III, double blinded international, multicentre clinical trial. SETTING 70 obstetrical centres in five countries (Argentina, Australia, Canada, Jamaica, and UK). PARTICIPANTS 2464 pregnant women with at least one high risk factor for pre-eclampsia were randomised between 2011 and 2015 (1144 to the folic acid group and 1157 to the placebo group); 2301 were included in the intention to treat analyses. INTERVENTION Eligible women were randomised to receive either daily high dose folic acid (four 1.0 mg oral tablets) or placebo from eight weeks of gestation to the end of week 16 of gestation until delivery. Clinicians, participants, adjudicators, and study staff were masked to study treatment allocation. MAIN OUTCOME MEASURE The primary outcome was pre-eclampsia, defined as hypertension presenting after 20 weeks' gestation with major proteinuria or HELLP syndrome (haemolysis, elevated liver enzymes, low platelets). RESULTS Pre-eclampsia occurred in 169/1144 (14.8%) women in the folic acid group and 156/1157 (13.5%) in the placebo group (relative risk 1.10, 95% confidence interval 0.90 to 1.34; P=0.37). There was no evidence of differences between the groups for any other adverse maternal or neonatal outcomes. CONCLUSION Supplementation with 4.0 mg/day folic acid beyond the first trimester does not prevent pre-eclampsia in women at high risk for this condition. TRIAL REGISTRATION Current Controlled Trials ISRCTN23781770 and ClinicalTrials.gov NCT01355159.
-
4.
Prediabetes in pregnancy, can early intervention improve outcomes? A feasibility study for a parallel randomised clinical trial.
Hughes, RCE, Rowan, J, Williman, J
BMJ open. 2018;(3):e018493
Abstract
OBJECTIVE Measurement of glycated haemoglobin (HbA1c) in early pregnancy is routine in New Zealand to identify women with diabetes and prediabetes. However, the benefit of early intervention in women with prediabetes is inconclusive. Our aim was to test the feasibility of a two-arm parallel randomised controlled trial of standard care versus early intervention in pregnancies complicated by prediabetes. SETTING Two tertiary referral centres in New Zealand. PARTICIPANTS Women <14 weeks' gestation and HbA1c ≥5.9%-6.4% (41-46 mmol/mol) measured at booking, without pre-existing diabetes. INTERVENTIONS Randomisation was done by remote web-based allocation into one of two groups. Women in the early intervention group attended an antenatal diabetes clinic, commenced daily home blood glucose monitoring, and medication was prescribed if lifestyle measures failed to maintain target blood glucose levels. Controls received lifestyle education, continued standard care with their midwife and/or obstetrician, and were asked to perform a 75 g oral glucose tolerance test at 24 weeks' gestation with a referral to clinic if this test was positive. Both groups received lifestyle questionnaires at recruitment and in late pregnancy. OUTCOME MEASURES Recruitment rate, adherence to protocol and validation of potential primary outcomes. RESULTS Recruitment rates were lower than expected, especially in Māori and Pacific women. Non-adherence to allocated treatment protocol was significant, 42% (95% CI 24% to 61%) in the early intervention group and 30% (95% CI 16% to 51%) in controls. Caesarean section and pre-eclampsia were signalled as potential primary outcomes, due to both the high observed incidence in the control group and ease of measurement. CONCLUSIONS For a future definitive trial, extending the gestation of eligibility and stepped-wedge cluster randomisation may overcome the identified feasibility issues. Consistent with published observational data, pre-eclampsia and emergency caesarean section could be included as primary outcome measures, both of which have a significant impact on maternal and neonatal morbidity and healthcare costs. TRIAL REGISTRATION NUMBER ACTRN12615000904572; Pre-results.
-
5.
Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial.
Costantine, MM, Cleary, K, Hebert, MF, Ahmed, MS, Brown, LM, Ren, Z, Easterling, TR, Haas, DM, Haneline, LS, Caritis, SN, et al
American journal of obstetrics and gynecology. 2016;(6):720.e1-720.e17
-
-
Free full text
-
Abstract
BACKGROUND Preeclampsia complicates approximately 3-5% of pregnancies and remains a major cause of maternal and neonatal morbidity and mortality. It shares pathogenic similarities with adult cardiovascular disease as well as many risk factors. Pravastatin, a hydrophilic, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor, has been shown in preclinical studies to reverse various pathophysiological pathways associated with preeclampsia, providing biological plausibility for its use for preeclampsia prevention. However, human trials are lacking. OBJECTIVE As an initial step in evaluating the utility of pravastatin in preventing preeclampsia and after consultation with the US Food and Drug Administration, we undertook a pilot randomized controlled trial with the objective to determine pravastatin safety and pharmacokinetic parameters when used in pregnant women at high risk of preeclampsia. STUDY DESIGN We conducted a pilot, multicenter, double-blind, placebo-controlled, randomized trial of women with singleton, nonanomalous pregnancies at high risk for preeclampsia. Women between 12(0/7) and 16(6/7) weeks' gestation were assigned to daily pravastatin 10 mg or placebo orally until delivery. Primary outcomes were maternal-fetal safety and pharmacokinetic parameters of pravastatin during pregnancy. Secondary outcomes included rates of preeclampsia and preterm delivery, gestational age at delivery, birthweight, and maternal and cord blood lipid profile (clinicaltrials.gov identifier NCT01717586). RESULTS Ten women assigned to pravastatin and 10 to placebo completed the trial. There were no differences between the 2 groups in rates of study drug side effects, congenital anomalies, or other adverse or serious adverse events. There was no maternal, fetal, or neonatal death. Pravastatin renal clearance was significantly higher in pregnancy compared with postpartum. Four subjects in the placebo group developed preeclampsia compared with none in the pravastatin group. Although pravastatin reduced maternal cholesterol concentrations, umbilical cord cholesterol concentrations and infant birthweight were not different between the groups. The majority of umbilical cord and maternal pravastatin plasma concentrations at the time of delivery were below the lower limit of quantification of the assay. Pravastatin use was associated with a more favorable pregnancy angiogenic profile. CONCLUSION This study provides preliminary safety and pharmacokinetic data regarding the use of pravastatin for preventing preeclampsia in high-risk pregnant women. Although the data are preliminary, no identifiable safety risks were associated with pravastatin use in this cohort. This favorable risk-benefit analysis justifies using pravastatin in a larger clinical trial with dose escalation.
-
6.
Serum oxidized low density lipoprotein levels in preeclamptic and normotensive pregnants.
Kozan, A, Yildirmak, ST, Mihmanli, V, Ayabakan, H, Cicek, YG, Kalaslioglu, V, Doean, S, Cebeci, HC
Clinical and experimental obstetrics & gynecology. 2015;(6):746-8
Abstract
UNLABELLED BACKGROUNDS/AIM: The aim of the study was to determine serum lipids and oxidized low density lipoprotein (ox-LDL) levels in preeclamptic pregnants and compare with those of normotensives. MATERIALS AND METHODS Ox-LDL levels were determined by enzyme linked immunosorbent assay (ELISA); total cholesterol, hight density lipoprotein (HDL)-cholesterol and triglyceride levels were measured by enzymatic colorimetric assay in 26 normotensive and 27 preeclamptic pregnants. LDL and very low density lipoprotein (VLDL) cholesterol was calculated by Friedwald formula. RESULTS Serum levels of Ox-LDL (U/L), total-cholesterol (mg/dL), HDL-cholesterol (mg/dL), LDL-cholesterol (mg/dL), triglyceride (mg/dL), and VLDL-cholesterol (mg/dL) in normotensive and preeclamptic pregnants were found as 130±60 and 133±69; 248±49 and 248±81; 67±14 and 61±16; 147±61 and 135±59; 207±76 and 256±87; 41±15 and 50±17, respectively. Mean values of Ox-LDL and other lipid parameters were higher than the upper limits of their reference ranges in both of groups. However no significant differences were found in Ox-LDL, total, HDL and LDL-cholesterol levels between two groups. However, the levels of triglyceride and VLDL-cholesterol were significantly higher in preeclampsia group. CONCLUSIONS The present results suggest that the levels of serum Ox-LDL and other lipid parameters rise as a result of pregnancy rather than as a result of preeclampsia.
-
7.
The effect of calcium supplementation on blood pressure in non-pregnant women with previous pre-eclampsia: An exploratory, randomized placebo controlled study.
Hofmeyr, GJ, Seuc, AH, Betrán, AP, Purnat, TD, Ciganda, A, Munjanja, SP, Manyame, S, Singata, M, Fawcus, S, Frank, K, et al
Pregnancy hypertension. 2015;(4):273-9
Abstract
BACKGROUND Epidemiological findings suggest that the link between poverty and pre-eclampsia might be dietary calcium deficiency. Calcium supplementation has been associated with a modest reduction in pre-eclampsia, and also in blood pressure (BP). METHODS This exploratory sub-study of the WHO Calcium and Pre-eclampsia (CAP) trial aims to determine the effect of 500mg/day elemental calcium on the blood pressure of non-pregnant women with previous pre-eclampsia. Non-pregnant women with at least one subsequent follow-up trial visit at approximately 12 or 24weeks after randomization were included. RESULTS Of 836 women randomized by 9 September 2014, 1st visit data were available in 367 women of whom 217 had previously had severe pre-eclampsia, 2nd visit data were available in 201 women. There was an overall trend to reduced BP in the calcium supplementation group (1-2.5mmHg) although differences were small and not statistically significant. In the subgroup with previous severe pre-eclampsia, the mean diastolic BP change in the calcium group (-2.6mmHg) was statistically larger than in the placebo group (+0.8mmHg), (mean difference -3.4, 95% CI -0.4 to -6.4; p=0.025). The effect of calcium on diastolic BP at 12weeks was greater than in those with non-severe pre-eclampsia (p=0.020, ANOVA analysis). CONCLUSIONS There is an overall trend to reduced BP but only statistically significant in the diastolic BP of women with previous severe pre-eclampsia. This is consistent with our hypothesis that this group is more sensitive to calcium supplementation, however results need to be interpreted with caution.
-
8.
Inherited thrombophilia and preeclampsia within a multicenter cohort: the Montreal Preeclampsia Study.
Kahn, SR, Platt, R, McNamara, H, Rozen, R, Chen, MF, Genest, J, Goulet, L, Lydon, J, Seguin, L, Dassa, C, et al
American journal of obstetrics and gynecology. 2009;(2):151.e1-9; discussion e1-5
Abstract
OBJECTIVE We sought to evaluate the association between inherited thrombophilia and preeclampsia. STUDY DESIGN From a multicenter cohort of 5337 pregnant women, we prospectively identified 113 women who developed preeclampsia and selected 443 control subjects who did not have preeclampsia or nonproteinuric gestational hypertension. Blood samples were tested for DNA polymorphisms affecting thrombophilia (factor V Leiden mutation, prothrombin G20210A mutation, methylenetetrahydrofolate reductase C677T polymorphism), homocysteine, and folate levels, and placentae underwent pathological evaluation. RESULTS Thrombophilia was present in 14% of patients and 21% of control subjects (adjusted logistic regression odds ratio, 0.6; 95% confidence interval, 0.3-1.3). Placental underperfusion was present in 63% of patients vs 46% of control subjects (P < .001) and was more frequent in women with folate levels in the lowest quartile (P = .04), but was not associated with thrombophilia. CONCLUSION We did not find evidence to support an association between inherited thrombophilia and increased risk of preeclampsia. Placental underperfusion is associated with preeclampsia, but this does not appear to be consequent to thrombophilia.
-
9.
World Health Organisation multicentre randomised trial of supplementation with vitamins C and E among pregnant women at high risk for pre-eclampsia in populations of low nutritional status from developing countries.
Villar, J, Purwar, M, Merialdi, M, Zavaleta, N, Thi Nhu Ngoc, N, Anthony, J, De Greeff, A, Poston, L, Shennan, A, ,
BJOG : an international journal of obstetrics and gynaecology. 2009;(6):780-8
Abstract
OBJECTIVE To determine if vitamin C and E supplementation in high-risk pregnant women with low nutritional status reduces pre-eclampsia. DESIGN Multicentred, randomised, controlled, double-blinded trial. SETTING Antenatal care clinics and Hospitals in four countries. POPULATION Pregnant women between 14 and 22 weeks' gestation. METHOD Randomised women received 1000 mg vitamin C and 400 iu of vitamin E or placebo daily until delivery. MAIN OUTCOME MEASURES Pre-eclampsia, low birthweight, small for gestational age and perinatal death. RESULTS Six hundred and eighty-seven women were randomised to the vitamin group and 678 to the placebo group. Groups had similar gestational ages (18.1; SD 2.4 weeks), socio-economic, clinical and demographical characteristics and blood pressure at trial entry. Risk factors for eligibility were similar, except for multiple pregnancies: placebo group (14.7%), vitamins group (11.8%). Previous pre-eclampsia, or its complications, was the most common risk factor at entry (vitamins 41.6%, placebo 41.3%). Treatment compliance was 87% in the two groups and loss to follow-up was low (vitamins 2.0%, placebo 1.3%). Supplementation was not associated with a reduction of pre-eclampsia (RR: 1.0; 95% CI: 0.9-1.3), eclampsia (RR: 1.5; 95% CI: 0.3-8.9), gestational hypertension (RR: 1.2; 95% CI: 0.9-1.7), nor any other maternal outcome. Low birthweight (RR: 0.9; 95% CI: 0.8-1.1), small for gestational age (RR: 0.9; 95% CI: 0.8-1.1) and perinatal deaths (RR: 0.8; 95% CI: 0.6-1.2) were also unaffected. CONCLUSION Vitamins C and E at the doses used did not prevent pre-eclampsia in these high-risk women.
-
10.
Antioxidant therapy to prevent preeclampsia: a randomized controlled trial.
Spinnato, JA, Freire, S, Pinto E Silva, JL, Cunha Rudge, MV, Martins-Costa, S, Koch, MA, Goco, N, Santos, Cde B, Cecatti, JG, Costa, R, et al
Obstetrics and gynecology. 2007;(6):1311-8
Abstract
OBJECTIVE To study whether antioxidant supplementation will reduce the incidence of preeclampsia among patients at increased risk. METHODS A randomized, placebo-controlled, double-blind clinical trial was conducted at four Brazilian sites. Women between 12 0/7 weeks and 19 6/7 weeks of gestation and diagnosed to have chronic hypertension or a prior history of preeclampsia were randomly assigned to daily treatment with both vitamin C (1,000 mg) and vitamin E (400 International Units) or placebo. Analyses were adjusted for clinical site and risk group (prior preeclampsia, chronic hypertension, or both). A sample size of 734 would provide 80% power to detect a 40% reduction in the risk of preeclampsia, assuming a placebo group rate of 21% and alpha=.05. The alpha level for the final analysis, adjusted for interim looks, was 0.0458. RESULTS Outcome data for 707 of 739 randomly assigned patients revealed no significant reduction in the rate of preeclampsia (study drug, 13.8% [49 of 355] compared with placebo, 15.6% [55 of 352], adjusted risk ratio 0.87 [95.42% confidence interval 0.61-1.25]). There were no differences in mean gestational age at delivery or rates of perinatal mortality, abruptio placentae, preterm delivery, and small for gestational age or low birth weight infants. Among patients without chronic hypertension, there was a slightly higher rate of severe preeclampsia in the study group (study drug, 6.5% [11 of 170] compared with placebo, 2.4% [4 of 168], exact P=.11, odds ratio 2.78, 95% confidence interval 0.79-12.62). CONCLUSION This trial failed to demonstrate a benefit of antioxidant supplementation in reducing the rate of preeclampsia among patients with chronic hypertension and/or prior preeclampsia. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, www.ClinicalTrials.gov, NCT00097110 LEVEL OF EVIDENCE I.