Pravastatin suppresses inflammatory cytokines and endothelial activation in patients at risk of developing preeclampsia INOVASIA Study

Introduction: The Indonesian INOVASIA study is an ongoing multicentre randomized, open controlled trial of pravastatin for the prevention of preeclampsia in patients deemed to be high risk. Here we evaluate the effects of pravastatin on circulating inflammatory and endothelial markers, i.e. Vascular Endothelial Growth Factor (VEGF), Interleukin-6 (IL-6), Endothelin-1 (ET-1), and Nitric Oxide (NO). Methods: Pregnant women deemed to be at a high risk of developing preeclampsia women were recruited based on the Fetal Medicine Foundation preeclampsia screening test or a history of preterm preeclampsia, or clinical risk factors in combination with an abnormal uterine artery Doppler flow pattern at 11-20 week's gestation. This is a nested cohort study within the larger trial (INOVASIA); 38 patients were consecutively recruited and assigned to the pravastatin group and the control group. Participants in the pravastatin group received pravastatin (2 × 20 mg p.o) in addition to a standard regimen of aspirin (80 mg p.o) and calcium (1 g p.o), from 14 to 20 weeks until delivery. Blood samples to measure the various biomarkers were obtained in consecutive patients before starting the research medication and just before delivery (pre and post-test examination). Result: The number of samples on the 2 time points for the various biomarkers was: VEGF: 38, IL-6: 30, ET-1: 38, and NO: 35. IL-6 levels decreased significantly in the pravastatin group (mean ± SD): (191.87 ± 82.99 vs. 151.85 + 48.46, p = .013), while levels in the control group did not change significantly (median (interquartile range)) (144.17 (53.91) vs. 140.82 (16.18), p = .177). ET-1 levels decreased significantly in the pravastatin group (3.64 ± 0.85 vs. 3.01 ± 0.74, p = .006) while the control group had more or less stable levels (3.57 ± 1.12 vs. 3.78 ± 0.73 p = .594). NO was the only serum marker that showed significant changes in both groups. NO levels increased in pravastatin group (11.30 (17.43) vs. 41.90 (53.18), p = .044) and decreased in control group (38.70 (34.80) vs. 10.03 (26.96), p = .002). VEGF levels appeared to follow opposite trends in the 2 groups (NS) (Pravastatin: 3.22 (0.62) vs. 3.28 (0.75), p = .402. Control: 3.38 (0.83) vs. 3.06 (0.74), p = .287). Conclusion: Administration of 40 mg pravastatin resulted in an improvement in NO levels, and a decrease in IL-6 and endothelin (ET-1) levels. The direction of the effect of pravastatin on these biomarkers appears to underpin the potential for a beneficial effect of pravastatin in the prevention of preeclampsia

Clinical, ultrasound and molecular biomarkers for early prediction of large for gestational age infants in nulliparous women: an international prospective cohort study

Objective: To develop a prediction model for term infants born large for gestational age (LGA) by customised birthweight centiles. Methods: International prospective cohort of nulliparous women with singleton pregnancy recruited to the Screening for Pregnancy Endpoints (SCOPE) study. LGA was defined as birthweight above the 90th customised centile, including adjustment for parity, ethnicity, maternal height and weight, fetal gender and gestational age. Clinical risk factors, ultrasound parameters and biomarkers at 14–16 or 19–21 weeks were combined into a prediction model for LGA infants at term using stepwise logistic regression in a training dataset. Prediction performance was assessed in a validation dataset using area under the Receiver Operating Characteristics curve (AUC) and detection rate at fixed false positive rates. Results: The prevalence of LGA at term was 8.8% (n = 491/5628). Clinical and ultrasound factors selected in the prediction model for LGA infants were maternal birthweight, gestational weight gain between 14–16 and 19–21 weeks, and fetal abdominal circumference, head circumference and uterine artery Doppler resistance index at 19–21 weeks (AUC 0.67; 95%CI 0.63–0.71). Sensitivity of this model was 24% and 49% for a fixed false positive rate of 10% and 25%, respectively. The addition of biomarkers resulted in selection of random glucose, LDL-cholesterol, vascular endothelial growth factor receptor-1 (VEGFR1) and neutrophil gelatinase-associated lipocalin (NGAL), but with minimal improvement in model performance (AUC 0.69; 95%CI 0.65–0.73). Sensitivity of the full model was 26% and 50% for a fixed false positive rate of 10% and 25%, respectively. Conclusion: Prediction of LGA infants at term has limited diagnostic performance before 22 weeks but may have a role in contingency screening in later pregnancy

Risk factors for preterm birth in an international prospective cohort of nulliparous women

To identify risk factors for spontaneous preterm birth (birth ,37 weeks gestation) with intact membranes(SPTB-IM) and SPTB after prelabour rupture of the membranes (SPTB-PPROM) for nulliparous pregnant women. DESIGN: Prospective international multicentre cohort. PARTICIPANTS: 3234 healthy nulliparous women with a singleton pregnancy, follow up was complete in 3184 of participants (98.5%). RESULTS: Of the 3184 women, 156 (4.9%) had their pregnancy complicated by SPTB; 96 (3.0%) and 60 (1.9%) in the SPTB-IM and SPTB-PPROM categories, respectively. Independent risk factors for SPTB-IM were shorter cervical length, abnormal uterine Doppler flow, use of marijuana pre-pregnancy, lack of overall feeling of well being, being of Caucasian ethnicity, having a mother with diabetes and/or a history of preeclampsia, and a family history of low birth weight babies. Independent risk factors for SPTB-PPROM were shorter cervical length, short stature, participant’s not being the first born in the family, longer time to conceive, not waking up at night, hormonal fertility treatment (excluding clomiphene), mild hypertension, family history of recurrent gestational diabetes, and maternal family history of any miscarriage (risk reduction). Low BMI (<20) nearly doubled the risk for SPTB-PPROM (odds ratio 2.64; 95% CI 1.07–6.51). The area under the receiver operating characteristics curve (AUC), after internal validation, was 0.69 for SPTB-IM and 0.79 for SPTB-PPROM. CONCLUSION: The ability to predict PTB in healthy nulliparous women using clinical characteristics is modest. The dissimilarity of risk factors for SPTB-IM compared with SPTB-PPROM indicates different pathophysiological pathways underlie these distinct phenotypes.Gustaaf Albert Dekker, Shalem Y. Lee, Robyn A. North, Lesley M. McCowan, Nigel A.B. Simpson and Claire T. Robert

Antenatal screening for heritable thrombophilia : assessment report

Tracy Merlin, Linda Mundy, Janet Hiller and John Mos

Clinical risk factors at 15 weeks, and ultrasound scan variables at 20 weeks in logistic regression model for SPTB-IM.

<p>Reference BMI 20–&lt;25.</p

Receiver-operating characteristic curve for SPTB-IM.

<p>Receiver-operating characteristic curve for SPTB-IM.</p

Clinical risk factors at 15 weeks, and ultrasound scan variables at 20 weeks in logistic regression model for SPTB-PPROM.

<p>1 =  hormonal fertility treatment other than clomiphene; GDM  =  gestational diabetes mellitus; participant’s position in family  =  index mother not being the first-born); Reference BMI 20–&lt;25.</p