Objective To determine if change in maternal angiogenic biomarkers between the first and second trimesters predicts pre-eclampsia in low-risk nulliparous women. Design A nested case–control study of change in maternal plasma soluble Flt-1 (sFlt-1), soluble endoglin (sEng) and placenta growth factor (PlGF). We studied 158 pregnancies complicated by pre-eclampsia and 468 normotensive nonproteinuric controls. Setting A multicentre study in 16 academic medical centres in the USA. Population Low-risk nulliparous women. Methods Luminex assays for PlGF, sFlt-1 and sEng performed on maternal EDTA plasma collected at 9–12, 15–18 and 23–26 weeks of gestation. Rate of change of analyte between first and either early or late second trimester was calculated with and without adjustment for baseline clinical characteristics. Main outcome measures Change in PlGF, sFlt-1 and sEng. Results Rates of change of PlGF, sEng and sFlt-1 between first and either early or late second trimesters were significantly different in women who developed pre-eclampsia, severe pre-eclampsia or early-onset pre-eclampsia compared with women who remained normotensive. Inclusion of clinical characteristics (race, body mass index and blood pressure at entry) increased sensitivity for detecting severe and particularly early-onset pre-eclampsia but not pre-eclampsia overall. Receiver operating characteristics curves for change from first to early second trimester in sEng, PlGF and sFlt-1 with clinical characteristics had areas under the curve of 0.88, 0.84 and 0.86, respectively, and for early-onset pre-eclampsia with sensitivities of 88% (95% CI 64–99%), 77% (95% CI 50–93%) and 77% (95%CI 50–93%) for 80% specificity, respectively. Similar results were seen in the change from first to late second trimester. Conclusion Change in angiogenic biomarkers between first and early second trimester combined with clinical characteristics has strong utility for predicting early-onset pre-eclampsia.

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OBJECTIVE Smoking and Preeclampsia (PE) are associated with increases in preterm birth, placental abruption and low birth weight. We evaluated the relationship between prenatal vitamin C/E supplementation and perinatal outcomes by maternal self-reported smoking status focusing on outcomes known to be impacted by maternal smoking. DESIGN/POPULATION A secondary analysis of a multi-center trial of vitamin C/E supplementation starting at 9–16 weeks in low-risk nulliparous women with singleton gestations. METHODS We examined the effect of C/E by smoking status at randomization using the Breslow-Day test for interaction. MAIN OUTCOME MEASURES The trial’s primary outcomes were PE and a composite outcome of pregnancy-associated hypertension (PAH) with serious adverse outcomes. Perinatal outcomes included preterm birth and abruption. RESULTS There were no differences in baseline characteristics within subgroups (smokers vs. non-smokers) by vitamin supplementation status. The effect of prenatal vitamin C/E on the risk of PE (p=0.66) or PAH composite outcome (p=0.86) did not differ by smoking status. Vitamin C/E was protective for placental abruption in smokers [RR of 0.09 (95% CI 0.00, 0.87)], but not in non-smokers [RR 0.92 (0.52, 1.62)] (p= 0.01), and for preterm birth in smokers [RR 0.76 (0.58, 0.99)] but not in non-smokers [RR 1.03 (0.90, 1.17)] (p= 0.046). CONCLUSION In this cohort of women, smoking was not associated with a reduction in PE or the composite outcome of PAH.. Vitamin C/E supplementation appears to be associated with a reduction in placental abruption and preterm birth among smokers. Tweetable abstract Vitamin C/E associated with a reduction in placental abruption and preterm birth among smokers.

Objective-The underlying pathophysiology of preeclampsia is thought to be abnormal trophoblast invasion of the spiral arteries, leading to maldevelopment of uteroplacental perfusion. We estimated whether uterine artery Doppler measurements made in the early second trimester would predict the subsequent development of preeclampsia.Methods-Uterine artery Doppler measurements prior to 21 weeks of gestation (median 16.6 weeks) were correlated with subsequent development of preeclampsia in a cohort of 2,188 lowrisk nulliparous women in a randomized control trial of antioxidant supplementation for prevention of preeclampsia. Preeclampsia developed in 165 (7.5%) women.Results-Development of preeclampsia overall was associated with increased resistance index (RI), pulsatility index (PI), a PI or RI multiples of the median (MoM) at or above the 75 th %ile, but not the presence of a notch or a bilateral notch prior to 21 weeks. The sensitivity was 43% (95% CI 35-51) and specificity 67% (95% CI 65-69) for prediction of preeclampsia overall. The presence of a notch or bilateral notch, RI and PI MoM were significantly associated with early onset (before 34 weeks of gestation) vs late onset or no preeclampsia (OR = 6.9 (95% CI 2.3-20.9), sensitivity 78% (95% CI 52-94), specificity 66% (95% CI 64-68)). The presence of a notch Conclusion-Our data show poor sensitivity of second-trimester Doppler ultrasound measurements for prediction of preeclampsia overall in a well-characterized, low-risk, nulliparous population. The technique has utility in identifying poor trophoblast invasion of spiral arteries of a magnitude that severely compromises uteroplacental blood flow and gives early-onset disease.