Early prediction and aspirin for prevention of pre-eclampsia (EPAPP) study: a randomized controlled trial.

OBJECTIVE: To estimate the effect of early administration of aspirin on the prevention of pre-eclampsia in high-risk women. METHODS: This was planned as a randomized, double-blind, placebo-controlled trial of aspirin for women with risk factors for pre-eclampsia. Participants were randomized to start either aspirin (81 mg/day) or placebo at 11 + 0 to 13 + 6 weeks of gestation. The primary outcome was pre-eclampsia and secondary outcomes included gestational hypertension and small-for-gestational age at birth. RESULTS: The trial suffered from slow recruitment, leading to a protocol change to broaden the inclusion criteria (from a minimum score of multiple risk factors to at least one risk factor for pre-eclampsia). The trial was then terminated prematurely due to continuing slow recruitment and a lack of equipoise given a change in national guidelines to administer aspirin to high-risk women. From the 53 women who were randomized, 30 were included in the final analysis. There was no evidence that the primary outcome of pre-eclampsia was prevented by low-dose aspirin (relative risk (RR) 0.88, 95% CI 0.21-3.66). Gestational hypertension was seen in two women, both in the aspirin group. There was no evidence that the occurrence of small-for-gestational age was reduced by aspirin (RR 0.88, 95% CI 0.06-12.72). CONCLUSIONS: Although this study was underpowered to show effectiveness of aspirin compared to placebo due to the premature termination and difficulties encountered, it highlights practical issues to inform future studies.

Timing of elective delivery in gastroschisis: a decision and cost-effectiveness analysis.

OBJECTIVE: To determine the most cost-effective timing of delivery in pregnancies complicated by gastroschisis, using a decision-analytic model. METHODS: We created a decision-analytic model to compare planned delivery at 35, 36, 37, 38 and 39 weeks' gestation. Outcomes considered were stillbirth, death within 1 year of birth and respiratory distress syndrome (RDS). Probability estimates of events (stillbirth, complex gastroschisis and RDS for each gestational age at delivery and risk of death with simple and complex gastroschisis), utilities and costs assigned to the outcomes were obtained from the published literature. Cost analysis was assessed from a societal perspective, using a willingness-to-pay threshold of $100,000 per surviving infant. Outcomes and costs were considered throughout 1 year of postnatal life. Multiway sensitivity analysis was performed to address uncertainties in baseline assumptions. RESULTS: In the base-case analysis, delivery at 38 weeks' gestation was the most cost-effective strategy. Planned delivery at 35 weeks was associated with the fewest stillbirths and deaths within 1 year of delivery, owing largely to a lower ongoing risk of stillbirth. In Monte Carlo simulation when every variable was varied over its entire range, delivery at 38 weeks was cost-effective compared to delivery at 39 weeks in 76% of trials and delivery at 37 weeks was cost-effective in 69% of trials. Delivery at 38 weeks resulted in three additional cases of RDS for every 100 stillbirths or deaths within 1 year that were prevented. CONCLUSIONS: For pregnancies complicated by gastroschisis, the most cost-effective timing of delivery is at 38 weeks. Few additional cases of RDS are caused for every one stillbirth or death within 1 year that was prevented with delivery at 37-38 weeks compared with at 39 weeks.

Sonographic predictors of postnatal bowel atresia in fetal gastroschisis.

OBJECTIVES: To estimate the association between antenatal bowel dilation and postnatal small-bowel atresia in fetal gastroschisis and to establish a threshold at which the risk of adverse neonatal outcome increases. METHODS: This was a retrospective cohort study of singleton gestations with an antenatal diagnosis of gastroschisis seen in our ultrasound unit from 2001 to 2010. We reviewed stored images from the last ultrasound examination before delivery, blinded to postnatal diagnoses and outcomes. Fetal intra- and extra-abdominal bowel dilation (IABD and EABD, respectively) and bowel-wall thickness were measured. Previously published definitions of bowel dilation, including > 6, > 10, > 14 and > 18 mm, were evaluated for association with the primary outcome of bowel atresia. The optimal threshold to define fetal bowel dilation was determined by evaluating the significance of association as well as test performance characteristics. RESULTS: Of 109 consecutive patients with fetal gastroschisis, there were four cases of intrauterine fetal demise and three neonatal deaths. Of the 94 live births with complete outcome data, 39 (41.5%) had measurable IABD. There were 14 (14.9%) cases of bowel atresia. Using a threshold of > 14 mm, IABD was significantly associated with an increased risk for bowel atresia (relative risk, 3.1 (95% CI, 1.2-8.2)) with a sensitivity of 57.1%, specificity of 75.0%, positive predictive value of 28.6% and negative predictive value of 90.9%. IABD > 14 mm was also associated with a significantly longer stay in neonatal intensive care unit. There was no significant association between EABD and bowel atresia at any of the thresholds evaluated. CONCLUSION: IABD > 14 mm is associated with an increased risk for postnatal bowel atresia in fetal gastroschisis. This finding may be useful in counseling patients regarding the anticipated postnatal course for their neonate.

First-trimester serum soluble fms-like tyrosine kinase-1, free vascular endothelial growth factor, placental growth factor and uterine artery Doppler in preeclampsia.

OBJECTIVE: To compare the first-trimester serum concentrations of soluble fms-like tyrosine kinase-1 (sFlt-1), free vascular endothelial growth factor (free-VEGF), placental growth factor (PlGF), and uterine artery pulsatility index (PI) in women who later developed preeclampsia (PE). STUDY DESIGN: Prospectively collected maternal serum samples were evaluated for sFlt-1, free VEGF, and PlGF levels in 63 cases who later developed PE compared with 252 unaffected controls. Serum levels of these angiogenic factors were measured using Quantikine immunoassays. Both univariate and multivariate analyses were used to evaluate the association between angiogenic factors and PE. The relationship between the angiogenic factors and mean maternal uterine artery PI was also evaluated. RESULT: Maternal serum sFlt-1 levels were not significantly different between the cases and controls. Mean free-VEGF levels were significantly higher in women destined to develop PE compared with the controls (P=0.04), and mean PlGF levels were significantly lower in women who later developed PE (P=0.01). There was no significant correlation between maternal mean uterine artery PI and angiogenic factors evaluated. Receiver-operating characteristic curves revealed that none of the factors were clinically useful for prediction in the first trimester of PE. CONCLUSION: Despite some significant differences in the first-trimester serum levels of angiogenic factors, our models suggest that these factors are not clinically useful for prediction in women who later developed PE.

Customized growth charts for twin gestations to optimize identification of small-for-gestational age fetuses at risk of intrauterine fetal death.

OBJECTIVE: Customized growth charts developed for singleton pregnancies have been shown to be more effective than population-based ones at identifying small-for-gestational age (SGA) fetuses at risk for intrauterine fetal death (IUFD). We sought to compare the association between SGA and IUFD in twins using customized growth charts designed for twin gestations compared to those designed for singletons. METHODS: This was a retrospective cohort study using a database including singleton and twin pregnancies undergoing ultrasound examination between 16 and 20 weeks' gestation. After excluding preterm births < 34 weeks, congenital anomalies and stillbirths, we identified 51, 150 singleton births. Coefficients for significant physiological and pathological variables affecting birth weight for singletons were derived using backward stepwise multiple regression. The same process was repeated for twin births (1608 pairs), also adjusting for chorionicity. Customized growth charts for each pregnancy were derived using these two regression models for optimal birth weight at term and a proportionality equation. The association between SGA < 10(th) percentile, defined using the twin and singleton-customized charts, and IUFD were compared. Statistical analysis, including calculation of adjusted odds ratios (OR) for IUFD and screening accuracy using each chart, was performed. RESULTS: The derived coefficients for optimal birth weight for twins were different from those for singletons, with lower constants and root mean square error (3422 and 288.9, respectively, in twins vs 3543 and 416 in singletons). Among 3786 twin infants, IUFD was seen in 123 (3.2%). The numbers of fetuses identified as SGA were 575 (15.2%) and 504 (13.3%) by the singleton and twin charts, respectively. Fetuses classified as SGA by the twin-specific customized charts were at a significantly increased risk for IUFD (adjusted OR, 2.3 (95% CI, 1.4-3.5)), whereas those classified as SGA by the singleton-customized charts were not (adjusted OR, 1.2 (95% CI, 0.7-2.0)). CONCLUSION: Customized charts designed specifically for twins are more effective at identifying twin pregnancies at risk for IUFD than are those derived using singleton birth data.

Screening for fetal growth disorders by clinical exam in the era of obesity.

OBJECTIVE: To evaluate the performance of clinical estimation of fetal weight as a screening test for fetal growth disorders and then to estimate the effect of maternal body mass index (BMI) on its screening efficiency. STUDY DESIGN: This was a retrospective cohort study of patients referred for third trimester ultrasound for the indication of 'size unequal to dates'. Patients with medical co-morbidities that may alter their a priori risk for fetal growth disorders were excluded. The incidence of fetal growth disorders as well as amniotic fluid disturbances was determined for each group and then compared across maternal BMI categories of <25 kg m(-2), 25-30 kg m(-2), ≥ 30 kg m(-2) and ≥ 40 kg m(-2). To evaluate the accuracy of clinical estimation of fetal weight in predicting fetal growth disorders, the sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratios, as well as number needed to scan (NNS) was calculated and compared across BMI categories. RESULT: Of 51366 patients, 1623 were referred for the indication of size>dates and 1543 for the indication of size90th percentile and 13.5 and 96.7% for predicting BW<10th percentile. The NNS to detect one neonate with a BW<10th percentile ranged from 5 to 19, whereas the NNS to detect one neonate with a BW>90th percentile ranged from 6 to 13 across BMI categories. CONCLUSION: Overall, clinical estimation of fetal weight yields a low detection rate of fetal growth abnormalities; however, its screening efficiency is not adversely impacted by maternal BMI.

First trimester serum analytes, maternal characteristics and ultrasound markers to predict pregnancies at risk for preterm birth.

INTRODUCTION: Markers of placental dysfunction are used for risk prediction of adverse obstetric outcomes including preeclampsia and growth restriction. Although medically indicated preterm birth is often distinguished from spontaneous preterm birth, we hypothesize that similar placental dysfunction may underlay all preterm birth. We aimed to investigate whether first trimester placental protein 13 (PP-13), pregnancy associated plasma protein A (PAPP-A) and uterine artery pulsatility index, with maternal characteristics could be used to predict all preterm birth. METHODS: Prospective cohort study of singleton gestations between 11 and 14 weeks who underwent serum measurement of PP-13, PAPP-A, and measurement of uterine artery Doppler pulsatility index. Primary outcomes were preterm birth (PTB) at less than 37 and 33 weeks. Analysis performed both including and excluding preeclampsia to assess the utility of the predictors for all types of preterm birth. Predictive models assembled using logistic regression with each predictor alone and in combination, along with maternal characteristics. Predictive utility of models was assessed using receiver operating curve (ROC) analysis and sensitivities for fixed false positive values. RESULTS: Of 471 women, PTB occurred in 12.5% and early PTB (<33 weeks) occurred in 4.7%. PP-13 was decreased in PTB <37 weeks. PAPP-A was decreased in a dose-response pattern for PTB at <37 weeks and <33 weeks. Uterine artery pulsatility index was increased in early PTB. All patterns of predictors remained the same whether patients with preeclampsia were excluded or included suggesting predictive utility for all causes of PTB. Predictive models all demonstrated good predictive ability with ROC ≥ 0.90. CONCLUSIONS: PP-13, PAPP-A, and uterine artery Doppler pulsatility index obtained in the first trimester are good predictors of all types of preterm birth, both indicated and spontaneous. Models including first trimester markers combined with maternal characteristics demonstrated good predictive ability and could be investigated for application of targeted prophylactic strategies.

First-trimester placental protein 13, PAPP-A, uterine artery Doppler and maternal characteristics in the prediction of pre-eclampsia.

OBJECTIVE: To test the hypothesis that a combination of PP13, PAPP-A and first-trimester uterine artery Doppler would improve the prediction of pre-eclampsia. METHODS: This is a prospective cohort study of pregnant women followed from the first-trimester to delivery. PP13 and PAPP-A were determined by immunoassay of maternal serum at 11-14 weeks', when uterine artery Doppler measurements were assessed. Cases identified with any form of pre-eclampsia were compared with a control group without pre-eclampsia. The sensitivity of each marker or their combinations in predicting pre-eclampsia for different fixed false positive rates was calculated from the ROC curves. RESULTS: Forty two women were diagnosed with pre-eclampsia and 410 women with pregnancies not complicated by pre-eclampsia were used as controls. For a fixed false positive rate (FPR) of 20%, PP13, PAPP-A and mean uterine artery pulsatility index identified 49%, 58% and 62% respectively, of women who developed any form of pre-eclampsia. PP13 was best in predicting early onset pre-eclampsia with a sensitivity of 79% at a 20% FPR. Combinations of the three first-trimester assessments did not improve the prediction of pre-eclampsia in later pregnancy. CONCLUSION: First-trimester PP13, PAPP-A and uterine artery PI are reasonable, individual predictors of women at risk to develop pre-eclampsia. Combinations of these assessments do not further improve the prediction of pre-eclampsia.

Placental volume and vascular flow assessed by 3D power Doppler and adverse pregnancy outcomes.

OBJECTIVE: To estimate the utility of first-trimester 3D-placental volume and vascular flow indices in the prediction of adverse pregnancy outcomes. METHODS: A prospective cohort study including women with singleton pregnancies seen between 11 and 14 weeks as part of a screening program for aneuploidy. Placental volume and vascularization indices were obtained using 3D power Doppler imaging and the VOCAL technique. Placental volume (PV), Vascularization Index (VI), Flow Index (FI) and Vascularization Flow Index (VFI) were calculated. The adverse pregnancy outcomes investigated include preeclampsia (PE), gestational hypertension (GH) and small for gestational age (SGA). The predictive ability of each variable was evaluated using receiver-operating characteristic (ROC) curves. RESULTS: Of 388 women included, PE was seen in 30 (7.7%), GH in 37 (9.0%) and SGA in 31 (8.0%). Placental volume was not significantly different between the pregnancies with adverse outcomes and those without. The mean values of the VI and VFI were significantly lower in the pregnancies that developed PE but not in GH or SGA. The area under the ROC curve for the prediction of PE was 0.71, 0.69 and 0.70 for VI, FI and VFI, respectively. CONCLUSION: The study confirms lower 3D power Doppler vascular flow indices in pregnancies that develop PE. The discriminatory ability of using these indices alone for predicting PE appears modest.