First trimester risk of preeclampsia and rate of spontaneous birth in patients without preeclampsia.

BACKGROUND: First-trimester screening for preeclampsia using a combination of maternal risk factors and mean arterial pressure, uterine artery pulsatility index, and placental growth factor, as proposed by the Fetal Medicine Foundation, provides effective prediction of preterm preeclampsia. Placental dysfunction is a potential precursor of spontaneous birth. OBJECTIVE: The objective of this study was to examine if the estimated risk of preeclampsia is associated with the gestational age at onset of spontaneous delivery in the absence of preeclampsia. STUDY DESIGN: This was a secondary analysis of the data from the Screening programme for pre-eclampsia trial in which there was a comparison of the performance of first-trimester screening for preterm preeclampsia using the Fetal Medicine Foundation model vs a traditional history-based risk scoring system. A subgroup of women from the trial with spontaneous onset of delivery (labor with intact membranes or preterm prelabor rupture of membranes) was included in this study and was arbitrarily divided into 3 groups according to the risk for preterm preeclampsia as determined by the Fetal Medicine Foundation model at 11 to 13 weeks' gestation as follows: group 1 low risk (˂1/100); group 2 intermediate risk (1/50 to 1/100); and group 3 high risk (˃1/50). A survival analysis was carried out using a Kaplan-Meier estimator and a Cox regression analysis with stratification by the 3 preeclampsia risk groups. Occurrence of spontaneous birth in the study groups was compared using log-rank tests and hazard ratios. RESULTS: The study population comprised 10,820 cases with delivery after spontaneous onset of labor among the 16,451 cases who participated in the Screening programme for pre-eclampsia trial. There were 9795 cases in group 1, 583 in group 2, and 442 in group 3. The gestational age at delivery was <28, <32, <35, <37, and <40 weeks in 0.29%, 0.64%, 1.68%, 4.52%, and 44.97% of cases, respectively, in group 1; 0.69%, 1.71%, 3.26%, 7.72%, and 55.23% of cases, respectively, in group 2; and 0.45%, 1.81%, 5.66%, 13.80%, and 63.12% of cases, respectively, in group 3. The curve profile of gestational age at spontaneous birth in the 3 study groups was significantly different overall and in pairwise comparisons (P values <.001). The Cox regression analysis showed that risks increased for spontaneous birth by 18% when the intermediate-risk group was compared with the low-risk group (P˂.001) and by 41% when the high-risk group was compared with the low-risk group (P˂.001). CONCLUSION: In this study that investigated birth after spontaneous onset of labor in women without preeclampsia, there were 2 major findings. First, the duration of pregnancy decreased with increasing first-trimester risk for preeclampsia. Second, in the high-risk group, when compared with the low-risk group, the risk for spontaneous birth was 4 times higher at a gestational age of 24 to 26 weeks, 3 times higher at 28 to 32 weeks, and 2 times higher at 34 to 39 weeks. These differences present major clinical implications for antepartum counselling, monitoring, and interventions in these pregnancies.

Blood pressure cutoffs at 11-13 weeks of gestation and risk of preeclampsia.

BACKGROUND: A parallel has been drawn between first-trimester placental vascular maturation and maternal cardiovascular adaptations, including blood pressure. Although 140/90 mm Hg is well-accepted as the threshold for chronic hypertension in the general obstetric population in early pregnancy, a different threshold could apply to stratify the risk of adverse outcomes, such as preeclampsia. This could have implications for interventions, such as the threshold for initiation of antihypertensive therapy and the target blood pressure level. OBJECTIVE: We evaluated the relationship between various blood pressure cutoffs at 11-13 weeks of gestation and the development of preeclampsia, overall and according to key maternal characteristics. STUDY DESIGN: This secondary analysis was of data from a prospective nonintervention cohort study of singleton pregnancies delivering at ≥24 weeks, without major anomalies, at 2 United Kingdom maternity hospitals, 2006-2020. Blood pressure at 11-13 weeks of gestation was classified according to American College of Cardiology/American Heart Association categories (mm Hg) as (1) normal blood pressure (systolic <120 and diastolic <80), (2) elevated blood pressure (systolic ≥120 and diastolic <80), stage 1 hypertension (systolic ≥130 or diastolic 80-89), and stage 2 hypertension (systolic ≥140 or diastolic ≥90). For blood pressure category thresholds and the outcome of preeclampsia, the following were calculated overall and across maternal age, body mass index, ethnicity, method of conception, and previous pregnancy history: detection rate, screen-positive rate, and positive and negative likelihood ratios, with 95% confidence intervals. A P value of <.05 was considered significant. RESULTS: There were 137,458 pregnancies screened at 11-13 weeks of gestation. The population was ethnically diverse, with 15.9% of Black ethnicity, 6.7% of South or East Asian ethnicity, and 2.7% of mixed ethnicity, with the remainder of White ethnicity. Compared with normal blood pressure, stage 2 hypertension was associated with both preterm preeclampsia (0.3% to 4.9%) and term preeclampsia (1.0% to 8.3%). A blood pressure threshold of 140/90 mm Hg was good at identifying women at increased risk of preeclampsia overall (positive likelihood ratio, 5.61 [95% confidence interval, 5.14-6.11]) and across maternal characteristics, compared with elevated blood pressure (positive likelihood ratio, 1.70 [95% confidence interval, 1.63-1.77]) and stage 1 hypertension (positive likelihood ratio, 2.68 [95% confidence interval, 2.58-2.77]). There were 2 exceptions: a blood pressure threshold of 130/80 mm Hg was better for the 2.1% of women with body mass index <18.5 kg/m2 (positive likelihood ratio, 5.13 [95% confidence interval, 3.22-8.16]), and a threshold of 135/85 mm Hg better for the 50.4% of parous women without a history of preeclampsia (positive likelihood ratio, 5.24, [95% confidence interval, 4.77-5.77]). There was no blood pressure threshold below which reassurance could be provided against the development of preeclampsia (all-negative likelihood ratios ≥0.20). CONCLUSION: The traditional blood pressure threshold of 140/90 mm Hg performs well to identify women at increased risk of preeclampsia. Women who are underweight or parous with no prior history of preeclampsia may be better identified by lower thresholds; however, a randomized trial would be necessary to determine any benefits of such an approach if antihypertensive therapy were also administered at this threshold. No blood pressure threshold is reassured against the development of preeclampsia, regardless of maternal characteristics.

Placental growth factor testing at 19-23 weeks of gestation as a guide to subsequent care in pregnancy: A prospective observational study.

OBJECTIVE: To determine whether serum placental growth factor (PlGF) at 19-23 weeks of gestation can improve the identification of risk for adverse outcomes. DESIGN: Prospective observational cohort study. SETTING: Two English maternity units. POPULATION: Unselected singleton pregnancies attending routine ultrasound at 19-23 weeks of gestation. METHODS: Outcomes ascertained by health record review. Diagnostic test properties evaluated clinical risk factors for pre-eclampsia (according to National Institute of Care Excellence) or fetal growth restriction (according to Royal College of Obstetricians and Gynaecologists), low PlGF at 19-23 weeks of gestation (<5th percentile) or both. MAIN OUTCOME MEASURES: Pre-eclampsia, gestational hypertension, stillbirth, birthweight below third percentile or neonatal intensive care unit (NICU) admission for ≥48 h. RESULTS: In 30 013 pregnancies, risk factors were present in 9941 (33.1%), low PlGF was present in 1501 (5.0%) and both ('two-stage' screening) were present in 547 (1.8%) pregnancies. Risk factors detected 41.7%-54.7% of adverse outcomes, and could not meaningfully revise the risk (all positive likelihood ratios, +LR, <5.0; all negative likelihood ratios, -LR, ≥0.2). Low PlGF detected 8.5%-17.4% of adverse outcomes, but meaningfully increased risks (other than NICU admission) associated with delivery <37 weeks of gestation (+LR = 5.03-15.55); all -LRs were ≥0.2. 'Two-stage' screening detected 4.2%-8.9% of adverse outcomes, with meaningful +LRs (6.28-18.61) at <37 weeks of gestation, except for NICU admission of ≥48 h, which had an +LR of 7.56 at <34 weeks of gestation; all -LRs were ≥0.2. No screening strategy meaningfully increased or decreased the detection of adverse outcome risk at term. CONCLUSIONS: Clinical risk factor screening has a high screen-positive rate and a poor detection of adverse outcomes. False positives cannot be reduced by PlGF testing at 19-23 weeks of gestation; therefore, this cannot be recommended as a useful strategy on its own.

Relation of antepartum stillbirth to birthweight and gestational age: Prospective cohort study.

OBJECTIVES: To investigate the incidence of antepartum stillbirth in relation to the distribution of neonatal/fetal weight for different gestational ages. DESIGN: Prospective observational cohort study. SETTING: Obstetric ultrasound departments in two UK maternity hospitals. POPULATION: 168 966 women with singleton pregnancies attending for routine antenatal care. METHODS: We examined the incidence of antepartum stillbirths, within different birthweight and fetal weight percentile subgroups, conditioning for gestational age. MAIN OUTCOME MEASURES: Incidence of antepartum stillbirth. RESULTS: The risk of stillbirth progressively increased for lower birthweight. Considering the 25-75th percentile as the reference category, the relative risks for stillbirth at <37 weeks' gestation were 7.6 (95% confidence interval [CI] 5.7-10.2) <1st percentile, 2.6 (95% CI 1.8-3.7) 1 to 10th percentile, 1.4 (95% CI 0.9-2.1) 10 to 25th percentile, 0.8 (95% CI 0.4-1.5) 75 to 90th percentile, 0.8 (95% CI 0.4-1.7) 90 to 99th percentile, 0.9 (95% CI 0.3-2.5) >99th percentile. The respective values for births at ≥37 weeks' gestation were 5.0 (95% CI 2.9-8.9), 2.1 (95% CI 1.4-3.3), 1.4 (95% CI 0.9-2.1), 1.2 (95% CI 0.7-1.8), 1.0 (95% CI 0.6-1.8) and 4.0 (95% CI 1.8-9.3). The incidence of stillbirth in ongoing low-risk singleton pregnancies gradually increases for smaller fetuses at any gestational point. The higher incidence (5.56%) was evident for fetal weight <1st percentile between 24 and 28 weeks' gestation. CONCLUSION: Fetal weight and the weight of the stillborn have a continuous association with the incidence of antepartum stillbirth which is affected by gestational age.

First-trimester prediction of preterm pre-eclampsia and prophylaxis by aspirin: Effect on spontaneous and iatrogenic preterm birth.

OBJECTIVE: To report the predictive performance for preterm birth (PTB) of the Fetal Medicine Foundation (FMF) triple test and National Institute for health and Care Excellence (NICE) guidelines used to screen for pre-eclampsia and examine the impact of aspirin in the prevention of PTB. DESIGN: Secondary analysis of data from the SPREE study and the ASPRE trial. SETTING: Multicentre studies. POPULATION: In SPREE, women with singleton pregnancies had screening for preterm pre-eclampsia at 11-13 weeks of gestation by the FMF method and NICE guidelines. There were 16 451 pregnancies that resulted in delivery at ≥24 weeks of gestation and these data were used to derive the predictive performance for PTB of the two methods of screening. The results from the ASPRE trial were used to examine the effect of aspirin in the prevention of PTB in the population from SPREE. METHODS: Comparison of performance of FMF method and NICE guidelines for pre-eclampsia in the prediction of PTB and use of aspirin in prevention of PTB. MAIN OUTCOME MEASURE: Spontaneous PTB (sPTB), iatrogenic PTB for pre-eclampsia (iPTB-PE) and iatrogenic PTB for reasons other than pre-eclampsia (iPTB-noPE). RESULTS: Estimated incidence rates of sPTB, iPTB-PE and iPTB-noPE were 3.4%, 0.8% and 1.6%, respectively. The corresponding detection rates were 17%, 82% and 25% for the triple test and 12%, 39% and 19% for NICE guidelines, using the same overall screen positive rate of 10.2%. The estimated proportions prevented by aspirin were 14%, 65% and 0%, respectively. CONCLUSION: Prediction of sPTB and iPTB-noPE by the triple test was poor and poorer by the NICE guidelines. Neither sPTB nor iPTB-noPE was reduced substantially by aspirin.

Personalized stratification of pregnancy care for small for gestational age neonates from biophysical markers at midgestation.

BACKGROUND: Antenatal identification of pregnancies at high risk of delivering small for gestational age neonates may improve the management of the condition and reduce the associated adverse perinatal outcomes. In a series of publications, we have developed a new competing-risks model for small for gestational age prediction, and we demonstrated that the new approach has a superior performance to that of the traditional methods. The next step in shaping the appropriate management of small for gestational age is the timely assessment of these high-risk pregnancies according to an antenatal stratification plan. OBJECTIVE: This study aimed to demonstrate the stratification of pregnancy care based on individual patient risk derived from the application of the competing-risks model for small for gestational age that combines maternal factors with sonographic estimated fetal weight and uterine artery pulsatility index at midgestation. STUDY DESIGN: This was a prospective observational study of 96,678 singleton pregnancies undergoing routine ultrasound examination at 19 to 24 weeks of gestation, which included recording of estimated fetal weight and measurement of uterine artery pulsatility index. The competing-risks model for small for gestational age was used to create a patient-specific stratification curve capable to define a specific timing for a repeated ultrasound examination after 24 weeks. We examined different stratification plans with the intention of detecting approximately 80%, 85%, 90%, and 95% of small for gestational age neonates with birthweight <3rd and <10th percentiles at any gestational age at delivery until 36 weeks; all pregnancies would be offered a routine ultrasound examination at 36 weeks. RESULTS: The stratification of pregnancy care for small for gestational age can be based on a patient-specific stratification curve. Factors from maternal history, low estimated fetal weight, and increased uterine artery pulsatility index shift the personalized risk curve toward higher risks. The degree of shifting defines the timing for assessment for each pregnancy. If the objective of our antenatal plan was to detect 80%, 85%, 90%, and 95% of small for gestational age neonates at any gestational age at delivery until 36 weeks, the median (range) proportions (percentages) of population examined per week would be 3.15 (1.9-3.7), 3.85 (2.7-4.5), 4.75 (4.0-5.4), and 6.45 (3.7-8.0) for small for gestational age <3rd percentile and 3.8 (2.5-4.6), 4.6 (3.6-5.4), 5.7 (3.8-6.4), and 7.35 (3.3-9.8) for small for gestational age <10th percentile, respectively. CONCLUSION: The competing-risks model provides an effective personalized continuous stratification of pregnancy care for small for gestational age which is based on individual characteristics and biophysical marker levels recorded at the midgestation scan.

First-trimester preterm preeclampsia prediction with metabolite biomarkers: differential prediction according to maternal body mass index.

BACKGROUND: Prediction of preeclampsia risk is key to informing effective maternal care. Current screening for preeclampsia at 11 to 13 weeks of gestation using maternal demographic characteristics and medical history with measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor can identify approximately 75% of women who develop preterm preeclampsia with delivery at <37 weeks of gestation. Further improvements to preeclampsia screening tests will likely require integrating additional biomarkers. Recent research suggests the existence of distinct maternal risk profiles. Therefore, biomarker evaluation should account for the possibility that a biomarker only predicts preeclampsia in a specific maternal phenotype. OBJECTIVE: This study aimed to verify metabolite biomarkers as preterm preeclampsia predictors early in pregnancy in all women and across body mass index groups. STUDY DESIGN: Observational case-control study drawn from a large prospective study on the early prediction of pregnancy complications in women attending their routine first hospital visit at King's College Hospital, London, United Kingdom, in 2010 to 2015. Pregnant women underwent a complete first-trimester assessment, including the collection of blood samples for biobanking. In 11- to 13-week plasma samples of 2501 singleton pregnancies, the levels of preselected metabolites implicated in the prediction of pregnancy complications were analyzed using a targeted liquid chromatography-mass spectrometry method, yielding high-quality quantification data on 50 metabolites. The ratios of amino acid levels involved in arginine biosynthesis and nitric oxide synthase pathways were added to the list of biomarkers. Placental growth factor and pregnancy-associated plasma protein A were also available for all study subjects, serving as comparator risk predictors. Data on 1635 control and 106 pregnancies complicated by preterm preeclampsia were considered for this analysis, normalized using multiples of medians. Prediction analyses were performed across the following patient strata: all subjects and the body mass index classes of <25, 25 to <30, and ≥30 kg/m2. Adjusted median levels were compared between cases and controls and between each body mass index class group. Odds ratios and 95% confidence intervals were calculated at the mean ±1 standard deviation to gauge clinical prediction merits. RESULTS: The levels of 13 metabolites were associated with preterm preeclampsia in the entire study population (P<.05) with particularly significant (P<.01) associations found for 6 of them, namely, 2-hydroxy-(2/3)-methylbutyric acid, 25-hydroxyvitamin D3, 2-hydroxybutyric acid, alanine, dodecanoylcarnitine, and 1-(1Z-octadecenyl)-2-oleoyl-sn-glycero-3-phosphocholine. Fold changes in 7 amino acid ratios, all involving glutamine or ornithine, were also significantly different between cases and controls (P<.01). The predictive performance of some metabolites and ratios differed according to body mass index classification; for example, ornithine (P<.001) and several ornithine-related ratios (P<.0001 to P<.01) were only strongly associated with preterm preeclampsia in the body mass index of <25 kg/m2 group, whereas dodecanoylcarnitine and 3 glutamine ratios were particularly predictive in the body mass index of ≥30 kg/m2 group (P<.01). CONCLUSION: Single metabolites and ratios of amino acids related to arginine bioavailability and nitric oxide synthase pathways were associated with preterm preeclampsia risk at 11 to 13 weeks of gestation. Differential prediction was observed according to body mass index classes, supporting the existence of distinct maternal risk profiles. Future studies in preeclampsia prediction should account for the possibility of different maternal risk profiles to improve etiologic and prognostic understanding and, ultimately, clinical utility of screening tests.

The implications of the Fetal Medicine Foundation 35- to 36-week preeclampsia prediction competing-risk model on timing of birth.

BACKGROUND: Preeclampsia is associated with increased risks of life-threatening, -altering, and -ending complications. Assessment of risk for preeclampsia at 35 to 36 weeks' gestation by the Fetal Medicine Foundation 36-week competing-risk model identifies approximately 75% of women who will develop term preeclampsia, at a 10% screen-positive rate. OBJECTIVE: This study aimed to assess whether the Fetal Medicine Foundation 36-week model can provide personalized guidance to women about the probable timing of their delivery, whether or not they develop pregnancy hypertension. STUDY DESIGN: In this prospective nonintervention screening study at 2 maternity hospitals in England, women who did not have preeclampsia (American College of Obstetricians and Gynecologists definition) and were attending a routine hospital visit at 35 0/7 to 36 6/7 weeks' gestation underwent assessment of risk for preeclampsia, including maternal demographic characteristics, medical history, mean arterial pressure, and serum placental growth factor and soluble fms-like tyrosine kinase-1. Fetal Medicine Foundation 36-week model risk categories for subsequent preeclampsia were defined as: A, ≥0.500; B, 0.20 to 0.499; C, 0.05 to 0.199; D, 0.020 to 0.049; and E, <0.020. Obstetrical records were examined for all women to identify their gestational age at delivery, and whether they experienced a spontaneous onset of labor (irrespective of mode of delivery) or had a medically indicated birth (either induction of labor or unlabored cesarean delivery). The cumulative incidence of delivery and risk ratios, for all deliveries and for spontaneous deliveries, was assessed. RESULTS: Among 29,035 women with singleton pregnancies, 1.0%, 2.9%, 3.3%, 5.0%, 9.9%, and 77.9% were in A, B, C, D, and E risk strata, respectively. In the A (vs E) stratum, 71.95% (vs 33.52%) of births were medically indicated. Compared with women in stratum E, women in higher risk strata were more likely to deliver, and to deliver following spontaneous labor, before their due date. For example, of the women in stratum A (vs E), 14.2% (vs 1.1%; risk ratio, 12.5 [95% confidence interval, 9.45-15.35]), 48.5% (vs 5.1%; risk ratio, 8.47 [7.48-9.35]), 69.6% (vs 15.5%; risk ratio, 3.86 [3.59-4.08]), and 90.1% (vs 44.8%; risk ratio, 6.72 [4.53-9.95]) gave birth before 37 0/7, 38 0/7, 39 0/7, and 40 0/7 weeks, respectively. For women in stratum A (vs E), when censored for medically indicated births, spontaneous labor occurred more commonly before 37 0/7 (risk ratio, 4.31 [1.99-6.57]), 38 0/7 (risk ratio, 3.71 [2.48-4.88]), 39 0/7 (risk ratio, 2.87 [2.22-3.46]), and 40 0/7 (risk ratio, 1.42 [1.14-1.77]) weeks. CONCLUSION: Women in higher-risk strata gave birth earlier, and more frequently following medically indicated delivery, compared with those in lower-risk strata. Importantly, the proportion of women who gave birth following spontaneous onset of labor before their due date was also greater in higher-risk than in lower-risk women. The Fetal Medicine Foundation 36-week competing-risk model incorporates biomarkers of placental aging, including angiogenic imbalance; these results imply that a fetoplacental response to placental aging may be an important trigger for the onset of labor at term.

Aspirin for evidence-based preeclampsia prevention trial: effects of aspirin on maternal serum pregnancy-associated plasma protein A and placental growth factor trajectories in pregnancy.

BACKGROUND: The exact mechanism by which aspirin prevents preeclampsia remains unclear. Its effects on serum placental biomarkers throughout pregnancy are also unknown. OBJECTIVE: To investigate the effects of aspirin on serum pregnancy-associated plasma protein A and placental growth factor trajectories using repeated measures from women at increased risk of preterm preeclampsia. STUDY DESIGN: This was a longitudinal secondary analysis of the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-based Preeclampsia Prevention trial using repeated measures of pregnancy-associated plasma protein A and placental growth factor. In the trial, 1620 women at increased risk of preterm preeclampsia were identified using the Fetal Medicine Foundation algorithm at 11 to 13+6 weeks of gestation, of whom 798 were randomly assigned to receive aspirin 150 mg and 822 to receive placebo daily from before 14 weeks to 36 weeks of gestation. Serum biomarkers were measured at baseline and follow-up visits at 19 to 24, 32 to 34, and 36 weeks of gestation. Generalized additive mixed models with treatment by gestational age interaction terms were used to investigate the effect of aspirin on biomarker trajectories over time. RESULTS: Overall, there were 5507 pregnancy-associated plasma protein A and 5523 placental growth factor measurements. Raw pregnancy-associated plasma protein A values increased over time, and raw placental growth factor increased until 32 weeks of gestation followed by a decline. The multiple of the median mean values of the same biomarkers were consistently below 1.0 multiple of the median, reflecting the high-risk profile of the study population. Trajectories of mean pregnancy-associated plasma protein A and placental growth factor multiple of the median values did not differ significantly between the aspirin and placebo groups (aspirin treatment by gestational age interaction P values: .259 and .335, respectively). CONCLUSION: In women at increased risk of preterm preeclampsia, aspirin 150 mg daily had no significant effects on pregnancy-associated plasma protein A or placental growth factor trajectories when compared to placebo.

Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in twin gestations: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy of vaginal progesterone for the prevention of preterm birth and adverse perinatal outcomes in twin gestations. DATA SOURCES: MEDLINE, Embase, LILACS, and CINAHL (from their inception to January 31, 2023), Cochrane databases, Google Scholar, bibliographies, and conference proceedings. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials that compared vaginal progesterone to placebo or no treatment in asymptomatic women with a twin gestation. METHODS: The systematic review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome was preterm birth <34 weeks of gestation. Secondary outcomes included adverse perinatal outcomes. Pooled relative risks with 95% confidence intervals were calculated. We assessed the risk of bias in each included study, heterogeneity, publication bias, and quality of evidence, and performed subgroup and sensitivity analyses. RESULTS: Eleven studies (3401 women and 6802 fetuses/infants) fulfilled the inclusion criteria. Among all twin gestations, there were no significant differences between the vaginal progesterone and placebo or no treatment groups in the risk of preterm birth <34 weeks (relative risk, 0.99; 95% confidence interval, 0.84-1.17; high-quality evidence), <37 weeks (relative risk, 0.99; 95% confidence interval, 0.92-1.06; high-quality evidence), and <28 weeks (relative risk, 1.00; 95% confidence interval, 0.64-1.55; moderate-quality evidence), and spontaneous preterm birth <34 weeks of gestation (relative risk, 0.97; 95% confidence interval, 0.80-1.18; high-quality evidence). Vaginal progesterone had no significant effect on any of the perinatal outcomes evaluated. Subgroup analyses showed that there was no evidence of a different effect of vaginal progesterone on preterm birth <34 weeks of gestation related to chorionicity, type of conception, history of spontaneous preterm birth, daily dose of vaginal progesterone, and gestational age at initiation of treatment. The frequencies of preterm birth <37, <34, <32, <30, and <28 weeks of gestation and adverse perinatal outcomes did not significantly differ between the vaginal progesterone and placebo or no treatment groups in unselected twin gestations (8 studies; 3274 women and 6548 fetuses/infants). Among twin gestations with a transvaginal sonographic cervical length <30 mm (6 studies; 306 women and 612 fetuses/infants), vaginal progesterone was associated with a significant decrease in the risk of preterm birth occurring at <28 to <32 gestational weeks (relative risks, 0.48-0.65; moderate- to high-quality evidence), neonatal death (relative risk, 0.32; 95% confidence interval, 0.11-0.92; moderate-quality evidence), and birthweight <1500 g (relative risk, 0.60; 95% confidence interval, 0.39-0.88; high-quality evidence). Vaginal progesterone significantly reduced the risk of preterm birth occurring at <28 to <34 gestational weeks (relative risks, 0.41-0.68), composite neonatal morbidity and mortality (relative risk, 0.59; 95% confidence interval, 0.33-0.98), and birthweight <1500 g (relative risk, 0.55; 95% confidence interval, 0.33-0.94) in twin gestations with a transvaginal sonographic cervical length ≤25 mm (6 studies; 95 women and 190 fetuses/infants). The quality of evidence was moderate for all these outcomes. CONCLUSION: Vaginal progesterone does not prevent preterm birth, nor does it improve perinatal outcomes in unselected twin gestations, but it appears to reduce the risk of preterm birth occurring at early gestational ages and of neonatal morbidity and mortality in twin gestations with a sonographic short cervix. However, more evidence is needed before recommending this intervention to this subset of patients.

Preterm and term pre-eclampsia: Relative burdens of maternal and perinatal complications.

OBJECTIVE: To determine the relative burdens of maternal and perinatal complications for preterm and term pre-eclampsia. DESIGN: Prospective observational cohort study. SETTING: Two English maternity units. POPULATION: Unselected women with singleton pregnancies who developed pre-eclampsia (International Society for the Study of Hypertension in Pregnancy definition). METHODS: Outcomes were ascertained by health record review and compared between pregnancies with preterm (versus term) pre-eclampsia. MAIN OUTCOME MEASURES: Severe maternal hypertension, maternal mortality or major maternal morbidity, perinatal mortality or major neonatal morbidity, neonatal unit (NNU) admission ≥48 hours, and birthweight <3rd percentile. RESULTS: Among 40 241 singleton pregnancies, 298 (0.7%, 95% confidence interval [CI] 0.66-0.83) and 1194 (3.0%, 95% CI 2.8-3.1) developed preterm and term pre-eclampsia, respectively. Women with preterm (versus term) pre-eclampsia more commonly experienced adverse maternal or perinatal events: severe hypertension 18.5% (95% CI 14.5-23.3) versus 13.6% (95% CI 11.7-15.6); maternal mortality/major morbidity 7.4% (95% CI 4.9-10.9) versus 2.2% (95% CI 1.5-3.2); perinatal mortality/major neonatal morbidity 29.5% (95% CI 24.6-34.9) versus 2.2% (95% CI 1.5-3.2); and birthweight <3rd percentile 54.4% (95% CI 48.7-59.9) versus 14.2% (95% CI 12.4-16.3). However, in absolute terms, most maternal complications occurred in women with term pre-eclampsia, as did a large proportion of perinatal complications: severe hypertension 74.7% (95% CI 68.5-80.0); maternal mortality/major morbidity 54.2% (95% CI 40.3-67.4); perinatal mortality/major neonatal morbidity 22.8% (95% CI 16.1-31.3); NNU admission ≥48 hours 38.1% (95% CI 32.4-44.1); and birthweight <3rd percentile 51.2% (95% CI 45.8-56.5). CONCLUSIONS: Although adverse event risks are greater with preterm (versus term) pre-eclampsia, term disease is associated with at least equivalent total numbers of maternal, and a significant proportion of perinatal, adverse events. Increased efforts should be made to decrease the incidence of term pre-eclampsia.

Effect of race on the measurement of angiogenic factors for prediction and diagnosis of pre-eclampsia.

OBJECTIVE: To examine the effect of self-declared race on serum placental growth factor (PlGF) and sFlt-1/PlGF ratio and the impact on pre-eclampsia (PE) prediction. DESIGN: Prospective observational study. SETTING: Two UK maternity hospitals. POPULATION: 29 035 women with singleton pregnancies attending a routine 35+0 to 36+6 weeks' gestation hospital visit, including 654 (2.3%) who subsequently developed PE. METHODS: The predictive performance of PlGF and sFlt-1/PlGF for PE in minority racial groups (versus white) was examined. MAIN OUTCOME MEASURE: Delivery with PE. RESULTS: Compared with white women, mean PlGF was higher and sFlt-1/PlGF ratio lower in black, South Asian, East Asian and mixed race women. In white women at a PlGF concentration cut-off corresponding to a screen-positive rate (SPR) of 10%, detection rates (DRs) were 49.1% for PE at any time and 72.3% for PE within 2 weeks after screening. In black women, at the same PlGF concentration cut-off for white women, the SPR was 5.5%, and DRs 33.6% and 55.0%, respectively; the number of PE cases was too small to evaluate screening performance in other racial groups. Using a fixed cut-off in sFlt-1/PlGF ratio to identify women at risk of developing PE, similarly diagnostically disadvantaged black women. Bias was overcome by adjusting metabolite concentrations for maternal characteristics and use of the competing risks model to estimate patient-specific risks. CONCLUSION: Screening for PE with fixed cut-offs in PlGF or sFlt-1/PlGF diagnostically disadvantages black women. It is essential that measured levels of PlGF be adjusted for race as well as other maternal characteristics.

Maternal plasma diacylglycerols and triacylglycerols in the prediction of gestational diabetes mellitus.

OBJECTIVE: To define the lipidomic profile in plasma across pregnancy, and identify lipid biomarkers for gestational diabetes mellitus (GDM) prediction in early pregnancy. DESIGN: Case-control study. SETTING: Tertiary referral maternity unit. POPULATION OR SAMPLE: Plasma samples from 100 GDM and 100 normal glucose tolerance (NGT) women, divided into a training set (GDM first trimester = 50, GDM second trimester = 40, NGT first trimester = 50, NGT second trimester = 50) and a validation set (GDM first trimester = 45, GDM second trimester = 34, NGT first trimester = 44, NGT second trimester = 40). METHODS: Plasma samples were collected in the first (11+0 to 13+6 weeks), second (19+0 to 24+6 weeks), and third trimesters (30+0 to 34+6 weeks), and tested by ultra-high-performance liquid chromatography coupled with electrospray ionisation-quadrupole-time of flight-mass spectrometry; The GDM prediction model was established by the machine-learning method of random forest. MAIN OUTCOME MEASURES: Gestational diabetes mellitus. RESULTS: In both the GDM and NGT group, lyso-glycerophospholipids were down-regulated, whereas ceramides, sphingomyelins, cholesteryl ester, diacylglycerols (DGs) and triacylglycerols (TGs) and glucosylceramide were up-regulated across the three trimesters of pregnancy. In the training dataset, seven TGs and five DGs demonstrated good performance in the prediction of GDM in the first and second trimesters (area under the curve [AUC] = 0.96 with 95% confidence interval [CI] of 0.93-1 and AUC = 0.97 with 95% CI of 0.95-1, respectively), independent of maternal body mass index (BMI) and ethnicity. In the validation dataset, the predictive model achieved an AUC of 0.88 and 0.94 at the first and second trimesters, respectively. CONCLUSIONS: Our results have proposed new lipid biomarkers for the first trimester prediction of GDM, independent of ethnicity and BMI.

Pravastatin Versus Placebo in Pregnancies at High Risk of Term Preeclampsia.

BACKGROUND: Effective screening for term preeclampsia is provided by a combination of maternal factors with measurements of mean arterial pressure, serum placental growth factor, and serum soluble fms-like tyrosine kinase-1 at 35 to 37 weeks of gestation, with a detection rate of ≈75% at a screen-positive rate of 10%. However, there is no known intervention to reduce the incidence of the disease. METHODS: In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1120 women with singleton pregnancies at high risk of term preeclampsia to receive pravastatin at a dose of 20 mg/d or placebo from 35 to 37 weeks of gestation until delivery or 41 weeks. The primary outcome was delivery with preeclampsia at any time after randomization. The analysis was performed according to intention to treat. RESULTS: A total of 29 women withdrew consent during the trial. Preeclampsia occurred in 14.6% (80 of 548) of participants in the pravastatin group and in 13.6% (74 of 543) in the placebo group. Allowing for the effect of risk at the time of screening and participating center, the mixed-effects Cox regression showed no evidence of an effect of pravastatin (hazard ratio for statin/placebo, 1.08 [95% CI, 0.78-1.49]; P=0.65). There was no evidence of interaction between the effect of pravastatin, estimated risk of preeclampsia, pregnancy history, adherence, and aspirin treatment. There was no significant between-group difference in the incidence of any secondary outcomes, including gestational hypertension, stillbirth, abruption, delivery of small for gestational age neonates, neonatal death, or neonatal morbidity. There was no significant between-group difference in the treatment effects on serum placental growth factor and soluble fms-like tyrosine kinase-1 concentrations 1 and 3 weeks after randomization. Adherence was good, with reported intake of ≥80% of the required number of tablets in 89% of participants. There were no significant between-group differences in neonatal adverse outcomes or other adverse events. CONCLUSIONS: Pravastatin in women at high risk of term preeclampsia did not reduce the incidence of delivery with preeclampsia. Registration: URL: https://www.isrctn.com; Unique identifier ISRCTN16123934.

Using ultrasound and angiogenic markers from a 19- to 23-week assessment to inform the subsequent diagnosis of preeclampsia.

BACKGROUND: A definition of preeclampsia that incorporates the assessment of maternal, fetal, and uteroplacental status would optimize the identification of pregnancies at risk of complications at term gestational age. This definition would include "carrying forward" angiogenic test results from 35 to 36 weeks of gestation to term gestational age. Would this approach still be useful if testing is performed earlier or at a routine midgestation scan and the result is used to inform the diagnosis of preeclampsia that developed thereafter? OBJECTIVE: This study aimed to evaluate whether fetoplacental assessment at a 19- to 23-week scan could be "carried forward" to contribute to the classification of preeclampsia and improve the detection of women and fetuses at risk of adverse outcomes associated with hypertension. STUDY DESIGN: In this prospective cohort study of singleton pregnancies at 2 maternity hospitals in England (October 2011 to March 2020), women attending a routine hospital visit at 19 to 23 weeks of gestation underwent an assessment that included history, ultrasonographic estimated fetal weight, Doppler measurements of the pulsatility index in uterine arteries, and serum placental growth factor. Preeclampsia was defined according to various definitions: (1) traditional, based on new-onset proteinuria at ≥20 weeks of gestation; (2) 2013 American College of Obstetricians and Gynecologists; (3) 2018 International Society for the Study of Hypertension in Pregnancy maternal factor; (4) 2018 International Society for the Study of Hypertension in Pregnancy maternal-fetal factor (death or growth restriction), based on ultrasound scans at the 19 0/7 to 23 6/7 week of gestation (an estimated fetal weight of <3rd percentile or estimated fetal weight between the 3rd and 10th percentiles with a uterine artery pulsatility index of >95th percentile); and (5) 2021 International Society for the Study of Hypertension in Pregnancy maternal-fetal factor plus placental growth factor (with abnormal placental growth factor defined as an estimated fetal weight of <5th percentile for gestational age). The detection rates for outcomes of interest (ie, severe maternal hypertension, major maternal morbidity, perinatal mortality or major neonatal morbidity, neonatal intensive care unit admission ≥48 hours, and birthweight of <3rd percentile) ascertained by health record review were compared using the chi-square test. A P value of <.05 was considered statistically significant. RESULTS: Among 40,241 singleton pregnancies, preeclampsia incidence varied by definition, from lows of 2.6% (traditional) and 3.0% (American College of Obstetricians and Gynecologists) to a high of 3.8% (International Society for the Study of Hypertension in Pregnancy maternal-fetal factor plus placental growth factor). The International Society for the Study of Hypertension in Pregnancy maternal-fetal factor plus placental growth factor definition (vs the traditional) best identified women who developed adverse outcomes: severe hypertension (detection rate: 70.6% vs 52.8%; P<.001), major maternal morbidity (detection rate: 100% vs 87.5%; P=.027), perinatal mortality or major morbidity (detection rate: 84.6% vs 69.5%; P=.004), neonatal intensive care unit admission ≥48 hours (detection rate: 76.6% vs 63.2%;, P=.0002), and birthweight of <3rd percentile (detection rate: 81.3% vs 61.9%; P<.0001]. The detection rates improved, going from the American College of Obstetricians and Gynecologists definition to the International Society for the Study of Hypertension in Pregnancy maternal-fetal factor plus placental growth factor definition, for severe hypertension (11.4%; P=.003), perinatal mortality or major morbidity (10.6%; P=.03), neonatal intensive care unit admission ≥48 hours (8.6%; P=.01), and birthweight of <3rd percentile (16.2%; P<.001). However, going from the International Society for the Study of Hypertension in Pregnancy maternal-fetal factor definition to the International Society for the Study of Hypertension in Pregnancy maternal-fetal factor plus placental growth factor definition, the detection of fetuses with a birthweight of <3rd percentile improved by 7.0% (P=.01), but no other improvement was seen for severe hypertension (1.7%; P=.33), major maternal morbidity (0%), perinatal mortality or major morbidity (4.0%; P=.20), and neonatal intensive care unit admission ≥48 hours (3.2%; P=.17). CONCLUSION: The criteria for uteroplacental dysfunction (including placental growth factor) from the 19- to 23-week assessment can be used in the assessment of women who are later suspected of having PE, to best identify pregnancies at risk of adverse outcomes.

Serum PlGF compared with PAPP-A in first trimester screening for preterm pre-eclampsia: Adjusting for the effect of aspirin treatment.

OBJECTIVE: To compare the predictive performance for preterm-pre-eclampsia (PE) in first-trimester screening by serum placental growth factor (PlGF) versus pregnancy associated plasma protein-A (PAPP-A), in combination with maternal risk factors, mean arterial pressure (MAP) and uterine artery pulsatility index (UtA-PI), after adjustment for the effect of aspirin in women receiving this treatment. DESIGN: Non-intervention multicentre screening studies for PE in singleton pregnancies. SETTING: Maternity hospitals. POPULATION: Two independent prospective studies of 8775 and 16 451 women with singleton pregnancies attending for routine assessment at 11+0 -13+6 weeks' gestation. METHODS: The competing risks model was used to estimate patient-specific risks of delivery with PE at <37 weeks' gestation based on maternal risk factors and combinations with MAP, UtA-PI and either PlGF or PAPP-A. McNemar's test was used to compare the detection rate (DR) of preterm-PE of screening utilising PlGF versus PAPP-A, after adjustments for the effects of aspirin. MAIN OUTCOME MEASURE: Predictive performance for preterm-PE. RESULTS: In the combined data of 25 226 women, including 678 (2.7%) who developed PE, there were 194(0.8%) with preterm-PE. Addition of PlGF improved the DR of preterm-PE, at 10% screen positive rate, by 18.4% (95% CI 12.2-24.6) in screening by maternal risk factors, by 19.9% (95% CI 13.6-26.2) in screening by maternal factors and MAP, and by 7.0% (95% CI 2.3-11.6) in screening by maternal factors, MAP and UtA-PI. PAPP-A did not significantly improve the DR provided by any combination of biomarkers. CONCLUSION: The predictive performance of first trimester PlGF for preterm-PE is superior to that of PAPP-A.

Predictive performance for placental dysfunction related stillbirth of the competing risks model for small-for-gestational-age fetuses.

OBJECTIVES: To examine the predictive performance for placental dysfunction related stillbirths of the competing risks model for small-for-gestational-age (SGA) fetuses based on a combination of maternal risk factors, estimated fetal weight (EFW) and uterine artery pulsatility index (UtA-PI); and second, to compare the performance of this model with that of a stillbirth-specific model using the same biomarkers and with the Royal College of Obstetricians and Gynecologists (RCOG) guideline for the investigation and management of the SGA fetus. DESIGN: Prospective observational study. SETTING: Two UK maternity hospitals. POPULATION: A total of 131 514 women with singleton pregnancies attending for routine ultrasound examination at 19-24 weeks of gestation. METHODS: The predictive performance for stillbirth achieved by three models was compared. MAIN OUTCOME MEASURE: Placental dysfunction related stillbirth. RESULTS: At 10% false-positive rate, the competing risks model predicted 59%, 66% and 71% of placental dysfunction related stillbirths, at any gestation, at <37 weeks and at <32 weeks, respectively, which were similar to the respective figures of 62%, 70% and 73% for the stillbirth-specific model. At a screen positive rate of 21.8%, as defined by the RCOG guideline, the competing risks model predicted 71%, 76% and 79% of placental dysfunction related stillbirths at any gestation, at <37 weeks and at <32 weeks, respectively, and the respective figures for the RCOG guideline were 40%, 44% and 42%. CONCLUSION: The predictive performance for placental dysfunction related stillbirths by the competing risks model for SGA was similar to that of the stillbirth-specific model and superior to that of the RCOG guideline. TWEETABLE ABSTRACT: The competing risks approach for SGA is superior to the RCOG guideline in the prediction of placental dysfunction related stillbirths.

Maternal race and pre-eclampsia: Cohort study and systematic review with meta-analysis.

OBJECTIVES: To examine the association between race and pre-eclampsia and gestational hypertension after adjustment for factors in maternal characteristics and medical history in a screening study from the Fetal Medicine Foundation (FMF) in England, and to perform a systematic review and meta-analysis of studies on pre-eclampsia. DESIGN: Prospective observational study and systematic review with meta-analysis. SETTING: Two UK maternity hospitals. POPULATION: A total of 168 966 women with singleton pregnancies attending for routine ultrasound examination at 11-13 weeks of gestation without major abnormalities delivering at 24 weeks or more of gestation. METHODS: Regression analysis examined the association between race and pre-eclampsia or gestational hypertension in the FMF data. Literature search to December 2021 was carried out to identify peer-reviewed publications on race and pre-eclampsia. MAIN OUTCOME MEASURE: Relative risk of pre-eclampsia and gestational hypertension in women of black, South Asian and East Asian race by comparison to white women. RESULTS: In black women, the respective risks of total-pre-eclampsia and preterm-pre-eclampsia were 2-fold and 2.5-fold higher, respectively, and risk of gestational hypertension was 25% higher; in South Asian women there was a 1.5-fold higher risk of preterm pre-eclampsia but not of total-pre-eclampsia and in East Asian women there was no statistically significant difference in risk of hypertensive disorders. The literature search identified 19 studies that provided data on several million pregnancies, but 17 were at moderate or high-risk of bias and only three provided risks adjusted for some maternal characteristics; consequently, these studies did not provide accurate contributions on different racial groups to the prediction of pre-eclampsia. CONCLUSION: In women of black and South Asian origin the risk of pre-eclampsia, after adjustment for confounders, is higher than in white women.

Competing risks model for prediction of small-for-gestational-age neonates from biophysical markers at 19 to 24 weeks' gestation.

BACKGROUND: Antenatal identification of women at high risk to deliver small-for-gestational-age neonates may improve the management of the condition. The traditional but ineffective methods for small-for-gestational-age screening are the use of risk scoring systems based on maternal demographic characteristics and medical history and the measurement of the symphysial-fundal height. Another approach is to use logistic regression models that have higher performance and provide patient-specific risks for different prespecified cutoffs of birthweight percentile and gestational age at delivery. However, such models have led to an arbitrary dichotomization of the condition; different models for different small-for-gestational-age definitions are required and adding new biomarkers or examining other cutoffs requires refitting of the whole model. An alternative approach for the prediction of small-for-gestational-age neonates is to consider small for gestational age as a spectrum disorder whose severity is continuously reflected in both the gestational age at delivery and z score in birthweight for gestational age. OBJECTIVE: This study aimed to develop a new competing risks model for the prediction of small-for-gestational-age neonates based on a combination of maternal demographic characteristics and medical history with sonographic estimated fetal weight, uterine artery pulsatility index, and mean arterial pressure at 19 to 24 weeks' gestation. STUDY DESIGN: This was a prospective observational study of 96,678 women with singleton pregnancies undergoing routine ultrasound examination at 19 to 24 weeks' gestation, which included recording of estimated fetal weight, uterine artery pulsatility index, and mean arterial pressure. The competing risks model for small for gestational age is based on a previous joint distribution of gestational age at delivery and birthweight z score, according to maternal demographic characteristics and medical history. The likelihoods of the estimated fetal weight, uterine artery pulsatility index, and mean arterial pressure were fitted conditionally to both gestational age at delivery and birthweight z score and modified the previous distribution, according to the Bayes theorem, to obtain an individualized posterior distribution for gestational age at delivery and birthweight z score and therefore patient-specific risks for any desired cutoffs for birthweight z score and gestational age at delivery. The model was internally validated by randomly dividing the data into a training data set, to obtain the parameters of the model, and a test data set, to evaluate the model. The discrimination and calibration of the model were also examined. RESULTS: The estimated fetal weight was described using a regression model with an interaction term between gestational age at delivery and birthweight z score. Folded plane regression models were fitted for uterine artery pulsatility index and mean arterial pressure. The prediction of small for gestational age by maternal factors was improved by adding biomarkers for increasing degree of prematurity, higher severity of smallness, and coexistence of preeclampsia. Screening by maternal factors with estimated fetal weight, uterine artery pulsatility index, and mean arterial pressure, predicted 41%, 56%, and 70% of small-for-gestational-age neonates with birthweights of <10th percentile delivered at ≥37, <37, and <32 weeks' gestation, at a 10% false-positive rate. The respective rates for a birthweight of <3rd percentile were 47%, 65%, and 77%. The rates in the presence of preeclampsia were 41%, 72%, and 91% for small-for-gestational-age neonates with birthweights of <10th percentile and 50%, 75%, and 92% for small-for-gestational-age neonates with birthweights of <3rd percentile. Overall, the model was well calibrated. The detection rates and calibration indices were similar in the training and test data sets, demonstrating the internal validity of the model. CONCLUSION: The performance of screening for small-for-gestational-age neonates by a competing risks model that combines maternal factors with estimated fetal weight, uterine artery pulsatility index, and mean arterial pressure was superior to that of screening by maternal characteristics and medical history alone.

Impact of new definitions of preeclampsia at term on identification of adverse maternal and perinatal outcomes.

BACKGROUND: Any definition of preeclampsia should identify women and babies at greatest risk of adverse outcomes. OBJECTIVE: This study aimed to investigate the ability of the American College of Obstetricians and Gynecologists and International Society for the Study of Hypertension in Pregnancy definitions of preeclampsia at term gestational age (≥37 0/7 weeks) to identify adverse maternal and perinatal outcomes. STUDY DESIGN: In this prospective cohort study at 2 maternity hospitals in England, women attending a routine hospital visit at 35 0/7 to 36 6/7 weeks' gestation underwent assessment that included history; ultrasonographic estimated fetal weight; Doppler measurements of the pulsatility index in the uterine, umbilical, and fetal middle cerebral arteries; and serum placental growth factor-to-soluble fms-like tyrosine kinase-1 ratio. Obstetrical records were examined for all women with chronic hypertension and those who developed new-onset hypertension, with preeclampsia (de novo or superimposed on chronic hypertension) defined in 5 ways: traditional, based on new-onset proteinuria; American College of Obstetricians and Gynecologists 2013 definition; International Society for the Study of Hypertension in Pregnancy maternal factors definition; International Society for the Study of Hypertension in Pregnancy maternal factors plus fetal death or fetal growth restriction definition, defined according to the 35 0/7 to 36 6/7 weeks' gestation scan as either estimated fetal weight <3rd percentile or estimated fetal weight at the 3rd to 10th percentile with any of uterine artery pulsatility index >95th percentile, umbilical artery pulsatility index >95th percentile, or middle cerebral artery pulsatility index <5th percentile; and International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance definition, defined as placental growth factor <5th percentile or soluble fms-like tyrosine kinase-1-to-serum placental growth factor >95th percentile. Detection rates for outcomes of interest (ie, severe maternal hypertension, major maternal morbidity, perinatal mortality or major neonatal morbidity, neonatal unit admission ≥48 hours, and birthweight <10th percentile) were compared using the chi-square test, and P<.05 was considered significant. RESULTS: Among 15,248 singleton pregnancies, the identification of women with preeclampsia varied by definition: traditional, 15 of 281 (1.8%; 248); American College of Obstetricians and Gynecologists, 15 of 326 (2.1%; 248); International Society for the Study of Hypertension in Pregnancy maternal factors, 15 of 400 (2.6%; 248); International Society for the Study of Hypertension in Pregnancy maternal-fetal factors, 15 of 434 (2.8%; 248); and International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance, 15 of 500 (3.3%; 248). Compared with the traditional definition of preeclampsia, the International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance best identified the adverse outcomes: severe hypertension (40.6% [traditional] vs 66.9% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance, P<.0001], 59.2% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors, P=.004], 56.2% [International Society for the Study of Hypertension in Pregnancy maternal factors, P=.013], 46.1% [American College of Obstetricians and Gynecologists, P=.449]); P<.0001); composite maternal severe adverse event (72.2% [traditional] vs 100% for all others; P=.046); composite of perinatal mortality and morbidity (46.9% [traditional] vs 71.1% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance, P=.002], 62.2% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors, P=.06], 59.8% [International Society for the Study of Hypertension in Pregnancy maternal factors, P=.117], 49.4% [American College of Obstetricians and Gynecologists, P=.875]); neonatal unit admission for ≥48 hours (51.4% [traditional] vs 73.4% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance, P=.001], 64.5% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors, P=.070], 60.7% [International Society for the Study of Hypertension in Pregnancy maternal factors, P=.213], 53.3% [American College of Obstetricians and Gynecologists, P=.890]); birthweight <10th percentile (40.5% [traditional] vs 78.7% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance, P<.0001], 70.1% [International Society for the Study of Hypertension in Pregnancy maternal-fetal, P<.0001], 51.3% [International Society for the Study of Hypertension in Pregnancy maternal factors, P=.064], 46.3% [American College of Obstetricians and Gynecologists, P=.349]). CONCLUSION: Our findings present an evidence base for the broad definition of preeclampsia. Our data suggest that compared with a traditional definition, a broad definition of preeclampsia can better identify women and babies at risk of adverse outcomes. Compared with the American College of Obstetricians and Gynecologists definition, the more inclusive International Society for the Study of Hypertension in Pregnancy definition of maternal end-organ dysfunction seems to be more sensitive. The addition of uteroplacental dysfunction to the broad definition optimizes the identification of women and babies at risk, particularly when angiogenic factors are included.