Incidence and causes of perinatal death in prenatally diagnosed vasa previa: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to estimate the perinatal mortality associated with prenatally diagnosed vasa previa and to determine what proportion of those perinatal deaths are directly attributable to vasa previa. DATA SOURCES: The following databases have been searched from January 1, 1987, to January 1, 2023: PubMed, Scopus, Web of Science, and Embase. STUDY ELIGIBILITY CRITERIA: Our study included all studies (cohort studies and case series or reports) that had patients in which a prenatal diagnosis of vasa previa was made. Case series or reports were excluded from the meta-analysis. All cases in which prenatal diagnosis was not made were excluded from the study. METHODS: The programming language software R (version 4.2.2) was used to conduct the meta-analysis. The data were logit transformed and pooled using the fixed effects model. The between-study heterogeneity was reported by I2. The publication bias was evaluated using a funnel plot and the Peters regression test. The Newcastle-Ottawa scale was used to assess the risk of bias. RESULTS: Overall, 113 studies with a cumulative sample size of 1297 pregnant individuals were included. This study included 25 cohort studies with 1167 pregnancies and 88 case series or reports with 130 pregnancies. Moreover, 13 perinatal deaths occurred among these pregnancies, consisting of 2 stillbirths and 11 neonatal deaths. Among the cohort studies, the overall perinatal mortality was 0.94% (95% confidence interval, 0.52-1.70; I2=0.0%). The pooled perinatal mortality attributed to vasa previa was 0.51% (95% confidence interval, 0.23-1.14; I2=0.0%). Stillbirth and neonatal death were reported in 0.20% (95% confidence interval, 0.05-0.80; I2=0.0%) and 0.77% (95% confidence interval, 0.40-1.48; I2=0.0%) of pregnancies, respectively. CONCLUSION: Perinatal death is uncommon after a prenatal diagnosis of vasa previa. Approximately half of the cases of perinatal mortality are not directly attributable to vasa previa. This information will help in guiding physicians in counseling and will provide reassurance to pregnant individuals with a prenatal diagnosis of vasa previa.

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.

Vasa previa in singleton pregnancies: diagnosis and clinical management based on an international expert consensus.

BACKGROUND: There are limited data to guide the diagnosis and management of vasa previa. Currently, what is known is largely based on case reports or series and cohort studies. OBJECTIVE: This study aimed to systematically collect and classify expert opinions and achieve consensus on the diagnosis and clinical management of vasa previa using focus group discussions and a Delphi technique. STUDY DESIGN: A 4-round focus group discussion and a 3-round Delphi survey of an international panel of experts on vasa previa were conducted. Experts were selected on the basis of their publication record on vasa previa. First, we convened a focus group discussion panel of 20 experts and agreed on which issues were unresolved in the diagnosis and management of vasa previa. A 3-round anonymous electronic survey was then sent to the full expert panel. Survey questions were presented on the diagnosis and management of vasa previa, which the experts were asked to rate on a 5-point Likert scale (from "strongly disagree"=1 to "strongly agree"=5). Consensus was defined as a median score of 5. Following responses to each round, any statements that had median scores of ≤3 were deemed to have had no consensus and were excluded. Statements with a median score of 4 were revised and re-presented to the experts in the next round. Consensus and nonconsensus statements were then aggregated. RESULTS: A total of 68 international experts were invited to participate in the study, of which 57 participated. Experts were from 13 countries on 5 continents and have contributed to >80% of published cohort studies on vasa previa, as well as national and international society guidelines. Completion rates were 84%, 93%, and 91% for the first, second, and third rounds, respectively, and 71% completed all 3 rounds. The panel reached a consensus on 26 statements regarding the diagnosis and key points of management of vasa previa, including the following: (1) although there is no agreement on the distance between the fetal vessels and the cervical internal os to define vasa previa, the definition should not be limited to a 2-cm distance; (2) all pregnancies should be screened for vasa previa with routine examination for placental cord insertion and a color Doppler sweep of the region over the cervix at the second-trimester anatomy scan; (3) when a low-lying placenta or placenta previa is found in the second trimester, a transvaginal ultrasound with Doppler should be performed at approximately 32 weeks to rule out vasa previa; (4) outpatient management of asymptomatic patients without risk factors for preterm birth is reasonable; (5) asymptomatic patients with vasa previa should be delivered by scheduled cesarean delivery between 35 and 37 weeks of gestation; and (6) there was no agreement on routine hospitalization, avoidance of intercourse, or use of 3-dimensional ultrasound for diagnosis of vasa previa. CONCLUSION: Through focus group discussion and a Delphi process, an international expert panel reached consensus on the definition, screening, clinical management, and timing of delivery in vasa previa, which could inform the development of new clinical guidelines.

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.

Maternal and neonatal complications in pregnancies with and without pre-gestational diabetes mellitus.

OBJECTIVES: To compare pregnancy complications in pregnancies with and without pre-gestational diabetes mellitus (DM) managed in a multidisciplinary high-risk diabetes antenatal clinic. METHODS: This screening cohort study was undertaken at a large maternity unit in the United Kingdom between January 2010 and December 2022. We included singleton pregnancies that booked at our unit at 11-13 weeks' gestation. Univariate and multivariate logistic regression analysis was carried out to determine risks of complications in pregnancies with type 1 and type 2 DM after adjusting for maternal and pregnancy characteristics. Effect sizes were expressed as absolute risks (AR) and odds ratio (OR) (95 % confidence intervals [CI]). RESULTS: The study population included 53,649 singleton pregnancies, including 509 (1.0 %) with pre-existing DM and 49,122 (99.0 %) without diabetes. Multivariate logistic regression analysis demonstrated that there was a significant contribution from pre-existing DM in prediction of adverse outcomes, including antenatal complications such as fetal defects, stillbirth, preterm delivery, polyhydramnios, preeclampsia and delivery of large for gestational age (LGA) neonates; intrapartum complications such as caesarean delivery (CS) and post-partum haemorrhage; and neonatal complications including admission to neonatal intensive care unit, hypoglycaemia, jaundice and hypoxic ischaemic encephalopathy (HIE). In particular, there was a 5-fold increased risk of stillbirth and HIE. CONCLUSIONS: The maternal and neonatal complications in pregnancies with pre-existing DM are significantly increased compared to those without DM despite a decade of intensive multidisciplinary antenatal care. Further research is required to investigate strategies and interventions to prevent morbidity and mortality in pregnancies with pre-gestational DM.

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.

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.

Maternal and neonatal complications following Kielland's rotational forceps delivery: A systematic review and meta-analysis.

BACKGROUND: There is conflicting evidence regarding the safety of Kielland's rotational forceps delivery (KRFD) in comparison with other modes of delivery for the management of persistent fetal malposition in the second stage of labour. OBJECTIVES: To derive estimates of risks of maternal and neonatal complications following KRFD, compared with rotational ventouse delivery (RVD), non-rotational forceps delivery (NRFD) or a second-stage caesarean section (CS), from a systematic review and meta-analysis of the literature. SEARCH STRATEGY: Standard search methodology, as recommended by the Cochrane Handbook for Systematic Reviews of Interventions. SELECTION CRITERIA: Case series, prospective or retrospective cohort studies and population-based studies. DATA COLLECTION AND ANALYSIS: A meta-analysis using a random-effects model was used to derive weighted pooled estimates of maternal and neonatal complications. MAIN RESULTS: Thirteen studies were included. For postpartum haemorrhage there was no significant difference between Kielland's and ventouse delivery; the rate was lower in Kielland's delivery compared with non-rotational forceps (RR 0.79, 95% CI 0.65-0.95) and second-stage CS (RR 0.45, 95% CI 0.36-0.58). There were no differences in the rates of anal sphincter injuries or admission to neonatal intensive care. Rates of shoulder dystocia were higher with Kielland's delivery compared with ventouse delivery (RR 1.79, 95% CI 1.08-2.98), but rates of neonatal birth trauma were lower (RR 0.49, 95% CI 0.26-0.91). There were no differences seen in the rates of 5-min APGAR score < 7 between Kielland's delivery and other instrumental births, but they were lower when compared with second-stage CS (RR 0.47, 95% CI 0.23-0.97). CONCLUSIONS: Kielland's rotational forceps delivery is a safe option for the management of fetal malposition in the second stage of labour.

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.

Gestational Diabetes Mellitus: Association with Maternal and Neonatal Complications.

Background and objectives: Gestational diabetes mellitus (GDM) is known to be associated with pregnancy complications but there is limited evidence about the strength of these associations in recent clinical practice, especially after the introduction of strict guidelines for the management of pregnancies with GDM in a multidisciplinary team setting. The objectives of our study were to first compare the rates of complications in pregnancies with GDM with those that had pre-existing diabetes mellitus and those without diabetes; and second, to derive measures of effect size expressed as odds ratios after adjustment for confounding factors to assess the independent association of GDM in prediction of these pregnancy complications. Materials and Methods: This was a prospective cohort study undertaken at a large maternity unit in the United Kingdom between January 2010 and June 2022. We included singleton pregnancies that were booked at our unit at 11-13 weeks' gestation. Multivariate regression analysis was carried out to determine the risks of complications in pregnancies with GDM after adjusting for pregnancy characteristics. Risks were expressed as odds ratio (OR) (95% confidence intervals [CI]) and expressed graphically in forest plots. Results: The study population included 53,649 singleton pregnancies including 509 (1%) with pre-existing DM, 2089 (4%) with GDM and 49,122 (95%) pregnancies without diabetes. Multivariate regression analysis demonstrated that there was a significant independent contribution from GDM in the prediction of adverse outcomes, including maternal complications such as preterm delivery, polyhydramnios, preeclampsia and delivery of large for gestational age neonates and elective caesarean section (CS); and neonatal complications including admission to neonatal intensive care unit, hypoglycaemia, jaundice and respiratory distress syndrome. Conclusions: GDM is associated with an increased rate of pregnancy complications compared to those without diabetes, even after adjustment for maternal and pregnancy characteristics. GDM does not increase the risk of stillbirth, hypoxic ischaemic encephalopathy or neonatal death.

Efficiency of the Cerebroplacental Ratio in Identifying High-Risk Late-Term Pregnancies.

Background and Objectives: Over the last few years, great interest has arisen in the role of the cerebroplacental ratio (CPR) to identify low-risk pregnancies at higher risk of adverse pregnancy outcomes. This study aimed to assess the predictive capacity of the CPR for adverse perinatal outcomes in all uncomplicated singleton pregnancies attending an appointment at 40-42 weeks. Materials and Methods: This is a retrospective cohort study including all consecutive singleton pregnancies undergoing a routine prenatal care appointment after 40 weeks in three maternity units in Spain and the United Kingdom from January 2017 to December 2019. The primary outcome was adverse perinatal outcomes defined as stillbirth or neonatal death, cesarean section or instrumental delivery due to fetal distress during labor, umbilical arterial cord blood pH < 7.0, umbilical venous cord blood pH < 7.1, Apgar score at 5 min < 7, and admission to the neonatal unit. Logistic mixed models and ROC curve analyses were used to analyze the data. Results: A total of 3143 pregnancies were analyzed, including 537 (17.1%) with an adverse perinatal outcome. Maternal age (odds ratio (OR) 1.03, 95% confidence interval (CI) 1.01 to 1.04), body mass index (OR 1.04, 95% CI 1.03 to 1.06), racial origin (OR 2.80, 95% CI 1.90 to 4.12), parity (OR 0.36, 95% CI 0.29 to 0.45), and labor induction (OR 1.79, 95% CI 1.36 to 2.35) were significant predictors of adverse perinatal outcomes with an area under the ROC curve of 0.743 (95% CI 0.720 to 0.766). The addition of the CPR to the previous model did not improve performance. Additionally, the CPR alone achieved a detection rate of only 11.9% (95% CI 9.3 to 15) when using the 10th centile as the screen-positive cutoff. Conclusions: Our data on late-term unselected pregnancies suggest that the CPR is a poor predictor of adverse perinatal outcomes.

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.

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.

Kielland's rotational forceps delivery: comparison of maternal and neonatal outcomes with pregnancies delivering by non-rotational forceps.

We compared complications in pregnancies that had Kielland's rotational forceps delivery (KRFD) with non-rotational forceps delivery (NRFD). Maternal outcomes included post-partum haemorrhage (PPH) and obstetric anal sphincter injury (OASIS); neonatal outcomes included admission to neonatal intensive care unit (NICU), 5-minute Apgar scores <7, hypoxic ischaemic encephalopathy (HIE), jaundice, shoulder dystocia and birth trauma. The study population included 491 (2.1%) requiring KRFD, 1,257 (5.3%) requiring NRFD and 22,111 (93.0%) that had SVD. In pregnancies with NRFD compared to KRFD, there was higher incidence of OASIS (8.5% vs. 4.7%; p = .006) and a non-significant increased trend for PPH (15.0% vs. 12.4%; p = .173). There was no significant difference in rates of admission to NICU (p = .628), 5-minute Apgar score <7 (p = .375), HIE (p = .532), jaundice (p = .809), severe shoulder dystocia (p = .507) or birth trauma (p = .514). Our study demonstrates that KRFD has lower rates of maternal complications compared to NRFD whilst the rates of neonatal complications are similar.IMPACT STATEMENTWhat is already known on this subject? Kielland's rotational forceps is used for achieving vaginal delivery in pregnancies with failure to progress in second stage of labour secondary to fetal malposition. The use of Kielland's forceps has significantly declined in the last few decades due to concerns about an increased risk of maternal and neonatal complications, despite the absence of any major studies demonstrating this increased risk.What do the results of this study add? There are some studies which compare the risks in pregnancies delivering by Kiellands forceps with rotational ventouse deliveries but there is limited evidence comparing the risks of rotational with non-rotational forceps deliveries. Our study compares the major maternal and neonatal complications in a large cohort of pregnancies undergoing rotational vs. non-rotational forceps deliveries.What are the implications of these findings for clinical practice and/or further research? The results of our study demonstrate that maternal and neonatal complications in pregnancies delivering by Kielland's rotational forceps undertaken by appropriately trained obstetricians are either lower or similar to those delivering by non-rotational forceps. Consideration should be given to ensure that there is appropriate training provided to obstetricians to acquire skills in using Kielland's forceps.

Early vaginal progesterone versus placebo in twin pregnancies for the prevention of spontaneous preterm birth: a randomized, double-blind trial.

BACKGROUND: In women with a singleton pregnancy and sonographic short cervix in midgestation, vaginal administration of progesterone reduces the risk of early preterm birth and improves neonatal outcomes without any demonstrable deleterious effects on childhood neurodevelopment. In women with twin pregnancies, the rate of spontaneous early preterm birth is 10 times higher than that in singletons, and in this respect, all twins are at an increased risk of preterm birth. However, 6 trials in unselected twin pregnancies reported that vaginal administration of progesterone from midgestation had no significant effect on the incidence of early preterm birth. Such apparent lack of effectiveness of progesterone in twins may be due to inadequate dosage or treatment that is started too late in pregnancy. OBJECTIVE: The early vaginal progesterone for the prevention of spontaneous preterm birth in twins, a randomized, placebo-controlled, double-blind trial, was designed to test the hypothesis that among women with twin pregnancies, vaginal progesterone at a dose of 600 mg per day from 11 to 14 until 34 weeks' gestation, as compared with placebo, would result in a significant reduction in the incidence of spontaneous preterm birth between 24+0 and 33+6 weeks. STUDY DESIGN: The trial was conducted at 22 hospitals in England, Spain, Bulgaria, Italy, Belgium, and France. Women were randomly assigned in a 1:1 ratio to receive either progesterone or placebo, and in the random-sequence generation, there was stratification according to the participating center. The primary outcome was spontaneous birth between 24+0 and 33+6 weeks' gestation. Statistical analyses were performed on an intention-to-treat basis. Logistic regression analysis was used to determine the significance of difference in the incidence of spontaneous birth between 24+0 and 33+6 weeks' gestation between the progesterone and placebo groups, adjusting for the effect of participating center, chorionicity, parity, and method of conception. Prespecified tests of treatment interaction effects with chorionicity, parity, method of conception, compliance, and cervical length at recruitment were performed. A post hoc analysis using mixed-effects Cox regression was used for further exploration of the effect of progesterone on preterm birth. RESULTS: We recruited 1194 women between May 2017 and April 2019; 21 withdrew consent and 4 were lost to follow-up, which left 582 in the progesterone group and 587 in the placebo group. Adherence was good, with reported intake of ≥80% of the required number of capsules in 81.4% of the participants. After excluding births before 24 weeks and indicated deliveries before 34 weeks, spontaneous birth between 24+0 and 33+6 weeks occurred in 10.4% (56/541) of participants in the progesterone group and in 8.2% (44/538) in the placebo group (odds ratio in the progesterone group, adjusting for the effect of participating center, chorionicity, parity, and method of conception, 1.35; 95% confidence interval, 0.88-2.05; P=.17). There was no evidence of interaction between the effects of treatment and chorionicity (P=.28), parity (P=.35), method of conception (P=.56), and adherence (P=.34); however, there was weak evidence of an interaction with cervical length (P=.08) suggestive of harm to those with a cervical length of ≥30 mm (odds ratio, 1.61; 95% confidence interval, 1.01-2.59) and potential benefit for those with a cervical length of <30 mm (odds ratio, 0.56; 95% confidence interval, 0.20-1.60). There was no evidence of difference between the 2 treatment groups for stillbirth or neonatal death, neonatal complications, neonatal therapy, and poor fetal growth. In the progesterone group, 1.4% (8/582) of women and 1.9% (22/1164) of fetuses experienced at least 1 serious adverse event; the respective numbers for the placebo group were 1.2% (7/587) and 3.2% (37/1174) (P=.80 and P=.06, respectively). In the post hoc time-to-event analysis, miscarriage or spontaneous preterm birth between randomization and 31+6 weeks' gestation was reduced in the progesterone group relative to the placebo group (hazard ratio, 0.23; 95% confidence interval, 0.08-0.69). CONCLUSION: In women with twin pregnancies, universal treatment with vaginal progesterone did not reduce the incidence of spontaneous birth between 24+0 and 33+6 weeks' gestation. Post hoc time-to-event analysis led to the suggestion that progesterone may reduce the risk of spontaneous birth before 32 weeks' gestation in women with a cervical length of <30 mm, and it may increase the risk for those with a cervical length of ≥30 mm.

Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia.

BACKGROUND: Preterm preeclampsia is an important cause of maternal and perinatal death and complications. It is uncertain whether the intake of low-dose aspirin during pregnancy reduces the risk of preterm preeclampsia. METHODS: In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1776 women with singleton pregnancies who were at high risk for preterm preeclampsia to receive aspirin, at a dose of 150 mg per day, or placebo from 11 to 14 weeks of gestation until 36 weeks of gestation. The primary outcome was delivery with preeclampsia before 37 weeks of gestation. The analysis was performed according to the intention-to-treat principle. RESULTS: A total of 152 women withdrew consent during the trial, and 4 were lost to follow up, which left 798 participants in the aspirin group and 822 in the placebo group. Preterm preeclampsia occurred in 13 participants (1.6%) in the aspirin group, as compared with 35 (4.3%) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004). Results were materially unchanged in a sensitivity analysis that took into account participants who had withdrawn or were lost to follow-up. Adherence was good, with a reported intake of 85% or more of the required number of tablets in 79.9% of the participants. There were no significant between-group differences in the incidence of neonatal adverse outcomes or other adverse events. CONCLUSIONS: Treatment with low-dose aspirin in women at high risk for preterm preeclampsia resulted in a lower incidence of this diagnosis than placebo. (Funded by the European Union Seventh Framework Program and the Fetal Medicine Foundation; EudraCT number, 2013-003778-29 ; Current Controlled Trials number, ISRCTN13633058 .).

Metformin use in obese mothers is associated with improved cardiovascular profile in the offspring.

BACKGROUND: Maternal obesity increases the risk for pregnancy complications and adverse neonatal outcome and has been associated with long-lasting adverse effects in the offspring, including increased body fat mass, insulin resistance, and increased risk for premature cardiovascular disease. Lifestyle interventions in pregnancy have produced no or modest effects in the reduction of adverse pregnancy outcomes in obese mothers. The Metformin in Obese Pregnant Women trial was associated with reduced adverse pregnancy outcomes and had no effect on birthweight. However, the long-term implications of metformin on the health of offspring remain unknown. OBJECTIVE: The purpose of this study was to assess whether prenatal exposure to metformin can improve the cardiovascular profile and body composition in the offspring of obese mothers. STUDY DESIGN: In 151 children from the Metformin in Obese Pregnant Women trial, body composition, peripheral blood pressure, and arterial pulse wave velocity were measured. Central hemodynamics (central blood pressure and augmentation index) were estimated with the use of an oscillometric device. Left ventricular cardiac function and structure were assessed by echocardiography. RESULTS: Children were 3.9±1.0 years old, and 77 of them had been exposed to metformin prenatally. There was no significant difference in peripheral blood pressure, arterial stiffness, and body composition apart from gluteal and tricep circumferences, which were lower in the metformin group (P<.05). The metformin group, compared with the placebo group, had lower central hemodynamics (mean adjusted decrease, -0.707 mm Hg for aortic systolic blood pressure, -1.65 mm Hg for aortic pulse pressure, and -2.68% for augmentation index; P<.05 for all) and lower left ventricular diastolic function (adjusted difference in left atrial area, -0.525 cm2, in isovolumic relaxation time, -0.324 msec, and in pulmonary venous systolic wave, 2.97 cm/s; P<.05 for all). There were no significant differences in metabolic profile between the groups. CONCLUSION: Children of obese mothers who were exposed prenatally to metformin, compared with those who were exposed to placebo, had lower central hemodynamic and cardiac diastolic indices. These results suggest that the administration of metformin in obese pregnant women potentially may have a beneficial cardiovascular effect for their offspring.