Prediction of adverse perinatal outcome by serum placental growth factor and soluble fms-like tyrosine kinase-1 in women undergoing induction of labor.

OBJECTIVE: To investigate the additive value of serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1), measured within 24 h prior to induction of labor, to the performance of screening for adverse perinatal outcome provided by maternal risk factors and the cerebroplacental ratio (CPR). METHODS: This was a prospective observational study of 795 singleton pregnancies undergoing induction of labor at ≥ 37 weeks' gestation. Before induction of labor, Doppler ultrasound was used to measure the pulsatility index (PI) in the umbilical artery (UA) and fetal middle cerebral artery (MCA) and maternal blood was obtained for measurement of serum PlGF and sFlt-1. The measured UA-PI, MCA-PI and their ratio (CPR) were converted to multiples of the median (MoM) after adjustment for gestational age, and the measured PlGF and sFlt-1 were converted to MoM after adjustment for gestational age, maternal characteristics and the machine used for the assays. Univariable and multivariable logistic regression analysis was used to determine factors that provided a significant contribution in the prediction of adverse perinatal outcome, defined as the presence of any one of Cesarean section for non-reassuring fetal status in labor, umbilical arterial or venous cord blood pH ≤ 7 and ≤ 7.1, respectively, 5-min Apgar score < 7 or admission to the neonatal intensive care unit for ≥ 24 h. The detection rate (DR) and false-positive rate (FPR) in screening for adverse perinatal outcome were determined. RESULTS: In pregnancies with adverse perinatal outcome, compared to those without, median serum PlGF MoM was lower (0.44; interquartile range (IQR), 0.30-0.82 vs 0.60; IQR, 0.36-1.07; P = 0.003), but median sFlt-1 MoM was not significantly different (P = 0.080). Multivariable regression analysis demonstrated that, in the prediction of adverse perinatal outcome, there was significant contribution from maternal risk factors and CPR MoM but not PlGF MoM or sFlt-1 MoM. The performance of screening for adverse perinatal outcome achieved by maternal risk factors alone (DR of 28.9% at FPR of 10%) was not improved by the addition of CPR (DR of 33.8% at FPR of 10%) (area under the curve, 0.702; 95% CI, 0.654-0.750 vs 0.712; 95% CI, 0.664-0.760; P = 0.233). CONCLUSION: Serum PlGF and sFlt-1, measured within 24 h prior to induction of labor, do not provide a significant additional contribution to maternal risk factors in the prediction of adverse perinatal outcome. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Maternal and neonatal complications of fetal macrosomia: cohort study.

OBJECTIVE: To estimate the risks of maternal and neonatal complications in pregnancies with macrosomia. METHODS: This was a retrospective cohort study conducted at a large maternity unit in the UK between January 2009 and December 2016. The incidence of maternal and neonatal complications in pregnancies with macrosomia, defined as birth weight (BW) > 4000 g, and in those with severe macrosomia, defined as BW > 4500 g, was compared with that in pregnancies with normal BW (2500-4000 g). Regression analysis was performed to determine odds ratios (ORs) for complications in macrosomic pregnancies compared to those with normal BW. RESULTS: The study population of 35 548 pregnancies included 4522 (12.7%) with macrosomia, of which 643 (1.8%) had severe macrosomia, and 31 026 (87.3%) with normal BW. In the macrosomia group, the adjusted OR was 3.1 (95% CI, 2.6-3.6) for Cesarean section for failure to progress, 2.4 (95% CI, 2.0-3.0) for severe postpartum hemorrhage, 2.3 (95% CI, 1.9-2.8) for obstetric anal sphincter injury, 10.4 (95% CI, 8.6-12.6) for shoulder dystocia, 28.5 (95% CI, 8.9-90.7) for obstetric brachial plexus injury, 32.3 (95% CI, 3.8-278.2) for birth fractures and 4.4 (95% CI, 2.2-8.8) for hypoxic-ischemic encephalopathy. The respective values in pregnancies with severe macrosomia were 4.3 (95% CI, 3.1-6.1), 2.9 (95% CI, 1.9-4.4), 3.1 (95% CI, 1.9-5.1), 28.7 (95% CI, 20.8-39.8), 73.9 (95% CI, 15.1-363.2), 87.2 (95% CI, 7.7-985.0) and 13.8 (95% CI, 5.2-36.8). CONCLUSION: Macrosomia is associated with serious adverse perinatal outcomes. This study provides accurate estimates of risks to aid in pregnancy management. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Complicaciones maternas y neonatales de la macrosomía fetal: estudio de cohorte OBJETIVO: Estimar los riesgos de complicaciones maternas y neonatales en embarazos con macrosomía. METHODS: Este fue un estudio de cohorte retrospectivo realizado en una unidad de maternidad de gran tamaño en el Reino Unido entre enero de 2009 y diciembre de 2016. La incidencia de complicaciones maternas y neonatales en los embarazos con macrosomía, definida como peso al nacer (PN) >4000 g, y en los embarazos con macrosomía grave, definida como PN >4500 g, se comparó con la de los embarazos con PN normal (2500-4000 g). Se realizó un análisis de regresión para determinar las razones de momios (RM) para las complicaciones en los embarazos macrosómicos en comparación con los que tenían un PN normal. RESULTADOS: La población estudiada de 35 548 embarazos incluyó 4522 (12,7%) casos con macrosomía, 643 (1,8%) con macrosomía grave y 31 026 (87,3%) con PN normal. En el grupo de macrosomía, la RM ajustada fue de 3,1 (IC 95%: 2,6-3,6) para la cesárea por no progresar, 2,4 (IC 95%: 2,0-3,0) para hemorragia posparto grave, 2,3 (IC 95%: 1,9-2,8) para la lesión obstétrica del esfínter anal, 10.4 (IC 95%, 8.6-12.6) para la distocia de hombro, 28.5 (IC 95%, 8.9-90.7) para la lesión obstétrica del plexo braquial, 32.3 (IC 95%, 3.8-278.2) para las fracturas de nacimiento y 4.4 (IC 95%, 2.2-8.8) para la encefalopatía hipóxica-isquémica. Los valores respectivos en los embarazos con macrosomía grave fueron 4,3 (IC 95%: 3,1-6,1), 2,9 (IC 95%: 1,9-4,4), 3,1 (IC 95%: 1,9-5,1), 28,7 (IC 95%: 20,8-39,8), 73,9 (IC 95%: 15,1-363,2), 87,2 (IC 95%: 7,7-985,0) y 13,8 (IC 95%: 5,2-36,8). CONCLUSIÓN: La macrosomía se asocia con resultados perinatales adversos graves. Este estudio proporciona estimaciones precisas de los riesgos para ayudar en el cuidado del embarazo.

Maternal and neonatal complications of fetal macrosomia: systematic review and meta-analysis.

OBJECTIVE: To determine accurate estimates of risks of maternal and neonatal complications in pregnancies with fetal macrosomia by performing a systematic review of the literature and meta-analysis. METHODS: A search of MEDLINE, EMBASE, CINAHL and The Cochrane Library was performed to identify relevant studies reporting on maternal and/or neonatal complications in pregnancies with macrosomia having a birth weight (BW) > 4000 g and/or those with birth weight > 4500 g. Prospective and retrospective cohort and population-based studies that provided data regarding both cases and controls were included. Maternal outcomes assessed were emergency Cesarean section (CS), postpartum hemorrhage (PPH) and obstetric anal sphincter injury (OASIS). Neonatal outcomes assessed were shoulder dystocia, obstetric brachial plexus injury (OBPI) and birth fractures. Meta-analysis using a random-effects model was used to estimate weighted pooled estimates of summary statistics (odds ratio (OR) and 95% CI) for each complication, according to birth weight. Heterogeneity between studies was estimated using Cochran's Q, I2 statistic and funnel plots. RESULTS: Seventeen studies reporting data on maternal and/or neonatal complications in pregnancy with macrosomia were included. In pregnancies with macrosomia having a BW > 4000 g, there was an increased risk of the maternal complications: emergency CS, PPH and OASIS, which had OR (95% CI) of 1.98 (1.80-2.18), 2.05 (1.90-2.22) and 1.91 (1.56-2.33), respectively. The corresponding values for pregnancies with BW > 4500 g were: 2.55 (2.33-2.78), 3.15 (2.14-4.63) and 2.56 (1.97-3.32). Similarly, in pregnancies with a BW > 4000 g, there was an increased risk of the neonatal complications: shoulder dystocia, OBPI and birth fractures, which had OR (95% CI) of 9.54 (6.76-13.46), 11.03 (7.06-17.23) and 6.43 (3.67-11.28), respectively. The corresponding values for pregnancies with a BW > 4500 g were: 15.64 (11.31-21.64), 19.87 (12.19-32.40) and 8.16 (2.75-24.23). CONCLUSION: Macrosomia is associated with serious maternal and neonatal adverse outcomes. This study provides accurate estimates of these risks, which can be used for decisions on pregnancy management. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Complicaciones maternas y neonatales de la macrosomía fetal: revisión sistemática y metaanálisis OBJETIVO: Determinar estimaciones precisas de los riesgos de complicaciones maternas y neonatales en embarazos con macrosomía fetal mediante la realización de una revisión sistemática de la literatura y un metaanálisis. MÉTODOS: Se realizó una búsqueda en MEDLINE, EMBASE, CINAHL y The Cochrane Library para identificar estudios relevantes que informaron sobre complicaciones maternas y/o neonatales en embarazos con macrosomía con un peso al nacer (PN) >4000 g y/o aquellos con un peso al nacer >4500 g. Se incluyeron estudios de cohortes prospectivos y retrospectivos y estudios basados en la población que proporcionaron datos con respecto a los casos y controles. Las medidas maternas de resultados evaluadas fueron la cesárea de urgencia (CU), la hemorragia posparto (HPP) y la lesión obstétrica del esfínter anal (LOEA). Los resultados neonatales evaluados fueron distocia de hombro, lesión obstétrica del plexo braquial (LOPB) y fracturas de nacimiento. Se utilizó un metaanálisis con un modelo de efectos aleatorios para estimar las estimaciones agrupadas ponderadas de los estadísticos resumen (razones de momios [RM] y IC del 95%) para cada complicación, según el peso al nacer. La heterogeneidad entre estudios se estimó mediante la prueba estadística Q de Cochran, la prueba estadística I2 y gráficos de embudo. RESULTADOS: Se incluyeron 17 estudios que reportaron datos sobre las complicaciones maternas y/o neonatales en embarazos con macrosomía. En aquellos con un PN >4000 g, hubo un mayor riesgo de complicaciones maternas: CU, HPP y LOEA de urgencia, que tuvieron una RM (IC 95%) de 1,98 (1,80-2,18), 2,05 (1,90-2,22) y 1,91 (1,56-2,33), respectivamente. Los valores correspondientes para los embarazos con PN >4500 g fueron: 2,55 (2,33-2,78), 3,15 (2,14-4,63) y 2,56 (1,97-3,32). De manera similar, en los embarazos con un PN >4000 g, hubo un mayor riesgo de complicaciones neonatales: distocia de hombro, LOEA y fracturas de nacimiento, que tuvieron una RM (IC 95%) de 9,54 (6,76-13,46), 11,03 (7,06-17,23) y 6,43 (3,67-11,28), respectivamente. Los valores correspondientes para los embarazos con un PN >4500 g fueron: 15,64 (11,31-21,64), 19,87 (12,19-32,40) y 8,16 (2,75-24,23). CONCLUSIÓN: La macrosomía se asocia con resultados adversos maternos y neonatales graves. Este estudio proporciona estimaciones precisas de estos riesgos, que pueden utilizarse para tomar decisiones sobre el cuidado del embarazo.

Prediction of adverse perinatal outcome by cerebroplacental ratio in women undergoing induction of labor.

OBJECTIVE: To investigate the performance of screening for adverse perinatal outcome by the cerebroplacental ratio (CPR) measured within 24 h prior to induction of labor. METHODS: This was a prospective observational study of 1902 singleton pregnancies undergoing induction of labor at ≥ 37 weeks' gestation. Doppler ultrasound was used to measure the pulsatility index (PI) in the umbilical artery (UA) and fetal middle cerebral artery (MCA) within 24 h before induction of labor. The measured UA-PI and MCA-PI and their ratio were converted to multiples of the median after adjustment for gestational age. Univariable and multivariable logistic regression analysis was used to determine whether CPR improved the prediction of adverse perinatal outcome provided by maternal characteristics, medical history and obstetric factors. The detection rate (DR) and false-positive rate (FPR) of screening by CPR were estimated for Cesarean section for presumed fetal distress and adverse neonatal outcome, which included umbilical arterial or venous cord blood pH ≤ 7 and ≤ 7.1, respectively, 5-min Apgar score < 7, admission to the neonatal intensive care unit for > 24 h or hypoxic ischemic encephalopathy. RESULTS: A combination of maternal and pregnancy characteristics, including age, weight, racial origin, previous obstetric history, pre-eclampsia, gestational age at delivery and amniotic fluid volume, identified 39% of pregnancies requiring Cesarean section for fetal distress at a FPR of 10%; addition of CPR did not improve the performance of screening. In screening for adverse neonatal outcome by a combination of parity and CPR, the DR was 17% at a FPR of 10%. CONCLUSION: Low CPR, measured within 24 h prior to induction of labor, is associated with increased risk of Cesarean section for fetal distress and adverse neonatal outcome, but the performance of CPR for such surrogate measures of fetal hypoxic morbidity is poor. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Multicenter screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation: comparison with NICE guidelines and ACOG recommendations.

OBJECTIVE: To compare the performance of screening for pre-eclampsia (PE) based on risk factors from medical history, as recommended by NICE and ACOG, with the method proposed by The Fetal Medicine Foundation (FMF), which uses Bayes' theorem to combine the a-priori risk from maternal factors, derived by a multivariable logistic model, with the results of various combinations of biophysical and biochemical measurements. METHODS: This was a prospective multicenter study of screening for PE in 8775 singleton pregnancies at 11-13 weeks' gestation. A previously published FMF algorithm was used for the calculation of patient-specific risk of PE in each individual. The detection rates (DRs) and false-positive rates (FPRs) for delivery with PE < 32, < 37 and ≥ 37 weeks were estimated and compared with those derived from application of NICE guidelines and ACOG recommendations. According to NICE, all high-risk pregnancies should be offered low-dose aspirin. According to ACOG, use of aspirin should be reserved for women with a history of PE in at least two previous pregnancies or PE requiring delivery < 34 weeks' gestation. RESULTS: In the study population, 239 (2.7%) cases developed PE, of which 17 (0.2%), 59 (0.7%) and 180 (2.1%) developed PE < 32, < 37 and ≥ 37 weeks, respectively. Screening with use of the FMF algorithm based on a combination of maternal factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF) detected 100% (95% CI, 80-100%) of PE < 32 weeks, 75% (95% CI, 62-85%) of PE < 37 weeks and 43% (95% CI, 35-50%) of PE ≥ 37 weeks, at a 10.0% FPR. Screening with use of NICE guidelines detected 41% (95% CI, 18-67%) of PE < 32 weeks, 39% (95% CI, 27-53%) of PE < 37 weeks and 34% (95% CI, 27-41%) of PE ≥ 37 weeks, at 10.2% FPR. Screening with use of ACOG recommendations detected 94% (95% CI, 71-100%) of PE < 32 weeks, 90% (95% CI, 79-96%) of PE < 37 weeks and 89% (95% CI, 84-94%) of PE ≥ 37 weeks, at 64.2% FPR. Screening based on the ACOG recommendations for use of aspirin detected 6% (95% CI, 1-27%) of PE < 32 weeks, 5% (95% CI, 2-14%) of PE < 37 weeks and 2% (95% CI, 0.3-5%) of PE ≥ 37 weeks, at 0.2% FPR. CONCLUSION: Performance of screening for PE at 11-13 weeks' gestation by the FMF algorithm using a combination of maternal factors, MAP, UtA-PI and PlGF, is by far superior to the methods recommended by NICE and ACOG. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Development of pre-eclampsia within 4 weeks of sFlt-1/PlGF ratio > 38: comparison of performance at 31-34 vs 35-37 weeks' gestation.

OBJECTIVE: To compare the performance of screening by soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) ratio > 38 for the prediction of delivery with pre-eclampsia (PE) at < 1 week and < 4 weeks from assessment when the test is carried out at 31-34 vs 35-37 weeks' gestation. METHODS: This was a prospective observational study in women attending a third-trimester ultrasound scan as part of routine pregnancy care; the visit was at 30-34 weeks' gestation in the first phase of the study and at 35-37 weeks in the second phase. Serum sFlt-1 and PlGF were measured and their ratio calculated. We estimated the detection rate (DR) and false-positive rate (FPR) of sFlt-1/PlGF ratio > 38 for predicting delivery with PE at < 1 week and < 4 weeks after assessment and compared the performance of screening when the test was carried out at 31 + 0 to 33 + 6 vs 35 + 0 to 36 + 6 weeks' gestation. RESULTS: The study population included 8063 singleton pregnancies that were examined at 31-34 weeks and 3703 at 35-37 weeks. Delivery with PE occurred at < 1, < 4 and ≥ 4 weeks from assessment in five (0.1%), 29 (0.4%) and 202 (2.5%) women assessed at 31-34 weeks, respectively, and in seven (0.2%), 39 (1.1%) and 21 (0.6%) of those assessed at 35-37 weeks. In women without PE, the median sFlt-1/PlGF ratio increased with gestational age at screening and a ratio of 38 was just below the 99th percentile at 32 weeks' gestation and just below the 90th percentile at 36 weeks. In the two gestational windows, the DR of PE delivering < 4 weeks from assessment was similar (75.9% (95% CI, 56.5-89.7%) vs 79.5% (95% CI, 63.5-90.7%)), but the FPR was substantially lower at 31-34 weeks than at 35-37 weeks (1.7% (95% CI, 1.4-2.0%) vs 9.6% (95% CI, 8.7-10.6%)). The number of cases with PE delivering < 1 week from assessment was small, but similarly, in the two gestational windows, the DR was comparable (80.0% (95% CI, 28.4-99.5%) vs 85.7% (95% CI, 42.1-99.6%)), and the FPR was substantially lower at 31-34 weeks than at 35-37 weeks (1.9% (95% CI, 1.6-2.2%) vs 10.2% (95% CI, 9.3-11.3%)). CONCLUSION: The performance of sFlt-1/PlGF ratio > 38 in the prediction of delivery with PE at < 1 and < 4 weeks from assessment is substantially different when the assessment is at 31-34 weeks' gestation compared to at 35-37 weeks. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Maternal plasma cell-free DNA in the prediction of pre-eclampsia.

OBJECTIVES: To examine whether maternal plasma concentrations of total cell-free (cf)DNA and fetal fraction at 11-13 and 20-24 weeks' gestation in pregnancies that subsequently develop pre-eclampsia (PE) are different from those without this complication. METHODS: Total cfDNA and fetal fraction were measured in 20 cases of early PE requiring delivery at < 34 weeks, in 20 cases of late PE with delivery at ≥ 34 weeks and in 200 normotensive controls, at 11-13 and 20-24 weeks' gestation. Total cfDNA and fetal fraction measured at 11-13 weeks were converted to multiples of the median (MoM), corrected for maternal characteristics and gestational age. The distributions of total cfDNA and fetal fraction at 20-24 weeks were expressed as MoM of values at 11-13 weeks. The Mann-Whitney U-test was used to determine the significance of differences in the median values in each outcome group relative to that in the controls. RESULTS: In the early-PE group at 11-13 weeks, compared with controls, there was a significant increase in median total cfDNA (2104 genome equivalents (GE)/mL vs 1590 GE/mL) and a decrease in median fetal fraction (6.8% vs 8.7%). In the late-PE group at 20-24 weeks, compared with controls, there was a significant decrease in median fetal fraction (8.2% vs 9.6%). These significant differences between groups were not observed when the values were converted to MoM. CONCLUSION: Measurements of total cfDNA and fetal fraction in maternal plasma at 11-13 and 20-24 weeks are not predictive of PE.