Maternal vascular indices at 36 weeks' gestation in small and growth restricted fetuses.

OBJECTIVE: To compare maternal vascular indices and hemodynamic parameters at 35-37 weeks' gestation, in pregnancies complicated by small for gestational age (SGA) fetuses and those with fetal growth restriction (FGR). METHODS: This was a prospective observational non-intervention study in women with singleton pregnancies attending for a routine hospital visit at 35+0 to 36+6 weeks' gestation. The visit included recording of maternal demographic characteristics and medical history, vascular indices and hemodynamic parameters obtained by a non-invasive operator independent device, including pulse wave velocity, augmention index, cardiac output, stroke volume, central systolic and diastolic blood pressure, total peripheral resistance and fetal heart rate. Hypertensive disorders of pregnancy were excluded and the values in the SGA and FGR groups were compared between them and with unaffected pregnancies. Diagnosis of SGA was based on the birth of a baby with birthweight below the 10th percentile for gestational age. In FGR, in addition to a birthweight below the 10th percentile, at the 35-37 weeks scan Doppler studies had shown that the uterine artery or umbilical artery pulsatility index (PI) was above the 95th percentile for gestational age or the fetal middle cerebral artery PI was below the 5th percentile. RESULTS: In the 6,413 women included in the study there were 605 (9.4%) cases of SGA, 133 (2.1%) of FGR and 5,675 (88.5%) unaffected by SGA or FGR. Women with SGA or FGR, compared to unaffected pregnancies, had increased peripheral vascular resistance and reduced cardiac output. Central systolic and diastolic blood pressure were also increased, whereas aortic stiffness assessed by pulse wave velocity and augmentation index did not differ between affected and unaffected pregnancies. In the FGR, compared to the SGA group, central systolic and diastolic blood pressure were higher, whereas, heart rate was lower. CONCLUSIONS: In SGA and FGR pregnancies there are deranged maternal hemodynamic responses when these are compared to normal pregnancies. Mothers with FGR babies have higher central blood pressure compared to SGA ones, but it remains unclear whether these differences are driven by the size of the fetus or pathological fetal growth. This article is protected by copyright. All rights reserved.

Impact of hypertensive disorders of pregnancy on offspring cardiovascular function. Study from fetal life to early childhood.

OBJECTIVE: Epidemiological studies suggest that children following in utero exposure to hypertensive disorders of pregnancy (HDP) may be at increased long term cardiovascular risk. However, data in early childhood are lacking. We aimed to investigate the independent influence of HDP on childhood heart after accounting for differences in childhood risk factor profile. METHODS: We performed detailed cardiovascular assessment in fetuses at mid-gestation and at a median of 2.3 years (IQR: 2.1, 2.4 years) postnatally in 71 cases where the mothers had HDP and 304 who did not have HDP. RESULTS: There were no differences in demographic characteristics between groups but in the HDP group delivery was earlier and birthweight was lower. In fetal life, there were no significant differences in cardiac function or structure between the HDP and non-HDP groups. In early childhood, in the HDP compared to the non-HDP group, there was greater relative wall thickness (0.7 SD 0.3 vs. 0.6 SD 0.3 mm, p=0.047) and increased left ventricular mass (80.9 SD 20.4 vs. 75.7 SD 16.5, p=0.024); however, these differences were abolished following multivariable analysis. Longitudinal analysis revealed that in HDP, compared to the non-HDP group, there was no difference in the change of cardiac functional indices from fetal life to early childhood. CONCLUSION: Epidemiological studies suggest that HDP have an adverse impact on offspring cardiovascular health, but such an effect is not apparent in fetal life or in early childhood. This article is protected by copyright. All rights reserved.

Long-term cardiovascular assessment of women who had a pregnancy complicated by a hypertensive disorder.

BACKGROUND: Women with hypertensive disorders of pregnancy (HDP) are at increased risk of developing hypertension and cardiovascular disease later in life. However, from studies so far, it is difficult to define whether this association reflects preexisting maternal cardiovascular risk or merely reflect a potentially causal relationship between HDP and later cardiovascular risk. OBJECTIVES: We performed detailed cardiovascular assessment in women at mid-gestation, prior to development of a HDP and at 2 years post-partum aiming to identify cardiovascular changes prior to development of HDP and to assess persistent cardiovascular alterations long after the HDP event. METHODS: This was a prospective observational study in which we performed detailed cardiovascular assessment at mid-gestation and at median of 2.3 years (interquartile range 2.1 to 2.4 years) post-partum. We examined 112 women who developed a HDP and 451 women whose pregnancy was not complicated by hypertension. We used conventional and more advanced echocardiographic techniques, i.e. speckle tracking, to accurately determine left ventricular systolic and diastolic function. We used M-mode measurements to determine left ventricular remodeling and estimate left ventricular mass. Maternal vascular status was assessed using ophthalmic artery Doppler and by calculating peak systolic velocity (PSV) ratio, as a marker of peripheral vascular resistance. RESULTS: At mid-gestation, women who subsequently developed HDP had increased ophthalmic artery PSV ratio. These women also had mild cardiac functional and morphological alterations which were mostly accounted for by maternal cardiovascular risk factors. At 2 years post-partum, women who experienced HDP, compared to those who did not, had cardiovascular abnormalities with reduction in left ventricular systolic and diastolic function which remained after multivariable analysis. Longitudinal analysis demonstrated that the evolution of cardiovascular changes in the HDP and non-HDP groups was similar. CONCLUSION: Mild cardiac functional and morphological alterations precede the development of HDP and such changes persist for at least 2 years postpartum. The cardiac changes are likely to be the consequence of preexisting maternal cardiovascular risk factors rather than an adverse consequence of HDP. This article is protected by copyright. All rights reserved.

Maternal cardiovascular function at mid-gestation is related to placental angiogenesis.

OBJECTIVE: To investigate whether placental function, reflected in the levels of angiogenic factors, is associated with maternal cardiac function and hemodynamic responses at 19 to 24 weeks' gestation after adjustment for maternal risk factors and pregnancy complications. METHODS: Prospective study on women with singleton pregnancies attending Kings' College Hospital, London, UK for a routine hospital visit at 19-24 weeks' gestation. We recorded maternal characteristics and measured mean arterial pressure, maternal heart rate, serum placental growth factor and soluble fms-like tyrosine kinase 1 (sFLT-1). We also performed maternal echocardiogram to assess cardiac output and peripheral vascular resistance as well as indices of diastolic and systolic function. RESULTS: Our cohort included 4006 women. Lower placental growth factor (PlGF) values were significantly associated with higher mean arterial pressure (MAP) (p<0.001), lower maternal heart rate (p<0.001), lower mitral valve s' velocity (p= 0.027) and higher left atrial volume (p=0.022) after adjustment for maternal characteristics and pregnancy complications. sFLT-1 was positively related to relative wall thickness (p= 0.012), whereas sFLT-1/ PlGF ratio was negatively associated with mitral valve A (p= 0.006) and positively associated with left atrial volume (p= 0.015) and MAP (p= 0.004). The magnitude of these associations was similar in the subgroup of women without any risk factors from their obstetric and medical history. CONCLUSION: A continuous link of moderate strength between angiogenic factors and subclinical maternal cardiac function alterations is present at mid-gestation, independently of preexisting maternal risk factors and pregnancy complications. Impaired placental function appears to be related to a mild systolic and diastolic dysfunction and cardiac remodeling. This article is protected by copyright. All rights reserved.

Evaluation of angiogenic factors in prediction of growth-related neonatal morbidity at term and comparison with competing-risks model.

OBJECTIVES: First, to describe the distribution of biomarkers of impaired placentation in small-for-gestational-age (SGA) pregnancies with neonatal morbidity; second, to examine the predictive performance for growth-related neonatal morbidity of a high soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio or low PlGF; and, third, to compare the performance of a high sFlt-1/PlGF ratio or low PlGF with that of the competing-risks model for SGA in predicting growth-related neonatal morbidity. METHODS: This was a prospective observational study of women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation in two maternity hospitals in England. The visit included recording of maternal demographic characteristics and medical history, an ultrasound scan and measurement of serum PlGF and sFlt-1. The primary outcome was delivery within 4 weeks after assessment and at < 42 weeks' gestation of a SGA neonate with birth weight < 10th or < 3rd percentile, combined with neonatal unit (NNU) admission for ≥ 48 h or a composite of major neonatal morbidity. The detection rates in screening by PlGF < 10th percentile, sFlt-1/PlGF ratio > 90th percentile, sFlt-1/PlGF ratio > 38 and the competing-risks model for SGA, using combinations of maternal risk factors and Z-scores of estimated fetal weight (EFW) with multiples of the median values of uterine artery pulsatility index, PlGF and sFlt-1, were estimated. The detection rates by the different methods of screening were compared using McNemar's test. RESULTS: In the study population of 29 035 women, prediction of growth-related neonatal morbidity at term provided by the competing-risks model was superior to that of screening by low PlGF concentration or a high sFlt-1/PlGF concentration ratio. For example, at a screen-positive rate (SPR) of 13.1%, as defined by the sFlt-1/PlGF ratio > 38, the competing-risks model using maternal risk factors and EFW predicted 77.5% (95% CI, 71.7-83.3%) of SGA < 10th percentile and 89.3% (95% CI, 83.7-94.8%) of SGA < 3rd percentile with NNU admission for ≥ 48 h delivered within 4 weeks after assessment. The respective values for SGA with major neonatal morbidity were 71.4% (95% CI, 56.5-86.4%) and 90.0% (95% CI, 76.9-100%). These were significantly higher than the respective values of 41.0% (95% CI, 34.2-47.8%) (P < 0.0001), 48.8% (95% CI, 39.9-57.7%) (P < 0.0001), 37.1% (95% CI, 21.1-53.2%) (P = 0.003) and 55.0% (95% CI, 33.2-76.8%) (P = 0.035) achieved by the application of the sFlt-1/PlGF ratio > 38. At a SPR of 10.0%, as defined by PlGF < 10th percentile, the competing-risks model using maternal factors and EFW predicted 71.5% (95% CI, 65.2-77.8%) of SGA < 10th percentile and 84.3% (95% CI, 77.8-90.8%) of SGA < 3rd percentile with NNU admission for ≥ 48 h delivered within 4 weeks after assessment. The respective values for SGA with major neonatal morbidity were 68.6% (95% CI, 53.1-83.9%) and 85.0% (95% CI, 69.4-100%). These were significantly higher than the respective values of 36.5% (95% CI, 29.8-43.2%) (P < 0.0001), 46.3% (95% CI, 37.4-55.2%) (P < 0.0001), 37.1% (95% CI, 21.1-53.2%) (P = 0.003) and 55.0% (95% CI, 33.2-76.8%) (P = 0.021) achieved by the application of PlGF < 10th percentile. CONCLUSION: At 36 weeks' gestation, the prediction of growth-related neonatal morbidity by the competing-risks model for SGA, using maternal risk factors and EFW, is superior to that of a high sFlt-1/PlGF ratio or low PlGF. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Validation of Fetal Medicine Foundation competing-risks model for small-for-gestational-age neonate in early third trimester.

OBJECTIVE: To evaluate the new 36-week Fetal Medicine Foundation (FMF) competing-risks model for the prediction of small-for-gestational age (SGA) at an earlier gestation of 30 + 0 to 34 + 0 weeks. METHODS: This was a retrospective multicenter cohort study of prospectively collected data on 3012 women with a singleton pregnancy undergoing ultrasound examination at 30 + 0 to 34 + 0 weeks' gestation as part of a universal screening program. We used the default FMF competing-risks model for prediction of SGA at 36 weeks' gestation combining maternal factors (age, obstetric and medical history, weight, height, smoking status, race, mode of conception), estimated fetal weight (EFW) and uterine artery pulsatility index (UtA-PI) to calculate risks for different cut-offs of birth-weight percentile and gestational age at delivery. We examined the accuracy of the model by means of discrimination and calibration. RESULTS: The prediction of SGA < 3rd percentile improved with the addition of UtA-PI and with a shorter examination-to-delivery interval. For a 10% false-positive rate, maternal factors, EFW and UtA-PI predicted 88.0%, 74.4% and 72.8% of SGA < 3rd percentile delivered at < 37, < 40 and < 42 weeks' gestation, respectively. The respective values for SGA < 10th percentile were 86.1%, 69.3% and 66.2%. In terms of population stratification, if the biomarkers used are EFW and UtA-PI and the aim is to detect 90% of SGA < 10th percentile, then 10.8% of the population should be scanned within 2 weeks after the initial assessment, an additional 7.2% (total screen-positive rate (SPR), 18.0%) should be scanned within 2-4 weeks after the initial assessment and an additional 11.7% (total SPR, 29.7%) should be examined within 4-6 weeks after the initial assessment. The new model was well calibrated. CONCLUSIONS: The 36-week FMF competing-risks model for SGA is also applicable and accurate at 30 + 0 to 34 + 0 weeks and provides effective risk stratification, especially for cases leading to delivery < 37 weeks of gestation. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Evaluation of screening performance of first-trimester competing-risks prediction model for small-for-gestational age in Asian population.

OBJECTIVE: To examine the external validity of the Fetal Medicine Foundation (FMF) competing-risks model for the prediction of small-for-gestational age (SGA) at 11-14 weeks' gestation in an Asian population. METHODS: This was a secondary analysis of a multicenter prospective cohort study in 10 120 women with a singleton pregnancy undergoing routine assessment at 11-14 weeks' gestation. We applied the FMF competing-risks model for the first-trimester prediction of SGA, combining maternal characteristics and medical history with measurements of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF) concentration. We calculated risks for different cut-offs of birth-weight percentile (< 10th , < 5th or < 3rd percentile) and gestational age at delivery (< 37 weeks (preterm SGA) or SGA at any gestational age). Predictive performance was examined in terms of discrimination and calibration. RESULTS: The predictive performance of the competing-risks model for SGA was similar to that reported in the original FMF study. Specifically, the combination of maternal factors with MAP, UtA-PI and PlGF yielded the best performance for the prediction of preterm SGA with birth weight < 10th percentile (SGA < 10th ) and preterm SGA with birth weight < 5th percentile (SGA < 5th ), with areas under the receiver-operating-characteristics curve (AUCs) of 0.765 (95% CI, 0.720-0.809) and 0.789 (95% CI, 0.736-0.841), respectively. Combining maternal factors with MAP and PlGF yielded the best model for predicting preterm SGA with birth weight < 3rd percentile (SGA < 3rd ) (AUC, 0.797 (95% CI, 0.744-0.850)). After excluding cases with pre-eclampsia, the combination of maternal factors with MAP, UtA-PI and PlGF yielded the best performance for the prediction of preterm SGA < 10th and preterm SGA < 5th , with AUCs of 0.743 (95% CI, 0.691-0.795) and 0.762 (95% CI, 0.700-0.824), respectively. However, the best model for predicting preterm SGA < 3rd without pre-eclampsia was the combination of maternal factors and PlGF (AUC, 0.786 (95% CI, 0.723-0.849)). The FMF competing-risks model including maternal factors, MAP, UtA-PI and PlGF achieved detection rates of 42.2%, 47.3% and 48.1%, at a fixed false-positive rate of 10%, for the prediction of preterm SGA < 10th , preterm SGA < 5th and preterm SGA < 3rd , respectively. The calibration of the model was satisfactory. CONCLUSION: The screening performance of the FMF first-trimester competing-risks model for SGA in a large, independent cohort of Asian women is comparable with that reported in the original FMF study in a mixed European population. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Comparison of competing-risks model with angiogenic factors in midgestation screening for preterm growth-related neonatal morbidity.

OBJECTIVES: First, to evaluate the predictive performance for preterm growth-related neonatal morbidity of high soluble fms-like tyrosine kinase-1 (sFLT-1) / placental growth factor (PlGF) ratio or low PlGF at mid-gestation, and second, to compare the performance of the high sFLT-1/PlGF ratio or low PlGF with that of the competing risks model for small for gestational age (SGA), utilizing a combination of maternal risk factors, sonographic estimated fetal weight (EFW) and uterine artery pulsatility index (UtA-PI). METHODS: This was a prospective observational study in women attending for a routine hospital visit at 19 to 24 weeks' gestation in two maternity hospitals in England. The visit included recording of maternal demographic characteristics and medical history, carrying out an ultrasound scan and measuring serum PlGF and sFLT-1. The primary outcome was delivery <32 and <37 weeks' gestation of SGA neonate with birth weight <10th or <3rd percentile for gestational age, combined with neonatal unit (NNU) admission for ≥48 hours or a composite of major neonatal morbidity. The detection rates in screening by either PlGF <10th percentile, sFLT-1/PlGF ratio >90th percentile and the competing risks model for SGA were estimated and they were compared using McNemar's test. RESULTS: In the study population of 40241 women prediction of preterm growth-related neonatal morbidity provided by the competing risks model for SGA was superior to that of screening by low PlGF concentration or high sFlt-1/PlGF concentration ratio. For example, at screen positive rate (SPR) of 10.0%, as defined by the sFLT-1/ PlGF ratio >90th percentile, the competing risks model predicted 70.1% (95% CI 61.0 - 79.2) of SGA <10th percentile and 76.9% (67.6-86.3) of SGA <3rd percentile with NNU admission for ≥48 hours delivered <32 weeks gestation and these were significantly higher than the respective values of 35.0% (25.6-44.6) and 35.9% (25.3 - 46.5), achieved by the application of the sFLT-1/ PlGF ratio >90th percentile (p<0.0001 for both). The respective values for SGA with major neonatal morbidity were 73.8% (64.4-83.2), 77.9% (68.0-87.8), 38.1% (27.7-48.5) and 39.7% (28.1-51.3) (Both p<0.0001). CONCLUSION: At mid-gestation, the prediction of growth-related neonatal morbidity by the competing risks model for SGA is superior to that of high sFlt-1/PlGF ratio or low PlGF. This article is protected by copyright. All rights reserved.

Prediction of adverse perinatal outcome at midgestation.

OBJECTIVES: First, to investigate the association between adverse neonatal outcomes and birth weight and gestational age at delivery. Second, to describe the distribution of adverse neonatal outcomes within different risk strata derived by a population stratification scheme based on the midgestation risk assessment for small-for-gestational-age (SGA) neonates using a competing-risks model. METHODS: This was a prospective observational cohort study in women with a singleton pregnancy attending a routine hospital visit at 19 + 0 to 23 + 6 weeks' gestation. The incidence of neonatal unit (NNU) admission for ≥ 48 h was evaluated within different birth-weight-percentile subgroups. The pregnancy-specific risk of delivery with SGA < 10th percentile at < 37 weeks was estimated by the competing-risks model for SGA, combining maternal factors and the likelihood functions of Z-score of sonographically estimated fetal weight and uterine artery pulsatility index multiples of the median. The population was stratified into six risk categories: > 1 in 4, > 1 in 10 to ≤ 1 in 4, > 1 in 30 to ≤ 1 in 10, > 1 in 50 to ≤ 1 in 30, > 1 in 100 to ≤ 1 in 50 and ≤ 1 in 100. The outcome measures were admission to the NNU for a minimum of 48 h, perinatal death and major neonatal morbidity. The incidence of each adverse outcome was estimated in each risk stratum. RESULTS: In the study population of 40 241 women, 0.8%, 2.5%, 10.8%, 10.2%, 19.0% and 56.7% were in the risk strata > 1 in 4, > 1 in 10 to ≤ 1 in 4, > 1 in 30 to ≤ 1 in 10, > 1 in 50 to ≤ 1 in 30, > 1 in 100 to ≤ 1 in 50 and ≤ 1 in 100, respectively. Women in higher-risk strata were more likely to deliver a baby that suffered an adverse outcome. The incidence of NNU admission for ≥ 48 h was highest in the > 1 in 4 risk stratum (31.9% (95% CI, 26.9-36.9%)) and it gradually decreased until the ≤ 1 in 100 risk stratum (5.6% (95% CI, 5.3-5.9%)). The mean gestational age at delivery in SGA cases with NNU admission for ≥ 48 h was 32.9 (95% CI, 32.2-33.7) weeks for risk stratum > 1 in 4 and progressively increased to 37.5 (95% CI, 36.8-38.2) weeks for risk stratum ≤ 1 in 100. The incidence of NNU admission for ≥ 48 h was highest for neonates with birth weight below the 1st percentile (25.7% (95% CI, 23.0-28.5%)) and decreased progressively until the 25th to < 75th percentile interval (5.4% (95% CI, 5.1-5.7%)). Preterm SGA neonates < 10th percentile had significantly higher incidence of NNU admission for ≥ 48 h compared with preterm non-SGA neonates (48.7% (95% CI, 45.0-52.4%) vs 40.9% (95% CI, 38.5-43.3%); P < 0.001). Similarly, term SGA neonates < 10th percentile had significantly higher incidence of NNU admission for ≥ 48 h compared with term non-SGA neonates (5.8% (95% CI, 5.1-6.5%) vs 4.2% (95% CI, 4.0-4.4%); P < 0.001). CONCLUSIONS: Birth weight has a continuous association with the incidence of adverse neonatal outcomes, which is affected by gestational age. Pregnancies at high risk of SGA, estimated at midgestation, are also at increased risk for adverse neonatal outcomes. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

External validation of Fetal Medicine Foundation competing-risks model for midgestation prediction of small-for-gestational-age neonates in Spanish population.

OBJECTIVE: To examine the external validity of the new Fetal Medicine Foundation (FMF) competing-risks model for prediction in midgestation of small-for-gestational-age (SGA) neonates. METHODS: This was a single-center prospective cohort study of 25 484 women with a singleton pregnancy undergoing routine ultrasound examination at 19 + 0 to 23 + 6 weeks' gestation. The FMF competing-risks model for the prediction of SGA combining maternal factors and midgestation estimated fetal weight by ultrasound scan (EFW) and uterine artery pulsatility index (UtA-PI) was used to calculate risks for different cut-offs of birth-weight percentile and gestational age at delivery. The predictive performance was evaluated in terms of discrimination and calibration. RESULTS: The validation cohort was significantly different in composition compared with the FMF cohort in which the model was developed. In the validation cohort, at a 10% false-positive rate (FPR), maternal factors, EFW and UtA-PI yielded detection rates of 69.6%, 38.7% and 31.7% for SGA < 10th percentile with delivery at < 32, < 37 and ≥ 37 weeks' gestation, respectively. The respective values for SGA < 3rd percentile were 75.7%, 48.2% and 38.1%. Detection rates in the validation cohort were similar to those reported in the FMF study for SGA with delivery at < 32 weeks but lower for SGA with delivery at < 37 and ≥ 37 weeks. Predictive performance in the validation cohort was similar to that reported in a subgroup of the FMF cohort consisting of nulliparous and Caucasian women. Detection rates in the validation cohort at a 15% FPR were 77.4%, 50.0% and 41.5% for SGA < 10th percentile with delivery at < 32, < 37 and ≥ 37 weeks, respectively, which were similar to the respective values reported in the FMF study at a 10% FPR. The model had satisfactory calibration. CONCLUSION: The new competing-risks model for midgestation prediction of SGA developed by the FMF performs well in a large independent Spanish population. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Competing-risks model for prediction of small-for-gestational-age neonate at 36 weeks' gestation.

OBJECTIVES: To develop further a competing-risks model for the prediction of a small-for-gestational-age (SGA) neonate by including sonographically estimated fetal weight (EFW) and biomarkers of impaired placentation at 36 weeks' gestation, and to compare the performance of the new model with that of the traditional EFW < 10th percentile cut-off. METHODS: This was a prospective observational study in 29 035 women with a singleton pregnancy undergoing routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation. A competing-risks model for the prediction of a SGA neonate was used. The parameters included in the prior-history model were provided in previous studies. An interaction continuous model was used for the EFW likelihood. A folded plane regression model was fitted to describe likelihoods of biomarkers of impaired placentation. Stratification plans were also developed. The new model was evaluated and compared with EFW percentile cut-offs. RESULTS: The performance of the model was better for predicting SGA neonates delivered closer to the point of assessment. The prediction provided by maternal factors alone was improved significantly by the addition of EFW, uterine artery pulsatility index (UtA-PI) and placental growth factor (PlGF) but not by mean arterial pressure or soluble fms-like tyrosine kinase-1. At a 10% false-positive rate, maternal factors and EFW predicted 77.6% and 65.8% of SGA neonates < 10th percentile delivered before 38 and 42 weeks, respectively. The respective figures for SGA < 3rd percentile were 85.5% and 74.2%. Addition of UtA-PI and PlGF resulted in marginal improvement in prediction of SGA < 3rd percentile requiring imminent delivery. A competing-risks approach that combines maternal factors and EFW performed better when compared with fixed EFW percentile cut-offs at predicting a SGA neonate, especially with increasing time interval between assessment and delivery. The new model was well-calibrated. CONCLUSIONS: A competing-risks model provides effective risk stratification for a SGA neonate at 35 + 0 to 36 + 6 weeks' gestation and is superior to EFW percentile cut-offs. The use of biomarkers of impaired placentation in addition to maternal factors and fetal biometry results in small improvement of the predictive performance for a neonate with severe SGA. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Second-trimester contingent screening for small-for-gestational-age neonate.

OBJECTIVES: First, to investigate the additive value of second-trimester placental growth factor (PlGF) for the prediction of a small-for-gestational-age (SGA) neonate. Second, to examine second-trimester contingent screening strategies. METHODS: This was a prospective observational study in women with singleton pregnancy undergoing routine ultrasound examination at 19-24 weeks' gestation. We used the competing-risks model for prediction of SGA. The parameters for the prior model and the likelihoods for estimated fetal weight (EFW) and uterine artery pulsatility index (UtA-PI) were those presented in previous studies. A folded-plane regression model was fitted in the dataset of this study to describe the likelihood of PlGF. We compared the prediction of screening by maternal risk factors against the prediction provided by a combination of maternal risk factors, EFW, UtA-PI and PlGF. We also examined the additive value of PlGF in a policy that uses maternal risk factors, EFW and UtA-PI. RESULTS: The study population included 40 241 singleton pregnancies. Overall, the prediction of SGA improved with increasing degree of prematurity, with increasing severity of smallness and in the presence of coexisting pre-eclampsia. The combination of maternal risk factors, EFW, UtA-PI and PlGF improved significantly the prediction provided by maternal risk factors alone for all the examined cut-offs of birth weight and gestational age at delivery. Screening by a combination of maternal risk factors and serum PlGF improved the prediction of SGA when compared to screening by maternal risk factors alone. However, the incremental improvement in prediction was decreased when PlGF was added to screening by a combination of maternal risk factors, EFW and UtA-PI. If first-line screening for a SGA neonate with birth weight < 10th percentile delivered at < 37 weeks' gestation was by maternal risk factors and EFW, the same detection rate of 90%, at an overall false-positive rate (FPR) of 50%, as that achieved by screening with maternal risk factors, EFW, UtA-PI and PlGF in the whole population can be achieved by reserving measurements of UtA-PI and PlGF for only 80% of the population. Similarly, in screening for a SGA neonate with birth weight < 10th percentile delivered at < 30 weeks, the same detection rate of 90%, at an overall FPR of 14%, as that achieved by screening with maternal risk factors, EFW, UtA-PI and PlGF in the whole population can be achieved by reserving measurements of UtA-PI and PlGF for only 70% of the population. The additive value of PlGF in reducing the FPR to about 10% with a simultaneous detection rate of 90% for a SGA neonate with birth weight < 3rd percentile born < 30 weeks, is gained by measuring PlGF in only 50% of the population when first-line screening is by maternal factors, EFW and UtA-PI. CONCLUSIONS: The combination of maternal risk factors, EFW, UtA-PI and PlGF provides effective second-trimester prediction of SGA. Serum PlGF is useful for predicting a SGA neonate with birth weight < 3rd percentile born < 30 weeks after an inclusive assessment by maternal risk factors and biophysical markers. Similar detection rates and FPRs can be achieved by application of contingent screening strategies. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Development and validation of model for prediction of placental dysfunction-related stillbirth from maternal factors, fetal weight and uterine artery Doppler at mid-gestation.

OBJECTIVE: To examine the performance of a model combining maternal risk factors, uterine artery pulsatility index (UtA-PI) and estimated fetal weight (EFW) at 19-24 weeks' gestation, for predicting all antepartum stillbirths and those due to impaired placentation, in a training dataset used for development of the model and in a validation dataset. METHODS: The data for this study were derived from prospective screening for adverse obstetric outcome in women with singleton pregnancy attending for routine pregnancy care at 19 + 0 to 24 + 6 weeks' gestation. The study population was divided into a training dataset used to develop prediction models for placental dysfunction-related antepartum stillbirth and a validation dataset to which the models were then applied. Multivariable logistic regression analysis was used to develop a model based on a combination of maternal risk factors, EFW Z-score and UtA-PI multiples of the normal median. We examined the predictive performance of the model by, first, the ability of the model to discriminate between the stillbirth and live-birth groups, using the area under the receiver-operating-characteristics curve (AUC) and the detection rate (DR) at a fixed false-positive rate (FPR) of 10%, and, second, calibration by measurements of calibration slope and intercept. RESULTS: The study population of 131 514 pregnancies included 131 037 live births and 477 (0.36%) stillbirths. There are four main findings of this study. First, 92.5% (441/477) of stillbirths were antepartum and 7.5% (36/477) were intrapartum, and 59.2% (261/441) of antepartum stillbirths were observed in association with placental dysfunction and 40.8% (180/441) were unexplained or due to other causes. Second, placental dysfunction accounted for 80.1% (161/201) of antepartum stillbirths at < 32 weeks' gestation, 54.2% (52/96) at 32 + 0 to 36 + 6 weeks and 33.3% (48/144) at ≥ 37 weeks. Third, the risk of placental dysfunction-related antepartum stillbirth increased with increasing maternal weight and decreasing maternal height, was 3-fold higher in black than in white women, was 5.5-fold higher in parous women with previous stillbirth than in those with previous live birth, and was increased in smokers, in women with chronic hypertension and in parous women with a previous pregnancy complicated by pre-eclampsia and/or birth of a small-for-gestational-age baby. Fourth, in screening for placental dysfunction-related antepartum stillbirth by a combination of maternal risk factors, EFW and UtA-PI in the validation dataset, the DR at a 10% FPR was 62.3% (95% CI, 57.2-67.4%) and the AUC was 0.838 (95% CI, 0.799-0.878); these results were consistent with those in the dataset used for developing the algorithm and demonstrate high discrimination between affected and unaffected pregnancies. Similarly, the calibration slope was 1.029 and the intercept was -0.009, demonstrating good agreement between the predicted risk and observed incidence of placental dysfunction-related antepartum stillbirth. The performance of screening was better for placental dysfunction-related antepartum stillbirth at < 37 weeks' gestation compared to at term (DR at a 10% FPR, 69.8% vs 29.2%). CONCLUSIONS: Screening at mid-gestation by a combination of maternal risk factors, EFW and UtA-PI can predict a high proportion of placental dysfunction-related stillbirths and, in particular, those that occur preterm. Such screening provides poor prediction of unexplained stillbirth or stillbirth due to other causes. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Evaluation of the RCOG guideline for the prediction of neonates that are small for gestational age and comparison with the competing risks model.

OBJECTIVE: To examine the predictive performance of the relevant guideline by the Royal College of Obstetricians and Gynaecologists (RCOG) for neonates that are small for gestational age (SGA), and to compare the performance of the RCOG guideline with that of our competing risks model for SGA. DESIGN: Prospective observational study. SETTING: Obstetric ultrasound departments in two UK maternity hospitals. POPULATION: A total of 96 678 women with singleton pregnancies attending for routine ultrasound examination at 19-24 weeks of gestation. METHODS: Risks for SGA for different thresholds were computed, according to the competing risks model using maternal history, second-trimester estimated fetal weight, uterine artery pulsatility index and mean arterial pressure. The detection rates by the RCOG guideline scoring system and the competing risks model for SGA were compared, at the screen positive rate (SPR) derived from the RCOG guideline. MAIN OUTCOME MEASURES: Small for gestational age (SGA), <10th or <3rd percentile, for different gestational age thresholds. RESULTS: At an SPR of 22.5%, as defined by the RCOG guideline, the competing risks model predicted 56, 72 and 81% of cases of neonates that are SGA, with birthweights of <10th percentile, delivered at ≥37, <37 and <32 weeks of gestation, respectively, which were significantly higher than the respective figures of 36, 44 and 45% achieved by the application of the RCOG guideline. The respective figures for neonates that were SGA with birthweights of <3rd percentile were 66, 79, 85 and 41, 45, 44%. CONCLUSION: The detection rate for neonates that were SGA with the competing risk approach is almost double than that obtained with the RCOG guideline. TWEETABLE ABSTRACT: The competing risks approach for the prediction of SGA performs better than the existing RCOG guideline.

Competing-risks model for prediction of small-for-gestational-age neonate from estimated fetal weight at 19-24 weeks' gestation.

OBJECTIVE: To develop further a new competing-risks model for the prediction of a small-for-gestational-age (SGA) neonate, by including second-trimester ultrasonographic estimated fetal weight (EFW). METHODS: This was a prospective observational study in 96 678 women with singleton pregnancy undergoing routine ultrasound examination at 19-24 weeks' gestation. All pregnancies had ultrasound biometry assessment, and EFW was calculated according to the Hadlock formula. We refitted in this large dataset a previously described competing-risks model for the joint distribution of gestational age (GA) at delivery and birth-weight Z-score, according to maternal demographic characteristics and medical history, to obtain the prior distribution. The continuous likelihood of the EFW was fitted conditionally to GA at delivery and birth-weight Z-score and modified the prior distribution, according to Bayes' theorem, to obtain individualized distributions for GA at delivery and birth-weight Z-score and therefore patient-specific risks for any cut-offs for GA at delivery and birth-weight Z-score. We assessed the discriminative ability of the model for predicting SGA with, without or independently of pre-eclampsia occurrence. A calibration study was carried out. Performance of screening was evaluated for SGA defined according to the Fetal Medicine Foundation birth-weight charts. RESULTS: The distribution of EFW, conditional to both GA at delivery and birth-weight Z-score, was best described by a regression model. For earlier gestations, the association between EFW and birth weight was steeper. The prediction of SGA by maternal factors and EFW improved for increasing degree of prematurity and greater severity of smallness but not for coexistence of pre-eclampsia. Screening by maternal factors predicted 31%, 34% and 39% of SGA neonates with birth weight < 10th percentile delivered at ≥ 37, < 37 and < 30 weeks' gestation, respectively, at a 10% false-positive rate, and, after addition of EFW, these rates increased to 38%, 43% and 59%, respectively; the respective rates for birth weight < 3rd percentile were 43%, 50% and 64%. The addition of EFW improved the calibration of the model. CONCLUSION: In the competing-risks model for prediction of SGA, the performance of screening by maternal characteristics and medical history is improved by the addition of second-trimester EFW. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Competing-risks model for prediction of small-for-gestational-age neonate from maternal characteristics, serum pregnancy-associated plasma protein-A and placental growth factor at 11-13 weeks' gestation.

OBJECTIVES: To expand a new competing-risks model for prediction of a small-for-gestational-age (SGA) neonate, by the addition of pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF), and to evaluate and compare PAPP-A and PlGF in predicting SGA. METHODS: This was a prospective observational study of 60 875 women with singleton pregnancy undergoing routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation. We fitted a folded-plane regression model for the PAPP-A and PlGF likelihoods. A previously developed maternal history model and the likelihood models were combined, according to Bayes' theorem, to obtain individualized distributions for gestational age (GA) at delivery and birth-weight Z-score. We assessed the discrimination and calibration of the model. McNemar's test was used to compare the detection rates for SGA with, without or independently of pre-eclampsia (PE) occurrence, of different combinations of maternal history, PAPP-A and PlGF, for a fixed false-positive rate. RESULTS: The distributions of PAPP-A and PlGF depend on both GA at delivery and birth-weight Z-score, in the same continuous likelihood, according to a folded-plane regression model. The new approach offers the capability for risk computation for any desired birth-weight Z-score and GA at delivery cut-off. PlGF was consistently and significantly better than PAPP-A in predicting SGA delivered before 37 weeks, especially in cases with co-existence of PE. PAPP-A had similar performance to PlGF for the prediction of SGA without PE. At a fixed false-positive rate of 10%, the combination of maternal history, PlGF and PAPP-A predicted 33.8%, 43.8% and 48.4% of all cases of a SGA neonate with birth weight < 10th percentile delivered at ≥ 37, < 37 and < 32 weeks' gestation, respectively. The respective values for birth weight < 3rd percentile were 38.6%, 48.7% and 51.0%. The new model performed well in terms of risk calibration. CONCLUSIONS: The combination of PAPP-A and PlGF values with maternal characteristics, according to Bayes' theorem, improves prediction of SGA. PlGF is a better predictor of SGA than PAPP-A, especially when PE is present. The new competing-risks model for SGA can be tailored to each pregnancy and to the relevant clinical requirements. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Competing-risks model for prediction of small-for-gestational-age neonate from biophysical and biochemical markers at 11-13 weeks' gestation.

OBJECTIVE: To develop a new competing-risks model for the prediction of a small-for-gestational-age (SGA) neonate, based on maternal factors and biophysical and biochemical markers at 11-13 weeks' gestation. METHODS: This was a prospective observational study in 60 875 women with singleton pregnancy undergoing routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation. All pregnancies had pregnancy-associated plasma protein-A and placental growth factor (PlGF) measurements, 59 001 had uterine artery pulsatility index (UtA-PI) measurements and 58 479 had mean arterial pressure measurements; 57 131 cases had complete data for all biomarkers. We used a previously developed competing-risks model for the joint distribution of gestational age (GA) at delivery and birth-weight Z-score, according to maternal demographic characteristics and medical history. The likelihoods of the biophysical markers were developed by fitting folded-plane regression models, a technique that has already been used in previous studies for the likelihoods of biochemical markers. The next step was to modify the prior distribution by the likelihood, according to Bayes' theorem, to obtain individualized distributions for GA at delivery and birth-weight Z-score. We used the 57 131 cases with complete data to assess the discrimination and calibration of the model for predicting SGA with, without or independently of pre-eclampsia, by different combinations of maternal factors and biomarkers. RESULTS: The distribution of biomarkers, conditional to both GA at delivery and birth-weight Z-score, was best described by folded-plane regression models. These continuous two-dimensional likelihoods update the joint distribution of birth-weight Z-score and GA at delivery that has resulted from a competing-risks approach; this method allows application of user-defined cut-offs. The best biophysical predictor of preterm SGA was UtA-PI and the best biochemical marker was PlGF. The prediction of SGA was consistently better for increasing degree of prematurity, greater severity of smallness, coexistence of PE and increasing number of biomarkers. The combination of maternal factors with all biomarkers predicted 34.3%, 48.6% and 59.1% of all cases of a SGA neonate with birth weight < 10th percentile delivered at ≥ 37, < 37 and < 32 weeks' gestation, at a 10% false-positive rate. The respective values for birth weight < 3rd percentile were 39.9%, 53.2% and 64.4%, and for birth weight < 3rd percentile with pre-eclampsia they were 46.3%, 66.8% and 80.4%. The new model was well calibrated. CONCLUSIONS: This study has presented a single continuous two-dimensional model for prediction of SGA for any desired cut-offs of smallness and GA at delivery, laying the ground for a personalized antenatal plan for predicting and managing SGA, in the milieu of a new inverted pyramid of prenatal care. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Competing-risks model for prediction of small-for-gestational-age neonate from maternal characteristics and serum pregnancy-associated plasma protein-A at 11-13 weeks' gestation.

OBJECTIVES: To develop a continuous likelihood model for pregnancy-associated plasma protein-A (PAPP-A), in the context of a new competing-risks model for prediction of a small-for-gestational-age (SGA) neonate, and to compare the predictive performance of the new model for SGA to that of previous methods. METHODS: This was a prospective observational study of 60 875 women with singleton pregnancy undergoing routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation. The dataset was divided randomly into a training dataset and a test dataset. The training dataset was used for PAPP-A likelihood model development. We used Bayes' theorem to combine the previously developed prior model for the joint Gaussian distribution of gestational age (GA) at delivery and birth-weight Z-score with the PAPP-A likelihood to obtain a posterior distribution. This patient-specific posterior joint Gaussian distribution of GA at delivery and birth-weight Z-score allows risk calculation for SGA defined in terms of different birth-weight percentiles and GA. The new model was validated internally in the test dataset and we compared its predictive performance to that of the risk-scoring system of the UK National Institute for Health and Care Excellence (NICE) and that of logistic regression models for different SGA definitions. RESULTS: PAPP-A has a continuous association with both birth-weight Z-score and GA at delivery according to a folded-plane regression. The new model, with the addition of PAPP-A, was equal or superior to several logistic regression models. The new model performed well in terms of risk calibration and consistency across different GAs and birth-weight percentiles. In the test dataset, at a false-positive rate of about 30% using the criteria defined by NICE, the new model predicted 62.7%, 66.5%, 68.1% and 75.3% of cases of a SGA neonate with birth weight < 10th percentile delivered at < 42, < 37, < 34 and < 30 weeks' gestation, respectively, which were significantly higher than the respective values of 46.7%, 55.0%, 55.9% and 52.8% achieved by application of the NICE guidelines. CONCLUSIONS: Using Bayes' theorem to combine PAPP-A measurement data with maternal characteristics improves the prediction of SGA and performs better than logistic regression or NICE guidelines, in the context of a new competing-risks model for the joint distribution of birth-weight Z-score and GA at delivery. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.