Screening For Fetal Growth Restriction Research Articles

Radiological Modalities for the Assessment of Fetal Growth Restriction: A Comprehensive Review

Fetal growth restriction is a significant contributor to fetal morbidity and mortality. In addition, there are heightened maternal risks associated with surgical operations and their accompanying dangers. Monitoring fetal development is a crucial objective of prenatal care and effective methods for early diagnosis of Fetal growth restriction, allowing prompt management and timely intervention to improve the outcomes. Screening for Fetal growth restriction can be achieved via many modalities; it can be medical, biochemical, or radiological. Some recommended combining more than one for better outcomes. Currently, there is inconsistency about the best method of Fetal growth restriction screening. In this review, a comprehensive evaluation of the current radiological methods used for Fetal growth restriction, including serial growth scan, Doppler velocimetry, and biophysical profile is offered. Limitations, and potential enhancements area were specifically analyzing the effectiveness. Moreover, recently developed experimental radiological techniques were presented and how to integrate them into practice to enhance follow-up performance and results.

Impact of Using Abdominal Circumference Independently in the Diagnosis of Fetal Growth Restriction

(Abstracted from J Ultrasound Med 2022;41:157–162) Screening for fetal growth restriction (FGR) to identify those fetuses at increased risk of adverse neonatal outcomes has been difficult. Investigators have defined FGR in different ways, which has complicated efforts to validate results.

First-Trimester Screening for Fetal Growth Restriction and Small-for-Gestational-Age Pregnancies without Preeclampsia Using Cardiovascular Disease-Associated MicroRNA Biomarkers.

The goal of the study was to determine the early diagnostical potential of cardiovascular disease-associated microRNAs for prediction of small-for-gestational-age (SGA) and fetal growth restriction (FGR) without preeclampsia (PE). The whole peripheral venous blood samples were collected within 10 to 13 weeks of gestation from singleton Caucasian pregnancies within the period November 2012 to March 2020. The case-control retrospective study, nested in a cohort, involved all pregnancies diagnosed with SGA (n = 37) or FGR (n = 82) without PE and 80 appropriate-for-gestational age (AGA) pregnancies selected with regard to equality of sample storage time. Gene expression of 29 cardiovascular disease-associated microRNAs was assessed using real-time RT-PCR. Upregulation of miR-16-5p, miR-20a-5p, miR-146a-5p, miR-155-5p, miR-181a-5p, and miR-195-5p was observed in SGA or FGR pregnancies at 10.0% false positive rate (FPR). Upregulation of miR-1-3p, miR-20b-5p, miR-126-3p, miR-130b-3p, and miR-499a-5p was observed in SGA pregnancies only at 10.0% FPR. Upregulation of miR-145-5p, miR-342-3p, and miR-574-3p was detected in FGR pregnancies at 10.0% FPR. The combination of four microRNA biomarkers (miR-1-3p, miR-20a-5p, miR-146a-5p, and miR-181a-5p) was able to identify 75.68% SGA pregnancies at 10.0% FPR in early stages of gestation. The detection rate of SGA pregnancies without PE increased 4.67-fold (75.68% vs. 16.22%) when compared with the routine first-trimester screening for PE and/or FGR based on the criteria of the Fetal Medicine Foundation. The combination of seven microRNA biomarkers (miR-16-5p, miR-20a-5p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-342-3p, and miR-574-3p) was able to identify 42.68% FGR pregnancies at 10.0% FPR in early stages of gestation. The detection rate of FGR pregnancies without PE increased 1.52-fold (42.68% vs. 28.05%) when compared with the routine first-trimester screening for PE and/or FGR based on the criteria of the Fetal Medicine Foundation. Cardiovascular disease-associated microRNAs represent promising early biomarkers with very suitable predictive potential for SGA or FGR without PE to be implemented into the routine screening programs.

Cost-Effectiveness of Routine Third Trimester Ultrasound Screening for Fetal Growth Restriction Compared to Care as Usual in Low-Risk Pregnancies: A Pragmatic Nationwide Stepped-Wedge Cluster-Randomized Trial in The Netherlands (the IRIS Study).

Routine third trimester ultrasonography is increasingly used to screen for fetal growth restriction. However, evidence regarding its cost-effectiveness is lacking. We aimed to evaluate the cost-effectiveness of routine third trimester ultrasonography to reduce adverse perinatal outcomes compared to usual care (selective ultrasonography). An economic evaluation alongside a stepped-wedge cluster-randomized trial was conducted. Via 60 midwifery practices 12,974 Dutch women aged ≥16 years with low-risk pregnancies were enrolled at 22.8 (SD = 2.4) weeks’ gestation. All practices provided usual care. At 3, 7, and 10 months a third of the practices were randomized to the intervention strategy providing routine ultrasonography at 28–30 and 34–36 weeks’ gestation and usual care. The primary clinical outcome was a dichotomous composite measure of 12 severe adverse perinatal outcomes (SAPO) up to one week postpartum. Information on perinatal care and societal costs was derived from Netherlands Perinatal Registry, hospital records and a survey. Cost-effectiveness analyses revealed no significant differences in SAPO and healthcare and societal costs between the intervention strategy (n = 7026) and usual care (n = 5948). Cost-effectiveness acceptability curves showed that the probability of cost-effectiveness was never higher than 0.6 for all possible ceiling ratios. Adding routine third trimester ultrasonography to usual care is not cost-effective in reducing SAPO.

Longitudinal assessment of spiral artery and intravillous arteriole blood flow and adverse pregnancy outcome.

Superb microvascular imaging (SMI) has been shown to improve visualization of small vessels by suppressing global motions while preserving low-flow components, such as the microvessels in the placenta. We sought to determine if SMI-aided visualization of flow velocity waveforms in the spiral arteries (SA) and intravillous fetal arterioles (IVA) could predict fetal growth restriction (FGR), gestational hypertension (GH) and/or pre-eclampsia (PE). This was a prospective longitudinal study of singleton pregnancies without fetal anomaly, receiving prenatal care in one of two medical centers over a 5-year period. Using SMI-aided color Doppler, SA and IVA flow velocity was measured at three timepoints: 11 + 0 to 14 + 0, 18 + 0 to 22 + 6 and 28 + 0 to 34 + 6 weeks of gestation. SA and IVA flow velocity waveforms were reported as resistance indices (RI). RI values were analyzed using multilevel modeling; individual regression curves were estimated and combined to obtain the reference intervals for SA-RI and IVA-RI in uncomplicated pregnancies. The primary clinical outcome was FGR and secondary outcomes were PE and GH. FGR was defined as estimated fetal weight < 10th percentile. Student's t-test was used to compare deviation from expected RI between normal and complicated pregnancies. Among 540 pregnancies included in the analysis, 18 (3.3%) had FGR, 31 (5.7%) PE and 61 (11.3%) GH. In uncomplicated pregnancies, the SA-RI decreased progressively with advancing gestation, whereas the IVA-RI increased with gestational age. In the third trimester, the mean SA-RI and IVA-RI values were significantly higher in the FGR group compared with pregnancies that did not develop FGR, while the mean SA-RI was significantly higher in PE compared with non-PE pregnancies. There was no significant difference in mean SA-RI or IVA-RI between pregnancies with vs those without GH at any gestational age. When all three adverse outcomes were combined, SA-RI was significantly higher in pregnancies with these outcomes when compared to uncomplicated pregnancies in the third trimester (mean ± SD, 0.29 ± 0.12 vs 0.26 ± 0.12; P = 0.02). In screening for FGR using SA-RI, the areas under the receiver-operating-characteristics curves (AUC) were 0.68, 0.73 and 0.73 in the first, second and third trimesters, respectively. The respective AUCs for IVA-RI were 0.72, 0.72 and 0.73 for each trimester. SA-RI and IVA-RI, measured using SMI technology, were significantly higher in pregnancies at risk for FGR in late gestation. Larger studies are needed to determine if SA and IVA flow are reliable predictors of adverse pregnancy outcome. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Diagnostic accuracy of fetal growth charts for placenta-related fetal growth restriction

IntroductionThe choice of fetal growth chart to be used in antenatal screening for fetal growth restriction (FGR) has an important impact on the proportion of fetuses diagnosed as small for gestational age (SGA), and on the detection rate for FGR. We aimed to compare diagnostic accuracy of SGA diagnosed using four different common fetal growth charts [Hadlock, Intergrowth-21st (IG21), World Health Organization (WHO), and National Institute of Child Health and Human Development (NICHD)], for abnormal placental pathology. MethodsA secondary analysis of data from a prospective cohort study in low-risk nulliparous women. The exposure was SGA (birthweight <10th centile for gestational age) using each of the four charts. The outcomes were one of three types of abnormal placental pathology associated with fetal growth restriction: maternal vascular malperfusion (MVM), chronic villitis, and fetal vascular malperfusion. ResultsA total of 742 nulliparous women met the study criteria. The proportion of SGA was closest to the expected rate of 10% using the Hadlock chart (12.7%). The detection rates (DR) and false positive rates (FPR) for MVM pathology were similar for the Hadlock (DR = 53.1%, FPR = 10.8%), WHO (DR = 59.4%, FPR = 14.2%), and NICHD (DR = 53.1%, FPR = 12.3%) charts, and each was superior when compared to the IG21 chart (DR = 34.4%, FPR = 3.8%, p < 0.001). The diagnosis of SGA was associated with increased risks of preeclampsia and preterm birth for all four charts. DiscussionThe selection of fetal growth chart to be used in screening programs for FGR has important implications with regard to the false positive and detection rate for FGR.

The Combined Influence of Maternal Medical Conditions on the Risk of Fetal Growth Restriction [34N

INTRODUCTION: Common maternal medical co-morbidities such as hypertensive disorders, diabetes, tobacco use, and extremes of maternal age, BMI, and gestational weight gain (GWG), are known individually to impact fetal growth restriction (FGR) risk. We aim to examine the risk of FGR in women with multiple maternal medical co-morbidities to determine the cumulative risk imposed on pregnancy. METHODS: In this population-based retrospective cohort study we analyzed data from Ohio live birth records from 2006–2015 to estimate the influence of individual and combinations of maternal co-morbidities on rates of FGR (birthweight &lt;10th percentile for gestational age) and severe FGR (&lt;5th percentile). The exposures were individual and combinations of maternal medical conditions (chronic hypertension, gestational hypertension, pre-gestational diabetes, tobacco use, advanced maternal age, underweight, and insufficient GWG) and outcomes were rates and adjusted relative risk (aRR) of FGR. RESULTS: There were 1,463,506 live births in Ohio during the study period, of which 734,672 (50.2%) had one or more maternal medical condition. Pregnancies complicated by multiple co-morbidities had higher rates of FGR compared to those with a single medical condition. The rate and aRR range of FGR &lt;10%ile and FGR &lt;5%ile ranged from 8.8–18.4% (aRR 0.91–1.51) and 4.3–9.3% (aRR 0.84–2.22), respectively in pregnancies with single medical conditions, which increased to 10.4–57.9% (aRR 1.03–3.16) and 5.9–36.9% (aRR 1.11–7.03), respectively in pregnancies complicated by multiple medical co-morbidities. CONCLUSION: A greater number of maternal medical co-morbidities during pregnancy is associated with increasing cumulative risk of fetal growth restriction, which may be useful in patient counseling and screening for FGR.

FGR: Risk Factors and Outcomes

Abstract Background Fetal Growth Restriction (FGR) is the one of largest contributing factor to perinatal morbidity in non-anomalous fetuses and is associated with an increased risk of stillbirth, neonatal death and short and long-term complications. Fetal growth restriction (FGR) is defined as an estimated fetal weight and/or abdominal circumference (AC) is less than the10th percentile. In order to avoid these adverse outcomes, the management of pregnancies with FGR involves close monitoring of fetal well-being and early delivery when necessary. Screening for FGR during pregnancy is thus a central component of prenatal care, as highlighted in recent national guidelines, first-line tools include risk factor assessment at the beginning and during pregnancy. Hence, in this study we evaluated the maternal risk factors and diagnosis-delivery intervals and perinatal outcomes in FGR. Aim To determine the effect of specific antenatal FGR risk factors on fetal growth trajectory and the outcomes using threshold of estimated fetal weight (EFW) and abdominal circumference (AC) &amp;lt;10th percentile. Methods Prospective observational analytical study was conducted in a tertiary care hospital in Cairo, Egypt on 100 pregnant women with documented fetal growth restriction attended Ain Shams University hospital over a period of 1 year and eight months. All fetuses considered as growth restrictions. Fetuses with multiple pregnancy, congenital malformation, chromosomal abnormality, and premature rupture of membrane were. Socio-demographic, maternal risk, Diagnosis- delivery interval in FGR and neonatal morbidities were studied. Results This study included 100 pregnant women with documented FGR fetuses, the mean maternal age at diagnosis was 28.6±2.7 years, the mean pregnant women weight at diagnosis was 72.7±5.1 (kg) with BMI range 25.6–29.8 (kg/m2) and their pregnancy weight gain was 12.0–25.0 (kg), 50 women used to consume caffeine more than 200 mg/day, and the percentage of nicotine exposure was 22% of total studied pregnants, 19 % were passive smokers and 3% of them were active. 73% were multigravida and the rest were primi-gravida, the mean inter-pregnancy interval was 17.3±4.7 months. Obstetric history of Previous placental mediated diseases included (prior FGR, previous intrauterine fetal death (IUFD), Pre-eclampsia and un-explained antepartum hemorrhage) were distributed as follows 16.0%, 6.0%, 12.0% and 2.0% respectively. Also we found 2.0% had an in vitro fertilization (IVF) and 26 women got regular antenatal care (ANC). At the end of our study 45% of fetuses were delivered at completed 37 weeks and 55% showed pre-term delivery (before 37 weeks). 95% of total were delivered by caesarean section. The indications for caesarean section were different. So, among 100 FGR fetuses, 35 fetus had abnormal Doppler pattern which considered the main indication for termination of pregnancy, the most frequent one was absent/reversed ductus venosus Doppler which was the cause of preterm immediate caesarean section in 4 of fetuses. We also found 2 fetuses with also absent/reversed EDV but with abnormal CTG, we found 20 fetuses with PI &amp;gt; 2SD with preserved EDV and completed 37 weeks, 13% had non-reactive non-stress test (NST) necessitating imminent delivery, also 3 fetuses with absent EDV &amp;gt; 34 weeks while only one fetus with reversed EDV &amp;gt;32 weeks. We found 1 fetus with static growth over 3 weeks during our follow up, also we discovered 1 pregnant women who developed accidental hemorrhage with placental separation and other 3 women developed sever pre-eclampsia who underwent emergency caesarean section after controlling their condition. Conclusion FGR is associated with sociodemographic status and various medical conditions. Analysis of various maternal and familial risk factors is an integral part of in-utero fetal surveillance to identify impending fetal hypoxia. Appropriate management should be offered to these FGR fetuses, is optimizing the timing of delivery to improve perinatal health in FGR.

First-trimester screening for fetal growth restriction using Doppler color flow analysis of the uterine artery and serum PAPP-A levels in unselected pregnancies

Purpose To explore an early diagnostic model for fetal growth restriction (FGR) at 11–13 (+6 days) gestational weeks using Doppler analysis of the uterine artery and measurements of pregnancy-associated plasma protein-A (PAPP-A). Methods This was a prospective study which included 1796 singleton pregnant women, who received routine pregnancy examination at 11–13 (+6 days) gestational weeks in Shanghai Changning Maternity and Infant Health Hospital between 1 June 2017 and 31 July 2018. Uterine artery pulsatility index (PI), uterine resistance index (RI), and notching were recorded using the Doppler ultrasound detector (Voluson E8; GE Healthcare, Kretztechnik, Zipf, Austria). Maternal serum PAPP-A was assayed using time-resolved fluorescence immunoassay (Perkin-Elmer Life Sciences, Waltham, MA, USA) and analyzed using Fetal Medicine Foundation software. Maternal and neonatal outcomes were followed. Results Out of 1796 pregnant women aged 18–42 years, 76 (4.2%) mothers had FGR fetus. In the FGR fetuses, the mean uterine artery PI and RI were higher, the PAPP-A levels were 0.42-fold lower (all p values < .05), and notching was 40% higher (p < .0001) than in non-FGR fetuses. The sensitivity and specificity of early diagnosis of FGR and the area under the curve for the combination of uterine artery PI and PAPP-A were 0.788 (95% CI: 0.735, 0.842), 0.816, and 0.758, respectively. A combination of PAPP-A and Doppler analysis of uterine artery was better than individual measurements for predicting FGR (all p values < .05), and the specificity was significantly improved after including serum PAPP-A. Conclusion The combination of uterine artery PI and PAPP-A measured at 11–13 (+6 days) gestational weeks provides a sensitive and specific predictor for early diagnosis of FGR.

Smoking cessation Through Optimisation of clinical care in Pregnancy: the STOP randomised controlled trial

BackgroundCigarette smoking negatively impacts on maternal and fetal health. Smoking cessation is one of the few interventions capable of improving pregnancy outcomes. Despite the risks, the most effective antenatal model of care for smokers is still unclear, and specific recommendations for screening for fetal growth restriction are absent.MethodsThis is a pragmatic randomised controlled trial of a dedicated smoking cessation clinic versus routine antenatal care as an intervention to reduce cigarette smoking behaviour. Smoking mothers randomised to the Smoking cessation Through Optimisation of clinical care in Pregnancy (STOP) clinic will have all antenatal care provided by a team comprising an obstetrician, a midwife, and a smoking cessation practitioner. This intervention includes ultrasound screening for fetal growth restriction. The control arm comprises two groups: one receiving standard care with ultrasound screening for fetal growth restriction, and one receiving standard care with ultrasound screening for growth restriction only if clinically indicated by their healthcare provider. Four hundred and fifty women will be recruited and randomised to either intervention or control arms stratifying for age, parity, and history of fetal growth restriction.ResultsThe primary outcome is self-reported, continuous abstinence from smoking between the quit date and end of pregnancy, validated by exhaled carbon monoxide or urinary cotinine. The quit date is targeted as being at or before 16 weeks’ gestation and no further than 28 weeks’ gestation. The secondary outcomes are a set of variables including maternal and fetal morbidity and mortality, neonatal complications and delivery outcomes, smoking and psychological outcomes, and qualitative measures.ConclusionsDespite much research into cigarette smoking in pregnancy, the optimal model of care for these women is still unknown. This study has the potential to improve the model of antenatal care provided to pregnant women who smoke and to improve outcomes for both mother and infant.Trial registrationISRCTN11214785. Registered on 8 February 2018.

182: Screening for fetal growth restriction in women of advanced maternal age

182: Screening for fetal growth restriction in women of advanced maternal age

Screening for fetal growth restriction using ultrasound and the sFLT1/PlGF ratio in nulliparous women: a prospective cohort study

Fetal growth restriction is a major determinant of perinatal morbidity and mortality. This condition has no gold standard definition, but a widely used proxy is delivery of a small for gestational age infant (<10th percentile) combined with an adverse pregnancy outcome. Effective screening for fetal growth restriction is an area of unmet clinical need. We aimed to determine the diagnostic effectiveness of a combination of ultrasonic fetal biometry and measurement of the ratio of soluble fms-like tyrosine kinase receptor 1 (sFLT1) to placental growth factor (PlGF) in predicting adverse pregnancy outcomes associated with delivery of a small for gestational age infant. In this prospective cohort study, using serial antenatal blood sampling and blinded ultrasound scans, we investigated the association between the combination of an elevated sFLT1/PlGF ratio (>85th percentile) and ultrasonically suspected small for gestational age (<10th percentile) at both 28 and 36 weeks of gestational age. The outcome following the 28 week measurement was preterm delivery of a small for gestational age infant. The outcome following the 36 week measurement was subsequent delivery of a small for gestational infant associated with maternal pre-eclampsia or perinatal morbidity or mortality. All definitions of exposure and outcome were predefined before we did our data analysis. Between Jan 14, 2008, and July 31, 2012, we recruited 4512 nulliparous women. 4098 women (91%) had a sFLT1/PlGF ratio measurement and estimated fetal weight at 28 or 36 weeks of gestational age, and outcome data available. 3981 women were analysed for 28 weeks of gestational age measurements and 3747 women were analysed for 36 weeks of gestational age measurements. At 28 weeks, 47 (1%) of 3981 women had the combination of ultrasonic small for gestational age and an elevated sFLT1/PlGF ratio. The positive likelihood ratio for preterm delivery of a small for gestational age infant associated with this combination was 41·1 (95% CI 23·0-73·6), the sensitivity was 38·5% (21·1-59·3), the specificity was 99·1% (98·7-99·3), and the positive predictive value was 21·3% (11·6-35·8). At 36 weeks, 102 (3%) of 3747 women had the combination of ultrasonic small for gestational age and an elevated sFLT1/PlGF ratio. The positive likelihood ratio for delivery of a small for gestational age infant associated with maternal pre-eclampsia or perinatal morbidity or mortality was 17·5 (95% CI 11·8-25·9), the sensitivity was 37·9% (26·1-51·4), the specificity was 97·8% (97·3-98·3), and the positive predictive value was 21·6% (14·5-30·8). The positive likelihood ratios at both gestational ages were higher than previously described definitions of suspected fetal growth restriction using purely ultrasonic assessment. The combination of ultrasonically suspected small for gestational age plus an elevated sFLT1/PlGF ratio in unselected nulliparous women identified a relatively small proportion of women who have high absolute risks of clinically important adverse outcomes. Screening and intervention based on this approach could result in net benefit and this could be an appropriate subject for a randomised controlled trial. NIHR Cambridge Comprehensive Biomedical Research Centre, Medical Research Council, and Stillbirth and neonatal death society (Sands).

Fetal growth velocity and body proportion in the assessment of growth.

Fetal growth restriction implies failure of a fetus to meet its growth potential and is associated with increased perinatal mortality and morbidity. Therefore, antenatal detection of fetal growth restriction is of major importance in an attempt to deliver improved clinical outcomes. The most commonly used approach towards screening for fetal growth restriction is by means of sonographic fetal weight estimation, to detect fetuses small for gestational age, defined by an estimated fetal weight <10th percentile for gestational age. However, the predictive accuracy of this approach is limited both by suboptimal detection rate (as it may overlook non-small-for-gestational-age growth-restricted fetuses) and by a high false-positive rate (as most small-for-gestational-age fetuses are not growth restricted). Here, we review 2 strategies that may improve the diagnostic accuracy of sonographic fetal biometry for fetal growth restriction. The first strategy involves serial ultrasound evaluations of fetal biometry. The information obtained through these serial assessments can be interpreted using several different approaches including fetal growth velocity, conditional percentiles, projection-based methods, and individualized growth assessment that can be viewed as mathematical techniques to quantify any decrease in estimated fetal weight percentile, a phenomenon that many care providers assess and monitor routinely in a qualitative manner. This strategy appears promising in high-risk pregnancies where it seems to improve the detection of growth-restricted fetuses at increased risk of adverse perinatal outcomes and, at the same time, decrease the risk of falsely diagnosing healthy constitutionally small-for-gestational-age fetuses as growth restricted. Further studies are needed to determine the utility of this strategy in low-risk pregnancies as well as to optimize its performance by determining the optimal timing and interval between exams. The second strategy refers to the use of fetal body proportions to classify fetuses as either symmetric or asymmetric using 1 of several ratios; these include the head circumference to abdominal circumference ratio, transverse cerebellar diameter to abdominal circumference ratio, and femur length to abdominal circumference ratio. Although these ratios are associated with small for gestational age at birth and with adverse perinatal outcomes, their predictive accuracy is too low for clinical practice. Furthermore, these associations become questionable when other, potentially more specific measures such as umbilical artery Doppler are being used. Furthermore, these ratios are of limited use in determining the etiology underlying fetal smallness. It is possible that the use of the 2 gestational-age-independent ratios (transverse cerebellar diameter to abdominal circumference and femur length to abdominal circumference) may have a role in the detection of mild-moderate fetal growth restriction in pregnancies without adequate dating. In addition, despite their limited predictive accuracy, these ratios may become abnormal early in the course of fetal growth restriction and may therefore identify pregnancies that may benefit from closer monitoring of fetal growth.

Screening for fetal growth restriction using fetal biometry combined with maternal biomarkers.

Fetal growth restriction is a major determinant of perinatal morbidity and mortality. Screening for fetal growth restriction is a key element of prenatal care but it is recognized to be problematic. Screening using clinical risk assessment and targeting ultrasound to high-risk women is the standard of care in the United States and United Kingdom, but the approach is known to have low sensitivity. Systematic reviews of randomized controlled trials do not demonstrate any benefit from universal ultrasound screening for fetal growth restriction in the third trimester, but the evidence base is not strong. Implementation of universal ultrasound screening in low-risk women in France failed to reduce the risk of complications among small-for-gestational-age infants but did appear to cause iatrogenic harm to false positives. One strategy to making progress is to improve screening by developing more sensitive and specific tests with the key goal of differentiating between healthy small fetuses and those that are small through fetal growth restriction. As abnormal placentation is thought to be the major cause of fetal growth restriction, one approach is to combine fetal biometry with an indicator of placental dysfunction. In the past, these indicators were generally ultrasonic measurements, such as Doppler flow velocimetry of the uteroplacental circulation. However, another promising approach is to combine ultrasonic suspicion of small-for-gestational-age infant with a blood test indicating placental dysfunction. Thus far, much of the research on maternal serum biomarkers for fetal growth restriction has involved the secondary analysis of tests performed for other indications, such as fetal aneuploidies. An exemplar of this is pregnancy-associated plasma protein A. This blood test is performed primarily to assess the risk of Down syndrome, but women with low first-trimester levels are now serially scanned in later pregnancy due to associations with placental causes of stillbirth, including fetal growth restriction. The development of "omic" technologies presents a huge opportunity to identify novel biomarkers for fetal growth restriction. The hope is that when such markers are measured alongside ultrasonic fetal biometry, the combination would have strong predictive power for fetal growth restriction and its related complications. However, a series of important methodological considerations in assessing the diagnostic effectiveness of new tests will have to be addressed. The challenge thereafter will be to identify novel disease-modifying interventions, which are the essential partner to an effective screening test to achieve clinically effective population-based screening.

First-trimester screening with specific algorithms for early- and late-onset fetal growth restriction

To develop optimal first-trimester algorithms for the prediction of early and late fetal growth restriction (FGR). This was a prospective cohort study of singleton pregnancies undergoing first-trimester screening. FGR was defined as an ultrasound estimated fetal weight < 10(th) percentile plus Doppler abnormalities or a birth weight < 3(rd) percentile. Logistic regression-based predictive models were developed for predicting early and late FGR (cut-off: delivery at 34 weeks). The model included the a-priori risk (maternal characteristics), mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1). Of the 9150 pregnancies included, 462 (5%) fetuses were growth restricted: 59 (0.6%) early and 403 (4.4%) late. Significant contributions to the prediction of early FGR were provided by black ethnicity, chronic hypertension, previous FGR, MAP, UtA-PI, PlGF and sFlt-1. The model achieved an overall detection rate (DR) of 86.4% for a 10% false-positive rate (area under the receiver-operating characteristics curve (AUC): 0.93 (95% CI, 0.87-0.98)). The DR was 94.7% for FGR with pre-eclampsia (PE) (64%of cases) and 71.4% for FGR without PE (36%of cases). For late FGR, significant contributions were provided by chronic hypertension, autoimmune disease, previous FGR, smoking status, nulliparity, MAP, UtA-PI, PlGF and sFlt-1. The model achieved a DR of 65.8% for a 10% false-positive rate (AUC: 0.76 (95% CI, 0.73-0.80)). The DR was 70.2% for FGR with PE (12%of cases) and 63.5% for FGR without PE (88%of cases). The optimal screening algorithm was different for early vs late FGR, supporting the concept that screening for FGR is better performed separately for the two clinical forms. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Re: Screening for fetal growth restriction with universal third trimester ultrasonography in nulliparous women in the Pregnancy Outcome Prediction (POP) study: A prospective cohort study. Lancet 2015; 386:2089‐97. Sovio U, White IR, Dacey A, Pasupathy D, Smith GC

The aim was to compare the diagnostic effectiveness of universal ultrasound as a screening test compared with selective ultrasound (based on a clinical indication) and to identify any link between ultrasound markers associated with fetal growth restriction and the risk of morbidity associated with small for gestational age fetuses.

Screening for Fetal Growth Restriction With Universal Third Trimester Ultrasonography in Nulliparous Women in the Pregnancy Outcome Prediction (POP) Study

Summary Background Fetal growth restriction is a major determinant of adverse perinatal outcome. Screening procedures for fetal growth restriction need to identify small babies and then differentiate between those that are healthy and those that are pathologically small. We sought to determine the diagnostic effectiveness of universal ultrasonic fetal biometry in the third trimester as a screening test for small-for-gestational-age (SGA) infants, and whether the risk of morbidity associated with being small differed in the presence or absence of ultrasonic markers of fetal growth restriction. Methods The Pregnancy Outcome Prediction (POP) study was a prospective cohort study of nulliparous women with a viable singleton pregnancy at the time of the dating ultrasound scan. Women participating had clinically indicated ultrasonography in the third trimester as per routine clinical care and these results were reported as usual (selective ultrasonography). Additionally, all participants had research ultrasonography, including fetal biometry at 28 and 36 weeks' gestational age. These results were not made available to participants or treating clinicians (universal ultrasonography). We regarded SGA as a birthweight of less than the 10th percentile for gestational age and screen positive for SGA an ultrasonographic estimated fetal weight of less than the 10th percentile for gestational age. Markers of fetal growth restriction included biometric ratios, utero-placental Doppler, and fetal growth velocity. We assessed outcomes for consenting participants who attended research scans and had a livebirth at the Rosie Hospital (Cambridge, UK) after the 28 weeks' research scan. Findings Between Jan 14, 2008, and July 31, 2012, 4512 women provided written informed consent of whom 3977 (88%) were eligible for analysis. Sensitivity for detection of SGA infants was 20% (95% CI 15–24; 69 of 352 fetuses) for selective ultrasonography and 57% (51–62; 199 of 352 fetuses) for universal ultrasonography (relative sensitivity 2·9, 95% CI 2·4–3·5, p interaction =0·005) if the fetal abdominal circumference growth velocity was in the lowest decile (RR 3·9, 95% CI 1·9–8·1, p=0·0001). 172 (4%) of 3977 pregnancies had both an estimated fetal weight of less than the 10th percentile and abdominal circumference growth velocity in the lowest decile, and had a relative risk of delivering an SGA infant with neonatal morbidity of 17·6 (9·2–34·0, p Interpretation Screening of nulliparous women with universal third trimester fetal biometry roughly tripled detection of SGA infants. Combined analysis of fetal biometry and fetal growth velocity identified a subset of SGA fetuses that were at increased risk of neonatal morbidity. Funding National Institute for Health Research, Medical Research Council, Sands, and GE Healthcare.

Does the Presence of Risk Factors for Fetal Growth Restriction Increase the Probability of Antenatal Detection? A French National Study

Screening for fetal growth restriction (FGR) is a major component of prenatal care. We investigated whether the presence of maternal and pregnancy risk factors for FGR improves the antenatal suspicion of FGR for infants born small-for-gestational age (SGA) as well as their impact on screening specificity. Data are from a representative sample of births from the 2010 French National Perinatal Survey (n = 14 100). Detection of FGR was determined by a suspicion of FGR noted in medical charts. Analyses were performed for singleton infants with birthweight under the 10th percentile (SGA), under the 3rd percentile (severely SGA), and above the 10th percentile (false positives) of French references. We studied risk factors for FGR (medical and obstetric conditions, advanced maternal age, nulliparity, body mass index and smoking) using multivariable Poisson regression to derive adjusted risk ratios (aRR). Of SGA infants, 21.7% were suspected of FGR. The presence of obstetric and medical risk factors for FGR was associated with higher suspicion among SGA infants [RR 2.1, 95% confidence interval (CI) 1.7, 2.7]. However, despite the presence of these factors, 60% and 40% of SGA and severely SGA infants, respectively, were not suspected of FGR. Two per cent of normal birthweight infants were suspected of FGR, increasing to 5% when obstetric and medical risk factors were present. Smoking and older maternal age were unrelated to suspicion while females were more likely to be suspected of FGR. Our results suggest that better risk assessment could improve antenatal identification of FGR. Sex-specific fetal growth references should be used to avoid systematic bias linked to sex.

Ultrasound screening for fetal growth restriction at 36 vs 32 weeks' gestation: a randomized trial (ROUTE).

To compare the utility of routine third-trimester ultrasound examination at 36 weeks' gestation with that at 32 weeks in detecting fetal growth restriction (FGR). This was an open-label parallel randomized trial (ROUTE study) conducted at a single general hospital serving a geographically well-defined catchment area in Barcelona, Spain, between May 2011 and April 2014. Women with no adverse medical or obstetric history and a singleton pregnancy without fetal abnormalities at routine second-trimester scan were assigned randomly to undergo a scan at 32 weeks' gestation (n = 1272) or at 36 weeks' gestation (n = 1314). Primary outcome measures were detection rates of FGR (customized birth weight < 10(th) centile) and severe FGR (customized birth weight < 3(rd) centile). There were no significant differences in perinatal outcome between those who underwent a scan at 32 weeks' gestation and those who underwent a scan at 36 weeks' gestation. Severe FGR at birth was associated significantly with emergency Cesarean delivery for fetal distress (odds ratio (OR), 3.4 (95% CI, 1.8-6.7)), neonatal admission (OR, 2.23 (95% CI, 1.23-4.05)), hypoglycemia (OR, 9.5 (95% CI, 1.8-49.8)) and hyperbilirubinemia (OR, 9.0 (95% CI, 4.6-17.6)). Despite similar false-positive rates (FPRs) (6.4% vs 8.2%), FGR detection rates were superior at 36 vs 32 weeks' gestation (sensitivity, 38.8% vs 22.5%; P = 0.006), with positive and negative likelihood ratios of 6.1 vs 2.7 and 0.65 vs 0.84, respectively. In cases of severe FGR, FPRs for both scans were also similar (8.5% vs 8.7%), but detection rates were superior at 36 vs 32 weeks' gestation (61.4% vs 32.5%; P = 0.008). Positive and negative likelihood ratios were 7.2 vs 3.7 and 0.4 vs 0.74, respectively. In low-risk pregnancies, routine ultrasound examination at 36 weeks' gestation was more effective than that at 32 weeks' gestation in detecting FGR and related adverse perinatal and neonatal outcomes.

Screening for fetal growth restriction with universal third trimester ultrasonography in nulliparous women in the Pregnancy Outcome Prediction (POP) study: a prospective cohort study

SummaryBackgroundFetal growth restriction is a major determinant of adverse perinatal outcome. Screening procedures for fetal growth restriction need to identify small babies and then differentiate between those that are healthy and those that are pathologically small. We sought to determine the diagnostic effectiveness of universal ultrasonic fetal biometry in the third trimester as a screening test for small-for-gestational-age (SGA) infants, and whether the risk of morbidity associated with being small differed in the presence or absence of ultrasonic markers of fetal growth restriction.MethodsThe Pregnancy Outcome Prediction (POP) study was a prospective cohort study of nulliparous women with a viable singleton pregnancy at the time of the dating ultrasound scan. Women participating had clinically indicated ultrasonography in the third trimester as per routine clinical care and these results were reported as usual (selective ultrasonography). Additionally, all participants had research ultrasonography, including fetal biometry at 28 and 36 weeks' gestational age. These results were not made available to participants or treating clinicians (universal ultrasonography). We regarded SGA as a birthweight of less than the 10th percentile for gestational age and screen positive for SGA an ultrasonographic estimated fetal weight of less than the 10th percentile for gestational age. Markers of fetal growth restriction included biometric ratios, utero-placental Doppler, and fetal growth velocity. We assessed outcomes for consenting participants who attended research scans and had a livebirth at the Rosie Hospital (Cambridge, UK) after the 28 weeks' research scan.FindingsBetween Jan 14, 2008, and July 31, 2012, 4512 women provided written informed consent of whom 3977 (88%) were eligible for analysis. Sensitivity for detection of SGA infants was 20% (95% CI 15–24; 69 of 352 fetuses) for selective ultrasonography and 57% (51–62; 199 of 352 fetuses) for universal ultrasonography (relative sensitivity 2·9, 95% CI 2·4–3·5, p<0·0001). Of the 3977 fetuses, 562 (14·1%) were identified by universal ultrasonography with an estimated fetal weight of less than the 10th percentile and were at an increased risk of neonatal morbidity (relative risk [RR] 1·60, 95% CI 1·22–2·09, p=0·0012). However, estimated fetal weight of less than the 10th percentile was only associated with the risk of neonatal morbidity (pinteraction=0·005) if the fetal abdominal circumference growth velocity was in the lowest decile (RR 3·9, 95% CI 1·9–8·1, p=0·0001). 172 (4%) of 3977 pregnancies had both an estimated fetal weight of less than the 10th percentile and abdominal circumference growth velocity in the lowest decile, and had a relative risk of delivering an SGA infant with neonatal morbidity of 17·6 (9·2–34·0, p<0·0001).InterpretationScreening of nulliparous women with universal third trimester fetal biometry roughly tripled detection of SGA infants. Combined analysis of fetal biometry and fetal growth velocity identified a subset of SGA fetuses that were at increased risk of neonatal morbidity.FundingNational Institute for Health Research, Medical Research Council, Sands, and GE Healthcare.