Delivered Small-for-gestational-age Neonates Research Articles

Perinatal Outcomes of Pregnancies with Borderline Oligohydramnios at Term

Introduction: Limited evidence exists on borderline oligohydramnios. Our objective was to determine perinatal outcomes in uncomplicated term pregnancies with borderline oligohydramnios. Methods: This retrospective analysis compared adverse perinatal outcomes among pregnancies during 2018–2022, between those with borderline oligohydramnios defined as amniotic fluid index (AFI) of 5.1–8.0 cm, those with oligohydramnios (AFI ≤5 cm), and those with normal AFI (8.1–25 cm). The latter matched one-to-one to the borderline oligohydramnios group and served as the control group. The outcomes compared included birthweight, cesarean delivery due to fetal distress, the presence of meconium-stained amniotic fluid, Apgar scores, neonatal intensive care unit admission, and the occurrence of small-for-gestational-age (SGA) neonates. Results: During the study period, 140 women had borderline oligohydramnios and 345 had oligohydramnios; the control group included 140 women. Borderline oligohydramnios was associated with increased rates of delivering SGA neonates (adjusted odds ratio [aOR] = 3.6, 95% confidence interval [CI] 1.1–11.6, p = 0.034) and cesarean delivery due to fetal distress (aOR = 3.0, 95% CI 1.1–8.3, p = 0.032). Rates of composite neonatal outcome (including at least one of the following: cesarean delivery due to fetal distress, meconium-stained amniotic fluid, 5-min Apgar score <7, umbilical artery pH <7.15, or neonatal intensive care unit admission) were higher in both the borderline oligohydramnios (20.7%) and oligohydramnios (18.6%) groups compared to the control group (9.3%) (p = 0.019). Conclusions: Pregnancies with borderline oligohydramnios were associated with increased risks of delivering SGA neonates and requiring cesarean delivery due to fetal distress. These findings support considering closer antepartum surveillance for these pregnancies, especially for identifying abnormal fetal growth.

Prediction by uterine artery Doppler screening of small-for-gestational-age neonates at 19-24 weeks' gestation.

Small-for-gestational-age (SGA) neonates are at increased risk of perinatal mortality and morbidity. We aimed to investigate the performance of uterine artery pulsatility index (UtA-PI) at 19-24 weeks' gestation to predict the delivery of a SGA neonate in a Chinese population. This was a retrospective cohort study using data obtained between January 2010 and June 2018. Doppler ultrasonography was performed at 19-24 weeks' gestation. SGA was defined as birth weight below the 10th centile according to the INTERGROWTH-21st fetal growth standards. The performance of UtA-PI to predict the delivery of a SGA neonate was assessed using receiver-operating-characteristics (ROC)-curve analysis. We included 6964 singleton pregnancies, of which 748 (11%) delivered a SGA neonate, including 115 (15%) women with preterm delivery. Increased UtA-PI was associated with an elevated risk of SGA, both in neonates delivered at or after 37 weeks' gestation (term SGA) and those delivered before 37 weeks (preterm SGA). The areas under the ROC curve (AUCs) for UtA-PI were 64.4% (95% CI, 61.5-67.3%) and 75.8% (95% CI, 69.3-82.3%) for term and preterm SGA, respectively. The performance of combined screening by maternal demographic/clinical characteristics and estimated fetal weight in the detection of term and preterm SGA was improved significantly by the addition of UtA-PI, although the increase in AUC was modest (2.4% for term SGA and 4.9% for preterm SGA). This is the first Chinese study to evaluate the role of UtA-PI at 19-24 weeks' gestation in the prediction of the delivery of a neonate with SGA. The addition of UtA-PI to traditional risk factors improved the screening performance for SGA, and this improvement was greater in predicting preterm SGA compared with term SGA. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Maternal and Placental Risk Factors for Small Gestational Age and Fetal Malnutrition.

This case-control study was conducted to identify maternal and placental risk factors of small-for-gestational-age (SGA) and fetal malnutrition. Cases comprised 104 consecutively delivered SGA neonates (determined as per INTERGROWTH- 21st standard). An equal number of next-born gestation and gender-matched appropriatefor- gestational age (AGA) neonates served as controls. Maternal risk factors were enquired, and placentae were evaluated by clinical and histopathological examination. Nutrition of the neonates was assessed by the clinical assessment of nutrition (CAN) score. Univariate and multivariate logistic regression analysis was done to identify the maternal and placental risk factors. The prevalence of SGA in the present study was 23.9%. Maternal fever [adjusted Odds Ratio (aOR), 95% confidence interval (CI), 16.3 (3.5-124.1); p = 0.001], presence of placental syncytial knots [aOR (95% CI), 2.9 (1.1-9.1); p = 0.04] and placental calcifications [aOR (95% CI), 3(1.1- 8.7); p = 0.03], were identified as independent predictors of SGA using multivariate logistic regression analysis. Malnutrition (SCORE <25) affected 64% of SGA and 16.3% of AGA neonates. The only risk factor significantly associated with malnourished SGA was prematurity, whereas malnourished AGA was significantly associated with prematurity and fetal distress. In-hospital morbidities significantly higher in SGA were perinatal asphyxia, respiratory distress, need for respiratory support, polycythemia, hypoglycemia, and feeding intolerance. Mortality before discharge was 4.8% and 3.8% in SGA and AGA population, respectively (p > 0.05). Neonatal outcomes were comparable among well-nourished, malnourished SGA and AGA groups. Maternal fever, placental syncytial knots, and calcifications were independent risk factors of SGA, whereas prematurity and fetal distress were responsible for malnutrition.

Undetected Fetal Growth Restriction During the Coronavirus Disease 2019 (COVID-19) Pandemic.

This was a retrospective cohort study of patients who delivered singleton, small-for-gestational-age (SGA) neonates between April and June 2019, before the coronavirus disease 2019 (COVID-19) pandemic (pre-COVID-19), and between April and July 2020, during the pandemic (COVID-19 epoch). The primary outcome was the rate of undetected antenatal fetal growth restriction (FGR) in the two periods. A total of 268 patients met inclusion criteria. Patients who delivered small-for-gestational-age neonates during the COVID-19 epoch were significantly more likely to have undetected FGR compared with those who delivered pre-COVID-19 (70.1% vs 58.1%, P =.04). Patients who delivered SGA neonates during the COVID-19 epoch had more telehealth visits but fewer in-person prenatal visits, recorded fundal height measurements, and growth ultrasonograms. As telemedicine continues to be incorporated into prenatal care, these data may lend further support toward self-assessment of fundal height or routine third-trimester growth ultrasonograms to identify fetal growth abnormalities.

AHA stage 1 hypertension and risk of small for gestational infants in nulliparous women

Non-Obstetric guidelines by the American Heart Association (AHA) have redefined hypertension (HTN) into stages with a systolic blood pressure (BP) of 130-139 mmHg and/or diastolic BP of 80-89 mmHg defined as stage 1. It is well known that stage 1 HTN confers a significantly elevated risk of hypertensive disorders of pregnancy, but less is known regarding effects on placental function and subsequent birth weight. This study aims to assess risk of small for gestational age (SGA) birth weight in women stratified by non-Obstetric HTN cut points. This was a secondary analysis of a large prospective observational study investigating birth outcomes in nulliparous women (nuMoM2b). Subjects were excluded from the current analysis for incomplete outcome data, lack of first trimester blood pressure, structural fetal anomaly, and pregestational diabetes. Women were stratified based on documented first trimester blood pressure defined as normotensive (< 120/< 80), elevated (120-129/< 80), stage 1 HTN (130-139/80-89), or stage 2 HTN (either by medical history or BP ≥140/≥90). Logistic regression was used to generate adjusted odds ratio (aOR) and 95% confidence intervals (CI) for SGA birth weight (< 10%) and pregnancy induced HTN ([PIH], gestational HTN or preeclampsia). 7,951 pregnancies were included in the analysis with 601 (7.6%) meeting criteria for stage 1 hypertension based on AHA guidelines and 754 (9.5%) delivered SGA neonates. There were no significant differences in rates of SGA among groups < 10% (p=0.184) or < 3% (p=.920), Figure 1. There were also no differences in SGA after regression analysis (Table 1). Women with stage 1 HTN had the highest risk of PIH (aOR 2.1, CI 1.7-2.6) while stage 2 HTN was not significant after adjustment (aOR 1.3, CI 0.92-1.8). Nulliparous women with stage 1 hypertension by non-obstetric guidelines do not have an elevated risk of SGA despite and increased risk of hypertensive disorders of pregnancy.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Adverse perinatal outcomes following the prenatal diagnosis of isolated single umbilical artery in singleton pregnancies: a systematic review and meta-analysis.

A systematic review and meta-analysis was conducted to quantitatively synthesize the current evidence on the association of prenatally diagnosed isolated single umbilical artery (iSUA) in singleton pregnancies with small for gestational age (SGA) neonates and other perinatal outcomes. A search of PubMed/Medline, Scopus and The Cochrane Library was conducted, from inception to February 2021, in order to identify studies comparing the risk of SGA and other perinatal adverse outcomes in prenatally diagnosed iSUA singleton pregnancies vs. those with a 3-vessel cord (3VC). The quality of eligible studies was assessed according to the improved Newcastle-Ottawa Scale (NOS). The heterogeneity of results across the studies was tested using the I2 test. Funnel plots and Egger's test were used to assess the possibility of publication bias. Prospero RN: CRD42020182586. The electronic search identified 7,605 studies, of which 11 were selected, including three retrospective cohort and eight retrospective case control studies, overall reporting on 1,533 iSUA cases. The risk of delivering SGA neonates was increased in cases with iSUA (OR: 2.90; 95% CI: 2.02-4.18; p<0.00001; I2=71%). Similarly, iSUA was associated with an increased risk of pregnancy-induced hypertension (PIH) (OR: 2.23; 95% CI: 1.41-3.54; p<0.000; I2=1%), intrauterine death (IUD) (OR: 2.62; 95% CI: 1.43-4.79; p=0.002; I2=0%), preterm birth (PTB) (OR: 2.48; 95% CI: 1.73-3.56; p<0.00001; I2=56%), cesarean section (CS) (OR: 1.64; 95% CI: 1.11-2.41; p=0.01; I2=78%) and admission to neonatal intensive care unit (NICU) (OR: 2.28; 95% CI: 1.52-3.44; p<0.000001; I2=73%). In prenatally diagnosed iSUA there is a higher risk of SGA, PIH, IUD, PTB, CS and NICU admission. These findings support the value of prenatal diagnosis of iSUA, which may subsequently intensify surveillance for the detection of specific pregnancy complications.

Longitudinal profile of sHLA-G during pregnancy and its association with small for gestational age births in North Indian pregnant females: A nested case-control study.

Small for gestational age (SGA) neonates are vulnerable to various long and short-term adverse health consequences. The expression of HLA-G in the placenta is crucial for establishment and maintenance of pregnancy. Its aberrant expression could lead to perturbed immunological interactions in the placenta which could be associated with SGA births. The objective of this study was to assess the difference in the trajectories of soluble HLA-G in maternal sera during pregnancy between women delivering SGA and appropriate for gestational age (AGA) neonates. Soluble HLA-G was estimated in the maternal sera collected at different time points in pregnancy of North-Indian pregnant females delivering SGA (N=23) or AGA (N=17) neonates using sandwich ELISA. Linear mixed models were built and compared to study the association between sHLA-G levels during pregnancy and SGA births. No significant difference was observed in the sHLA-G trajectories during pregnancy in mothers delivering SGA as compared to those delivering AGA (P-value=.5677). A trend towards higher sHLA-G levels at the first trimester of pregnancy (<14weeks of gestation) was observed in mothers delivering SGA neonates (Median=41.71, IQR=21.31-71.38) as compared to those delivering AGA neonates (Median=37.58, IQR=19.05-73.57). During pregnancy, sHLA-G trajectories do not differ significantly between mothers delivering SGA and those delivering AGA neonates. However, sHLA-G trends towards higher levels during early pregnancy in mothers delivering SGA neonates.

The mediating role of gestational diabetes mellitus in the associations of maternal prepregnancy body mass index with neonatal birth weight.

BackgroundBoth prepregnancy obesity and gestational diabetes mellitus (GDM) have been linked to adverse neonatal birth weight. However, the mediating role of GDM between prepregnancy obesity and neonatal birth weight is unclear.MethodThe cohort study included 17 260 singleton pregnant women and their newborns. Participants' demographic characteristics, disease history, family history of the disease, and the perinatal outcomes were recorded. The association between maternal prepregnancy body mass index (BMI) status and small for gestational age (SGA) or large for gestational age (LGA) neonates was analyzed using logistic regressions, before and after adjusting for covariates and GDM. The potential mediation of GDM on the association between prepregnancy BMI and adverse birth weight was examined.ResultMultivariate logistic regression demonstrated that prepregnancy underweight women were more likely to deliver SGA neonates compared to those who had normal weights, whereas prepregnancy obese pregnant women were more likely to have LGA neonates. The RMediation analyses illustrated that the mediation effect of GDM on the maternal prepregnancy BMI (continuous variable) and the risk of SGA was not significant, whereas the association between prepregnancy BMI and LGA was statistically mediated by GDM (95%CI of a*b: 0.009‐0.051). The Iacobacci (2012) method indicated that the impact of maternal prepregnancy overweight (Zmediation = 2.418, P = .015) and obesity (Zmediation = 2.165, P = .030) on LGA was partially mediated by GDM, with an indirect effect of 16.3% and 13.1%, respectively.ConclusionPrepregnancy BMI was observed to be associated with SGA and LGA. The association of prepregnancy overweight and obesity with LGA was found to be partially mediated by GDM.

\u201cScreening for small-for-gestational age neonates at early third trimester in a high-risk population for preeclampsia\u201d

BackgroundStrategies to improve prenatal detection of small-for-gestational age (SGA) neonates are necessary because its association with poorer perinatal outcome. This study evaluated, in pregnancies with first trimester high risk of early preeclampsia, the performance of a third trimester screening for SGA combining biophysical and biochemical markers.MethodsThis is a prospective longitudinal study on 378 singleton pregnancies identified at high risk of early preeclampsia according to a first trimester multiparametric algorithm with the cutoff corresponding to 15% false positive rate. This cohort included 50 cases that delivered SGA neonates with birthweight < 10th centile (13.2%) and 328 cases with normal birthweight (86.8%). At 27–30 weeks’ gestation, maternal weight, blood pressure, estimated fetal weight, mean uterine artery pulsatility index and maternal biochemical markers (placental growth factor and soluble FMS-Like Tyrosine Kinase-1) were assessed. Different predictive models were created to evaluate their performance to predict SGA neonates.ResultsFor a 15% FPR, a model that combines maternal characteristics, estimated fetal weight, mean uterine artery pulsatility index and placental growth factor achieved a detection rate (DR) of 56% with a negative predictive value of 92.2%. The area under receiver operating characteristic curve (AUC) was 0.79 (95% confidence interval (CI), 0.72–0.86). The DR of a model including maternal characteristics, estimated fetal weight and mean uterine artery pulsatility index was 54% (AUC, 0.77 (95% CI, 0.70–0.84)). The DR of a model that includes maternal characteristics and placental growth factor achieved a similar performance (DR 56%, AUC 0.75, 95% CI (0.67–0.83)).ConclusionsThe performance of screening for SGA neonates at early third trimester combining biophysical and biochemical markers in a high-risk population is poor. However, a high negative predictive value could help in reducing maternal anxiety, avoid iatrogenic interventions and propose a specific plan for higher risk patients.

Comparison of Placental Three-Dimensional Power Doppler Vascular Indices and Placental Volume in Pregnancies with Small for Gestational Age Neonates.

This prospective observational study aimed to compare the changes in placental vascular indices and placental volume using three-dimensional power Doppler (3DPD) ultrasound in pregnancies with small for gestational age (SGA) neonates. We enrolled 396 women with singleton pregnancies from September 2013 to June 2016. Placental vascular indices, including the vascularization index (VI), flow index (FI), and vascularization flow index (VFI), and placental volume were obtained using 3DPD ultrasound in the first and second trimesters. Of the enrolled women, 21 delivered SGA neonates and 375 did not. In the first trimester, the SGA group had a significantly lower mean FI (25.10 ± 7.51 versus 33.10 ± 10.97, p < 0.001) and VFI (4.59 ± 1.95 versus 6.28 ± 2.35, p = 0.001) than the non-SGA group. However, there was no significant difference in the placental volume between the two groups during the first trimester. In the second trimester, the SGA group also had a significantly lower mean FI (27.08 ± 7.97 versus 31.54 ± 11.01, p = 0.022) and VFI (6.68 ± 1.71 versus 8.68 ± 3.09, p < 0.001) than the non-SGA group. In addition, a significantly smaller placental volume was noted in the SGA group (104.80 ± 24.23 cm3 versus 122.67 ± 26.35 cm3, p = 0.003) than in the non-SGA group during the second trimester. The results showed that a decreased placental VFI occurred earlier than a decreased placental volume in SGA pregnancies.

Maternal serum placental growth factor combined with second trimester aneuploidy screening to predict small-for-gestation neonates without preeclampsia

ObjectiveTo investigate the role of maternal serum placenta growth factor (PlGF) and quadruple test parameters in predicting the risk of small for gestational age (SGA) infants of mothers without preeclampsia. Materials and methodsWe prospectively enrolled 300 pregnant patients who underwent blood sampling at 15–18 weeks gestation and followed them until delivery. Cases with SGA neonate delivery (n = 100) were compared with matched AGA neonate controls (n = 200). The plasma PlGF and quadruple markers were measured by enzyme-linked immunosorbent assay. The results were analyzed with Mann–Whitney U tests, and regression analysis was used to develop a model for the prediction of SGA. ResultsWomen who delivered SGA neonates had decreased levels of PlGF (median 0.71 MoM versus 0.7 MoM; p < 0.01), hCG (median 0.97 MoM versus 1.06 MoM; p = 0.046) and uE3 (median 0.92 MoM versus 1.04 MoM) compared to the AGA group. AFP, hCG and inhibin-A levels did not differ significantly. A PlGF concentration <0.37 MoM had a sensitivity of 28.0% (95% CI: 19.5–37.9) and a specificity of 89.5% (95% CI: 84.4–93.4) for the prediction of SGA neonates without PE. ConclusionSGA neonates in the absence of PE could potentially be identified at 15–18 weeks of pregnancy.

Maternal cardiac function at 35-37 weeks' gestation: relationship with birth weight.

To evaluate the relationship between maternal cardiovascular parameters and neonatal birth weight and examine the potential value of these parameters in improving the prediction of small-for-gestational-age (SGA) and large-for-gestational-age (LGA) neonates provided by maternal characteristics and medical history. In 2835 singleton pregnancies maternal characteristics and medical history were recorded and maternal cardiovascular parameters were measured. The observed measurements of cardiovascular parameters were expressed as multiples of the normal median (MoM) values after adjustment for those characteristics found to provide a substantial contribution to their measurement. Regression analysis was used to determine the significance of association between the normalized values of the cardiovascular parameters with birth-weight Z-score. Multivariable logistic regression analysis was then used to determine if the maternal factors, fetal biometry and maternal cardiovascular parameters had a significant contribution to predicting SGA and LGA neonates. The performance of screening was determined by the area under receiver-operating characteristics curves (AUC). In the study population there were significant positive associations between maternal cardiac output and heart rate with neonatal birth-weight Z-score, and significant negative associations between total peripheral resistance and mean arterial pressure (MAP) with neonatal birth-weight Z-score. In pregnancies delivering SGA neonates (n = 249 (8.8%)), cardiac output and heart rate were lower and total peripheral resistance and MAP were higher, whereas in pregnancies delivering LGA neonates (n = 292 (10.3%)) cardiac output and heart rate were higher and total peripheral resistance and MAP were lower. The performance of screening for delivery of SGA neonates achieved by maternal characteristics and fetal biometry was not improved by the measurement of maternal cardiovascular parameters. There was a small but significant improvement in the performance of screening for delivery of LGA neonates by maternal factors and fetal biometry with the addition of maternal heart rate (comparison of AUC, P = 0.0095). There are significant associations between maternal cardiac output, heart rate, total peripheral resistance and MAP and neonatal birth-weight Z-score; such findings reflect the close relationship between maternal cardiac function and fetal demands. However, assessment of these parameters at 35-37 weeks' gestation is unlikely to improve substantially the performance of screening for SGA or LGA neonates provided by a combination of maternal factors and fetal biometry. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Investigation on the ability of first trimester glycodelin and angiopoietin-2 to predict small-for-gestational age pregnancies at delivery.

The aim was to investigate whether first trimester glycodelin and angiopoietin-2 can predict small-for-gestational age (SGA) at delivery, individually or in combination. In this case-control study we measured glycodelin and angiopoietin-2 on serum from 170 singleton pregnant women delivering SGA neonates and 985 singleton pregnant women delivering normal-weighted neonates. All values were converted to multiples of the medians (MoM). Pregnant women delivering SGA neonates had lower first trimester glycodelin and angiopoietin-2 MoM values [median (interquartile range)] compared with pregnant women delivering normal-weighted neonates for glycodelin: 0.86 (0.58-1.24) vs. 1.03 (0.74-1.45), p<0.001, and for angiopoietin-2: 0.89 (0.69-1.19) vs. 1.01 (0.78-1.31), p<0.001. The prediction performances of the biomarkers showed that the areas under the curve (AUC) were 0.59 (glycodelin), 0.58 (angiopoietin-2), and 0.60 (glycodelin and angiopoietin-2). We demonstrated that first trimester glycodelin and angiopoietin-2 were associated with SGA, but they were, individually and in combination, poor predictors of SGA at delivery. The AUCs were low which indicate low detection rates and high false positive rates.

Prediction of small-for-gestational-age neonates: screening by biophysical and biochemical markers at 19-24 weeks.

To investigate the value of combined screening by maternal characteristics and medical history, fetal biometry and biophysical and biochemical markers at 19-24 weeks' gestation, for prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE), and examine the potential value of such assessment in deciding whether the third-trimester scan should be at 32 and/or 36 weeks' gestation. This was a screening study in 7816 singleton pregnancies, including 389 (5.0%) that delivered SGA neonates with birth weight < 5(th) percentile (SGA < 5(th) ), in the absence of PE. Multivariable logistic regression analysis was used to determine if screening by a combination of maternal factors, fetal biometry, uterine artery pulsatility index (UtA-PI) and maternal serum concentrations of placental growth factor (PlGF) and α-fetoprotein (AFP) had significant contribution in predicting SGA neonates. A model was developed for selecting the gestational age for third-trimester assessment, at 32 and/or 36 weeks, based on the results of screening at 19-24 weeks. Significant independent contributions to the prediction of SGA < 5(th) were provided by maternal factors, fetal biometry, UtA-PI and serum PlGF and AFP. The detection rate (DR) of such combined screening at 19-24 weeks was 100%, 78% and 42% for SGA < 5(th) delivering < 32, at 32-36 and ≥ 37 weeks' gestation, respectively, at a false-positive rate (FPR) of 10%. In a hypothetical model, it was estimated that if the desired objective of prenatal screening is to predict about 80% of the cases of SGA < 5(th) , it would be necessary to select 11% of the population at the 19-24-week assessment to be reassessed at 32 weeks and 44% to be reassessed at 36 weeks; 57% would not require a third-trimester scan. Prenatal prediction of a high proportion of SGA neonates necessitates the undertaking of screening in the third trimester of pregnancy, in addition to assessment in the second trimester, and the timing of such screening, at 32 and/or 36 weeks, should be contingent on the results of the assessment at 19-24 weeks.

Prediction of small-for-gestational-age neonates: screening by biophysical and biochemical markers at 30-34 weeks.

To investigate the potential value of combined screening by maternal characteristics and medical history (maternal factors), estimated fetal weight (EFW), uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP) and serum levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) at 30-34 weeks' gestation in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE). This was a screening study in 9472 singleton pregnancies at 30-34 weeks' gestation, comprising 469 that delivered SGA neonates and 9003 cases unaffected by SGA, PE or gestational hypertension. Multivariable logistic regression analysis was used to determine if UtA-PI, MAP and serum PlGF or sFlt-1, individually or in combination, improved the prediction of SGA neonates provided from screening by maternal factors and EFW. Compared to the normal group, mean log10 multiples of the median (MoM) values of UtA-PI, MAP and serum sFlt-1 were significantly higher and log10 MoM PlGF was lower in the SGA group. Multivariable logistic regression analysis demonstrated that in the prediction of SGA neonates with a birth weight < 5(th) percentile, delivering < 5 weeks and ≥ 5 weeks after assessment, there were significant independent contributions from maternal factors, EFW, UtA-PI, MAP, and serum PlGF and sFlt-1, but the best performance was provided by a combination of maternal factors, EFW, UtA-PI, MAP and serum PlGF, excluding sFlt-1. Combined screening predicted, at a 10% false-positive rate, 89%, 94%, 96% of SGA neonates delivering at 32-36 weeks' gestation with birth weight < 10(th) , < 5(th) and < 3(rd) percentiles, respectively; the respective detection rates of combined screening for SGA neonates delivering ≥ 37 weeks were 57%, 65% and 72%. Combined screening by maternal factors and biophysical and biochemical markers at 30-34 weeks' gestation could identify a high proportion of pregnancies that will deliver SGA neonates.

Prediction of small‐for‐gestational‐age neonates: screening by maternal biochemical markers at 30–34 weeks

To investigate the potential value of serum placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), pregnancy-associated plasma protein-A (PAPP-A), free β-human chorionic gonadotropin (β-hCG) and α-fetoprotein (AFP) at 30-34 weeks' gestation in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE). This was a screening study in singleton pregnancies at 30-34 weeks' gestation, including 490 that delivered SGA neonates and 9360 cases that were unaffected by SGA, PE or gestational hypertension (normal outcome). Multivariable logistic regression analysis was used to determine if screening by serum PlGF, sFlt-1, PAPP-A, free β-hCG and AFP, individually or in combination, improved the prediction of SGA neonates provided by screening with maternal characteristics and medical history (maternal factors), and estimated fetal weight (EFW) from fetal head circumference, abdominal circumference and femur length. Compared to the normal group, the mean log10 multiples of the median (MoM) values of PlGF and AFP were significantly lower and the mean log10 MoM values of sFlt-1 and free β-hCG were significantly higher in the SGA group with a birth weight < 5(th) percentile (SGA < 5(th)) delivering < 5 weeks following assessment. The best model for prediction of SGA was provided by a combination of maternal factors, EFW and serum PlGF. Such combined screening, predicted, at a 10% false-positive rate, 85%, 93% and 92% of SGA neonates delivering < 5 weeks following assessment with birth weight < 10(th), < 5(th) and < 3(rd) percentiles, respectively; the respective detection rates of combined screening for SGA neonates delivering ≥ 5 weeks following assessment were 57%, 64% and 71%. Combined screening by maternal factors, EFW and serum PlGF at 30-34 weeks' gestation can identify a high proportion of pregnancies that subsequently deliver SGA neonates.

Prediction of small-for-gestational-age neonates: screening by fetal biometry at 19-24 weeks.

To investigate the value of fetal biometry at 19-24 weeks' gestation in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE), and examine the potential value of such assessment in deciding whether the third-trimester scan should be at 32 and/or 36 weeks' gestation. This was a screening study in 88,187 singleton pregnancies, including 5003 (5.7%) that delivered SGA neonates with birth weight < 5(th) percentile (SGA < 5(th)). Multivariable logistic regression analysis was used to determine if screening by a combination of maternal characteristics and medical history and Z-scores of fetal head circumference (HC), abdominal circumference (AC) and femur length (FL) had significant contribution in predicting SGA neonates. A model was developed for selecting the gestational age for third-trimester assessment, at 32 and/or 36 weeks, based on the results of screening at 19-24 weeks. Combined screening by maternal factors and fetal biometry at 19-24 weeks, predicted 76%, 58% and 44% of SGA < 5(th) delivering < 32, 32-36 and ≥ 37 weeks' gestation, respectively, at a false-positive rate (FPR) of 10%. The detection rate (DR) of SGA < 5(th) delivering at 32-36 weeks improved from 58% to 82% with screening at 32 weeks rather than at 19-24 weeks. Similarly, the DR of SGA < 5(th) delivering ≥ 37 weeks improved from 44% with screening at 19-24 weeks to 61% and 76% with screening at 32 and 36 weeks, respectively. In a hypothetical model, it was estimated that if the desired objective of prenatal screening is to predict about 80% of the cases of SGA < 5(th), it would be necessary to select 28% of the population at the 19-24-week assessment to be reassessed at 32 weeks and 41% to be reassessed at 36 weeks; in 59% of pregnancies there would be no need for a third-trimester scan. Prenatal prediction of a high proportion of SGA neonates necessitates the undertaking of screening in the third trimester of pregnancy, in addition to assessment in the second trimester, and the timing of such screening, either at 32 and/or 36 weeks, should be contingent on the results of the assessment at 19-24 weeks.

Prediction of small-for-gestational-age neonates: screening by placental growth factor and soluble fms-like tyrosine kinase-1 at 35-37 weeks.

To investigate the potential value of maternal serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) at 35-37 weeks' gestation in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE). This was a screening study in singleton pregnancies at 35-37 weeks, including 158 that delivered SGA neonates with birth weight < 5(th) percentile and 3701 cases unaffected by SGA, PE or gestational hypertension. Multivariable logistic regression analysis was used to determine if measuring serum levels of PlGF and sFlt-1 improved the prediction of delivery of SGA neonates provided by screening with maternal characteristics and medical history (maternal factors), and estimated fetal weight (EFW) from fetal head circumference, abdominal circumference and femur length. Compared to the normal group, the median PlGF multiples of the median (MoM) was significantly lower and the median sFlt-1 MoM was significantly higher in the SGA group. Combined screening by maternal factors and EFW at 35-37 weeks predicted, at 10% false-positive rate (FPR), 90%, 92% and 94% of SGA neonates with birth weight < 10(th), < 5(th) and < 3(rd) percentiles, respectively, delivering < 2 weeks following assessment; the respective values for SGA delivering ≥ 37 weeks were 66%, 73% and 80%. When PlGF and sFlt-1 were added to a model that combines maternal factors and EFW, sFlt-1 did not remain as a significant independent predictor of SGA < 5(th). Combined screening by maternal factors, EFW and serum PlGF, predicted, at a 10% FPR, 88%, 96% and 94% of SGA neonates with birth weight < 10(th), < 5(th) and < 3(rd) percentiles, respectively, delivering < 2 weeks following assessment and the respective values for SGA delivering ≥ 37 weeks were 64%, 75% and 80%. sFlt-1 does not provide significant independent prediction of SGA, in the absence of PE, in addition to combined testing by maternal factors and fetal biometry at 35-37 weeks; whilst the addition of PlGF alone marginally improves the performance of screening.

First trimester PAPP-A2, PAPP-A and hCGβ in small-for-gestational-age pregnancies.

Pregnancy-associated plasma protein-A2 (PAPP-A2) is a recently discovered protease that cleaves a subset of insulin-like growth factor binding proteins (IGFBP). The molecular function suggests its involvement in the IGF system that is vital for fetal growth and development. Our objectives were to establish first trimester median curves of PAPP-A2, PAPP-A and hCGβ for singleton normal pregnancies and to investigate whether an altered level of one or more of the biomarkers is associated with small-for-gestational-age (SGA) neonates before and after stratification according to maternal hypertension and/or proteinuria. This was a case-control study based on 985 pregnant women delivering normal-weighted neonates and 170 pregnant women delivering SGA neonates. PAPP-A2 was measured by ELISA. PAPP-A and hCGβ were measured by an automatic analyzer. Median curves from 8+1 to 14+0 were established and all concentration values were converted to multiples of the median (MoM) values. Before stratification the SGA cases had unaffected PAPP-A2 MoM and hCGβ MoM levels but lower PAPP-A MoM compared with normal controls. After stratification the SGA normotensive subgroup had lower PAPP-A2 MoM and PAPP-A MoM levels than the normal normotensive subgroup. Severe preeclamptic women delivering SGA neonates had higher PAPP-A2 MoM compared to the normotensive women delivering SGA neonates. Pregnant women delivering SGA neonates did not have altered levels of PAPP-A2 or hCGβ but had lower PAPP-A level in the first trimester compared with pregnant women delivering normal-weighted neonates. Pregnancies complicated with severe preeclampsia and SGA may be associated with high PAPP-A2 level.

Prediction of small-for-gestational-age neonates: screening by uterine artery Doppler and mean arterial pressure at 35-37 weeks.

To investigate the potential value of uterine artery (UtA) pulsatility index (PI) and mean arterial pressure (MAP) at 35-37 weeks' gestation in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE). This was a screening study in singleton pregnancies at 35-37 weeks, including 245 that delivered SGA neonates with birth weight < 5(th) percentile and 4876 cases unaffected by SGA, PE or gestational hypertension. Multivariable logistic regression analysis was used to determine if UtA-PI and MAP improved the prediction of SGA neonates provided by screening with maternal characteristics and medical history (maternal factors), and estimated fetal weight (EFW) from fetal head circumference, abdominal circumference and femur length. Compared to the normal group, the median multiple of the median (MoM) values of UtA-PI and MAP were significantly higher in the SGA < 5(th) group. Combined screening by maternal factors, EFW Z-score, UtA-PI and MAP at 35-37 weeks predicted, at a 10% false-positive rate, 90%, 86% and 90% of SGA neonates with birth weight < 10(th) , < 5(th) and < 3(rd) percentiles, respectively, delivering < 2 weeks following assessment; the respective values for SGA delivering ≥ 37 weeks were 66%, 74% and 80%. Such performance was not significantly different from screening by maternal factors and EFW Z-score alone. Addition of UtA-PI and MAP to combined testing by maternal factors and fetal biometry at 35-37 weeks does not improve the performance of screening for delivery of SGA neonates.