Prediction of small for gestational age neonates: screening by maternal factors, fetal biometry, and biomarkers at 35-37 weeks' gestation

Background: Small for gestational age (SGA) neonates are at increased risk of perinatal mortality and morbidity, but the risks can be substantially reduced if the condition is identified prenatally, because in such cases close monitoring and appropriate timing of delivery and prompt neonatal care can be undertaken. The traditional approach of identifying pregnancies with SGA fetuses is maternal abdominal palpation and serial measurements of symphysial-fundal height, but the detection rate of this approach is less than 30%. A higher performance of screening for SGA is achieved by sonographic fetal biometry during the third trimester; screening at 30-34 weeks’ gestation identifies about 80% of SGA neonates delivering preterm but only 50% of those delivering at term, at screen positive rate of 10%. There is some evidence that routine ultrasound examination at 36 weeks' gestation is more effective than that at 32 weeks in predicting birth of SGA neonates. Objective: To investigate the potential value of maternal characteristics and medical history, sonographycally estimated fetal weight (EFW) and biomarkers of impaired placentation at 35+0 - 36+6 weeks’ gestation in the prediction of delivery of small for gestational age (SGA) neonates. Methods: A dataset of 124,443 prospectively examined singleton pregnancies at 11+0 - 13+6 weeks’ gestation was used to derive, through multivariable logistic regression analysis, the patient-specific prior risk for delivery of SGA neonate with birthweight <10th percentile for gestational age from maternal characteristics and medical history. A dataset of 19,209 singleton pregnancies undergoing screening at 35+0 - 36+6 weeks’ gestation was divided into a training set and a validation set. The training dataset was used to develop models from multivariable logistic regression analysis to determine whether addition of uterine artery pulsatility index (UtA-PI), umbilical artery PI (UA-PI), fetal middle cerebral artery PI (MCA-PI), maternal serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFLT) improved the performance of maternal factors and EFW in the prediction of delivery of SGA neonates. The models were then tested in the validation dataset to assess performance of screening. Results In the training dataset, in the SGA group, compared to those with birthweight ≥10th percentile, the median multiple of the median (MoM) values of PLGF and MCA-PI were reduced, whereas UtA-PI, UA-PI and sFLT were increased. Multivariable regression analysis demonstrated that in the prediction of SGA <10th there were significant contributions from maternal factors, EFW Z-score, UtA-PI MoM, MCA-PI MoM and PlGF MoM. In the validation dataset, prediction of 90% of SGA neonates delivering within two weeks of assessment was achieved by a screen positive rate of 67% in screening by maternal factors, 23% by maternal factors and EFW and 21% by the addition of biomarkers; the respective values for prediction of SGA neonates delivering at any stage after assessment were 66%, 32% and 30%. Conclusion: Addition of biomarkers of impaired placentation only marginally improves the predictive performance for delivery of SGA neonates achieved by maternal factors and fetal biometry at 35+0 - 36+6 weeks’ gestation

Prediction of small-for-gestational-age neonates at 35-37 weeks' gestation: contribution of maternal factors and growth velocity between 32 and 36 weeks

Objective: To assess the additive value of fetal growth velocity between 32 and 36 weeks’ gestation on the performance of ultrasonographic estimated fetal weight (EFW) at 35+0 - 36+6 weeks’ gestation for prediction of small for gestational age (SGA) neonates and adverse perinatal outcome. Methods: This was a prospective study of 14,497 singleton pregnancies that had undergone routine ultrasound examination at 28+0 - 34+6 and at 35+0 - 36+6 weeks’ gestation. Multivariable logistic regression analysis was used to determine whether addition of growth velocity, defined by a difference in EFW and abdominal circumference (AC) Z-scores between the early and late third trimester scans divided by the time interval between them, improved the performance of EFW at 35+0 - 36+6 weeks in the prediction of first, delivery of SGA neonates with birthweight <10th and <3rd percentiles within two weeks and at any stage after assessment and second, composite of adverse perinatal outcome defined as stillbirth, neonatal death or admission to the neonatal unit for ≥48 hours. Results Multivariable logistic regression analysis demonstrated that significant contributors to prediction of SGA neonates were EFW Z-score at 35+0 - 36+6 weeks’ gestation, fetal growth velocity by either AC or EFW Z-scores and maternal risk factors. The area under the receiver operating characteristic curves (AUROC) and detection rate (DR) with 95% confidence interval, at 10% screen positive rate, for prediction of SGA neonates <10th percentile born within two weeks of assessment achieved by EFW Z-score at 35+0 - 36+6 weeks (AUROC 0.938, 0.928 - 0.947; DR 80.7, 77.6 - 83.9) were not significantly improved by addition of EFW growth velocity and maternal risk factors (AUROC 0.941, 0.932 - 0.950; p=0.061; DR 82.5, 79.4 - 85.3). Similar results were obtained when growth velocity was defined by AC rather than EFW growth velocity. Similarly, there was no significant improvement in AUROC and DR, at 10% screen positive rate, for prediction of SGA neonates <10th percentile born at any stage after assessment or SGA neonates <3rd percentile born within two weeks or at any stage after assessment achieved by EFW Z-score at 35+0 - 36+6 weeks by addition of maternal factors and either EFW growth velocity of AC growth velocity. Multivariable logistic regression analysis demonstrated that the only significant contributor to adverse perinatal outcome was maternal risk factors. Multivariable logistic regression analysis in the group with EFW <10th percentile demonstrated that significant contribution to prediction of birth of neonates with birthweight <10th and <3rd percentiles and adverse perinatal outcome was provided by EFW Z-score at 35+0 - 36+6 weeks, but not by AC growth velocity <1st decile. Conclusion: The predictive performance of EFW at 35+0 - 36+6 weeks’ gestation for birth of SGA neonates and adverse perinatal outcome is not improved by addition of estimated growth velocity between 32 and 36 weeks’ gestation

Routine assessment of cerebroplacental ratio at 35-37 weeks' gestation in the prediction of adverse perinatal outcome

Background: Third trimester studies in selected high-risk pregnancies have reported that low cerebroplacental ratio (CPR), due to high pulsatility index (PI) in the umbilical artery (UA), and or decreased PI in the fetal middle cerebral artery (MCA), is associated with increased risk of adverse perinatal outcomes. Objective: To investigate the predictive performance of screening for adverse perinatal outcome by the cerebroplacental ratio (CPR) measured routinely at 35+6 - 36+6 weeks’ gestation. Methods: This was a prospective observational study in 47,211 women with singleton pregnancies undergoing routine ultrasound examination at 35+6 - 36+6 weeks’ gestation, including measurement of UA-PI and MCA-PI. The measured UA-PI and MCA-PI and their ratio were converted to multiples of the median (MoM) after adjustment for gestational age. Multivariable logistic regression analysis was used to determine whether CPR improved the prediction of adverse perinatal outcome that was provided by maternal characteristics, medical history and obstetric factors. The following outcome measures were considered: first, adverse perinatal outcome consisting of stillbirth, neonatal death or hypoxic ischemic encephalopathy grades 2 and 3, second, presence of surrogate markers of perinatal hypoxia consisting of umbilical arterial or venous cord blood pH ≤7 and ≤7.1, respectively, 5-minute Apgar score 24 hours, third, cesarean section for presumed fetal distress in labor, and fourth, neonatal birthweight <3rd percentile for gestational age. Results: Low CPR was associated with increased risk of adverse perinatal outcome, presence of surrogate markers of perinatal hypoxia, cesarean section for presumed fetal distress in labor and birth of neonates with birthweight <3rd percentile. However, multivariable regression analysis demonstrated that the prediction of these adverse outcomes by maternal demographic characteristics and medical history was only marginally improved by the addition of CPR. The performance of low CPR in the prediction of each adverse outcome was poor, with detection rates of 13–26% and false positive rate of about 10%. In appropriate for gestational age (AGA) neonates with birthweight ≥10th percentile the predictive accuracy of CPR was low with positive and negative likelihood ratios (LRs) ranging from 1.21 to 1.82, and 0.92 to 0.98, respectively; although the accuracy was better in small for gestational age (SGA) neonates this was also low with positive LRs of 1.31 to 2.26 and negative LRs of 0.69 to 0.92. Similar values were obtained in fetuses classified as SGA and AGA according to the estimated fetal weight. In the prediction of adverse outcomes within two weeks, rather than at any stage, after assessment the detection rate was higher but this was achieved at higher false positive rate and therefore similar positive and negative LRs. Conclusion: In pregnancies undergoing routine antenatal assessment at 35+0 - 36+6 weeks’ gestation measurement of CPR provides poor prediction of adverse perinatal outcome in both SGA and AGA fetuses. Consequently, there is no justification in a shift of the focus of prenatal care from identification of pregnancies with low estimated fetal weight to that of pregnancies with low CPR

Prediction of small-for-gestational-age neonates at 35-37 weeks' gestation: contribution of maternal factors and growth velocity between 20 and 36 weeks

Objective: To evaluate the performance of ultrasonographic estimated fetal weight (EFW) at 35+0 - 36+6 weeks’ gestation in the prediction of small for gestational age (SGA) neonates and assess the additive value of first, maternal risk factors and second, fetal growth velocity between 20 and 36 weeks’ gestation in improving such prediction. Methods: This was a prospective study of 44,043 singleton pregnancies that had undergone routine ultrasound examination at 19+0 - 23+6 and at 35+0 - 36+6 weeks’ gestation. Multivariable logistic regression analysis was used to determine whether addition of maternal risk factors and growth velocity, defined by a difference in EFW Z-scores or fetal abdominal circumference (AC) Z-scores between the third and second trimester scans divided by the time interval between them, improved the performance of EFW at 35+0 - 36+6 weeks in the prediction of delivery of SGA neonates with birthweight <10th and <3rd percentiles within two weeks and at any stage after assessment. Results: Screening by EFW at 35+0 - 36+6 weeks’ gestation <10th percentile predicted 63.4% (95% CI 62.0, 64.7) of neonates with birthweight <10th percentile and 74.2% (95% CI 72.2, 76.1) of neonates with birthweight <3rd percentile born at any stage after assessment, at screen positive rate of 10%. The respective values for SGA neonates born within two weeks of assessment were 76.8% (95% CI 74.4, 79.0) and 81.3% (95% CI 78.2, 84.0). In the group of fetuses with EFW <10th percentile, 43.7% were born with birthweight ≥10th percentile. For a desired 90% detection rate of SGA neonates delivering at any stage after assessment the necessary screen positive rate would be 33.7% for SGA <10th percentile and 24.4% for SGA <3rd percentile. Multivariable logistic regression analysis demonstrated that in the prediction of SGA neonates with birthweight <10th and <3rd percentiles there was a significant contribution from EFW Z-score at 35+0 - 36+6 weeks’ gestation, maternal risk factors and AC growth velocity, but not EFW growth velocity. However, the area under the receiver operating characteristic curves for SGA neonates in screening by maternal risk factors and EFW Z-score was not improved by addition of AC growth velocity. Conclusion: Screening for SGA neonates by EFW at 35+0 - 36+6 weeks’ gestation and use of a cut-off of the 10th percentile predicts 63% of affected neonates. Prediction of 90% of SGA neonates necessitates classification of about 35% of the population as being screen positive use of the 35th percentile cut-off in EFW. The predictive performance of EFW is not improved by addition of estimated growth velocity between the second and third trimesters of pregnancy

ALEX Fetal Medicine Foundation reference ranges for umbilical artery and middle cerebral artery pulsatility index and cerebroplacental ratio

Objective: To develop reference ranges with gestational age for the pulsatility index in the umbilical artery (UA-PI) and fetal middle cerebral artery (MCA-PI and the cerebroplacental ratio (MCA-PI / UA-PI) and examine the maternal characteristics and medical history that affect these measurements. Patients and methods: This was a cross-sectional study of 72,417 pregnancies undergoing routine ultrasound examination at 20+0 to 22+6 weeks’ gestation (n=3,712), or at 31+0 to 33+6 weeks (n=29,035) or at 35+0 to 36+6 weeks (n=37,282) or at 41+0 to 41+6 weeks (n=2,388). For the purpose of this study we included data for only one of the second or third trimester visits. The inclusion criteria were singleton pregnancy, dating by fetal crown-rump length at 11+0 to 13+6 weeks’ gestation, livebirth of morphologically normal neonate and ultrasonographic measurements by sonographers that had received the Fetal Medicine Foundation Certificate of competence in Doppler ultrasound. Since the objectives of the study were to establish reference ranges, rather than normal ranges, and to examine factors from maternal characteristics and medical history that affect these measurements, we included all pregnancies having routine ultrasound examinations irrespective of whether the mothers had a pre-existing medical condition, such as diabetes mellitus, or a pregnancy complication, such as preeclampsia or suspected fetal growth restriction. Median and standard deviation (SD) models were fitted between UA-PI, MCA-PI and CPR and gestational age. Assessment of goodness of fit of the models was by inspection of quantile to quantile (q-q) plots of z-scores calculated via the mean and SD models. The distributions of MCA PI, UA PI and CPR z-scores were examined in relation to maternal characteristics and medical history. Results: The relationship between the median and gestation age was linear for UA-PI and cubic for MCA-PI and CPR and the SD was log quadratic for all three. MCA-PI and CPR increased with gestational age from 20 weeks’ gestation to reach a peak at around 32 and 34 weeks’ respectively, and decreased thereafter, whereas UA-PI decreased linearly with gestation from 20 to 42 weeks. Compared to the general population, significant deviations in MoM values of UA-PI, MCA-PI and CPR were observed in subgroups of maternal age, BMI, racial origin, method of conception and parity. Conclusion: The study established new reference ranges of UA-PI, MCA-PI and CPR with gestational age and reports maternal characteristics and medical history that affect these measurements

Value of routine ultrasound examination at 35-37 weeks' gestation in diagnosis of fetal abnormalities

Objective: To investigate the potential value of routine ultrasound examination at 35-37 weeks’ gestation in the diagnosis of previously unknown fetal abnormalities. Methods: This was a prospective study in 52,401 singleton pregnancies attending for a routine ultrasound examination at 35+0 - 36+6 weeks’ gestation; all pregnancies had a previous scan at 18-24 weeks and 47,215 also had a scan at 11-13 weeks. We included pregnancies resulting in livebirth or stillbirth but excluded those with known chromosomal abnormalities. The abnormalities were classified according to affected major organ system and the type and incidence of new abnormalities was determined. Results: In the study population the incidence of fetal abnormalities was 2.2% (1,168 / 52,401), including 847 (72.5%) that had been previously diagnosed during the first and / or second trimester, 247 (21.2%) that were detected for the first time at 35-37 weeks and 74 (6.3%) that were detected for the first time postnatally. The most common abnormalities that were diagnosed during the first and / or second trimester, that were also observed at 35-37 weeks, included aberrant right subclavian artery, ventricular septal defect, talipes, unilateral renal agenesis and / or pelvic kidney, hydronephrosis, duplex kidney or unilateral multicystic kidney, cystic pulmonary airway malformation, ventriculomegaly, cleft lip and palate, polydactyly,abdominal cyst or gastroschisis. The most common abnormalities seen at 35-37 weeks were hydronephrosis, mild ventriculomegaly, ventricular septal defect, duplex kidney, ovarian cyst and arachnoid cyst. The incidence of abnormalities first seen at 35-37 weeks was 0.5% and the most common were ovarian cysts, microcephaly, achondroplasia, dacryocystocele and hematocolpos. The incidence of abnormalities first seen postnatally was 0.1% and the most common were isolated cleft palate, polydactyly or syndactyly and ambiguous genitalia or hypospadias; prenatal examination of the genitalia was not a compulsory part of the protocol. Conclusions: A high proportion of fetal abnormalities are detected for the first time during a routine ultrasound examination at 35-37 weeks’ gestation. Such diagnosis and subsequent management, including selection of time and place for delivery and postnatal investigations, could potentially improve postnatal outcome

Two-stage approach for prediction of small-for-gestational-age neonate and adverse perinatal outcome by routine ultrasound examination at 35-37 weeks' gestation

Background: Justification of prenatal screening for small for gestational age (SGA) fetuses near term is based on first, evidence that such fetuses / neonates are at increased risk of stillbirth and adverse perinatal outcome, and second, the expectation that these risks can be reduced by medical interventions, such as early delivery. However, there are no randomized studies demonstrating that routine screening for SGA fetuses and appropriate interventions in the high risk group can reduce adverse perinatal outcome. Before such meaningful studies can be undertaken it is essential that first, the best approach for effective identification of SGA neonates is determined, and second, the contribution of SGA neonates to the overall rate of adverse perinatal outcome is established. In a previous study of pregnancies that had undergone routine ultrasound examination at 35+0 36+6 weeks’ gestation, we found that first, screening by estimated fetal weight (EFW) 85% of SGA neonates requires use of EFW <40th percentile. Objectives: First, to examine the contribution of SGA fetuses to the overall rate of adverse perinatal outcome and second, to propose a two stage approach for prediction of SGA neonates at routine ultrasound examination at 35+0 36+6 weeks’ gestation. Methods: This was a prospective study of 45,847 singleton pregnancies that had undergone routine ultrasound examination at 35+0 36+6 weeks’ gestation. First we examined the relationship between birthweight percentile and adverse perinatal outcome, defined as stillbirth, neonatal death or admission to the neonatal unit for ≥48 hours. Second, we used a two stage approach for prediction of SGA neonates and adverse perinatal outcome; in the first stage fetal biometry was used to distinguish pregnancies at very low risk (EFW ≥40th percentile) and those at increased risk (EFW 4 weeks after assessment was determined. We propose that the high risk group would require monitoring from initial assessment to delivery, the intermediate risk group would require monitoring from two weeks after initial assessment to delivery, the low risk group would require monitoring from four weeks after initial assessment to delivery, and the very low risk group would not require any further reassessment. Results: First, although in babies with low birthweight (4 (40% and 30%) from assessment. Third, improved performance of screening, especially for those delivering after two weeks from assessment, is potentially achieved by a proposed new approach for stratifying pregnancies into management groups based on findings of EFW and Doppler indices (prediction of birthweight 4 weeks from assessment: 89% and 75%, 83% and 74% and 88% and 82%, respectively). Fourth, the predictive performance for adverse perinatal outcome of EFW 4 weeks from assessment, respectively) and this is improved by the proposed new approach (31%, 22% and 29%). Conclusion: The study presents an approach for stratifying the pregnancies undergoing routine ultrasound examination at 35+0 36+6 weeks’ gestation into four management groups based on findings of EFW and Doppler indices. This approach can potentially have a higher predictive performance for SGA neonates and adverse perinatal outcome than screening by EFW <10th percentile

Impaired placental perfusion and major fetal cardiac defects

Objectives: To investigate the relationship between fetal congenital heart defects (CHD) and placental perfusion assessed by uterine artery pulsatility index (UtA-PI) in relation to development of preeclampsia (PE). Methods: This was a prospective screening study in singleton pregnancies at 19-24 weeks’ gestation. Transvaginal ultrasound was used to measure the UtA-PI and the values were converted into multiples of the normal median (MoM). Median MoM values in pregnancies with fetuses with isolated major CHD were compared to those without CHD in relation to development of PE. Results: The 91,407 singleton pregnancies fulfilling the entry criteria included 206 (0.23%) with isolated major fetal CHD and 91,201 without CHD. The prevalence of PE was 4.4% in those with CHD and 2.7% in those without CHD (RR 1.6, 95% CI 0.84-3.04; p=0.150); the respective values for preterm-PE, with delivery at <37 weeks’ gestation, were 2.4% and 0.7%, (RR 3.4, 95% CI 1.42-8.09; p=0.006). In the total population, the median UtA-PI MoM was significantly higher in those that developed PE compared to those without PE (1.22, IQR 0.94-1.57 vs. 1.00, IQR 0.84-1.19; p<0.0001) and in the PE group the median UtA-PI MoM was inversely related to gestational age at delivery (r=-0.458; p<0.0001). The same pattern of inverse relationship between UtA-PI MoM and gestational age at delivery with PE was observed in pregnancies with and without CHD, but in the CHD group, compared to those without CHD, UtA-PI was significantly higher both in pregnancies with and in those without PE. Conclusions: In both pregnancies with and without fetal CHD that develop PE impedance to flow in the uterine arteries is increased and this increase is particularly marked in those with preterm-PE. The prevalence of preterm-PE is more than 3 times higher in pregnancies with than without fetal major CHD and the prevalence of major CHD in pregnancies with preterm-PE is also more than 3 times higher than in those without PE. However, >97% of pregnancies with fetal CHD do not develop preterm-PE and >99% of pregnancies with preterm-PE are not associated with fetal CHD

Fetal Medicine Foundation fetal and neonatal population weight charts

Objective: To develop fetal and neonatal population weight charts. The rationale for this objective is that while reference ranges of estimated fetal weight (EFW) are representative of the whole population, the traditional approach of deriving birth-weight (BW) charts is misleading because a high proportion of babies born preterm arises from pathological pregnancies. We propose that the reference population for BW charts, as in the case of EFW charts, should be all babies at a given gestational age including those still in utero. Patients: Two sources of data were used for this study and in both the inclusion criteria were singleton pregnancy, dating by fetal crown-rump length at 11+0 to 13+6 weeks’ gestation, ultrasonographic measurements of fetal head circumference (HC), abdominal circumference (AC) and femur length (FL), and livebirth of phenotypically normal neonate. Dataset 1, comprised a sample of 5,163 paired measurements of EFW and BW; the ultrasound scans were carried out at 22-43 weeks’ gestation and birth occurred within 2 days of the ultrasound examination. The EFW was derived from the measurements of HC, AC and FL using the formula reported by Hadlock et al. in 1985. Dataset 2, comprised a sample of 95,579 pregnancies with EFW obtained by routine ultrasonographic fetal biometry at 20+0 to 23+6 weeks’ gestation (n=45,034), or at 31+0 to 33+6 weeks (n=19,224) or at 35+0 to 36+6 weeks (n=31,321); for the purpose of this study we included data for only one of the three visits. Methods: In the development of reference ranges of EFW and BW with gestational age the following assumptions were made: first, the EFW and BW have a common median, dependent on gestational age and second, deviations from the median occur in both EFW and BW and these deviations are correlated with different levels of spread for EFW and BW, dependent on gestational age. We adopted a Bayesian approach to inference combining information from the two datasets using Markov Chain Monte–Carlo sampling (MCMC). The fitted model assumed that the mean log transformed measurements of EFW and BW are related to gestational age according to a cubic equation and that deviations about the mean follow a bivariate Gaussian distribution. Results: In the case of EFW in dataset 2 there was a good distribution of values 90th, >95th and >97th percentiles of the reference range of EFW with gestational age throughout the gestational age range of 20+0- 36+6 weeks. In the case of BW there was a good distribution of values only for the cases born at >39 weeks’ gestation. For preterm births, particularly at 27-36 weeks, the BW was below the 3rd, 5th and 10th percentiles in a very high proportion of cases and this was particularly marked for cases of iatrogenic birth. The incidence of SGA fetuses and neonates in the respective EFW and BW charts was higher in women of Black than White racial origin. Conclusion: We established a BW chart for the population of all babies at a given gestational age, including those still in utero, which overcomes the problem of underestimation of growth restriction in preterm births. The BW and EFW charts have a common median but they differ in the levels of spread from the median

Prediction of stillbirth from maternal factors, fetal biometry and uterine artery Doppler at 19-24 weeks

Objectives: To evaluate the performance of screening for all stillbirths and those due to impaired placentation and unexplained or other causes by a combination of maternal factors, fetal biometry and uterine artery pulsatility index (UT-PI) at 19-24 weeks’ gestation and compare this performance to that of screening by UT-PI alone. Methods: This was a prospective screening study of 70,003 singleton pregnancies including 69,735 live births and 268 (0.38%) antepartum stillbirths; 159 (59%) were secondary to impaired placentation and 109 (41%) were due to other or unexplained causes. Multivariate logistic regression analysis was used to develop a model for prediction of stillbirth based on a combination of maternal factors, fetal biometry and UT-PI. Results: Combined screening predicted 55% of all stillbirths, including 75% of those due to impaired placentation and 23% of those that were due to other causes or unexplained, at false positive rate of 10%; within the impaired placentation group the detection rate of stillbirth at 37 weeks (88% vs 46%; p<0.001). The performance of screening by the combined test was superior to that of selecting the high-risk group on the basis of UT-PI being above the 90th percentile for gestational age, which predicted 48% of all stillbirths, 70% of those due to impaired placentation and 15% of those that were due to other causes or unexplained. Conclusions: Second-trimester screening by a combination of UT-PI with maternal factors and fetal biometry can predict a high proportion of stillbirths and in particular those due to impaired placentation