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

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

Objective: To investigate the performance of screening for adverse perinatal outcome by the cerebroplacental ratio (CPR) measured within 24 hours of induction of labor. Methods: This was a prospective observational study in 1,902 singleton pregnancies undergoing induction of labor at ≥ 37 weeks’ gestation. Doppler ultrasound was used to measure the pulsatility index (PI) in the umbilical artery (UA) and fetal middle cerebral artery (MCA) before induction of labor. The measured UA PI and MCA PI and their ratio were converted to multiples of the median (MoM) after adjustment for gestational age. Univariate and multivariate 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 detection rate (DR) and false-positive rate (FPR) of screening by CPR were estimated for cesarean section for presumed fetal distress and neonatal adverse outcome, which included umbilical arterial or venous cord blood pH ≤7 and ≤7.1, respectively, 5-minute Apgar score 24 hours, or hypoxic ischemic encephalopathy. Results: A combination of maternal and pregnancy characteristics, including age, weight, racial origin, previous obstetric history, preeclampsia, gestational age at delivery and amniotic fluid volume, identified 39% of pregnancies requiring cesarean section for fetal distress at FPR of 10%; addition of CPR did not improve the performance of screening. In screening for adverse neonatal outcome by a combination of parity and CPR the DR was 17% at FPR of 10%. Conclusion: Low CPR, measured within 24 hours of induction of labor, is associated with increased risk of cesarean section for fetal distress and adverse neonatal outcome, but the performance of CPR for such surrogates of adverse perinatal outcome is poor

Routine first-trimester screening for fetal trisomies in twin pregnancy: cell-free DNA test contingent on results from combined test

Objective: To report on the routine clinical implementation of cell-free (cf)DNA analysis of maternal blood for trisomies 21, 18 and 13 contingent on the results of the first-trimester combined test in twin pregnancies. Methods: Screening for trisomies 21, 18 and 13 was carried out by a combination of maternal age, fetal nuchal translucency (NT) thickness, and serum free ß-hCG and PAPP-A at 11-13 weeks’ gestation in 959 twin pregnancies in two UK NHS hospitals. Women in the high-risk group (risk >1 in 100) were offered options of invasive testing, cfDNA testing or no further testing and those in the intermediate-risk group (risk 1 in 101 to 1 in 2500 in the first phase of the study and 1 in 101 to 1 in 500 in the second phase) were offered cfDNA or no further testing. The trisomic status of the pregnancies was determined by prenatal or postnatal karyotyping or examination of the neonates. Results: In 42 (4.4%) of the 959 pregnancies there was termination, miscarriage or stillbirth with no known karyotype or there was loss to follow up. The 917 pregnancies with known trisomic status of both twins, included 6 that were discordant for trisomy 21, 4 discordant for trisomy 18 and 896 with no trisomies 21, 18 or 13. Following combined screening, 47 (5.1%), 203 (22.2%) and 667 (72.7%) of the pregnancies were classified as high-risk, intermediate-risk and low-risk, respectively. The high-risk group included 5 (83.3%) cases of trisomy 21 and 3 (75.0%) of trisomy 18. The cfDNA test was carried out in 224 pregnancies and results were provided in 214 (95.5%); this group included 6 with trisomy 21, 3 with trisomy 18 and 206 with no trisomies 21, 18 or 13. The cfDNA test correctly classified as screen positive all 6 cases of trisomy 21 and 2 of the 3 with trisomy 18 and as screen negative for each of the trisomies all 206 unaffected pregnancies. Contingent screening, led to prenatal detection of all cases of trisomy 21 and 3 of 4 with trisomy 18. Conclusions: The study has demonstrated the feasibility of introducing cfDNA testing, contingent on the results of the first-trimester combined test for major trisomies, in a routine population of twin pregnancies

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

Association of chronic hypertension with birth of small-for-gestational-age neonate

Objective: To examine the effect of chronic hypertension (CH), with and without superimposed preeclampsia (PE), on the incidence of small for gestational age (SGA) neonates, and explore possible mechanisms for such association. Methods: The data for the study were derived from prospective screening for adverse pregnancy outcomes in women with singleton pregnancies attending for their first routine hospital visit at 11-13 weeks’ gestation, which included recording of maternal characteristics and medical history and measurement of mean arterial pressure (MAP). Birth weight z-score, adjusted for gestational age and for maternal and pregnancy characteristics, and incidence of SGA were compared between those with and without CH in the total population and in the subgroups with and without PE. Regression analysis was used to examine the relationship between MAP and birth weight z-score and incidence of SGA and PE in those with and without CH. Results: The study population constituted 74,226 pregnancies, including 1,052 (1.4%) with CH and 73,174 without CH. Preeclampsia developed in 233 (22.1%) cases of the group with CH and in 1,662 (2.3%) of those without CH. In the group that developed PE, there was no significant difference between those with CH and those without CH in either the median birth weight z-score or the incidence of SGA. In the group without PE, the incidence of SGA was twice as high in those with than in those without CH. There was a significant association between log10 MAP multiple of the median and incidence of SGA and PE which was more marked in those with CH than in those without CH. Conclusion: CH is associated with increased risk of SGA and PE and this is related to MAP at 11-13 weeks’ gestation

Comparison of screening for pre-eclampsia at 31-34 weeks' gestation by sFlt-1/PlGF ratio and a method combining maternal factors with sFlt-1 and PlGF

Objective: To estimate the patient-specific risk of preeclampsia (PE) at 31-34 weeks’ gestation by a combination of maternal characteristics and medical history with multiple of the median (MoM) values of serum placental growth factor (PLGF) and serum soluble fms-like tyrosine kinase-1 (sFLT-1) and compare the performance of screening to that achieved by the sFLT-1 to PLGF ratio. Methods: This was a prospective observational study in women attending for a third-trimester ultrasound scan at 31-34 weeks as part of routine pregnancy care. We estimated the performance of screening of PE with delivery within four weeks of assessment (PE at <4 weeks) and PE from four weeks after assessment and up to 40 weeks’ gestation (PE at 4w-40GW) in screening by the sFLT-1 to PLGF ratio and by a to PLGF ratio and by a method utilizing Bayes theorem to combine maternal factors and MoM values of sFLT-1 and PLGF. The significance of difference in performance of screening between the method utilising Bayes theorem and that of the sFLT-1 to PLGF ratio was assessed by comparison of the areas under the receiver operating characteristic curves (AUROC). Results: The study population of 8,063 singleton pregnancies included 231 (2.9%) that subsequently developed PE. In the prediction of delivery with PE at <4 weeks the performance of the method utilising Bayes theorem was similar to that of the sFLT-1 to PLGF (AUROC: 0.987, 95%CI 0.979-0.995 vs. 0.988, 95%CI: 0.981-0.994; p=0.961). and at fixed fixed screen positive rate (SPR) of 3.9% the detection rate (DR) was 87.1% for both methods. In contrast, the performance of screening for delivery with PE at 4w-40GW was better with the method utilising Bayes theorem than with the sFLT-1 to PLGF ratio (AUROC: 0.884, 95%CI 0.854-0.914 vs. 0.818, 95%CI: 0.775--0.860 ; p<0.0001) and at total fixed SPR of 25.7% the DRs were 84.4% vs. 73.0%. Conclusion: At 31-34 weeks’ gestation the performance of screening for PE at <4 weeks from assessment by the method utilising Bayes theorem is similar to that of the sFLT-1 to PLGF ratio, but the former is superior to the latter in prediction of PE >>4 weeks

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

IONA test for first-trimester detection of trisomies 21, 18 and 13

OBJECTIVE: To assess the potential performance of screening for fetal trisomies 21, 18 and 13 by cell-free DNA (cfDNA) analysis of maternal blood using the IONA\uae test. METHODS: This was a nested case-control study of cfDNA analysis of maternal plasma using the IONA test. Samples were obtained at 11-13 weeks' gestation, before chorionic villus sampling, from 201 euploid pregnancies, 35 with trisomy 21, four with trisomy 18 and two with trisomy 13. Laboratory personnel were blinded to the fetal karyotype. RESULTS: Probability scores for trisomies 21, 18 and 13 were given for 241/242 samples analyzed. No probability score was provided for one (0.5%) euploid pregnancy because of low fetal fraction. In all 35 cases of trisomy 21 the probability score for trisomy 21 was > 95% and the scores for trisomies 18 and 13 were 64 0.0001%. In all four cases of trisomy 18, the probability score for trisomy 18 was > 77% and the scores for trisomies 21 and 13 were 64 0.0001%. In the two cases of trisomy 13, the probability score for trisomy 13 was > 59% and the scores for trisomies 21 and 18 were 64 0.0001%. In the 200 euploid pregnancies with a test result, the probability score was < 0.08% for trisomy 21, < 0.001% for trisomy 18 and < 0.002% for trisomy 13. Therefore, the IONA test detected 100% of all three trisomies, with a false-positive rate of 0%. CONCLUSION: The IONA test successfully differentiated all cases of trisomies 21, 18 and 13 from euploid pregnancies