Cerebroplacental Ratio Prediction of Intrapartum Fetal Compromise according to the Interval to Delivery.

INTRODUCTION: A controversy exists about the accuracy of the cerebroplacental ratio (CPR) for the prediction of cesarean section for intrapartum fetal compromise (CS-IFC). Our aim was to evaluate whether the interval to delivery modifies the accuracy of CPR either as a single marker or combined with estimated fetal weight centile (EFWc), type of labor onset (TLO), and other clinical variables. METHODS: This was a multicenter retrospective study of 5,193 women with singleton pregnancies who underwent an ultrasound scan at 35+0-41+0 weeks and gave birth within 1 month of examination, at any of the participating hospitals in Spain, UK, and Italy. CS-IFC was diagnosed in case of an abnormal intrapartum fetal heart rate or intrapartum fetal scalp pH <7.20, requiring urgent cesarean section. The diagnostic ability of CPR in multiples of the median (CPR MoM) was evaluated at different intervals to delivery, alone and combined with EFWc, TLO, and other pregnancy data such as maternal age, maternal body mass index, parity, and fetal sex, for the prediction of CS-IFC by means of ROC curves and logistic regression analysis. RESULTS: The predictive ability of CPR MoM for CS-IFC worsened with the interval to delivery. In general, the best prediction was obtained prior to labor and by adding information related to EFWc and TLO (AUC 0.71 [95% CI: 0.64-0.79], 0.73 [95% CI: 0.66-0.80], and 0.75 [95% CI: 0.69-0.81]; p < 0.0001). Addition of more clinical data did not improve prediction. In addition, results did not vary when only cases with spontaneous onset of labor were studied. CONCLUSION: CPR MoM prediction of CS-IFC at the end of pregnancy worsens with the interval to delivery. Accordingly, it should be done in the short term and considering EFWc and TLO.

Predictors of adverse perinatal outcome up to 34 weeks, a multivariable analysis study.

The objective was to evaluate the best predictors of adverse perinatal outcome (APO) in foetuses examined up to 34 weeks and delivered by spontaneous or induced labour. This was a retrospective study of 129 pregnancies that underwent an ultrasound Doppler examination at 23-34 weeks and entered into labour within 30 days. Cerebroplacental ratio (CPR) and mean uterine artery pulsatility index (mUtA PI) were converted into multiples of the median (MoM) and estimated foetal weight (EFW) into centiles to adjust for gestational age (GA). Sonographic and clinical parameters were evaluated using logistic regression analysis.The multivariable model for the prediction of APO presented a notable accuracy: Detection rate (DR) was 39.5% for a false positive rate (FPR) of 5% and 56.8% for a FPR of 10%, AUC 0.82, p < .0001. Significant predictors were GA, EFW centile, and CPR MoM, but not mUtA PI MoM. Moreover, the type of labour onset did not exert any influence on APO. In conclusion, up to 34 weeks, prediction of APO after spontaneous or induced labour may be done measuring CPR and EFW.IMPACT STATEMENTWhat is already known on this subject? Earlier in pregnancy, foetal growth restriction is caused by placental disease causing progressive hemodynamic changes. These changes have been exhaustively described. Conversely, information about the best predictors of adverse outcome is scarce.What do the results of this study add? The findings of this study show that prior to 34 weeks and up to 1 month before labour, labour outcome might be predicted by gestational age, foetal cerebroplacental ratio (CPR) and estimated foetal weight (EFW).What are the implications of these findings for clinical practice and/or further research? If CPR behaves as a good marker of outcome not only at the end of pregnancy but also earlier in gestation, it might be interrogated along with EFW in foetuses attempting vaginal delivery to determine the risk of adverse outcome.

Maternal profile according to Mediterranean diet adherence and small for gestational age and preterm newborn outcomes.

OBJECTIVE: The objective was to evaluate maternal Mediterranean diet (MD) pattern adherence during pregnancy and its association with small for gestational age (SGA) and preterm birth. A secondary objective of the current study was to describe the sociodemographic, lifestyle and obstetric profile of the mothers studied as well as the most relevant paternal and newborn characteristics. DESIGN: The current study is a two-phase retrospective population-based study of maternal dietary habits during pregnancy and their effect on newborn size and prematurity. The descriptive first phase examined maternal dietary habits during pregnancy along with the maternal sociodemographic, lifestyle and obstetric profile in a cross-sectional period study. In the second phase, newborn outcomes were evaluated in a nested case-control study. Adherence to MD during pregnancy was measured with the Spanish version of Kidmed index. SETTING: Obstetrics ward of the La Fe Hospital in Valencia. PARTICIPANTS: All mother-child pairs admitted after delivery during a 12-month period starting from January 2018 were assessed for eligibility. A total of 1118 provided complete outcome data after signing informed consent. RESULTS: 14·5 % met the criteria of poor adherence (PA); 34·8 %, medium adherence (MA); and 50·7 %, optimal adherence (OA). Medium adherence to MD was associated in the adjusted scenarios with a higher risk of giving birth to a preterm newborn. No association was found between MD adherence and SGA. CONCLUSIONS: Early intervention programmes geared towards pregnant women, where women were aided in reaching OA to MD, might reduce the risk of preterm newborn.

The Diagnostic Ability of the Cerebroplacental Ratio for the Prediction of Adverse Perinatal Outcome and Intrapartum Fetal Compromise within One Day of Delivery.

OBJECTIVES: The objectives of this study were to evaluate the diagnostic abilities of the cerebroplacental ratio (CPR) for the prediction of adverse perinatal outcome (APO) and cesarean section for intrapartum fetal compromise (CS-IFC) within 1 day of delivery. DESIGN: Retrospective observational case-control study. METHODS: This was a study of 254 high-risk fetuses attending the day hospital unit of a tertiary referral hospital that underwent an ultrasound examination at 32-41 weeks and gave birth within 1 day of examination. APO was defined as a composite of abnormal intrapartum fetal heart rate or intrapartum fetal scalp pH <7.20 requiring urgent cesarean section, neonatal umbilical cord pH <7.10, 5-min Apgar score <7, and postpartum admission to neonatal or pediatric intensive care units. CS-IFC was defined in case of abnormal intrapartum fetal heart rate or intrapartum fetal scalp pH <7.20 requiring urgent cesarean section. The diagnostic ability of CPR for the prediction of APO and CS-IFC was calculated alone and in combination with estimated fetal weight and gestational clinical parameters, including the type of labor onset, using ROC curves and logistic regression analysis. RESULTS: CPR in multiples of the median (MoM) was a moderate predictor of APO (area under the curve [AUC] = 0.77, p < 0.0001) and CS-IFC (AUC = 0.82, p < 0.0001). The predictive abilities of the multivariable model for APO (AUC = 0.81, p < 0.0001) and CS-IFC (AUC = 0.82, p < 0.0001) did not differ from those of CPR alone . LIMITATIONS: The small number of cases and the scarcity of information concerning labor induction. CONCLUSION: In high-risk pregnancies, CPR MoM is a moderate predictor of APO and CS-IFC when performed within 24 h of delivery.

Optimization of Imminent Labor Prediction Systems in Women with Threatened Preterm Labor Based on Electrohysterography.

Preterm birth is the leading cause of death in newborns and the survivors are prone to health complications. Threatened preterm labor (TPL) is the most common cause of hospitalization in the second half of pregnancy. The current methods used in clinical practice to diagnose preterm labor, the Bishop score or cervical length, have high negative predictive values but not positive ones. In this work we analyzed the performance of computationally efficient classification algorithms, based on electrohysterographic recordings (EHG), such as random forest (RF), extreme learning machine (ELM) and K-nearest neighbors (KNN) for imminent labor (<7 days) prediction in women with TPL, using the 50th or 10th-90th percentiles of temporal, spectral and nonlinear EHG parameters with and without obstetric data inputs. Two criteria were assessed for the classifier design: F1-score and sensitivity. RFF1_2 and ELMF1_2 provided the highest F1-score values in the validation dataset, (88.17 ± 8.34% and 90.2 ± 4.43%) with the 50th percentile of EHG and obstetric inputs. ELMF1_2 outperformed RFF1_2 in sensitivity, being similar to those of ELMSens (sensitivity optimization). The 10th-90th percentiles did not provide a significant improvement over the 50th percentile. KNN performance was highly sensitive to the input dataset, with a high generalization capability.

Gestational Age-Specific Reference Ranges for the sFlt-1/PlGF Immunoassay Ratio in Twin Pregnancies.

OBJECTIVE: Establish reference ranges for the Elecsys® soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) immunoassay ratio in twin pregnancies. METHODS: Data analyzed were from 3 prospective studies: Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia (PE) (PROGNOSIS), Study of Early-onset PE in Spain (STEPS), and a multicenter case-control study. Median, 5th, and 95th percentiles for sFlt-1, PlGF, and the sFlt-1/PlGF ratios were determined for normal twin pregnancies for 7 gestational windows and compared with the previous data for singleton pregnancies. RESULTS: The reference range analysis included 269 women with normal twin pregnancies. Before 29 weeks' gestation, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios did not differ between twin and singleton pregnancies. From 29 weeks' gestation to delivery, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios were substantially higher in twin versus singleton pregnancies. sFlt-1 values were higher in women with twin pregnancies across all gestational windows. PlGF values were similar or higher in twin versus singleton pregnancies; PlGF concentrations increased from 10 weeks + 0 days to 28 weeks + 6 days' gestation. CONCLUSIONS: Reference ranges for the sFlt-1/PlGF ratio are similar in women with twin and singleton pregnancies until 29 weeks' gestation but appear higher in twin pregnancies thereafter.

Overexpression of microRNAs miR-25-3p, miR-185-5p and miR-132-3p in Late Onset Fetal Growth Restriction, Validation of Results and Study of the Biochemical Pathways Involved.

In a prospective study, 48 fetuses were evaluated with Doppler ultrasound after 34 weeks and classified, according to the cerebroplacental ratio (CPR) and estimated fetal weight (EFW), into fetuses with normal growth and fetuses with late-onset fetal growth restriction (LO-FGR). Overexpression of miRNAs from neonatal cord blood belonging to LO-FGR fetuses, was validated by real-time PCR. In addition, functional characterization of overexpressed miRNAs was performed by analyzing overrepresented pathways, gene ontologies, and prioritization of synergistically working miRNAs. Three miRNAs: miR-25-3p, miR-185-5p and miR-132-3p, were significantly overexpressed in cord blood of LO-FGR fetuses. Pathway and gene ontology analysis revealed over-representation of certain molecular pathways associated with cardiac development and neuron death. In addition, prioritization of synergistically working miRNAs highlighted the importance of miR-185-5p and miR-25-3p in cholesterol efflux and starvation responses associated with LO-FGR phenotypes. Evaluation of miR-25-3p; miR-132-3p and miR-185-5p might serve as molecular biomarkers for the diagnosis and management of LO-FGR; improving the understanding of its influence on adult disease.

Does Uterine Doppler Add Information to the Cerebroplacental Ratio for the Prediction of Adverse Perinatal Outcome at the End of Pregnancy?

OBJECTIVE: To evaluate whether the addition of the mean uterine arteries pulsatility index (mUtA PI) to the cerebroplacental ratio (CPR) improves its ability to predict adverse perinatal outcome (APO) at the end of pregnancy. METHODS: This was a prospective study of 891 fetuses that underwent an ultrasound examination at 34-41 weeks. The CPR and the mUtA PI were converted into multiples of the median (MoM) and the estimated fetal weight (EFW) into centiles according to local references. APO was defined as a composite of abnormal cardiotocogram, intrapartum pH requiring cesarean section, 5' Apgar score <7, neonatal pH <7.10 and admission to pediatric care units. The accuracies of the different parameters were evaluated alone and in combination with gestational characteristics using univariate and multivariate analyses by means of the Akaike Information Criteria (AIC) and the area under the curve (AUC). Finally, a comparison was similarly performed between the CPR and the cerebro-placental-uterine ratio (CPUR; CPR/mUtA PI) for the prediction of APO. RESULTS: The univariate analysis showed that CPR MoM was the best parameter predicting APO (AIC 615.71, AUC 0.675). The multivariate analysis including clinical data showed that the best prediction was also achieved with the CPR MoM (AIC 599.39, AUC 0.718). Moreover, when EFW centiles were considered, the addition of UtA PI MoM did not improve the prediction already obtained with CPR MoM (AIC 591.36, AUC 0.729 vs. AIC 589.86, AUC 0.731). Finally, the prediction by means of CPUR did not improve that of CPR alone (AIC 623.38, AUC 0.674 vs. AIC 623.27, AUC 0.66). CONCLUSION: The best prediction of APO at the end of pregnancy is obtained with CPR whatever is the combination of parameters. The addition of uterine Doppler to the information yielded by CPR does not result in any prediction improvement.

MicroRNA-148b-3p and MicroRNA-25-3p Are Overexpressed in Fetuses with Late-Onset Fetal Growth Restriction.

OBJECTIVE: It was the aim of this study to describe a micro-RNA (miRNA) profile characteristic of late-onset fetal growth restriction (FGR) and to investigate the pathways involved in their biochemical action. METHODS: In this prospective study, 25 fetuses (16 normal and 9 with FGR [estimated fetal weight <10th centile plus cerebroplacental ratio <0.6765 multiples of the median]) were evaluated with Doppler ultrasound after 36 weeks. Afterwards, for every fetus, plasma from umbilical vein blood was collected at birth, miRNA was extracted, and full miRNA sequencing was performed. Subsequently, comparisons were done in order to obtain those miRNAs that were differentially expressed. RESULTS: The FGR fetuses expressed upregulation of two miRNAs: miR-25-3p and, especially, miR-148b-3p, a miRNA directly involved in Schwann cell migration, neuronal plasticity, and energy metabolism (p = 0.0072, p = 0.0013). CONCLUSIONS: FGR fetuses express a different miRNA profile, which includes overexpression of miR-25-3p and miR-148b-3p. This information might improve our understanding of the pathophysiological processes involved in late-onset FGR. Future validation and feasibility studies will be required to propose miRNAs as a valid tool in the diagnosis and management of FGR.

Robust Characterization of the Uterine Myoelectrical Activity in Different Obstetric Scenarios.

Electrohysterography (EHG) has been shown to provide relevant information on uterine activity and could be used for predicting preterm labor and identifying other maternal fetal risks. The extraction of high-quality robust features is a key factor in achieving satisfactory prediction systems from EHG. Temporal, spectral, and non-linear EHG parameters have been computed to characterize EHG signals, sometimes obtaining controversial results, especially for non-linear parameters. The goal of this work was to assess the performance of EHG parameters in identifying those robust enough for uterine electrophysiological characterization. EHG signals were picked up in different obstetric scenarios: antepartum, including women who delivered on term, labor, and post-partum. The results revealed that the 10th and 90th percentiles, for parameters with falling and rising trends as labor approaches, respectively, differentiate between these obstetric scenarios better than median analysis window values. Root-mean-square amplitude, spectral decile 3, and spectral moment ratio showed consistent tendencies for the different obstetric scenarios as well as non-linear parameters: Lempel-Ziv, sample entropy, spectral entropy, and SD1/SD2 when computed in the fast wave high bandwidth. These findings would make it possible to extract high quality and robust EHG features to improve computer-aided assessment tools for pregnancy, labor, and postpartum progress and identify maternal fetal risks.

Maternal telomere length is shorter in intrauterine growth restriction versus uncomplicated pregnancies, but not in the offspring or in IVF-conceived newborns.

RESEARCH QUESTION: The study aimed to determine whether IVF or intrauterine growth restriction (IUGR) result in short neonatal telomeres, which could explain the higher risk of cardiovascular and metabolic disease described in these populations. DESIGN: This was an observational, analytical, cross-sectional, prospective study with controls in a tertiary hospital. The main outcome was to determine the leukocyte telomere length in 126 newborns and their mothers (n = 109). Newborns were conceived spontaneously or by IVF, and uncomplicated and IUGR pregnancies were studied. Telomere lengths were measured using high-throughput telomere quantitative fluorescent in-situ hybridization. RESULTS: There was no difference in average telomere length between newborns conceived by IVF or those with IUGR and spontaneously conceived healthy newborns (P = 0.466 and P = 0.732, respectively); this remained after controlling for confounders (P = 0.218 and P = 0.991, respectively). Mothers of newborns with IUGR had a shorter average telomere length than women with uncomplicated pregnancies (P = 0.023), which was confirmed after controlling for age, body mass index and smoking habit (P = 0.034). CONCLUSIONS: The results support the safety of IVF and IUGR in terms of the postnatal health of the newborns. The shorter telomeres of IUGR mothers may represent a higher cardiovascular risk, which would have clinical implications under the stress of pregnancy in otherwise healthy adults.

Comparison of Cerebroplacental Ratio, Intergrowth-21st Standards, Customized Growth, and Local Population References for the Prediction of Fetal Compromise: Which Is the Best Approach?

OBJECTIVE: The aim of this work was to compare the accuracy of the cerebroplacental ratio (CPR), Intergrowth 21st standards (IG21), customized growth (CG), and local population references (LPR) in the prediction of intrapartum fetal compromise (IFC). METHODS: This was a prospective study of 714 fetuses that underwent an ultrasound examination at 34-41 weeks and were delivered within a 2-week interval. The CPR was converted into multiples of the median and the estimated fetal weight (EFW) transformed into CG, IG21, and LPR centiles. IFC was defined as a composite of abnormal cardiotocogram, intrapartum pH requiring cesarean section, 5-min Apgar score, and admission to pediatric care units. The accuracies of the CPR and the EFW centiles for the prediction of IFC were evaluated alone and in combination with other gestational characteristics using univariate and multivariate analysis. RESULTS: Individually, the CPR was the parameter that best predicted the existence of IFC (AUC = 0.66). The multivariate analysis showed that the best prediction was again achieved with the CPR, alone or in combination with any of the EFW centiles (AUC = 0.74). No significant differences were seen between the different centile methods. CONCLUSION: The best prediction of IFC is obtained with CPR. Evaluation of CPR should be encouraged in term and late-preterm fetuses.

Protein S100ß in Late-Pregnancy Fetuses with Low Birth Weight and Abnormal Cerebroplacental Ratio.

OBJECTIVE: To evaluate the umbilical cord venous S100ß levels in late-pregnancy fetuses with abnormal growth and cerebral redistribution. METHODS: The pulsatility index of the umbilical and middle cerebral arteries and the cerebroplacental ratio (CPR) were measured in 132 fetuses at ≥34 weeks, and the CPR was converted into multiples of the median (MoM). A blood sample from the umbilical vein was collected at birth, and the umbilical venous S100ß levels were evaluated in small and non-small for gestational age (SGA) fetuses, with and without abnormal Doppler indices. The levels of S100ß were correlated with birth weight (BW) centile, CPR MoM and cord venous pH. RESULTS: While CPR MoM correlated with BW centile, S100ß showed no correlation with any of the studied fetal parameters. In addition, no differences were observed in S100ß level according to BW centile or Doppler parameters, neither was there any difference between SGA with low CPR MoM and non-SGA with normal CPR MoM. CONCLUSION: Late-pregnancy fetuses with abnormal growth or cerebral redistribution have normal cord blood levels of S100ß at birth. In these fetuses, the potential consequences of chronic hypoxemia on the fetal brain might not be detectable using tissue necrosis markers.

Abnormal Middle Cerebral Artery Doppler Associates with Spontaneous Preterm Birth in Normally Grown Fetuses.

OBJECTIVE: Our aim was to evaluate whether Doppler changes in the fetal middle cerebral (MCA) and umbilical arteries (UA) suggesting fetal hypoxemia precede the onset of spontaneous preterm birth (PTB). METHODS: We studied 2,340 appropriate-for-gestational-age singleton pregnancies that had MCA and UA pulsatility indices (PI) recorded at 28-32 weeks. Values including the cerebroplacental ratio (CPR) were converted into multiples of the median and evaluated according to both gestational age at the onset of labor and the interval between ultrasound and labor. ROC analysis was used to calculate the ability in the prediction of spontaneous PTB before 32, 34 and 37 weeks' gestation. RESULTS: While no correlations were observed for the UA PI and CPR, lower MCA PI values were associated with an earlier onset of labor (p < 0.001) and a shorter ultrasound-labor interval (p = 0.028). The ROC analysis at different gestational ages and intervals to labor indicated that MCA PI values were poorly predictive of spontaneous PTB (all areas under the curve <0.7). CONCLUSIONS: Low MCA PI values at 28-32 weeks are associated with subsequent spontaneous PTB, indicating that fetal hypoxemia unrelated with placental disease might be implicated in the onset of labor. This association, however, is unlikely to be useful in the prediction of PTB.

Neonatal Acid-Base Status in Fetuses with Abnormal Vertebro- and Cerebro-Placental Ratios.

OBJECTIVE: A low cerebro-placental ratio (CPR) at term suggests the existence of failure to reach growth potential (FRGP) with a higher risk of poor neonatal acid-base status. This study aimed to evaluate whether similar findings were also seen in the vertebral artery (vertebro-placental ratio, VPR), supplying 30% of the cerebral flow. METHODS: We studied term fetuses classified into groups according to birth weight (BW), CPR and VPR. BW was expressed in centiles and ratios in multiples of the median (MoM). Subsequently, associations with neonatal pH values were evaluated by means of regression curves and Mann-Whitney tests. RESULTS: VPR MoM correlated with BW centiles (p < 0.0001, R2 = 0.042) and its distribution resembled that of CPR MoM (p < 0.001). When both arteries were compared, adequate-for-gestational-age (AGA) fetuses with either low CPR or low VPR had lower neonatal venous pH values (p < 0.05, p < 0.01, respectively). However, in case of small-for-gestational-age (SGA) fetuses, only those with low VPR had significantly lower neonatal arterial and venous pH values (p < 0.05). CONCLUSIONS: Blood flow in the vertebral artery mimics that in the middle cerebral artery supporting the FRGP model. Both CPR and VPR identify AGA fetuses with lower neonatal pH values, but only VPR identifies SGA with lower pH values. Hypoxemia might be reflected as a generalized cerebral vasodilation demonstrated as low CPR and VPR.

Neonatal Acid-Base Status in Term Fetuses: Mathematical Models Investigating Cerebroplacental Ratio and Birth Weight.

OBJECTIVE: Cerebroplacental ratio (CPR) is emerging as a marker of fetal hypoxia at term. The aim of this study was to demonstrate graphically the interrelationships among CPR, birthweight (BW), and neonatal pH, and construct 2D and 3D representations of the areas with potential low pH. METHODS: This was a retrospective study of 2,927 term fetuses evaluated according to BW and CPR. The outcome was the acid-base status at birth. Multivariate relationships among CPR, BW, and arterial and venous pH were depicted in 3D scattergrams. Subsequently, trend surfaces were calculated and represented in 2D contour graphs. Finally, 3D representations were constructed by smothering pH data using moving average filters. RESULTS: The trend surfaces and the 2D and 3D contour graphs showed the complex association among the three variables. Although pH changed with CPR and BW, the influence of the BW was smaller than the influence of the CPR, with this effect being more evident in the venous than in the arterial pH. CONCLUSIONS: Two scenarios threaten fetal well-being at term: a very low birth weight and a very low fetal CPR. Our findings suggest that the importance of fetal hemodynamics in determining the acid-base status at birth surpasses that of fetal weight.