Association between Plasma HLA-DR+ Placental Vesicles and Preeclampsia: A Pilot Longitudinal Cohort Study.

(1) Background: Preeclampsia (PE) usually presents with hypertension and proteinuria, related to poor placentation. Reduced maternal-fetal immunological tolerance is a possible trigger of inadequate placentation. Aberrant antigen expression of HLA-DR has been observed in the syncytiotrophoblast of PE patients. In this study, we analyzed plasma levels of Human Leukocyte Antigen (HLA)-DR+ syncytiotrophoblast-derived extracellular vesicles (STEVs) during the three trimesters of pregnancy in relation to PE onset. (2) Methods: Pregnant women underwent venous blood sampling during the three trimesters. STEVs were collected from plasma via ultracentrifugation (120,000 g) and characterized by Western blot, nanotracking analysis and flow cytometry for the expression of Placental Alkaline Phosphatase (PLAP), a placental-derived marker, and HLA-DR. (3) Results: Out of 107 women recruited, 10 developed PE. STEVs were detected in all three trimesters of pregnancy with a zenith in the second trimester. A significant difference was found between the non-PE and PE groups in terms of plasma levels of HLA-DR+ STEVs during all three trimesters of pregnancy. (4) Conclusions: More research is needed to investigate HLA-DR+ as a potential early marker of PE.

Does emigration by itself improve birth weight? Study in European newborns of Indo-Pakistan origin.

Objective: Our aim was to evaluate the effect of emigration on fetal birth weight (BW) in a group of pregnant women coming from the Indian subcontinent. Methods: This was a retrospective study in a mixed population of pregnant women from the Indian subcontinent that either moved to Europe or stayed in their original countries. The influence of emigration along with several pregnancy characteristics: GA at delivery, fetal gender, maternal age, height, weight, body mass index (BMI) and parity on BW was evaluated by means of multivariable linear regression analysis. Results: According to European standards, babies born to Indo-Pakistan emigrants and babies born to women staying in the Indian subcontinent were similarly small (BW centile 30± 29 and 30.1 ± 28, p<0.68). Multivariable regression demonstrated that emigration by itself did not exert a direct influence on BW (p  = 0.27), being BMI and gestational age at delivery the true determinants of BW (p<0.0001). Conclusions: Maternal BMI is the most relevant parameter affecting fetal growth regardless of the place of residence.

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.

Healthy mothers with normal cardiotocograms at term. Is maternal age a true determinant of perinatal outcome?

OBJECTIVE: to study the true determinants of adverse perinatal outcome (APO) in term healthy mothers with normal cardiotocograph (CTG), evaluating the real influence of maternal age. MATERIAL AND METHODS: In a retrospective study, we assessed a group of 529 term healthy mothers with normal CTGs that regardless of maternal age, evolved spontaneously up to 41 ± 2 weeks. The result of the conservative management was evaluated by means of univariable and multivariable logistic regression analysis, determining the association of maternal age and other clinical and ultrasonographical parameters with APO. RESULT: In contrast with low CPR MoM (OR = 0.155, p = .014), induction of labor (OR = 2.273, p = .023) and low parity (OR = 0.494, p = .026), maternal age and birth weight centile did not prove to be true determinants of perinatal outcome. The multivariable model for prediction of APO using clinical parameters presented a sensitivity of 35% and 27% for a false positive rate of 10% and 5%, AUC 0.736 (95% CI 0.655-0.818), p < .0001). CONCLUSIONS: in healthy old mothers with normal CTGs at term, APO is determined by low CPR, the existence of labor induction and low parity, while no real influence was observed for maternal age, fetal smallness, and interval examination-delivery. These results do not support the current consensus on induction at earlier weeks to prevent adverse outcomes in all cases of advanced maternal age, advocating for a more individualized, customized, and less interventional management based on fetal hemodynamics.

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.

Congenital knee dislocation, case report and review of the literature.

Congenital dislocation of the knee (CDK) is characterized by hyperextension of the knee with forward displacement of the proximal tibia. It is associated with other joint dislocations and deformities and may occur isolated or as part of different systemic syndromes. Despite its characteristic postnatal morphology, prenatal descriptions are very scarce. We report a case of CDK diagnosed at 20 weeks, discuss its physiopathology, diagnosis and management and review the current literature.

Sirenomelia, case report and review of the literature.

We present a case of sirenomelia diagnosed in the first trimester of pregnancy. The ultrasound examination showed fused lower extremities and an anechoic structure in the lower abdomen that is clue in the early diagnosis. The postmortem study showed the existence of a single umbilical artery (vitelline artery), with an origin in the abdominal aorta. This finding not only explained the presence of a vascular steal with subsequent underdeveloped of pelvic organs, but also differentiated this condition from caudal regression syndrome.

Birth-weight differences at term are explained by placental dysfunction and not by maternal ethnicity. Study in newborns of first generation immigrants.

OBJECTIVE: The aim of the study was to investigate the influence of ethnicity and cerebroplacental ratio (CPR) on the birth weight (BW) of first generation Indo-Pakistan immigrants' newborns. METHODS: This was a retrospective study in a mixed population of 620 term Caucasian and Indo-Pakistan pregnancies, evaluated in two reference hospitals of Spain and Italy. All fetuses underwent a scan and Doppler examination within two weeks of delivery. The influence of fetal gender, ethnicity, GA at delivery, CPR, maternal age, height, weight and parity on BW was evaluated by multivariable regression analysis. RESULTS: Newborns of first generation Indo-Pakistan immigrants were smaller than local Caucasian newborns (mean BW mean= 3048 ± 435 g versus 3269 ± 437 g, p < .001). Multivariable regression analysis demonstrated that all studied parameters, but maternal age and ethnicity, were significantly associated with BW. The most important were GA at delivery (partial R2 = 0.175, p < .001), CPR (partial R2 = 0.032, p < .001), and fetal gender (partial R2 = 0,029, p < .001). CONCLUSIONS: The propensity to a lower BW, explained by placental dysfunction but not by maternal ethnicity is transmitted to newborns of first generation immigrants. Whatever are the factors implied they persist in the new residential setting.

Reference values for pulsatility index of fetal anterior and posterior cerebral arteries in prolonged pregnancy.

OBJECTIVE: To establish consistent normal reference values for fetal anterior cerebral artery (ACA) and posterior cerebral artery (PCA) pulsatility index (PI) in prolonged pregnancy. METHODS: This prospective cross-sectional observational study included singleton normal prolonged pregnancies into two study groups according to the gestational age: from 40 + 0 to 40 + 6 and from 41 + 0 to 41 + 6 weeks. The PI was assessed in both anatomical segments of ACA (ACA-S1 and ACA-S2) and of PCA (PCA-S1 and PCA-S2) with color Doppler imaging and pulsed Doppler examination, and reference centiles charts were generated. PI values from the two investigated segments of each vessel were also compared. RESULTS: Data were obtained in 771 patients: n = 448 in the 40 + 0 and 40 + 6 weeks group, and n = 323 in the 41 + 0 and 41 + 6 weeks group. A moderate decrease in PI was observed as pregnancy progressed. No differences in PI values were found between the two anatomical segments of ACA and PCA. CONCLUSION: This study provides Doppler reference values for the fetal ACA and PCA PI. It also shows that Doppler examination could be performed indifferently in one of the two anatomical segments of these arteries.

Fetal brain hemodynamics in pregnancies at term: correlation with gestational age, birthweight and clinical outcome.

INTRODUCTION: The primary aim of this study was to ascertain the strength of association between cerebral blood flow assessed in anterior (ACA), middle (MCA), and posterior (PCA) cerebral arteries and the following clinical outcomes: small for gestational age (SGA), induction of labor (IOL) for oligohydramnios and caesarean section (CS) for nonreassuring fetal status (NRFS) during labor. MATERIAL AND METHODS: Retrospective analysis of prospectively collected data on consecutive singleton pregnancies from 40 0/7 to 41 6/7 week of gestation. UA, ACA, MCA, PCA pulsatility index (PI) were measured from 40 weeks of gestations. Furthermore, the ratios between cerebral blood flow and UA (CPR, ACA/UA and PCA/UA) were calculated and correlated with the observed outcomes. RESULTS: Two hundred twenty-four singleton pregnancies were included in the study. Mean PI of either ACA (p = .04), MCA (p = .008), and PCA (p = .003) were lower in the SGA compared to non-SGA group; furthermore, mean PCA PI was significantly lower than MCA PI (p = .04). Furthermore, CPR (p = .016), ACA/UA (p = .02), and PCA/UA (p = .003) were significantly lower in the SGA group compared to controls. UA, ACA, MCA, and PCA PI were higher in women undergoing IOL for oligohydramnios compared to controls. Logistic regression analysis showed that CPR and PCA/UA ratio were independently associated with SGA. SGA, ACA PI, and ACA/UA were independently associated with CS for NRFS. Finally, birthweight centile, were independently associated with IOL oligohydramnios. Despite this, the predictive accuracy of Doppler in detecting any of the explored outcome was only poor to moderate. CONCLUSION: Redistribution of cerebral blood flow at term is significantly associated with SGA, IOL for oligohydramnios and CS for NRFS in labor. However, the predictive accuracy of Doppler at term is only poor to moderate, thus advising against its use in clinical practice as a standalone screening test for adverse perinatal outcome in pregnancies at term. Key Message Redistribution of cerebral blood flow at term is significantly associated with SGA, IOL for oligohydramnios and CS for NRFS in labor.

Mathematical simulation of Doppler changes in late-onset smallness; progression patterns of cerebral and umbilical anomalies define two types of late-onset fetal growth restriction.

OBJECTIVE: To evaluate the progression of Doppler abnormalities in fetuses with late-onset fetal smallness (SGA) that become growth restricted (FGR). METHODS: 524 Doppler examinations of the umbilical and cerebral arteries systems, belonging to 442 late-onset SGA fetuses after week 34, were studied, evaluating by means of the statistical difference with the respective abnormal centiles, the pattern of progression into abnormal Doppler values and the distribution and cumulative sum of Doppler anomalies according to the interval to delivery. RESULTS: Only one third (33.5%, N = 148) of late-onset SGA fetuses presented Doppler anomalies, suggesting that most were of constitutional origin. The most frequent progression pattern into abnormal Doppler (N = 127, 85.81%) was that in which only one system (umbilical or cerebral) became abnormal. Half of fetuses debuted with abnormal umbilical flow (52%, N = 77) and half with cerebral anomalies (47.97%, N = 71), which were more likely to appear later and at shorter intervals to delivery (p = .007). These progression patters defined two varieties of late-onset FGR (type I and II) with similar outcome but different birth weight centiles (BW centile = 2.51, SD 2.91 versus 3.97, SD 3.17, p < .01). CONCLUSION: Two thirds of late-onset fetal smallness occurs without hemodynamic changes. In half of the remaining cases an initial cerebral vasodilation defines a group of fetuses with similar outcome but higher BW centile.

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.

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.

Fetal Doppler velocimetry and bronchopulmonary dysplasia risk among growth-restricted preterm infants: an observational study.

OBJECTIVE: To investigate whether fetal growth restriction (FGR) diagnosis, based on pathological prenatal fetal Doppler velocimetry, is associated with bronchopulmonary dysplasia (BPD) independently of being small for gestational age (SGA) per se at birth among very preterm infants. DESIGN: Prospective, observational study. FGR was defined as failing fetal growth in utero and fetal Doppler velocimetry abnormalities. SETTING: Policlinico Universitario Agostino Gemelli, Roma, Italy. PATIENTS: Preterm newborns with gestational age ≤30 weeks and birth weight (BW) ≤1250 g. MAIN OUTCOME MEASURES: Bronchopulmonary dysplasia. RESULTS: In the study period, 178 newborns were eligible for the study. Thirty-nine infants (22%) were considered fetal growth-restricted infants. Among the 154 survived babies at 36 weeks postmenstrual age, 12 out of 36 (33%) of the FGR group developed BPD versus 8 out of 118 (7%) of the NO-FGR group (p<0.001). BPD rate was sixfold higher among the SGA-FGR infants compared with the SGA-NO-FGR infants. In a multivariable model, FGR was significantly associated with BPD risk (OR 5.1, CI 1.4 to 18.8, p=0.01), independently from BW z-score that still remains a strong risk factor (OR 0.5, CI 0.3 to 0.9, p=0.01). CONCLUSION: Among SGA preterm infants, BPD risk dramatically increases when placenta dysfunction is the surrounding cause of low BW. Antenatal fetal Doppler surveillance could be a useful tool for studying placenta wellness and predicting BPD risk among preterm babies. Further research is needed to better understand how FGR affects lung development.

A comparison between amniotic fluid index and the single deepest vertical pocket technique in predicting adverse outcome in prolonged pregnancy.

OBJECTIVE: to compare perinatal outcome in induced postterm pregnancies with normal amniotic volume and in patients with prolonged pregnancy undergone induction for oligohydramnios, evaluated by two different ultrasonographic methods. METHODS: amniotic fluid volume was measured, using Single Deepest Vertical Pocket (SDVP) and Amniotic Fluid Index (AFI), in 961 singleton uncomplicated prolonged pregnancies. In 109 of these patients, hospitalization was planned for induction of labor, during or after 42 weeks of gestation, for oligohydramnios, postterm pregnancy and other indications in 47, 51 and 11 cases, respectively. Perinatal outcome included: rate of caesarean section, fetal distress, non reassuring fetal heart tracing, presence of meconium, umbilical artery pH < 7.1, Apgar score at 5 minutes < 7, admission to neonatal intensive care unit (NICU). RESULTS: oligohydramnios was diagnosed in 4.89% of cases, when at least one of the two methods was used. A reduced AFI and SDVP value identified 4.47% and 3.75% of cases, respectively, even if without statistical difference. No statistical differences were reported in perinatal outcomes in postterm versus prolonged pregnancies with oligohydramnios, also in relation to the two different ultrasonographic methods. CONCLUSIONS: oligohydramnios is more frequently diagnosed using AFI than SDVP, consequently determining a higher rate of induction of labor. Moreover, perinatal outcome in prolonged induced pregnancies is not affected by oligohydramnios.

Succenturiate lobe of placenta with vessel anomaly: a case report of prenatal diagnosis and literature review.

We report the case of a 33-year-old woman with antenatal ultrasound diagnosis of succenturiate placental lobe at 33 weeks confirmed by B-flow rendering, describing the advantages of the application of color Doppler to diagnosis and management of placental anomalies. We searched studies about antenatal diagnosis of succenturiate placental lobe, including only cases in which color Doppler was used. This case underlines the importance of color Doppler in increasing the accuracy of diagnosis and achieving an improved differential diagnosis.