Fetal aortic isthmus Doppler assessment to predict the adverse perinatal outcomes associated with fetal growth restriction: systematic review and meta-analysis.

PURPOSE: Fetal growth restriction (FGR) management and delivery planning is based on a multimodal approach. This meta-analysis aimed to evaluate the prognostic accuracies of the aortic isthmus Doppler to predict adverse perinatal outcomes in singleton pregnancies with FGR. METHODS: PubMed, EMBASE, the Cochrane Library, ClinicalTrials.gov and Google scholar were searched from inception to May 2021, for studies on the prognostic accuracy of anterograde aortic isthmus flow compared with retrograde aortic isthmus flow in singleton pregnancy with FGR. The meta-analysis was registered on PROSPERO and was assessed according to PRISMA and Newcastle-Ottawa Scale. DerSimonian and Laird's random-effect model was used for relative risks, Freeman-Tukey Double Arcsine for pooled estimates and exact method to stabilize variances and CIs. Heterogeneity was quantified using I2 statistics. RESULTS: A total of 2933 articles were identified through the electronic search, of which 6 studies (involving 240 women) were included. The quality evaluation of studies revealed an overall acceptable score for study group selection and comparability and substantial heterogeneity. The risk of perinatal death was significantly greater in fetuses with retrograde Aortic Isthmus blood flow, with a RR of 5.17 (p value 0.00001). Similarly, the stillbirth rate was found to have a RR of 5.39 (p value 0.00001). Respiratory distress syndrome had a RR of 2.64 (p value = 0.03) in the group of fetuses with retrograde Aortic Isthmus blood flow. CONCLUSION: Aortic Isthmus Doppler study may add information for FGR management. However, additional clinical trial are required to assess its applicability in clinical practice.

Recurrent Cesarean scar pregnancy: case series and literature review.

OBJECTIVES: To determine the rate of recurrent Cesarean scar pregnancy (CSP) in our clinical practices and to evaluate whether the mode of treatment of a CSP is associated with the risk of recurrent CSP, as well as to review the published literature on recurrent CSP. METHODS: We performed a retrospective search of our six obstetric and gynecological departmental ultrasound databases for all CSPs and recurrent CSPs between 2010 and 2019. We extracted various data, including number of CSPs with follow-up, number of cases attempting and number achieving pregnancy following treatment of CSP and number of recurrent CSPs, as well as details of the treatment of the original CSP. After analyzing the clinical data, we evaluated whether the mode of treatment terminating the previous CSP was associated with the risk of recurrent CSP. We also performed a PubMed search for: 'recurrent Cesarean scar pregnancy' and 'recurrent Cesarean scar ectopic pregnancy'. Articles were reviewed for year of publication, and extraction and analysis of the same data as those obtained from our departmental databases were performed. RESULTS: Our database search identified 252 cases of CSP. The overall rate of clinical follow-up ranged between 71.4% and 100%, according to treatment site (mean, 90.9%). Among these, 105 women had another pregnancy after treatment of the previous CSP. Of these, 36 (34.3%) pregnancies were recurrent CSP, with 27 women having a single recurrence and three women having multiple recurrences, one with two, one with three and one with four. We did not find any particular single or combination treatment mode terminating the previous CSP to be associated with recurrent CSP. The literature search identified 17 articles that yielded sufficient information for us to evaluate their reported prevalence of recurrent CSP. These reported 1743 primary diagnoses of CSP, of which 944 had reliable follow-up. Data were available for 489 cases that attempted to conceive again after treatment of a previous CSP, and on the 327 pregnancies achieved. Of these, 67 (20.5%) were recurrent CSP. CONCLUSIONS: On the basis of our pooled clinical data and review of the literature, recurrent CSP is apparently more common than was previously assumed based upon mostly single-case reports or series with few cases. This should be borne in mind when counseling patients undergoing treatment for CSP regarding their risk of recurrence. We found no obvious causal relationship or association between the type of treatment of the previous CSP and recurrence of CSP. Patients who become pregnant after treatment of a CSP should be encouraged to have an early (5-7-week) first-trimester transvaginal scan to determine the location of the gestation. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Diagnostic accuracy of magnetic resonance imaging in assessing placental adhesion disorder in patients with placenta previa: Correlation with histological findings.

OBJECTIVE: To evaluate MRI accuracy in assessing placental adhesion disorders (PAD) in patients with placenta previa correlating imaging results with histological findings. MATERIALS AND METHODS: Sixty-one patients who underwent abdomino-pelvic magnetic resonance imaging (MRI) for ultrasound suspicion of PAD were prospectively evaluated. T1- and T2-weighted images, with and without fat suppression, were obtained in the three conventional planes using a 1.5 T MRI scanner. MRI accuracy to evaluate the presence of PAD was assessed on the basis of the occurrence of the following abnormal MRI signs: 1) intraplacental dark bands; 2) focal interruption of myometrial border; 3) intraplacental abnormal vascularity; 4) uterine bulging; 5) tenting of the bladder and/or 6) direct visualization of adjacent tissues invasion only in case of percretism. Imaging results were classified as suggestive or not of PAD using histological data as standard of reference; two methods of imaging analysis were used represented by the presence of at least one (Method A) or two (Method B) abnormal MRI signs; the correlation between the presence of each abnormal MRI sign of PAD and the corresponding histological finding was also assessed. RESULTS: The accuracy, as the area under the receiver operating characteristic curve, was significantly (p = 0.001) higher for Method B (0.92, C.I. 95%: 0.82-0.97) compared to Method A (0.764, C.I. 95%: 0.64-0.86). Among the abnormal MRI signs, intraplacental dark bands and focal interruption of myometrial border were those highly correlated with histological proof of PAD (ρ > 0.71, p < 0.001, for both); as result, a modified version of Method B (Method C) was identified considering as criterion for PAD the combined presence of the two abnormal MRI signs highly correlated with histologically proven PAD; however, the accuracy of Method C was significantly (p = 0.005) lower (0.80, C.I. 95%: 0.67-0.89) than Method B and comparable to Method A. CONCLUSIONS: MRI is a useful imaging technique to assess PAD in patients with placenta previa; in particular, the presence of at least two among all the abnormal MRI signs represents the most accurate criterion (Method B) to identify PAD. Although intraplacental dark bands and focal interruption of myometrial border showed the highest correlation with histological proof of PAD as well as this association was the most frequent in PAD, the combination of these latter MRI signs along with other abnormal signs should be considered diagnostic for PAD.

First-trimester ultrasound determination of chorionicity in twin gestations using the lambda sign: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the accuracy of first-trimester sonographic determination of chorionicity in twin gestations using the lambda sign. STUDY DESIGN: Electronic databases (MEDLINE, PROSPERO, Scopus, ClinicalTrials.gov, EMBASE, Sciencedirect) were searched from their inception until April 2016. We included only study assessing the accuracy lambda sign in prediction of monochorionicity in the first trimester. Forest plots for pooled sensitivity and specificity with 95% confidence intervals (CI) were generated. In addition, symmetric summary receiver-operating characteristic curves were plotted. The area under the curve (AUC) was also computed to evaluate the overall accuracy of the diagnostic test. RESULTS: Nine studies, including 2292 twins, were analysed. In all of these studies, identification of the lambda sign was used to diagnose chorionicity on real-time B-mode imaging. Twins were classified as monochorionic if there was a single placental mass in the absence of the lambda sign, and dichorionic if there was a single placental mass but the lambda sign was present or the placentas were not adjacent to each other. In all nine studies, placental histology or discordant fetal sex were used to confirm chorionicity. Pooled results from the meta-analysis showed that sensitivity of the presence of the lambda sign in the prediction of dichorionicity was 99% (95% CI 98-100%), and specificity was 95% (95% CI 92-97%). Pooled sensitivity of the absence of the lambda sign in the prediction of monochorionicity was 96% (95% CI 92-98%) and pooled specificity was 99% (95% CI 98-99%). The AUC for diagnostic accuracy was 0.99, and suggested very high diagnostic accuracy. CONCLUSION: The lambda sign predicts chorionicity with a high degree of accuracy before 14 weeks of gestation. Presence of the lambda sign indicates dichorionicity, and absence of the lambda sign indicates monochorionicity. All hospitals should encourage departments providing ultrasound services to determine chorionicity when examining women with twin pregnancies in the first trimester. As determination of chorionicity is most accurate before 14 weeks when the amnion and chorion have not yet fused, the first-trimester scan in twin pregnancy is paramount.

The lack of the Celf2a splicing factor converts a Duchenne genotype into a Becker phenotype.

Substitutions, deletions and duplications in the dystrophin gene lead to either the severe Duchenne muscular dystrophy (DMD) or mild Becker muscular dystrophy depending on whether out-of-frame or in-frame transcripts are produced. We identified a DMD case (GSΔ44) where the correlation between genotype and phenotype is not respected, even if carrying a typical Duchenne mutation (exon 44 deletion) a Becker-like phenotype was observed. Here we report that in this patient, partial restoration of an in-frame transcript occurs by natural skipping of exon 45 and that this is due to the lack of Celf2a, a splicing factor that interacts with exon 45 in the dystrophin pre-mRNA. Several experiments are presented that demonstrate the central role of Celf2a in controlling exon 45 splicing; our data point to this factor as a potential target for the improvement of those DMD therapeutic treatments, which requires exon 45 skipping.

Value of third-trimester cerebroplacental ratio and uterine artery Doppler indices as predictors of stillbirth and perinatal loss.

OBJECTIVE: Placental insufficiency contributes to the risk of stillbirth. Cerebroplacental ratio (CPR) is an emerging marker of placental insufficiency. The aim of this study was to evaluate the association of third-trimester fetal CPR, uterine artery (UtA) Doppler and estimated fetal weight (EFW) with stillbirth and perinatal death. METHODS: This was a retrospective cohort study including 2812 women with a singleton pregnancy who underwent an ultrasound scan in the third trimester. EFWs were converted into centiles, and Doppler indices (UtA and CPR) were converted into multiples of the median (MoM), adjusting for gestational age. Regression analysis was performed to identify, and adjust for, potential confounders, and receiver-operating characteristics (ROC) curve analysis was used to assess the predictive value. RESULTS: When adjusting for EFW centile and UtA mean pulsatility index (UtA-PI) MoM, CPR-MoM remained an independent predictor of stillbirth (odds ratio (OR) = 0.003 (95% CI, 0.00-0.11), P = 0.003) and perinatal mortality (OR = 0.001 (95% CI, 0.00-0.03), P < 0.001). UtA-PI ≥ 1.5 MoM was significantly associated with low CPR-MoM, even after adjusting for EFW centile (OR = 5.22 (95% CI, 3.88-7.04), P < 0.001) or small-for-gestational age (SGA; OR = 4.73 (95% CI, 3.49-6.41), P < 0.001). These associations remained significant, even when excluding pregnancies with SGA or including only cases in which Doppler indices were recorded at term (P < 0.01). For prediction of stillbirth, the area under the ROC curve, using a combination of these three parameters, was 0.88 (95% CI, 0.77-0.99) with a sensitivity of 66.7%, specificity of 92.1%, positive likelihood ratio (LR) of 8.46 and negative LR of 0.36. CONCLUSIONS: Third-trimester CPR is an independent predictor of stillbirth and perinatal mortality. The role of UtA Doppler, CPR and EFW in assessing risk of adverse pregnancy outcome should be evaluated prospectively.

Predictive accuracy of second-trimester uterine artery Doppler indices for stillbirth: a systematic review and meta-analysis.

OBJECTIVE: To assess the predictive accuracy for stillbirth of second-trimester uterine artery Doppler. METHODS: We searched MEDLINE, EMBASE and The Cochrane Library databases from inception until March 2015 without language restrictions. The included studies were those that assessed the association of abnormal uterine artery Doppler parameters and stillbirth. Two independent reviewers selected the studies, extracted data and assessed quality. Results for studies that were performed in the second trimester were pooled and summary estimates of sensitivity, specificity, likelihood ratios and their 95% confidence intervals were obtained. An overall summary of test accuracy was provided by the diagnostic odds ratio. Subgroup analysis was performed according to whether the study population was high risk or unselected. RESULTS: Literature searches returned 338 relevant citations with 32 considered in full. Thirteen studies met our search criteria (85 845 women, 508 stillbirths) and were included in the review. Bivariate pooled estimate for sensitivity was 65% (95% CI, 38-85%) and for specificity 82% (95% CI, 72-88%). The positive likelihood ratio was 3.5 (95% CI, 2.3-5.5) and negative likelihood ratio 0.43 (95% CI, 0.22-0.85). The diagnostic odds ratio was 8.3 (95% CI, 3.0-22.4). Heterogeneity was high in the studies of high-risk women. CONCLUSIONS: Abnormal uterine artery Doppler indices are associated with a three- to four-fold increase in the risk of stillbirth. The heterogeneity was particularly high in the high-risk group rendering it impossible to draw firm conclusions. In view of this, there is a role for individual patient data meta-analysis to define which Doppler parameter and threshold value should be measured.

Dichorionic triplet pregnancies: risk of miscarriage and severe preterm delivery with fetal reduction versus expectant management. Outcomes of a cohort study and systematic review.

BACKGROUND: In trichorionic pregnancies, fetal reduction from three to two lowers the risk of severe preterm delivery, but provides no advantage in survival. Similar data for dichorionic triamniotic (DCTA) triplets is not readily available. OBJECTIVES: To document the natural history of DCTA triplets and the effect of reduction on the risk of miscarriage and severe preterm delivery, compared with expectant management. SEARCH STRATEGY: Systematic search on MEDLINE, EMBASE, and the Cochrane Library. SELECTION CRITERIA: DCTA triplets with three live fetuses at 8-14 weeks of gestation, outcome data with expectant management and/or reduction, miscarriage before 24 weeks of gestation and/or severe preterm delivery before 32-33 weeks of gestation. DATA COLLECTION AND ANALYSIS: Five studies were included. Data from these were combined with data from three centres. MAIN RESULTS: There were 331 DCTA triplets. The miscarriage rate was 8.9% (95% CI 5.8-13.3%) and the severe preterm delivery rate was 33.3% (95% CI 27.5-39.7%), with expectant management. The miscarriage rate was 14.5% (95% CI 7.6-26.2%) with a reduction of the monochorionic pair, 8.8% (95% CI 3.0-23.0%) with a reduction of one fetus of the monochorionic pair, and 23.5% (9.6-47.3%) with a reduction of the fetus with a separate placenta. Severe preterm delivery rates were 5.5% (95% CI 1.9-14-9%), 11.8% (95% CI 4.7-26.6%), and 17.6% (95% CI 6.2-41.0%), respectively. CONCLUSIONS: In DCTA triplets, expectant management is a reasonable choice when the top priority is a liveborn infant. Where the priority is to minimise severe preterm delivery, the most advisable option is fetal reduction. Further studies are needed to clarify which particular technique is advisable to optimise the outcome.

Poor neonatal acid-base status in term fetuses with low cerebroplacental ratio.

OBJECTIVE: To determine whether small- and appropriate-for-gestational-age (SGA and AGA) term fetuses with a low cerebroplacental ratio (CPR) have worse neonatal acid-base status than those with normal CPR. METHODS: This was a retrospective study of 2927 term fetuses divided into groups according to birth-weight centile and CPR multiple of the median. The acid-base status at birth as determined by arterial and venous umbilical cord blood pH was compared between weight-centile groups with and without low CPR. RESULTS: CPR was better correlated with umbilical cord blood pH (arterial pH, r(2) = 0.008, P < 0.0001 and venous pH, r(2) = 0.01, P < 0.0001) than was birth weight (arterial pH, r(2) = 0.001, P =0.180 and venous pH, r(2) = 0.005, P < 0.001). AGA fetuses with low CPR were more academic than were those with normal CPR (P = 0.0359 and 0.0006, respectively, for arterial and venous pH). CONCLUSIONS: The findings of this study demonstrate that low CPR in AGA fetuses is an equally important marker of low neonatal pH secondary to placental underperfusion as is being SGA. Although the relative importance of low CPR and birth weight in identifying pregnancies at risk of placental hypoxemia and adverse fetal and neonatal outcome remains to be determined, this finding may be of particular value in the prediction and prevention of stillbirth and long-term neurodevelopmental disability.

The Rapid Alert System: implementation in NA 2 North LHA over the five-year period from 2008 to 2012.

INTRODUCTION: The Rapid Alert System was established by the European Union (EC Regulation 178/2002 Art.50, paragraph 1) for food intended for human consumption and for animal feed, with the aim of ensuring the protection of public, animal and environmental health. The purpose of the Rapid Alert System for Food and Feed (RASFF) is to provide the control authorities with the means of exchanging information on the measures taken to ensure food safety. This system allows for a rapid intervention following the discovery of food or feed already placed on the market and which represent, directly or indirectly, a serious risk for human, animal or environmental health. METHODS: Our work intends to examine all alert and information notified to the Hygiene Department of Food and Nutrition of what was formerly NA3 LHU in the last 5 years (2008-2012), and is now Naples 2 North LHU, bearing in mind that, according to regional law 16/2008 (10), the Local Health Units in Campania have been redefined. The types of risk regarding the food subject of the alerts received are: chemical, physical and biological. Food frauds (adulteration, counterfeiting, sophistication and alteration) and the poor state of preservation were considered separately. RESULTS: Out of 146 cases of non-conformity reported, 87 involved chemical risk, 28 biological risk and 17 included foreign bodies; there were also 7 food frauds and 1 case of poor state of preservation. As for the origin, the food subject of non-conformity were for the most part (61,64%) of national origin, while 34.24% came from abroad. Of these, about 66% were of non-EU origin. CONCLUSIONS: The experience gained during the period from 2008 to 2012 allows us to state that the information flow has been improved allowing local services that have been assigned the control to act more rapidly. A critical issue sometimes remains concerning the completeness of the given data, above all regarding the type of risk that, when well reported, provides a valuable contribution to the success of a comprehensive and responsible risk management programme. The encouraging fact that emerges from this study, however, is that, despite the premises made about the characteristics of the area examined, the number of alerts we received involving production sites located in the area of the LHU jurisdiction is less than what we might have expected.

Widening of the femoral proximal diaphysis--metaphysis angle in fetuses with achondroplasia.

OBJECTIVES: It has recently been reported that fetuses with achondroplasia have a wider than expected femoral proximal diaphysis-metaphysis angle (femoral angle). The aim of this case-control study was to investigate this finding. METHODS: Cases with confirmed achondroplasia (n = 6), small-for-gestational-age fetuses (n = 70) and a group of normal fetuses (n = 377) were included in this study. The ultrasound image of the femur was examined by two independent experienced observers blinded to the diagnosis, who measured the femoral angle. These values were converted into multiples of the expected median (MoM), after adjustment for gestational age and femur length. Prevalence of various prenatal ultrasound signs of achondroplasia was determined in affected fetuses. Intra- and interobserver agreement of measurement of femoral angle was assessed using 95% limits of agreement and kappa statistics. RESULTS: The femoral angle can be measured accurately by ultrasound, and increases with both increasing gestational age and increasing femur length. The femoral angle-MoM was significantly higher in fetuses with achondroplasia than in the control group (1.36 vs 1.00 MoM, P < 0.001) and in the SGA group (1.36 vs 1.04 MoM, P < 0.001). It measured more than 130° in five of the six cases with achondroplasia (83.3%), which was the most consistent finding other than shortening of the long bones. CONCLUSIONS: The femoral angle is wider in fetuses with achondroplasia. This new ultrasound sign appears promising as an additional discriminatory marker when clinicians are faced with a case of short long bones in the third trimester.

Changes in fetal Doppler indices as a marker of failure to reach growth potential at term.

OBJECTIVE: To evaluate whether changes in the middle cerebral artery (MCA), umbilical artery (UA) and cerebroplacental ratio (CPR) Doppler indices at term might be used to identify those appropriate-for-gestational-age (AGA) fetuses that are failing to reach their growth potential (FRGP). METHODS: This was a retrospective cohort study of data obtained in a single tertiary referral center over a 10-year period from 2002 to 2012. The UA pulsatility index (PI), MCA-PI and CPR were recorded between 37+0 and 41+6 weeks within 14 days before delivery. The Doppler parameters were converted into multiples of the median (MoM), adjusting for gestational age, and their correlation with birth-weight (BW) centiles was evaluated by means of regression analysis. Doppler indices were also grouped according to BW quartiles and compared using Kruskal-Wallis and Dunn's post-hoc tests. RESULTS: The study included 11576 term fetuses, with 8645 (74.7%) classified as AGA. Within the AGA group, fetuses with lower BW had significantly higher UA-PI, lower MCA-PI and lower CPR MoM values. Large-for-gestational-age (LGA) fetuses were considered as the group least likely to be growth-restricted. The CPR MoM < 5(th) centile (0.6765 MoM) in these fetuses was used as a threshold for diagnosing FRGP. Using this definition, in the AGA pregnancies the percentage of fetuses with FRGP was 1% in the 75-90(th) BW centile group, 1.7% in the 50-75(th) centile group, 2.9% in the 25-50(th) centile group and 6.7% in the 10-25(th) centile group. CONCLUSION: AGA pregnancies may present with fetal cerebral and placental blood flow redistribution indicative of fetal hypoxemia. Fetal Doppler assessment may be of value in detecting AGA pregnancies that are subject to placental insufficiency, fetal hypoxemia and FRGP. Future studies are needed to evaluate the appropriate threshold for the diagnosis of FRGP and the diagnostic performance of this new approach for the management of growth disorders.

MicroRNAs and hematopoietic differentiation.

The discovery of microRNAS (miRNAs) and of their mechanism of action has provided some very new clues on how gene expression is regulated. These studies established new concepts on how posttranscriptional control can fine-tune gene expression during differentiation and allowed the identification of new regulatory circuitries as well as factors involved therein. Because of the wealth of information available about the transcriptional and cellular networks involved in hematopoietic differentiation, the hematopoietic system is ideal for studying cell lineage specification. An interesting interplay between miRNAs and lineage-specific transcriptional factors has been found, and this can help us to understand how terminal differentiation is accomplished.

Yeast snoRNA accumulation relies on a cleavage-dependent/polyadenylation-independent 3'-processing apparatus.

In Saccharomyces cerevisiae, snoRNAs are encoded by independent genes and within introns. Despite this heterogenous organization, snoRNA biosynthesis relies on a common theme: entry sites for 5'-3' and 3'-5' exonucleases are created on precursor molecules allowing the release of mature snoRNAs. In independently transcribed snoRNAs, such entry sites are often produced by the Rnt1p endonuclease. In many cases, cleavage sites are absent in the 3' portion of the pre-snoRNAs, suggesting that processing starts from the 3' end of the primary transcript. Here we show that cleavage/polyadenylation sites driving efficient polyadenylation, such as CYC1, prevent production of mature and functional snoRNPs. With these sites, snoRNA accumulation is restored only if polyadenylation activity is inhibited. Analysis of sequences downstream of snoRNA-coding units and the use of strains carrying mutations in RNA polymerase II (polII) cleavage/polyadenylation activities allowed us to establish that formation of snoRNA mature 3' ends requires only the cleavage activity of the polII 3'-processing machinery. These data indicate that, in vivo, uncoupling of cleavage and polyadenylation is necessary for an essential cellular biosynthesis.