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Objective: Second- and third-trimester SARS-CoV-2 infections may have an increased risk of obstetric complications. However, data on first-trimester infections are scarce. We sought to characterize the clinical and inflammatory presentations and pregnancy outcomes of first-trimester infections. Methods: A population-based multicenter study including 817 singleton pregnancies with SARS-CoV-2 serologic testing at 8–14 weeks between March and May 2020. Blood count, uterine artery Doppler, and pregnancy-associated plasma protein A (PAPP-A) were performed in all women. Placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), IL-6, and ferritin were determined in positive women. Obstetric outcomes were evaluated. Results: The prevalence of first-trimester infection was 15.2% (n = 124). 72.6% of positive women were asymptomatic. Symptomatic women had higher rates of lymphopenia (1.91 × 109/L vs. 2.16 × 109/L, p = 0.017) and increased levels of IL-6 (9.1% vs. 1.2%, p = 0.051), but lower rates of decreased ferritin (6.3% vs. 19.8%, p = 0.015). PAPP-A was higher in symptomatic women compared with asymptomatic and negative women (1.44 [IQR 0.90–1.82] vs. 1.08 [IQR 0.66–1.61] p = 0.014, vs. 1.08 [IQR 0.77–1.55] p = 0.019, respectively). Obstetric outcomes were not increased. Conclusions: First-trimester SARS-CoV-2 infections are mostly asymptomatic, with a mild increase of inflammatory markers in symptomatic women. Obstetric complications were not increased, but PAPP-A levels were higher in symptomatic women. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to determine the effect and clinical impact of physiological characteristics on the 95th/5th centile of the umbilical artery (UA) Doppler and the cerebroplacental ratio (CPR), at 36+ weeks. Methods: From the multicenter randomized trial "Ratio37," we selected 4,505 low-risk pregnant women between June 2016 and January 2020. We registered physiological characteristics and the pulsatility indexes (PI) of the UA and middle cerebral artery (36–39 weeks). The 95th/5th centile of the UA PI and CPR was modeled by quantile regression. To evaluate the clinical impact of adjusting Doppler, we retrospectively applied gestational age (GA) and fully adjusted standards to 682 small for gestational age (SGA)-suspected fetuses (37 weeks) from a cohort of consecutive patients obtained between January 2010 and January 2020. Results: Several physiological characteristics significantly influenced the 95th/5th centile of the UA and CPR PI. The fully adjusted 95th centile of the UA was higher, and the 5th centile of the CPR was lower than GA-only-adjusted standards. Of the 682 SGA fetuses, 150 (22%) were classified as late fetal growth restricted only by GA and 112 (16.4%) when we adjusted Doppler. These 38 fetuses had similar perinatal outcome than the SGA group. Discussion: The 95th/5th centile of the UA and CPR PI is significantly influenced by physiological characteristics. Adjusting Doppler standards could differentiate better between FGR and SGA. [ABSTRACT FROM AUTHOR]

Introduction: Preterm prelabor rupture of membranes (PPROM) is a common complication after fetal surgeries. The aim of this study was to assess risk factors for and outcomes after PPROM following cord occlusion (CO) in monochorionic diamniotic (MCDA) pregnancies. Methods: This was a retrospective cohort study of 188 consecutive MCDA pregnancies treated by bipolar or laser CO, either primarily because of discordant malformation (dMF) or severe selective fetal growth restriction (sFGR), or secondarily when complete bichorionization was not possible in case of twin-to-twin transfusion syndrome (TTTS) or sFGR. Intentional septostomy was performed when needed. The procedure-related PPROM was defined as rupture of membranes <32 weeks' gestation (PROM <32 weeks). Selected pre-, intra-, and early postoperative variables were analyzed by univariate and binomial logistic regression to determine they are correlated to PROM <32 weeks after CO. Results: Between 2006 and 2017, 188 cases underwent CO. Diagnosis was TTTS in 28.2% (n = 53), severe sFGR in 49.5% (n = 93), and dMF in 22.3% (n = 42). PROM <32 weeks occurred in 21.3% (n = 40), resulting in worse perinatal outcomes, as preterm birth <32 weeks occurred in 80.7% (vs. 8.3%, p = 0.000), procedure-to-delivery interval was 47.5 days (vs. 125, p = 0.000), gestational age (GA) at birth 30.0 weeks (vs. 37.7 weeks, p = 0.000), and survival 65.0% (vs. 91.1%, p = 0.000). In univariate analysis, indication, anterior placenta, cervical length, GA at surgery, operation time, amniodistention and drainage fluid volumes, chorioamniotic membrane separation, and septostomy were selected as relevant factors to be included in the regression model. In a multivariate analysis, TTTS was the only factor associated to PROM <32 weeks (OR 3.5 CI 95% 1.5–7.9). Conclusions: PROM <32 weeks after CO increases the risk of preterm delivery. In this cohort, the membrane rupture was more likely when CO was done in the context of TTTS. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to derive longitudinal reference values of fetal growth (estimated fetal weight [EFW] and abdominal circumference [AC]) during the third trimester and to develop coefficients for conditional growth assessment.Patients and Methods: A prospective cohort study was conducted involving consecutive singleton pregnancies in a low-risk population for a routine third-trimester scan at 30+0-34+6 weeks and follow-up at 37+0-38+6 weeks for an additional ultrasound. Statistical analysis was based on multilevel modeling using MLwiN software. Unconditional centiles were calculated from z-values at each gestational age, and conditional centiles were calculated from z-values at a given measurement (30-34 weeks) and the expected measurement (37-38 weeks).Results: At 30-34 weeks, 8 and 9.3% of the fetuses had an unconditional EFW below the 10th and above the 90th centile, respectively. At 37-38 weeks, these figures were 10.3 and 9.3%, respectively. Regarding the unconditional AC, at the first scan, 8.9 and 9.6% had values below the 10th and above the 90th centile, while at the second scan 10.5 and 10.5% had values below the 10th and above the 90th centile, respectively. The proportion with a conditional EFW below the 10th and above the 90th centile was 10.2 and 9.4% at the second scan, respectively. For conditional AC, these figures were 10.7 and 10.3%, respectively.Conclusion: We have produced reference centiles for EFW and AC growth during the third trimester as a useful tool for quantifying growth. [ABSTRACT FROM AUTHOR]

Objectives: Quantitative texture analysis has been proposed to extract robust features from the ultrasound image to detect subtle changes in the textures of the images. The aim of this study was to evaluate the feasibility of quantitative cervical texture analysis to assess cervical tissue changes throughout pregnancy.Methods: This was a cross-sectional study including singleton pregnancies between 20.0 and 41.6 weeks of gestation from women who delivered at term. Cervical length was measured, and a selected region of interest in the cervix was delineated. A model to predict gestational age based on features extracted from cervical images was developed following three steps: data splitting, feature transformation, and regression model computation.Results: Seven hundred images, 30 per gestational week, were included for analysis. There was a strong correlation between the gestational age at which the images were obtained and the estimated gestational age by quantitative analysis of the cervical texture (R = 0.88).Discussion: This study provides evidence that quantitative analysis of cervical texture can extract features from cervical ultrasound images which correlate with gestational age. Further research is needed to evaluate its applicability as a biomarker of the risk of spontaneous preterm birth, as well as its role in cervical assessment in other clinical situations in which cervical evaluation might be relevant. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the rate of pulmonary stenosis and functional pulmonary atresia (PS/PA) in recipient twins prior to fetal surgery for twin-twin transfusion syndrome (TTTS) and their pre- and postnatal outcomes.Methods: We carried out a prospective study including 260 cases of TTTS. Echocardiography was performed before laser surgery to detect the presence of PS/PA. The outcomes of recipients with and without PS/PA were compared. The need of postnatal cardiac interventions and the survival rate at 6 months of age were also evaluated.Results: PS was observed in 16/260 (6.2%) of recipient twins and PA in 12/260 (4.6%). After fetal surgery, 10/28 (35.7%) recipients died, 9/28 (32.1%) showed in utero regression, and 9/28 (32.1%) had persistence of PS/PA. Postnatally, seven recipients underwent percutaneous balloon pulmonary valvuloplasty, one required surgical valvotomy and one palliative surgery. Pregnancies with recipient twins with PS/PA had lower survival of at least one twin (67.9 vs. 83.6%, p = 0.045) and lower overall survival (57.1 vs. 72.8%, p = 0.015) at 6 months of age.Conclusion: PS and PA were observed in 10.8% of recipients. Among these, about one third showed persistence of pulmonary valve pathology after delivery, which stresses the need for strict follow-up. [ABSTRACT FROM AUTHOR]

Objectives: To report the feasibility and main factors affecting the success of a fetal magnetic resonance imaging (MRI) and MR spectroscopy (MRS) research protocol performed at term using a 3-tesla scanner.Methods: Pregnant patients at term underwent an MRI. Specific measures were taken to prevent maternal discomfort and distress, such as detailed counseling and maternal repositioning if needed. MRS data were acquired from the frontal lobe and basal ganglia, and processed applying quality control criteria.Results: The mean gestational age at MRI was 37.4 ± 0.9 weeks. From a total of 245 patients that showed up for the MRI, 11 referred claustrophobia which prevented the test from starting, and 30 patients started the test but decided to discontinue due to discomfort. Thus, the examination was complete in 204 patients. MRS data could be obtained in 170 cases from the frontal lobe and 165 cases from the basal ganglia, of which 52.4 and 68.6%, respectively, complied with our defined quality criteria. The mean scanning time was 34:16 ± 9:30 min:s after excluding those cases presenting initial intolerance to the test. Minor abnormalities were described in 11 MRI reports.Conclusions: The fetal MRI/MRS protocol was feasible and generally well tolerated at term on a 3-tesla scanner, but a significant number of cases were lost to analysis. The rate of patients that eventually provided usable research information was 95.5% for anatomical examination and 52.4-68.6% for MRS. This information should be taken into account in the design of fetal brain MRI studies. [ABSTRACT FROM AUTHOR]

Objective: The aortic isthmus (AoI) blood flow has a characteristic shape with a small end-systolic notch observed during the third trimester of pregnancy. However, what causes the appearance of this notch is not fully understood. We used a lumped model of the fetal circulation to study the possible factors causing the end-systolic notch and the changes of AoI flow through gestation. Methods: A validation of the model was performed by fitting patient-specific data from two normal fetuses. Then, different parametric analyses were performed to evaluate the major determinants of the appearance of the end-systolic notch. The changes in the AoI flow profile through gestation were assessed. Results: Our model allows to simulate the AoI waveform. The delay in the onset of ejection together with the longer ejection duration of the right ventricle are the most relevant factors in the origin of the notch. It appears around 25 weeks of gestation and becomes more pronounced with advancing gestation. Discussion: We demonstrated that the end-systolic notch on the AoI flow occurs mainly as a result of a delayed and longer ejection of the right ventricle. Our findings improve the understanding of hemodynamic changes in the fetal circulation and the interpretation of clinical imaging. [ABSTRACT FROM AUTHOR]

Objectives: We used magnetic resonance spectroscopy (MRS) to evaluate brain metabolic differences in small fetuses near term as compared to appropriate for gestational age (AGA) fetuses. Study Design: 71 term small fetuses (estimated fetal weight <10th centile for gestational age with normal umbilical artery Doppler sonography) were subclassified as late intrauterine growth restriction (IUGR) (n = 50) or small for gestational age (SGA) (n = 21), and compared with 65 AGA fetuses. IUGR was defined by either abnormal middle cerebral artery, abnormal uterine artery Doppler sonography or estimated fetal weight <3rd centile. All participants underwent brain magnetic resonance imaging at 37 weeks of gestation, and single-voxel magnetic resonance spectra were obtained from the frontal lobe on a 3-tesla scanner. N-acetylaspartate (NAA)/choline (Cho), NAA/creatine (Cr) and Cho/Cr ratios were calculated and compared between cases and controls. The association of the metabolic ratios with the study groups was tested. Results: After MRS processing and applying quality control criteria, 31 spectra from late-onset IUGR, 11 from SGA and 30 from AGA fetuses were selected for further analysis. Both SGA and late-onset IUGR fetuses showed significantly reduced NAA/Cho levels when compared to AGA fetuses. This decrease followed a linear trend across the three clinical groups that were considered. Conclusions: Both SGA and late-onset IUGR fetuses showed differences in MRS brain metabolic ratios. The findings suggest that despite near-normal perinatal outcomes, SGA fetuses are not constitutionally small and may represent a form of growth disorder that needs to be clarified. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To provide a snapshot of the current trends in managing intrauterine growth restriction (IUGR) and to assess the agreement on the gestational age and the way of delivery in different clinical scenarios. Methods: A PubMed search was performed to identify all original articles on IUGR in the last 6 years. The most active 20 authors were selected as experts and were invited to respond to a survey on their preferred gestational age for elective delivery in several IUGR cases depending on Doppler measurements (including umbilical artery (UA), middle cerebral artery, cerebroplacental ratio, uterine artery and ductus venosus), biophysical profile and cardiotocography. Results: 15 of the 20 selected experts agreed to participate in the survey, of which 3 failed to meet the deadline to complete the survey. Management of IUGR was relatively uniform for abnormal UA, uterine artery or cerebroplacental ratio. Although average gestational age at delivery reflected a clear progression with accepted markers of severity, discrepancies of up to 4 weeks were found for abnormal middle cerebral artery Doppler and absent end-diastolic velocity in the UA, and of up to 8 weeks for reverse end-diastolic velocity in the UA and abnormalities in the ductus venosus Doppler. Conclusions: Management of IUGR is still far from being uniform among centers, with most controversy surrounding the management of early-onset IUGR. There is a need of prospective studies to address this issue. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: The terms early- and late-onset fetal growth restriction (FGR) are commonly used to distinguish two phenotypes characterized by differences in onset, fetoplacental Doppler, association with preeclampsia (PE) and severity. We evaluated the optimal gestational age (GA) cut-off maximizing differences among these two forms. Patients and Methods: A cohort of 656 consecutive singleton pregnancies with FGR was created. We used the decision tree analysis to evaluate the GA cut-off that best discriminated perinatal mortality, association with PE and adverse perinatal outcome (fetal demise, early neonatal death, neonatal acidosis at birth, and 5-min Apgar score <7). Results: We identified 32 weeks at diagnosis as the optimal cut-off, resulting in two groups with 7.1 and 0%, p < 0.001 perinatal mortality, 35.1 and 12.1%, p < 0.001 association with PE, and 13.4 and 4.6%, p < 0.001 composite adverse perinatal outcome. Abnormal versus normal umbilical artery (UA) Doppler classified two groups with 10.6 and 0.2%, p < 0.001 perinatal mortality, 50.0 and 11.8%, p < 0.001 association with PE, and 18.2 and 4.2%, p < 0.001 composite adverse perinatal outcome. Conclusions: UA Doppler discriminated better the two forms of FGR with average early- and late-onset presentation, higher association with PE and poorer outcome. In the absence of UA information, a GA cut-off of 32 weeks at diagnosis maximizes differences between early- and late-onset FGR. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To explore the predictive role of angiogenic factors for the prediction of early and late preeclampsia (PE) in the first trimester. Methods: A nested case-control study, within a cohort of 5,759 pregnancies, including 28 cases of early, 84 of late PE (cut-off 34 weeks) and 84 controls. Maternal characteristics, mean blood pressure (MAP), uterine artery (UtA) Doppler (11-13 weeks), vascular endothelial growth factor, placental growth factor (PlGF), soluble Fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (8-11 weeks) were measured/recorded. All parameters were normalized by logarithmic transformation; logistic regression analysis was used to predict PE. Results: For early PE, significant contributions were chronic hypertension, previous PE, MAP, UtA Doppler, PlGF and sFlt-1. A model including these predictors achieved detection rates (DR) of 77.8 and 88.9% for 5 and 10% false-positive rates (FPR), respectively (AUC 0.958; 95% CI 0.920-0.996). For late PE, significant contributions were provided by body mass index, previous PE, UtA Doppler, PlGF and sFlt-1. The model including these factors achieved DR of 51.2 and 69% at 5 and 10% FPR, respectively (AUC 0.888; 95% CI 0.840-0.936). Conclusions: Among angiogenic factors, not only PlGF but also sFlt-1 substantially improve the prediction for early and late PE. The data need confirmation in larger studies. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction: The association between maternal plasma levels of neutrophil gelatinase-associated lipocalin (NGAL) and maternal complications in women admitted with severe early-onset preeclampsia was evaluated. Material and Methods: Plasma levels of NGAL were measured at admission in patients with severe early-onset (presenting before 34 weeks) preeclampsia. The maternal outcome of women with elevated plasma levels was compared with those with normal levels. Maternal complications included eclampsia, HELLP syndrome, acute renal failure, subcapsular hepatic hematoma, pulmonary edema and disseminated intravascular disease. Results: Sixty-seven patients were included. The median NGAL plasma levels in the group of women who subsequently had a complication were significantly higher than in those uncomplicated cases (114.8 vs. 84.2 ng/ml; Mann-Whitney U test p = 0.03). Maternal complications were more common in the elevated (>100 ng/ml) NGAL group (58.3 vs. 25.6%; χ2 test p = 0.008), with an OR of 4.1 (95% CI 1.4-11.8). After adjustment by gestational age at onset, the association between elevated NGAL plasma levels and maternal complications remained significant (OR 4.2; 95% CI 1.4-12.4). Discussion: Women with severe early-onset preeclampsia are at higher risk of maternal complications if plasma levels of NGAL are elevated. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To explore the association between fetal cerebroplacental ratio (CPR) and frontal brain perfusion at third trimester with neonatal neurobehavioral performance in normally grown fetuses. Methods: CPR and frontal brain perfusion measured by fractional moving blood volume (FMBV) were assessed in 258 consecutive healthy fetuses at routine third trimester scan (32-35.6 weeks). Neonates were evaluated with the Neonatal Behavioral Assessment Scale. The association between Doppler parameters and neurobehavior was analyzed by MANCOVA (multiple analysis of covariance) and logistic regression, with adjustment for smoking, socioeconomic class, mode of delivery, gestational age at birth, postnatal days at examination and gender. Results: Fetuses with increased FMBV (in the upper quartile) had lower neurobehavioral scores in all areas, reaching significance in motor (5.6 vs. 5.8; p = 0.049), social (6 vs. 6.4; p = 0.006) and attention (5.3 vs. 5.9; p = 0.032). Fetuses with increased FMBV had higher risk of abnormal (<10th centile) motor (OR 3.3; 95% CI 1.36-8.1), social (OR 2.9; 95 CI% 1.33-6.5) and attention (OR 2.5; 95% CI 1.1-5.8) scores. Fetuses with lower CPR (in the lower quartile) did not differ in their neurobehavioral scores from those with normal values. Conclusions: Normally grown fetuses with increased frontal brain perfusion have poorer neurobehavioral competences, suggesting a disrupted neurological maturation. The results support the existence of forms of placental insufficiency not detected by current definitions of growth restriction. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Over half of the cases of congenital diaphragmatic hernia are picked up prenatally. Prenatal assessment aims to rule out associated anomalies and to make an individual prognosis. Prediction of outcome is based on measurements of lung size and vasculature as well as on liver herniation. A subset of fetuses likely to die in the postnatal period is eligible for a fetal intervention that can promote lung growth. Two randomized trials have shown that fetal surgery using open anatomical repair or tracheal occlusion via hysterostomy has no benefit. Since then, a percutaneous fetoscopic technique has been introduced, which has been shown to be safe and seems to improve survival when compared to historical controls. Rupture of the fetal membranes and early delivery, nevertheless, remain an issue, but are less likely as compared to earlier experience. Improved outcomes are confirmed in two other studies published in this issue of Fetal Diagnosis and Therapy. This paper summarizes the experimental and clinical history of fetal surgery for congenital diaphragmatic hernia. It stresses the need for another randomized trial. This trial started in Europe and patients should be asked whether they would like to participate. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Pulmonary Doppler may play an important role in the prediction of survival and postnatal morbidity in fetuses with congenital diaphragmatic hernia treated with fetoscopic tracheal occlusion (FETO). Spectral Doppler indexes such as pulsatility index and peak early diastolic reversed flow could help to refine the selection of fetuses that might benefit from fetal therapy. When combined with lung-to-head ratio (LHR), these Doppler indices allow to discriminate cases with moderate-to-high survival rates from fetuses with extremely low chances to survive after FETO. In addition, they discriminate groups with a high or low risk of serious neonatal morbidity in surviving fetuses. After therapy, the combined evaluation of the relative increase of LHR with the increase in lung tissue perfusion by power Doppler seems to improve the prediction of fetal survival. In conclusion, while LHR remains the strongest predictive index, Doppler measurements allow to substantially improve the accuracy in the prediction of the chances of survival of fetuses with congenital diaphragmatic hernia treated with FETO. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The role of prenatal ultrasound and magnetic resonance imaging in the diagnosis and management of congenital diaphragmatic hernia (CDH) is reviewed. Topics include morphologic imaging and vascular assessment of the developing lung, the value of imaging parameters as prognostic predictors in CDH and the role of imaging following percutaneous fetoscopic endoluminal tracheal occlusion. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To analyze the impact of in utero tracheal occlusion (TO) on lung tissue blood perfusion, as measured by fractional moving blood volume (FMBV) and conventional spectral Doppler, in a rabbit model of congenital diaphragmatic hernia (CDH). Methods: In 50 fetal rabbits, a left CDH was surgically created at 23 days of gestational age (GA). At 28 days of GA, the surviving CDH fetuses were randomly assigned to undergo either TO (CDH+TO group) or a sham operation (CDH group). Twenty littermates, which were not operated on, served as internal normal controls. At 30 days of GA, lung perfusion estimated by FMBV and spectral Doppler of the proximal intrapulmonary artery were evaluated in the right lung during cesarean section. Doppler waveform analysis included the pulsatility index (PI), peak early diastolic reverse flow and peak systolic velocity. Results: Eleven CDH fetuses, 9 CDH+TO and 20 controls were suitable for the study. CDH fetuses showed a significantly higher PI [8.0 (SD 1.8) vs. 5.22 (SD 1.1), p < 0.001] and lower FMBV [13.5% (SD 4.6) vs. 23.0% (SD 2.1), p < 0.001] than the controls. In contrast, CDH+TO fetuses had a significantly lower PI [5.8 (SD 2.3) vs. 8.0 (SD 1.8), p = 0.015] and higher FMBV [27.6% (SD 7.1) vs. 13.5% (SD 4.6), p < 0.001] than CDH fetuses, with values similar to the controls. Peak early diastolic reverse flow and peak systolic velocity showed nonsignificant differences among the study groups. The lung to body weight ratio at necropsy correlated positively with lung FMBV (r = 0.60, p < 0.001) and negatively with the pulmonary artery PI (r = –0.48, p < 0.01). Conclusion: Tracheal occlusion is consistently associated with increased lung tissue perfusion and decreased intrapulmonary impedance in a rabbit model of CDH. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]