Prenatal diagnosis of isolated coronary artery fistula: systematic review, analysis of perinatal prognostic factors and case report.

BACKGROUND: Isolated coronary artery fistula (CAF) is a rare entity in which evidence for both prognosis and need for perinatal treatment is lacking. We aim to evaluate the characteristics, evolution and perinatal outcomes of reported cases, including one from our center. MATERIAL AND METHODS: We performed a systematic review in Medline, Pubmed, and Embase databases for cohort studies or case series related to prenatally diagnosed isolated congenital CAF according to PRISMA guidelines. The search was restricted to articles published until January 2022, including a case report from our center. A descriptive analysis was performed, and perinatal characteristics were dichotomized by outcome (development of symptoms, as well as the need for surgery during the neonatal period). Strength of association between prenatal variables and outcome was evaluated through Odds Ratio. RESULTS: Only 27 cases of prenatal diagnosis of isolated CAF have been published, including our patient. Most had their origin in the right coronary artery (63%) and drained in the right ventricle (55.6%). Most cases (72%) developed progressive intrauterine dilation of the fistulous tract, which was usually associated with symptoms of cardiac overload, such as cardiomegaly (57.7%). Up to two-thirds of prenatally diagnosed patients developed heart failure symptoms in the neonatal period, and 84% required postnatal intervention. Prenatal diagnosis of both cardiomegaly and diastolic steal is associated with an OR of 52 and 41 of developing postnatal symptoms. CONCLUSION: Prenatal diagnosis of isolated CAF can be achieved with adequate tools and trained sonographers. The development of cardiomegaly and diastolic steal significantly increases the risk of developing postnatal symptoms.

Prenatal Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy: A Promising Way to Change the Impact of Cystic Fibrosis.

INTRODUCTION: Cystic fibrosis (CF) is a potentially severe disease. The development of new therapies with cystic fibrosis transmembrane conductance regulator (CFTR) modulators has been a great advance in the management of this condition because they improve the function of the faulty CFTR protein rather than palliate its consequences. CFTR modulator therapy improves pancreatic and lung function and, therefore, quality of life, with greater benefits the sooner treatment is started. For this reason, the use of these therapies is being approved for increasingly younger patients. Only two cases of pregnant women taking CFTR modulator therapy with CF fetuses have been reported, suggesting that it could resolve meconium ileus (MI) prenatally and delay/prevent other consequences of CF. CASE PRESENTATION: We report a case of a healthy pregnant patient who underwent CFTR modulator therapy with elexacaftor-tezacaftor-ivacaftor (ETI) in order to treat her fetus with CF (F508del homozygous CFTR mutation) and MI. Ultrasound findings suggestive of MI were observed at 24 weeks. Both parents were tested for CFTR mutations, and both were carriers of the F508del CFTR mutation. The fetus was diagnosed with CF by amniocentesis at 26+2 weeks. Maternal ETI therapy was initiated at 31+1 weeks, and no dilated bowel was observed at 39 weeks. There were no signs of bowel obstruction after birth. Maternal ETI treatment was continued during breastfeeding, with normal liver function. Immunoreactive trypsinogen in the newborn was 58.1 ng/mL, sweat chloride test was 80 mmol/L, and fecal elastase on the second day of life was 58 µg/g. CONCLUSION: Prenatal ETI treatment, as well as during breastfeeding, could solve, prevent, and/or delay CF complications.

The role of the T-cell mediated immune response to Cytomegalovirus infection in intrauterine transmission.

INTRODUCTION: Prognostic markers for fetal transmission of Cytomegalovirus (CMV) infection during pregnancy are poorly understood. Maternal CMV-specific T-cell responses may help prevent fetal transmission and thus, we set out to assess whether this may be the case in pregnant women who develop a primary CMV infection. METHODS: A multicenter prospective study was carried out at 8 hospitals in Spain, from January 2017 to April 2020. Blood samples were collected from pregnant women at the time the primary CMV infection was diagnosed to assess the T-cell response. Quantitative analysis of interferon producing specific CMV-CD8+/CD4+ cells was performed by intracellular cytokine flow cytometry. RESULTS: In this study, 135 pregnant women with a suspected CMV infection were evaluated, 60 of whom had a primary CMV infection and samples available. Of these, 24 mothers transmitted the infection to the fetus and 36 did not. No association was found between the presence of specific CD4 or CD8 responses against CMV at the time maternal infection was diagnosed and the risk of fetal transmission. There was no transmission among women with an undetectable CMV viral load in blood at diagnosis. CONCLUSIONS: In this cohort of pregnant women with a primary CMV infection, no association was found between the presence of a CMV T-cell response at the time of maternal infection and the risk of intrauterine transmission. A detectable CMV viral load in the maternal blood at diagnosis of the primary maternal infection may represent a relevant biomarker associated with fetal transmission.

Common Arterial Trunk in Fetal Life: Accuracy of Diagnosis and Prediction of Outcome.

INTRODUCTION: Common arterial trunk (CAT) is a congenital heart disease with significant perinatal mortality in which diagnostic agreement remains low. METHODS: We conducted a retrospective cohort study on fetuses with suspected CAT. Diagnostic accuracy was tested considering gold-standard postnatal ultrasound or necropsy. Prenatal sonographic markers were evaluated by logistic regression for perinatal survival. RESULTS: There were 79 fetuses with suspected CAT, and 55 cases had available necropsy/postnatal ultrasound confirming the study population. The diagnostic accuracy was 90.9% for CAT and 83.6% at a subtype level. In those with a confirmed diagnosis and intention-to-treat (n = 28) composite early mortality (intrauterine, presurgical, and early surgery) was of 25%, 10.5% in isolated cases. The OR for early-mortality of isolated cases was 0.13 (95% confidence interval [CI]: 0.03-0.75). After adjusting for isolated cases, the only prognostic prenatal markers of perinatal mortality were a dysplastic truncal valve OR 7.78 (95% CI: 1.23-49.13) and a stenotic flow OR 8.48 (95% CI: 1.40-51.10). CONCLUSION: CAT is a condition that if evaluated by experts, can be diagnosed with a high degree of accuracy. It remains an entity with high perinatal mortality. Its most important prognostic factor is its association with other anomalies. In isolated cases, the presence of a dysplastic truncal valve and a stenotic flow increase the chances of perinatal death.

Retos en el diagnóstico prenatal de coartación de aorta: actualización y perspectiva actual / Challenges associated with the prenatal diagnosis of aortic coarctation: update and current perspectives

Resumen La coartación de aorta es una cardiopatía congénita frecuente y potencialmente mortal. Su diagnóstico prenatal es un reto, ya que está dificultado por características inherentes a la circulación fetal, siendo relativamente bajas sus tasas de detección (30-50%). A diferencia de lo que sucede con otras cardiopatías congénitas, el diagnóstico prenatal de la coartación de aorta es en la mayoría de los casos solo de sospecha y únicamente podrá confirmarse de forma posnatal. Su identificación es de gran importancia, ya que mejora el pronóstico neonatal, y se basa sobre todo en la visualización de signos indirectos, como asimetría de cavidades o grandes vasos, con dominancia derecha. La principal limitación de estos es su bajo valor predictivo positivo, en especial en edades gestacionales tardías. Existen otros signos directos con mayor especificidad, como la hipoplasia de arco, el cociente istmo/ductus o el shelf contraductal, que en ocasiones solo son evidentes en el tercer trimestre dado el carácter evolutivo de la enfermedad. No obstante, ningún parámetro aislado presenta un rendimiento diagnóstico adecuado, siendo la combinación de algunos en distintos modelos multiparamétricos la que ha presentado mejores valores predictivos. Estos permiten al clínico un mejor asesoramiento a los padres, así como una planificación de la asistencia perinatal.

Abstract Coarctation of the aorta is a relatively common and potentially fatal congenital cardiac defect. Prenatal diagnosis remains a challenge, as it is limited by the inherent characteristics of the fetal circulation, with overall low detection rates (30-50%). Opposite to other congenital cardiac defects, prenatal diagnosis of coarctation of the aorta will be a suspicion one and can only be confirmed postnatally. Its identification is of paramount importance as it improves neonatal prognosis and is mainly based on the identification of indirect signs such as cardiac or great vessels asymmetry with right dominance. The main limitation of these signs is their low positive predictive value, especially in later gestational ages. There are direct signs with higher specificity such as arch hypoplasia, the isthmus/ductus ratio or the contraductal shelf, which may only be apparent in the third trimester given the progressive nature of the disease. However, no isolated parameter has an adequate diagnostic performance and it is their combination in multiparametric models that has shown the best predictive values. These models allow clinicians to give parents better counselling as well as tailor perinatal management.

Application of a Global Multiparameter Scoring System for the Prenatal Prediction of Coarctation of the Aorta.

To assess prospectively the capability of our previously reported global multiparameter scoring system to predict coarctation of the aorta (CoAo) in fetuses with cardiac asymmetry, we applied and analyzed the performance of our scoring system in predicting postnatal CoAo in fetuses undergoing prenatal echocardiographic assessment because of cardiac asymmetry between 2011 and 2021, and we determined the cut-off points of the score with the best balance between specificity and sensitivity, and of maximum sensitivity and specificity. CoAo was confirmed in 39/179 newborns (21.8%). We found a significantly higher probability of CoAo in fetuses with CoAo than in cases without CoAo (84.2 ± 18.2% vs. 26.0 ± 28.6%, p < 0.001). The AUC of the ROC of the score was 0.93 (95% CI 0.89-0.97). The cut-off value with the best balance between specificity and sensitivity was a predicted risk of ≥53% (sensitivity 92.3% and specificity 80.0%). The cut-off point of maximum sensitivity was ≥35% (sensitivity 100% and specificity 72.9%), and that of maximum specificity was ≥96% (sensitivity 43.6% and specificity 96.4%). In none of the fetuses with a probability of CoAo < 35% was this condition confirmed after birth. This occurred in 102 fetuses in the whole study population (57%) and in 84 of the 111 in whom CoAo was suspected beyond 28 weeks (75.7%). This multiparameter score allows an adequate discrimination between fetuses without CoAo and those with CoAo, reducing the false positive diagnoses in cardiac asymmetry.

Prediction of Perinatal Mortality in Ebstein's Anomaly Diagnosed in the Second Trimester of Pregnancy.

OBJECTIVES: Firstly, to describe the outcome of a series of fetuses with Ebstein's anomaly (EA) and, secondly, to study the utility of different second-trimester echocardiographic parameters to predict fetal and neonatal mortality. METHODS: 39 fetuses with EA diagnosed between 18 and 28 weeks of gestation were included. Fetal echocardiography included the cardiothoracic ratio (CTR); right atrial (RA) area index; displacement of the tricuspid valve (TV); tricuspid regurgitation; pulmonary artery; and ductus arteriosus flow characteristics. Additionally, 2 novel parameters were obtained: the relative RA area ratio (RA area/cardiac area) and the TV displacement index (TVDI, TV displacement distance/longi-tudinal diameter of the left ventricle). Correlation between the echocardiographic variables and the primary outcome of perinatal mortality or survival at 1 year of life was evaluated. RESULTS: From the initial cohort, 8 cases were excluded due to complex congenital heart defects. Termination of pregnancy (TOP) was performed in 15 cases, and fetal death was diagnosed in 3 cases. In the live-born cohort of 13 patients, 4 died in the neonatal period, yielding a perinatal survival rate of 29 and 56%, respectively, after excluding TOP cases. Compared with survivors, nonsurvivors showed a significantly higher CTR (56.7 ± 16.2 vs. 42.6 ± 8.6; p = 0.04), relative RA area ratio (0.39 ± 0.13 vs. 0.25 ± 0.05; p = 0.01), and TVDI (0.62 ± 0.17 vs. 0.44 ± 0.12; p = 0.03) at diagnosis. The best model to predict perinatal mortality was obtained by using a scoring system which included the relative RA area ratio and TVDI (AUC 0.905 [95% CI 0.732-1.000]). CONCLUSIONS: Fetuses with a relative RA area ratio ≥0.29 and TVDI ≥0.65 at the second trimester have the highest risk of dying in the perinatal stage.

Prognostic Factors of Successful Cervical Ripening and Labor Induction in Late-Onset Fetal Growth Restriction.

OBJECTIVE: The aim of this work was to identify independent risk factors influencing the achievement of vaginal delivery among women undergoing labor induction for late-onset fetal growth restriction (FGR). METHODS: This was a retrospective cohort study of 201 singleton pregnancies with late-onset FGR (diagnosed >32 + 0 weeks) that required labor induction with cervical ripening from 37 + 0 weeks, either with dinoprostone (from 2014 to 2015) or Foley balloon (from 2016 to 2018). Independent factors for successful vaginal delivery were identified. A prediction model of vaginal delivery with the identified factors was made using logistic regression and bootstrapping with 1,000 re-samples performed for bias correction. RESULTS: Perinatal results were more favorable in the vaginal delivery group, with significantly lower neonatal admission rates (4.0 vs. 13.7%) and lower composite neonatal morbidity (4.0 vs. 15.7%). The labor induction method (Foley balloon), higher cerebro-placental ratio, lower pre-gestational BMI, and absence of pre-eclampsia were identified as independent factors associated to vaginal delivery. The area under the curve of the model was of 0.75 (95% CI 0.70-0.79). CONCLUSIONS: The use of a Foley balloon is the only modifiable risk factor to improve the chances of vaginal delivery when attempting induction of labor in singleton pregnancies with late-onset FGR.

Prognostic value of the aortic isthmus Doppler assessment on late onset fetal growth restriction.

Background As conflicting results have been reported about the association of reversed flow on the aortic isthmus (AoI) and adverse perinatal results in fetal growth restriction (FGR), we aim to compare perinatal outcomes (including tolerance to labor induction) of late-onset FGR between those with anterograde and reversed AoI flow. Methods This was an observational retrospective cohort study on 148 singleton gestations diagnosed with late-onset FGR (diagnosis ≥32+0 weeks), with an estimated fetal weight (EFW) <10th centile and mild fetal Doppler alteration: umbilical artery (UA) pulsatility index (PI) >95th centile, middle cerebral artery (MCA)-PI <5th centile or cerebral-placental ratio <5th centile. Anterograde AoI flow was present in n=79 and reversed AoI flow in n=69. Delivery was recommended from 37 weeks in both groups. Perinatal results were compared between the groups. Results The global percentage of vaginal delivery of fetuses with anterograde and reversed blood flow was 55.7% vs. 66.7% (P=0.18) and the percentage of cesarean section (C-section) for non-reassuring fetal status was 12.7% vs. 15.9% (P=0.29), respectively. When evaluating those that underwent labor induction, the vaginal delivery rate was 67.9% vs. 77.2% (P=0.17), respectively. There were no significant differences regarding any other perinatal variables and there were no cases of severe morbidity or mortality. Conclusion We observed that the presence of reversed AoI flow does not worsen perinatal outcomes on fetuses with late-onset growth restriction with mild Doppler alterations. Attempt of labor induction is feasible in these fetuses regardless of the direction of AoI flow.

Labor Induction in Late-Onset Fetal Growth Restriction: Foley Balloon versus Vaginal Dinoprostone.

OBJECTIVE: To compare vaginal delivery rate and perinatal outcomes of fetuses with late-onset fetal growth restriction (FGR) undergoing labor induction, depending on the method for cervical ripening (dinoprostone vs. Foley balloon). MATERIAL AND METHODS: We conducted a retrospective cohort study of 148 consecutive singleton gestations diagnosed with stage I late-onset FGR and Bishop score < 7, in which labor induction was indicated at ≥37 + 0 weeks. Before January 2016, cervical ripening was achieved with 10 mg of vaginal dinoprostone (n = 77) and afterwards with Fo-ley balloon (n = 71). Logistic regression analysis was used to estimate the association between mode of delivery and induction method. RESULTS: Foley balloon had lower percentages of uterine tachysystole with fetal repercussion (4.2 vs. 16.9%, p = 0.01) and cesarean sections for suspected fetal distress (7.0 vs. 26.0%, p < 0.01) when compared to dino-prostone. Lower percentages of cesarean sections were found in the Foley balloon group (15.5 vs. 37.7%, p < 0.01). The odds ratio and adjusted odds ratio of cesarean section with dinoprostone were of 3.3 and 4.4, respectively. Perinatal mortality and severe morbidity were null in both groups. CONCLUSION: The use of Foley balloon resulted in a higher percentage of vaginal delivery compared to dinoprostone, with a favorable safety profile in both groups.

Fetal Biometry and Doppler Study for the Assessment of Perinatal Outcome in Stage I Late-Onset Fetal Growth Restriction.

OBJECTIVE: To compare perinatal outcomes on fetuses classified as stage I late-onset fetal growth restriction (FGR) depending on the estimated fetal weight (EFW) centile category and the fetal and maternal Doppler study. MATERIAL AND METHODS: Retrospective cohort study on 131 cases of stage I late-onset FGR (diagnosis ≥32+0 weeks), defined as: EFW < 3rd centile and normal Doppler (G1) or EFW < 10th centile and mean uterine artery pulsatility index (PI) > 95th centile (G2) or EFW < 10th centile and mild fetal Doppler alteration: umbilical artery PI > 95th centile, middle cerebral artery PI < 5th centile, or cerebroplacental ratio < 5th centile (G3). All groups were compared to their perinatal results. RESULTS: There were 37, 30, and 64 cases in G1, G2, and G3, respectively. G1 and G2 showed lower percentages of cesarean section when compared with G3 (18.4, 22.5, and 45.3% (p < 0.01), respectively), being attributable to an excess of cesarean sections for non-reassuring fetal status. These differences remained when definitive birth weight centile was above that considered to define FGR, being 5.9, 12.5, and 41.8% (p < 0.01), respectively. DISCUSSION: In stage I late-onset FGR fetuses, abnormal fetal Doppler is associated with a poorer tolerance to vaginal delivery, even when the birth weight is > 10th centile.

Fetal Aortic Valvuloplasty: Experience and Results of Two Tertiary Centers in Spain.

OBJECTIVE: Fetal aortic valvuloplasty (FAV) may avoid progression of critical aortic stenosis (CAS) to hypoplastic left ventricle, improving the options for biventricular circulation (BVC). We describe the results of FAV in 2 referral centers in Spain. METHODS: We analyzed all FAVs performed in the period 2007-2015. The selection of candidates, the technique, and postnatal management were made following an agreed protocol. A descriptive analysis of survival, type of circulation after birth, and complications was made, considering all deaths in the first 48 h after FAV as FAV-related. RESULTS: FAV was performed in 28 fetuses at a median gestational age (GA) of 23 weeks (range, 20-32). FAV was technically successful in 22 (78.6%), of whom 11 were born alive and with intention to treat. Eight (72.7%) resulted in BVC and 3 (27.3%) in univentricular circulation. The rate of FAV-related deaths was 32%. These patients underwent FAV earlier than live-born fetuses (median GA at FAV 22 weeks [range, 20.0-25.0] vs. 24.5 weeks [range, 21.0-32.0], respectively, p = 0.031). CONCLUSIONS: A significant proportion of fetuses with CAS who undergo technically successful FAV have BVC postnatally. However, FAV implies a high risk of fetal death, which highly depends on the GA at which this intervention is required.

Gestational age-specific scoring systems for the prediction of coarctation of the aorta.

OBJECTIVES: To determine which combination of cardiac parameters provides the best prenatal prediction of coarctation of aorta (CoAo). METHODS: We selected all cases of simple cardiac asymmetry prenatally diagnosed in 2003-2013. Logistic regression was used to select the best predictors of CoAo. RESULTS: The study population included 115 fetuses. CoAo was confirmed in 52 neonates (45%). The sample was divided in two groups according to the gestational age (GA) at diagnosis: early group (EG) ≤28 weeks (n = 57), and late group (LG) >28 weeks (n = 58). CoAo was confirmed in 75% and 16% of cases, respectively. GA-specific scoring systems with maximum two parameters were made, and the pairwise combination with the best diagnostic performance for each group was selected. In EG, the z-score of ascending aorta (AAo) and aortic isthmus (three vessels and trachea view) showed the best diagnostic accuracy [area under receiver-operating curve (AUC) 0.98, 95% confidence interval (CI) 0.94-1.00]. In the LG, the best results were provided by the tricuspid valve/mitral valve ratio with the main pulmonary artery/AAo ratio (AUC 0.84, 95% CI 0.67-1.00). CONCLUSIONS: Gestational age-specific scoring systems combining size-based cardiac parameters may improve the accuracy of fetal echocardiography to stratify the risk of CoAo. The objectivity and simplicity of its components may facilitate its implementation in fetal cardiology units.

Characterization of the soluble fms-like tyrosine kinase-1 to placental growth factor ratio in pregnancies complicated by fetal growth restriction.

OBJECTIVE: To characterize the values of the soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio in pregnancies with fetal growth restriction with or without concurrent preeclampsia or hemolysis, elevated liver enzymes and low platelets syndrome (HELLP) and in pregnancies with normally grown fetuses with or without concurrent preeclampsia or HELLP. METHODS: This is a case-control study performed in two centers (Berlin and Madrid) consisting of 171 singleton pregnancies complicated by fetal growth restriction (n=27), preeclampsia or HELLP (n=105) or preeclampsia or HELLP and fetal growth restriction (n=39) pairwise matched by gestational age with 171 healthy control pregnancies. Automated measurement of sFlt-1 and PlGF in maternal serum samples was performed after diagnosis (cases) and in gestational-age matched healthy control samples. Samples were analyzed for two timeframes: before and at or after 34 weeks of gestation. RESULTS: Pregnancies with fetal growth restriction, preeclampsia or HELLP, and preeclampsia or HELLP and fetal growth restriction showed higher median values of sFlt-1/PlGF ratio than control pregnancies both before 34 weeks of gestation (90, 231, 514, and 3, respectively, P<.001) and at or after 34 weeks of gestation (117, 66, 165, and 11, respectively, P<.001). The differences among the case subgroups were not statistically different. CONCLUSION: Fetal growth restriction is characterized by elevated maternal sFlt-1/PlGF ratio, reaching values as high as those observed in preeclampsia or HELLP. LEVEL OF EVIDENCE: II.

Prenatal prediction of surgical approach for coarctation of the aorta repair.

OBJECTIVE: To evaluate the capacity of fetal echocardiography for predicting the more likely surgical approach in newborns with coarctation of the aorta (CoAo) (left thoracotomy vs. median sternotomy). MATERIAL AND METHODS: We selected all cases of suspected CoAo prenatally diagnosed in 2003-2012 (n = 95). 49/95 were considered at high-risk and 46/95 at low-risk of CoAo, and 38/49 and 7/46 were postnatally confirmed, respectively. We firstly evaluated in 40 cases of CoAo surgically repaired (24 thoracotomy, 16 sternotomy) whether there were differences in fetal echocardiographic parameters between both groups. Secondly, we assessed the performance of these parameters for predicting the surgical approach in fetuses at high risk of CoAo. RESULTS: Sternotomy approach was associated with higher rate of postoperative complications and longer hospital stay compared with thoracotomy (81.3 vs. 41.7%, p = 0.014; 30.5 vs. 15.4 days, p = 0.0004, respectively). The Z-score of the aortic isthmus, measured in the sagittal plane, was significantly smaller in the sternotomy group. In fetuses at high-risk of having CoAo a cut-off value of the isthmus Z-score ≤ -2.5 had sensitivity of 78% and specificity of 82% for predicting sternotomy approach, with 9% false positive cases in which CoAo was not confirmed. DISCUSSION: The surgical approach for CoAo repair may be prenatally predicted by means of the Z-score of aortic isthmus, measured in the sagittal plane.

[Prenatal diagnosis of isolated otocefalia. Usefulness of three-dimensional ultrasound]. / Diagnóstico prenatal de otocefalia aislada. Utilidad de la ecografía tridimensional.

Otocephaly is a rare and lethal congenital malformation characterized by the presence of agnathia, microstomia, aglossia and synotia. Despite its frequent association with severe malformations, diagnosis in the few published cases is usually made at III trimester. In this case, three-dimensional ultrasound scan was performed in a Chinese primigravida with no remarkable personal nor familiar history since mandible was difficulty visualized with two-dimensional sonography at 21 weeks of gestation. Multiplanar and rendering mode showed the typical cervicofacial features of otocephaly without associated malformations. After parental counselling, they opted for termination of pregnancy and necropsy confirmed our prenatal findings. Our case shows the usefulness of three-dimensional ultrasound in assessing fetal cervicofacial pathology. Volumetric capture allows a delayed study of fetal anatomy and multiplanar mode offers the reconstruction of views whose achivement is difficult with conventional 2D ultrasound. Surface rendering provides excellent spatial vision and enables parents to understand the severity of the malformation thus helping with their decisions.