Extended period of ventilation before delayed cord clamping augments left-to-right shunting and decreases systemic perfusion at birth in preterm lambs.

Previous studies have suggested that an extended period of ventilation before delayed cord clamping (DCC) augments birth-related rises in pulmonary arterial (PA) blood flow. However, it is unknown whether this greater rise in PA flow is accompanied by increases in left ventricular (LV) output and systemic arterial perfusion or whether it reflects enhanced left-to-right shunting across the ductus arteriosus and/or foramen ovale (FO), with decreased systemic arterial perfusion. Using an established preterm lamb birth transition model, this study compared the effect of a short (∼40 s, n = 11), moderate (∼2 min, n = 11) or extended (∼5 min, n = 12) period of initial mechanical lung ventilation before DCC on flow probe-derived perinatal changes in PA flow, LV output, total systemic arterial blood flow, ductal shunting and FO shunting. The LV output was relatively stable during initial ventilation but increased after DCC, with similar responses in all groups. Systemic arterial flow patterns displayed only minor differences during brief and moderate periods of initial ventilation and were similar after DCC. However, an increase in PA flow was augmented with an extended initial ventilation (P < 0.001), owing to an earlier onset of left-to-right ductal and FO shunting (P < 0.001), and was accompanied by a pronounced reduction in total systemic arterial flow (P = 0.005) that persisted for 4 min after DCC (P ≤ 0.039). These findings suggest that, owing to increased left-to-right shunting and a greater reduction in systemic arterial perfusion, an extended period of ventilation before DCC does not result in greater perinatal circulatory benefits than shorter periods of initial ventilation in the birth transition. KEY POINTS: Previous studies suggest that an extended period of initial ventilation before delayed cord clamping (DCC) augments birth-related rises in pulmonary arterial (PA) blood flow. It is unknown whether this greater rise in PA flow is accompanied by an increased left ventricular output and systemic arterial perfusion or whether it reflects enhanced left-to-right shunting across the ductus arteriosus and/or foramen ovale, with decreased systemic arterial perfusion. Anaesthetized preterm fetal lambs instrumented with central arterial flow probes underwent a brief (∼40 s), moderate (∼2 min) or extended (∼5 min) period of ventilation before DCC. Perinatal changes in left ventricular output were similar in all groups, but extended initial ventilation augmented both perinatal increases in PA flow, owing to earlier onset and greater left-to-right ductal and foramen ovale shunting, and perinatal reductions in total systemic arterial perfusion. Extended ventilation before DCC does not confer a greater perinatal circulatory benefit than shorter periods of initial ventilation.

Prenatal Predictors for Pulmonary Balloon Valvuloplasty in the Newborn.

Pulmonary balloon valvuloplasty (PBV) is the treatment of choice for subjects with isolated pulmonary valve stenosis (IPS). The purpose of this study was to define fetal echocardiographic features associated with an inpatient PBV prior to newborn hospital discharge and characterize resource utilization of IPS fetuses among participating centers. Six center, retrospective case series of singleton fetuses identified between 2010 and 2020 with IPS. Third-trimester echocardiogram data was compared with postnatal data, included pulmonary valve Doppler velocities, pulmonary valve insufficiency and ductus arteriosus flow direction. Comparison between subjects who underwent inpatient PBV during their newborn hospital admission versus those infants referred for outpatient PBV after initial hospital discharge. We analyzed data by logistic regression, student t test and Chi-Square testing with a p value of ≤ 0.05 considered statistically significant. Forty-nine IPS fetuses were identified. Thirty-eight (78%) underwent inpatient PBV at 5 (range 1-58) days and 11 (22%) underwent outpatient PBV at 51.8 (11-174) days. Newborns requiring an inpatient PBV were more likely to have one or more characteristics on 3rd-trimester fetal echocardiogram: left to right or bidirectional ductus arteriosus flow (61% vs 0%), and/or a peak pulmonary valve velocity > 3.0 m/s (odds ratio 16.9, 95% confidence interval 3.02-94.17) with a sensitivity of 90.4% and specificity of 97.7%. Ductus arteriosus flow direction and pulmonary valve peak velocity in the 3rd trimester can successfully predict the need for newborn inpatient PBV. We speculate these findings may be useful in choosing delivery site for the pregnancy complicated by fetal IPS.

Diagnostic accuracy of prenatal ultrasound in coarctation of aorta: systematic review and individual participant data meta-analysis.

OBJECTIVE: To determine the diagnostic accuracy of prenatal ultrasound in detecting coarctation of the aorta (CoA). METHODS: An individual participant data meta-analysis was performed to report on the strength of association and diagnostic accuracy of different ultrasound signs in detecting CoA prenatally. MEDLINE, EMBASE and CINAHL were searched for studies published between January 2000 and November 2021. Inclusion criteria were fetuses with suspected isolated CoA, defined as ventricular and/or great vessel disproportion with right dominance on ultrasound assessment. Individual participant-level data were obtained by two leading teams. PRISMA-IPD and PRISMA-DTA guidelines were used for extracting data, and the QUADAS-2 tool was used for assessing quality and applicability. The reference standard was CoA, defined as narrowing of the aortic arch, diagnosed after birth. The most commonly evaluated parameters on ultrasound, both in B-mode and on Doppler, constituted the index test. Summary estimates of sensitivity, specificity, diagnostic odds ratio (DOR) and likelihood ratios were computed using the hierarchical summary receiver-operating-characteristics model. RESULTS: The initial search yielded 72 studies, of which 25 met the inclusion criteria. Seventeen studies (640 fetuses) were included. On random-effects logistic regression analysis, tricuspid valve/mitral valve diameter ratio > 1.4 and > 1.6, aortic isthmus/arterial duct diameter ratio < 0.7, hypoplastic aortic arch (all P < 0.001), aortic isthmus diameter Z-score of < -2 in the sagittal (P = 0.003) and three-vessel-and-trachea (P < 0.001) views, pulmonary artery/ascending aorta diameter ratio > 1.4 (P = 0.048) and bidirectional flow at the foramen ovale (P = 0.012) were independently associated with CoA. Redundant foramen ovale was inversely associated with CoA (P = 0.037). Regarding diagnostic accuracy, tricuspid valve/mitral valve diameter ratio > 1.4 had a sensitivity of 72.6% (95% CI, 48.2-88.3%), specificity of 65.4% (95% CI, 46.9-80.2%) and DOR of 5.02 (95% CI, 1.82-13.9). The sensitivity and specificity values were, respectively, 75.0% (95% CI, 61.1-86.0%) and 39.7% (95% CI, 27.0-53.4%) for pulmonary artery/ascending aorta diameter ratio > 1.4, 47.8% (95% CI, 14.6-83.0%) and 87.6% (95% CI, 27.3-99.3%) for aortic isthmus diameter Z-score of < -2 in the sagittal view and 74.1% (95% CI, 58.0-85.6%) and 62.0% (95% CI, 41.6-78.9%) for aortic isthmus diameter Z-score of < -2 in the three-vessel-and-trachea view. Hypoplastic aortic arch had a sensitivity of 70.0% (95% CI, 42.0-88.6%), specificity of 91.3% (95% CI, 78.6-96.8%) and DOR of 24.9 (95% CI, 6.18-100). The diagnostic yield of prenatal ultrasound in detecting CoA did not change significantly when considering multiple categorical parameters. Five of the 11 evaluated continuous parameters were independently associated with CoA (all P < 0.001) but all had low-to-moderate diagnostic yield. CONCLUSIONS: Several prenatal ultrasound parameters are associated with an increased risk for postnatal CoA. However, diagnostic accuracy is only moderate, even when combinations of parameters are considered. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Renal function after ductus arteriosus transcatheter closure with or without angiography in very preterm infants.

AIM: Transcatheter closure of the patent ductus arteriosus (TCPDA) is increasingly used in preterm infants as an alternative to surgical ligation. However, clinically ill preterm infants are at risk of contrast nephropathy due to the angiography contrast agents used during the procedure. METHODS: We performed a single-centre before-and-after comparative study in VLBW infants to compare the kinetics of serum creatinine during the first 4 days after TCPDA with or without angiography. RESULTS: 69 patients were included and divided into two groups: TCPDA with (contrast+; n = 37) and without (contrast-, n = 32) use of contrast agent. The median dose [range] of contrast agent was 1.0 mL/kg [0.6-2.4 mL/kg]. The change in serum creatinine level between day 2 to 4 after TCPCA and baseline decreased in the contrast- group (-17% [-46%; 18%]), while it increased in the contrast+ group (7% [-24%; 202%] p = 0.002). Comparison of blood urea levels between groups showed similar significant differences. The change in serum creatinine between day 2 to 4 and baseline was significantly correlated with the dose of contrast agent (r2 = 0.682; p < 0.001). CONCLUSION: The use of contrast agents during TCPDA can potentially harm the renal function of very preterm infants. Therefore, we advise minimising or avoiding the use of contrast agents.

Fetal circular shunt in Ebstein's anomaly and non-steroidal anti-inflammatory treatment.

A circular shunt is a poor prognostic factor associated with Ebstein's anomaly. Targeting the constriction of the ductus arteriosus (DA) in order to limit or resolve the circular shunt, has been shown to improve fetal outcomes. Prenatal non-steroidal anti-inflammatory drugs (NSAIDs) have been known to constrict the DA. Recently, prenatal NSAIDs have been used for that purpose in the treatment of circular shunt. Limited research shows that it may be an effective treatment leading to improved fetal outcomes. In this article, we did an extensive review of literature to describe this therapy's effectiveness and outcomes. 82% of fetuses were able to achieve ductal constriction with prenatal NSAID therapy. For fetuses who achieved ductal constriction, fetal demise was less likely (6%) when compared to those who were unable to achieve the same (50%). Of all the fetuses with hydrops, 50% had resoluation of hydrops with prenatal NSAID treatment.

Three- and Four-Dimensional Imaging of Ductus Arteriosus in Fetuses With Pulmonary Atresia and Aortic Arch Abnormalities.

Advances in fetal echocardiography including newer techniques like 4D spatio-temporal image correlation technology has improved our understanding of fetal cardiac and extracardiac abnormalities. High resolution ultrasound combined with color Doppler and 3D rendering have contributed to an improved understanding of the fetal vascular system and its anomalies. This pictorial essay including ultrasound images and videos alongside their respective clay models, provides precise information of duct anatomy in fetuses with pulmonary atresia and aortic arch abnormalities.

Aortic dissection in a young male with persistent ductus arteriosus and a novel variant in MYLK.

Pathogenic variants in several genes involved in the function or regulation of smooth muscle cells (SMC) are known to predispose to congenital heart disease and thoracic aortic aneurysm and dissection (TAAD). Variants in MYLK are primarily known to predispose to TAAD, but a growing body of evidence points toward MYLK also playing an essential role in the regulation of SMC contraction outside the aorta. In this case report, we present a patient with co-occurrence of persistent ductus arteriosus (PDA) and thoracic aortic dissection. Genetic analyses revealed a novel splice acceptor variant (c.3986-1G > A) in MYLK, which segregated with disease in the family. RNA-analyses on fibroblasts showed that the variant induced skipping of exon 24, which resulted in an in-frame deletion of 101 amino acids. These findings suggest that MYLK-associated disease could include a broader phenotypic spectrum than isolated TAAD, including PDA and obstructive pulmonary disease. Genetic analyses could be considered in families with TAAD and PDA or obstructive pulmonary disease.

Patent ductus arteriosus stenting as therapeutic bridge in a patient with type A3 truncus arteriosus variant with multiple comorbidities.

Type A3 truncus arteriosus describes pulmonary atresia with non-confluent mediastinal pulmonary arteries in which one pulmonary artery arises from a patent ductus arteriosus and the contralateral pulmonary artery from the aorta resulting in ductal dependent pulmonary blood flow. We describe a premature neonate with caudal regression syndrome and type A3 truncus arteriosus who was palliated with a ductal stent allowing completion of a prolonged neonatal ICU hospitalisation for multiple comorbidities.

Intravenous prostaglandin E1 (alprostadil) bolus in ductus arteriosus-dependent CHD: valid or absolutely contraindicated?

The use of prostaglandin E1 is well documented in ductus arteriosus-dependent CHD or in neonatal pulmonary pathologies that cause severe pulmonary hypertension. The intravenous infusion is well established in loading infusion and maintenance with an onset of action of 30 minutes until 2 hours or even more. Our aim is to report three patients with pulmonary atresia that presented hypercyanotic spell due to a ductal spasm during cardiac catheterisation in whom the administration of a bolus of alprostadil reversed the spasm and increased pulmonary flow, immediately stabilising the condition of the patients allowing subsequent successful stent placement with no serious complications or sequelae after the administration of the bolus. More studies are needed to make a recommendation regarding the use of alprostadil in bolus in cases where the ductal spasm might jeopardise the life of the patient.

A histological study of the adult ligamentum arteriosum: Novel findings with application to a patent ductus arteriosus.

The ligamentum arteriosum (LA) is the vestigial fibrous remnant of the ductus arteriosus (DA), a fetal vessel arising from the left dorsal segment of the sixth aortic arch that connects the left pulmonary artery to the aortic arch. Incomplete obliteration of the DA results in a patent ductus arteriosus (PDA), causing the shunting of oxygen-rich blood to recirculate to the lungs, which can lead to pulmonary hypertension. The current study aims to further elucidate the structural characteristics of the LA via histological analysis with data gathered from adult cadaveric specimens. The LA was harvested and histologically observed with Hematoxylin and Eosin, van Gieson, and Masson's trichrome staining. Fibrous and muscle tissues were observed in all 25 specimens. The LA was categorized into three types based on the morphological features of the LA. Type I (vessel-like structure), type II (fibrotic tissue with duct-like structure), and type III (no duct-like structure) were found in 4.0%, 80.0%, and 16.0%, respectively. Finally, the remnant of a valve in the LA was also observed at the junction between the AA and LA. We suggest that this valve be called the "pulmonary-aortic valve." In the majority of the adult LAs, a duct-like structure was still present. These data could better elucidate our understanding of the pathology and etiology of a PDA.

Prenatal Diagnosis of Ductus Arteriosus Anomalies: A Single-Center Study.

To evaluate the fetal ductus arteriosus anomalies diagnosed by fetal echocardiography. The perinatal outcomes and associated cardiac and genetic anomalies are also explored. The fetal echocardiography records of 2366 fetuses were evaluated retrospectively. Thirty-seven pregnancies prenatally diagnosed with ductus arteriosus anomalies and evaluated after delivery were enrolled in the study. Perinatal and obstetric outcomes were analyzed. The incidence of ductus arteriosus anomaly in our series was 1.5% (37/2366). The most frequent ductus arteriosus anomaly detected was right-sided ductus arteriosus followed by aneurysm, constriction and bilateral ductus arteriosus with an incidence of 51.3%, 27.1%, 18.9% and 2.7%, respectively. There were 19 fetuses with right-sided ductus arteriosus, of which 15 had tetralogy of Fallot. There were 2 chromosomal anomalies (22q11 microdeletion) in this group. Of the 7 fetuses with ductus arteriosus constriction, 3 (3/7, 42.9%) died in-utero. There were 2 (2/10, 20%) neonatal deaths due to hypoplastic left heart syndrome in the ductus arteriosus aneurysm group. Various types of ductus arteriosus anomalies can be diagnosed prenatally. Perinatal outcomes mostly dependent on the type of the ductus arteriosus anomaly and accompanying cardiac malformations.

Confusion from prenatal diagnosis: Type C persistent fifth aortic arch or right-side ductus arteriosus.

We described a case of a double aortic arch (DAA) with a subaortic left brachiocephalic vein (LBCV) and right-side ductus arteriosus using high-definition (HD) flow render mode and spatiotemporal image correlation (STIC). We experienced uncertainty regarding this interesting case despite the diagnosis of right-sided ductus arteriosus. The ductus arteriosus originates from the right pulmonary artery (PA) and converges into the descending aorta (DAO), whereas the vessel originated from the PA and converged into the ascending aorta (AAO). Therefore, we assumed that the vessel connecting the PA to AAO may be a type-C persistent fifth aortic arch (PFAA).

Trends in Ductus Arteriosus Stent Versus Blalock-Taussig-Thomas Shunt Use and Comparison of Cost, Length of Stay, and Short-Term Outcomes in Neonates With Ductal-Dependent Pulmonary Blood Flow: An Observational Study Using the Pediatric Health Information Systems Database.

BACKGROUND: The modified Blalock-Taussig-Thomas shunt is the gold standard palliation for securing pulmonary blood flow in infants with ductal-dependent pulmonary blood flow. Recently, the ductus arteriosus stent (DAS) has become a viable alternative. METHODS AND RESULTS: This was a retrospective multicenter study of neonates ≤30 days undergoing DAS or Blalock-Taussig-Thomas shunt placement between January 1, 2017 and December 31, 2020 at hospitals reporting to the Pediatric Health Information Systems database. We performed generalized linear mixed-effects modeling to evaluate trends in intervention and intercenter variation, propensity score adjustment and inverse probability weighting with linear mixed-effects modeling to analyze length of stay and cost of hospitalization, and generalized linear mixed modeling to analyze differences in 30-day outcomes. There were 1874 subjects (58% male, 61% White) from 45 centers (29% DAS). Odds of DAS increased with time (odds ratio [OR] 1.23, annually, P<0.01 [95% CI, 1.10-1.38]) with significant intercenter variation (median OR, 3.81 [95% CI, 2.74-5.91]). DAS was associated with shorter hospital length of stay (ratio of geometric means, 0.76 [95% CI, 0.63-0.91]), shorter intensive care unit length of stay (ratio of geometric means, 0.77 [95% CI, 0.61-0.97]), and less expensive hospitalization (ratio of geometric means, 0.70 [95% CI, 0.56-0.87]). Intervention was not significantly associated with odds of 30-day transplant-free survival (OR,1.18 [95% CI, 0.70-1.99]) or freedom from catheter reintervention (OR, 1.02 [95% CI, 0.65-1.58]), but DAS was associated with 30-day freedom from composite adverse outcome (OR, 1.51 [95% CI, 1.11-2.05]). CONCLUSIONS: Use of DAS is increasing, but there is variability across centers. Though odds of transplant-free survival and reintervention were not significantly different after DAS, and DAS was associated with shorter length of stay and lower in-hospital costs.

Multiple vascular malformations in a newborn.

We describe the case of a term newborn who presented with congenital testicular torsion at 10 hours of age. During the evaluation of this problem, additional malformations were encountered. Diagnostic and therapeutic considerations are addressed.

Premature closure of the arterial duct presenting with right heart failure of the fetus and ductal aneurysm postnatally.

In utero idiopathic constriction of the arterial duct is a rare condition with only a handful reported cases. Ductal aneurysms with thrombus formations on the other hand are significantly more common. We report a case of a term infant who presented with right heart failure due to premature ductal closure and postnatal severe respiratory distress. Subsequent diagnostics revealed paresis of left laryngeal nerve and obstruction of the left pulmonary artery secondary to a ductal aneurysm. Consequently, surgical intervention was considered necessary. Post-operatively, right ventricular function and hoarseness resolved slowly.

Vav2 promotes ductus arteriosus anatomic closure via the remodeling of smooth muscle cells by Rac1 activation.

The ductus arteriosus (DA), bridging the aorta and pulmonary artery, immediately starts closing after birth. Remodeling of DA leads to anatomic obstruction to prevent repatency. Several histological changes, especially extracellular matrices (ECMs) deposition and smooth muscle cells (SMCs) migration bring to anatomic closure. The genetic etiology and mechanism of DA closure remain elusive. We have previously reported a novel copy number variant containing Vav2 in patent ductus arteriosus (PDA) patients, but its specific role in DA closure remains unknown. The present study revealed that the expression of Vav2 was reduced in human patent DA, and it was less enrichment in the adjacent aorta. Matrigel experiments demonstrated that Vav2 could promote SMC migration from PDA patient explants. Smooth muscle cells with Vav2 overexpression also presented an increased capacity in migration and downregulated contractile-related proteins. Meanwhile, SMCs with Vav2 overexpression exhibited higher expression of collagen III and lessened protein abundance of lysyl oxidase, and both changes are beneficial to DA remodeling. Overexpression of Vav2 resulted in increased activity of Rac1, Cdc42, and RhoA in SMCs. Further investigation noteworthily found that the above alterations caused by Vav2 overexpression were particularly reversed by Rac1 inhibitor. A heterozygous, rare Vav2 variant was identified in PDA patients. Compared with the wild type, this variant attenuated Vav2 protein expression and weakened the activation of downstream Rac1, further impairing its functions in SMCs. In conclusion, Vav2 functions as an activator for Rac1 in SMCs to promote SMCs migration, dedifferentiation, and ECMs production. Deleterious variant potentially induces Vav2 loss of function, further providing possible molecular mechanisms about Vav2 in PDA pathogenesis. These findings enriched the current genetic etiology of PDA, which may provide a novel target for prenatal diagnosis and treatment. KEY MESSAGES: Although we have proposed the potential association between Vav2 and PDA incidence through whole exome sequencing, the molecular mechanisms underlying Vav2 in PDA have never been reported. This work, for the first time, demonstrated that Vav2 was exclusively expressed in closed DAs. Moreover, we found that Vav2 participated in the process of anatomic closure by mediating SMCs migration, dedifferentiation, and ECMs deposition through Rac1 activation. Our findings first identified a deleterious Vav2 c.701C>T variant that affected its function in SMCs by impairing Rac1 activation, which may lead to PDA defect. Vav2 may become an early diagnosis and an effective intervention target for PDA clinical therapy.

The so-called ligamentum arteriosum is innervated.

The ductus arteriosus is a muscular artery connecting the pulmonary trunk directly to the aorta in fetal circulation in order to by-pass the fluid filled lungs. Post-natally, this vessel is speculated to undergo obliteration, fibrosis and ultimately metamorphosize into a band of ligament, thereby changing name from the ductus arteriosus to the ligamentum arteriosum (LA). Earlier studies into the innervation of the ductus arteriosus reported innervation from the left aortic and vagus nerves. However, information of what becomes of the innervation is scanty and contradictory. I hypothesized that; this fetal shunt still receives innervation even in post-uterine life. To test this, LA of human, pig, and wild-type mice were studied using double-immunofluorescence labeling using antibodies directed against structural and general neuronal marker proteins (Smooth muscle actin and Protein gene product 9.5 (PGP 9.5, respectively). Additionally, TEM studies were performed on mouse LA. Results from the present study demonstrates an extensive innervation of the LA in animals (mice and pigs) and in senescent humans validated by two independent methods, i.e., immunolabeling with antibody directed against PGP 9.5 and TEM. Intense immunoreactivity was clearly visible in samples subjected to PGP-immunolabeling. TEM revealed the presence of nerve terminals with about 30% of all nerve terminals observed less than 1 µm away from smooth muscle cells within the LA. This clearly differs from elastic arteries, where the distance between autonomic terminals and smooth muscle cells is rarely less than 1 µm. Conceivably, these results imply that the so- called LA receives innervation representative of that present within the ductus arteriosus during fetal life. This provides the first reliable study of innervation of the LA and makes room for further investigation into the neurochemistry of this innervation. This is crucial as the presence of nerve terminals may play a role in vessel compliance or impedance of the two great vessels related to this structure. The substances released by these fibers may also have an influence on cells and tissues in the immediate microenvironment of this structure.