Treatment, not delivery, of the late preterm and term fetus with supraventricular arrhythmia.

OBJECTIVE: While in-utero treatment of sustained fetal supraventricular arrhythmia (SVA) is standard practice in the previable and preterm fetus, data are limited on best practice for late preterm (34 + 0 to 36 + 6 weeks), early term (37 + 0 to 38 + 6 weeks) and term (> 39 weeks) fetuses with SVA. We reviewed the delivery and postnatal outcomes of fetuses at ≥ 35 weeks of gestation undergoing treatment rather than immediate delivery. METHODS: This was a retrospective case series of fetuses presenting at ≥ 35 weeks of gestation with sustained SVA and treated transplacentally at six institutions between 2012 and 2022. Data were collected on gestational age at presentation and delivery, SVA diagnosis (short ventriculoatrial (VA) tachycardia, long VA tachycardia or atrial flutter), type of antiarrhythmic medication used, interval between treatment and conversion to sinus rhythm and postnatal SVA recurrence. RESULTS: Overall, 37 fetuses presented at a median gestational age of 35.7 (range, 35.0-39.7) weeks with short VA tachycardia (n = 20), long VA tachycardia (n = 7) or atrial flutter (n = 10). Four (11%) fetuses were hydropic. In-utero treatment led to restoration of sinus rhythm in 35 (95%) fetuses at a median of 2 (range, 1-17) days; this included three of the four fetuses with hydrops. Antiarrhythmic medications included flecainide (n = 11), digoxin (n = 7), sotalol (n = 11) and dual therapy (n = 8). Neonates were liveborn at 36-41 weeks via spontaneous vaginal delivery (23/37 (62%)) or Cesarean delivery (14/37 (38%)). Cesarean delivery was indicated for fetal SVA in two fetuses, atrial ectopy or sinus bradycardia in three fetuses and obstetric reasons in nine fetuses that were in sinus rhythm at the time of delivery. Twenty-one (57%) cases were treated for recurrent SVA after birth. CONCLUSION: In-utero treatment of the near term and term (≥ 35-week) SVA fetus is highly successful even in the presence of hydrops, with the majority of cases delivered vaginally closer to term, thereby avoiding unnecessary Cesarean section. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Improved detection of coarctation of the aorta using speckle-tracking analysis of fetal heart on last examination prior to delivery.

OBJECTIVE: The false-positive rate for prenatal diagnosis of coarctation of the aorta (FP-CoA) commonly exceeds 50%, with an accurate detection rate of < 50%. This study was conducted to determine if the sensitivity for prenatal detection of true CoA and the FP-CoA rate could be improved by evaluating the fetal epicardial size and shape in the four-chamber view (4CV) and the endocardial right (RV) and left (LV) ventricular size, shape and contractility. METHODS: We analyzed retrospectively Digital Imaging and Communications in Medicine (DICOM) clips of the 4CV from the last examination prior to delivery in a series of 108 fetuses with CoA suspected prenatally by pediatric cardiologists using traditional diagnostic criteria. Postnatal evaluation distinguished those fetuses which subsequently required CoA surgery (true positives; true CoA) from those that were FP-CoA. Postnatal cardiac abnormalities were identified for each group. For the prenatal evaluation, we measured the 4CV end-diastolic epicardial area, circumference, length, width and global sphericity index. Speckle-tracking analysis was used to compute the endocardial RV and LV end-diastolic area, length, 24-segment sphericity index, 24-segment transverse width and the following functional parameters: fractional area change; global longitudinal, free-wall and septal-wall strain; basal-apical-length, basal free-wall and basal septal-wall fractional shortening; septal-wall annular plane systolic excursion; 24-segment transverse-width fractional shortening; and LV end-diastolic and end-systolic volumes, stroke volume, cardiac output and ejection fraction. In addition, the RV/LV end-diastolic area ratio was computed. Using a control group of 200 normal fetuses, the mean and SD for each of the above cardiac measurements was used to compute the Z-scores for each measurement in each of the 108 study fetuses. Logistic regression analysis was then performed on the Z-score values to identify variables that separated the true CoA group from the FP-CoA group. RESULTS: Of the 108 study fetuses, 54 were confirmed postnatally to have true CoA and 54 were FP-CoA. Right/left area disproportion > 90th centile was present in 80% (n = 43) of the true-CoA fetuses and 76% (n = 41) of the FP-CoA fetuses. Fetuses with true CoA had a significantly greater number of associated cardiac abnormalities (93%, n = 50) compared with the FP-CoA fetuses (61%, n = 33) (P < 0.001). The most common associated malformations were bicuspid aortic valve (true CoA, 46% (n = 25) vs FP-CoA, 22% (n = 12); P < 0.01), aortic arch hypoplasia (true CoA, 31% (n = 17) vs FP-CoA, 11% (n = 6); P < 0.01), ventricular septal defect (true CoA, 33% (n = 18) vs FP-CoA, 11% (n = 6); P < 0.05) and mitral valve abnormality (true CoA, 30% (n = 16) vs FP-CoA, 4% (n = 2); P < 0.01). Logistic regression analysis identified 28 variables that correctly identified 96% (52/54) of the fetuses with true CoA, with a false-positive rate of 4% (2/54) and a false-negative rate of 4% (2/54). These variables included the epicardial size in the 4CV, size and shape of RV and LV, and abnormal contractility of RV and LV. The area under the receiver-operating-characteristics curve was 0.98 (SE, 0.023; 95% CI, 0.84-1). There was no significant difference in the percent of fetuses with RV/LV area disproportion between those with CoA and those that were FP-CoA. CONCLUSIONS: Speckle-tracking analysis of multiple ventricular measurements may be helpful to refine the diagnosis in fetuses that are suspected to have CoA prenatally. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Keeping upbeat to prevent the heartbreak of anti-Ro/SSA pregnancy.

Linked Comment: Ultrasound Obstet Gynecol 2019; 54: 87-95.

Assessment of atrioventricular conduction by echocardiography and magnetocardiography in normal and anti-Ro/SSA-antibody-positive pregnancies.

OBJECTIVES: The objectives of this study were, first, to evaluate the association between fetal echocardiographic atrioventricular (AV) and magnetocardiographic (fMCG) PR intervals at different gestational ages (GAs) in normal and anti-Ro/SSA-antibody-positive pregnancies; second, to determine if PR interval could be predicted by AV interval; and third, to assess the neonatal outcome of fetuses with prolonged AV and PR intervals, with the goal of developing criteria for fetal first-degree AV block (AVB-I). METHODS: This was a retrospective study of anti-Ro/SSA-antibody-positive pregnancies (cases) and controls that underwent fMCG and fetal echocardiography at the same recording session. Cardiac cycle length, GA and AV (by mitral inflow/aortic outflow Doppler) and PR (by fMCG) intervals were measured. We tested for significant differences between AV and PR intervals using generalized estimating equations to account for repeat measurements, and assessed whether PR interval could be predicted reliably by AV interval. After delivery, infants with fetal AV or PR interval Z-score ≥ 3 underwent 12-lead electrocardiography. RESULTS: Thirty-nine controls and 31 cases underwent 46 and 36 simultaneous fMCG and echocardiographic examinations, respectively; 101 controls and nine cases underwent fMCG only. AV and PR intervals increased with GA (P < 0.05 for both). Overall, AV and PR intervals were significantly different from each other (P < 0.001); this difference was not significant when compared between cases and controls (P = 0.222). PR interval could not be predicted accurately from AV interval and GA alone. Three of four cases with AV and PR interval Z-scores > + 3 had postnatal AVB-I despite treatment. The fourth fetus, which had predominately second-degree AVB and rare periods of AVB-I, progressed to third-degree AVB despite treatment with dexamethasone. CONCLUSIONS: The diagnostic threshold for AVB-I, defined by AV interval Z-score, is GA dependent. Based on the observed data, an AV interval Z-score threshold of 3 (AV interval, 151-167 ms) may be appropriate. Echocardiographic AV interval was not predictive of fMCG-PR interval. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Heart sounds at home: feasibility of an ambulatory fetal heart rhythm surveillance program for anti-SSA-positive pregnancies.

OBJECTIVE: Fetuses exposed to anti-SSA (Sjögren's) antibodies are at risk of developing irreversible complete atrioventricular block (CAVB), resulting in death or permanent cardiac pacing. Anti-inflammatory treatment during the transition period from normal heart rhythm (fetal heart rhythm (FHR)) to CAVB (emergent CAVB) can restore sinus rhythm, but detection of emergent CAVB is challenging, because it can develop in ⩽24 h. We tested the feasibility of a new technique that relies on home FHR monitoring by the mother, to surveil for emergent CAVB. STUDY DESIGN: We recruited anti-SSA-positive mothers at 16 to 18 weeks gestation (baseline) from 8 centers and instructed them to monitor FHR two times a day until 26 weeks, using a Doppler device at home. FHR was also surveilled by weekly or every other week fetal echo. If FHR was irregular, the mother underwent additional fetal echo. We compared maternal stress/anxiety before and after monitoring. Postnatally, infants underwent a 12-lead electrocardiogram. RESULTS: Among 133 recruited, 125 (94%) enrolled. Among those enrolled, 96% completed the study. Reasons for withdrawal (n=5) were as follows: termination of pregnancy, monitoring too time consuming or moved away. During home monitoring, 9 (7.5%) mothers detected irregular FHR diagnosed by fetal echo as normal (false positive, n=2) or benign atrial arrhythmia (n=7). No CAVB was undetected or developed after monitoring. Questionnaire analysis indicated mothers felt comforted by the experience and would monitor again in future pregnancies. CONCLUSION: These data suggest ambulatory FHR surveillance of anti-SSA-positive pregnancies is feasible, has a low false positive rate and is empowering to mothers.

Frequency of 22q11 deletions in patients with conotruncal defects.

OBJECTIVES: This study was designed to determine the frequency of 22q11 deletions in a large, prospectively ascertained sample of patients with conotruncal defects and to evaluate the deletion frequency when additional cardiac findings are also considered. BACKGROUND: Chromosome 22q11 deletions are present in the majority of patients with DiGeorge, velocardiofacial and conotruncal anomaly face syndromes in which conotruncal defects are a cardinal feature. Previous studies suggest that a substantial number of patients with congenital heart disease have a 22q11 deletion. METHODS: Two hundred fifty-one patients with conotruncal defects were prospectively enrolled into the study and screened for the presence of a 22q11 deletion. RESULTS: Deletions were found in 50.0% with interrupted aortic arch (IAA), 34.5% of patients with truncus arteriosus (TA), and 15.9% with tetralogy of Fallot (TOF). Two of 6 patients with a posterior malalignment type ventricular septal defect (PMVSD) and only 1 of 20 patients with double outlet right ventricle were found to have a 22q11 deletion. None of the 45 patients with transposition of the great arteries had a deletion. The frequency of 22q11 deletions was higher in patients with anomalies of the pulmonary arteries, aortic arch or its major branches as compared to patients with a normal left aortic arch regardless of intracardiac anatomy. CONCLUSIONS: A substantial proportion of patients with IAA, TA, TOF and PMVSD have a deletion of chromosome 22q11. Deletions are more common in patients with aortic arch or vessel anomalies. These results begin to define guidelines for deletion screening of patients with conotruncal defects.

Evolution of latent hypoparathyroidism in familial 22q11 deletion syndrome.

Latent hypoparathyroidism (LHP), the inability to increase midmolecular parathyroid hormone levels appropriately during a hypocalcemic challenge, was reported previously in an asymptomatic woman with tetralogy of Fallot. This women's fourth child died with DiGeorge anomaly. Seven years later, we restudied the index patient with LHP and evaluated three generations of her family for parathyroid dysfunction, cardiac abnormalities, and del 22(q11). Deletions were found in six relatives, three with conotruncal cardiac defects and three with a structurally normal heart. We found significant transgenerational noncardiac phenotypic variability, including learning difficulties, dysmorphic facial appearance, and psychiatric illness. A spectrum of parathyroid gland dysfunction associated with the del 22(q11) was seen, ranging from hypocalcemic hypoparathyroidism to normocalcemia with abnormally low basal intact parathyroid hormone (iPTH) levels. In addition, LHP found in the index patient 7 years ago had evolved to frank hypocalcemic hypoparathyroidism. In this family, which is the largest family with 22q11 deletions studied to date, parathyroid gland dysfunction evolved over time. We suggest that the calcium parathyroid hormone axis of unrelated patients with del 22(q11) be followed closely for the development of hypocalcemic hypoparathyroidism.

Autosomal dominant transmission of familial laterality defects.

Heterotaxy results from failure to establish normal left-right asymmetry during embryonic development. Most familial cases are thought to be autosomal recessive. We have identified a family in which 4 individuals from 3 generations manifest laterality defects. Twenty-five family members have been examined. Two have complete reversal of normal laterality (situs inversus) while 2 others have asplenia, midline liver, and complex cardiac malformations (situs ambiguus). Two additional obligate gene carriers are anatomically normal (situs solitus). Male-to-male transmission confirms autosomal inheritance. Identification of this family establishes an autosomal dominant form of laterality defect, suggesting that a portion of sporadic cases may be new-mutation dominant or unrecognized familial cases. The finding of all forms of laterality (solitus, ambiguus, and inversus) among obligate disease gene carriers within a single family may be relevant to genetic evaluation and counseling in apparently isolated patients with laterality disturbance.

Management strategy for fetal tachycardia.

OBJECTIVE: To develop a management strategy for fetal tachycardia. METHODS: Forty-four fetuses (20-40 weeks' gestation) with nonsinus tachycardia were divided into three groups based on duration of tachycardia and degree of heart failure. Fetuses with intermittent tachycardia were treated expectantly. Fetuses with sustained tachycardia were treated with transplacental antiarrhythmic agents alone if heart failure was mild to moderate, and with direct intramuscular therapy if heart failure was severe. Degree of heart failure was determined by echocardiographic variables of ventricular function, atrioventricular valve insufficiency, and hydrops. Fetal well-being and response to treatment were evaluated by daily heart rate surveillance and frequent fetal echocardiograms and ultrasounds. RESULTS: Fifteen fetuses with intermittent tachycardia (n = 15, group 1) did not progress to sustained tachycardia or heart failure. Fetuses with sustained tachycardia and mild-to-moderate heart failure (n = 14, group 2) were cardioverted or rate controlled with transplacental agents (n = 9); three term fetuses were delivered electively without treatment and two progressed to severe heart failure and were treated in group 3. Seventeen fetuses (15 initially, two progressing) with severe heart failure were cardioverted (in 0. 25-21 days; mean 4.3 days) with fetal intramuscular plus transplacental antiarrhythmic therapy (group 3). Overall, 43 of 44 fetuses were delivered at 32 to 41 (mean 37) weeks with minimal morbidity and a mortality rate of 2.2% (95% confidence interval 0. 06%, 12.0%). CONCLUSION: Perinatal mortality and morbidity were low after following a management strategy based on duration of tachycardia, degree of heart failure, and biophysical profile combined with vigilant ongoing fetal surveillance.

22q11.2 deletion syndrome: DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes.

A microdeletion of chromosome 22q11.2 is found in most patients with velocardiofacial syndrome, DiGeorge syndrome, and conotruncal anomaly face syndrome, and in some patients with Cayler cardiofacial and autosomal dominant Opitz-G/BBB syndromes. A wide spectrum of clinical findings accompanies the 22q11.2 deletion, without genotype or phenotype correlation even among affected family members. Classic features are dysmorphic facies, conotruncal cardiac defects, hypocalcemic hypoparathyroidism, T-cell mediated immune deficiency, and palate abnormalities. Less well recognized are learning, speech, feeding, and psychiatric disorders, and renal and musculoskeletal defects. Parathyroid and immune deficiencies in the same individual can progress or resolve with time. The 22q11.2 deletion can be inherited as an autosomal dominant or arise as a de novo deletion or translocation. Fluorescent in situ hybridization using cosmid probes mapping to the DiGeorge chromosomal region is a widely available method to detect the 22q11.2 deletion in metaphase chromosomes from cultured lymphocytes, amniocytes, or chorionic villi. The ubiquitin-fusion-degradation-1-like gene, expressed in embryonic branchial arches and in the conotruncus, appears to play a prominent role in the pathogenesis of the 22q11.2 deletion syndrome.

Pharmacodynamics and pharmacokinetics of esmolol, a short-acting beta-blocking agent, in children.

Esmolol, a short-acting intravenous cardioselective beta-blocking agent, was evaluated for age-dependent pharmacodynamic and pharmacokinetic features in 17 young patients (6 months to 14 years). A loading dose (500 micrograms/kg/min) alternating with a maintenance dose (25-200 micrograms/kg/min, titrating by 25 micrograms/kg/min every 4 min) was infused until the heart rate or mean arterial pressure decreased 10%. Cardiac index, left ventricular shortening fraction, and systemic vascular resistance were measured at baseline, peak esmolol effect, and recovery. Serum esmolol concentrations were obtained to determine the half-life and the elimination rate constant. Esmolol reduced the heart rate, blood pressure, shortening fraction, and cardiac index in all patients, but it did not change systemic vascular resistance. Maintenance esmolol dose was 118 +/- 49 micrograms/kg/min, and the half-life was 2.88 +/- 2.67 min. Blood pressure and heart rate returned to normal within 2-16 min, but cardiac index and shortening fraction took longer to recover. There were no statistically significant age-dependent pharmacodynamic effects, but blood pressure decreased prior to heart rate and cardiac index took longer to recovery in patients who weighed < or = 15 kg. The pharmacokinetic profile in young patients was similar to that of older patients, but the half-life was shorter. The only side effect was transient nausea and vomiting in one patient. Esmolol is a safe and efficacious beta-blocking agent in young patients.

Dysregulation of calcium homeostasis after severe burn injury in children: possible role of magnesium depletion.

OBJECTIVE: To determine the cause and extent of hypocalcemia observed in children after severe burns. DESIGN: We studied 10 children with burns covering 57% +/- 17% (SD) body surface area, ages 9.6 +/- 4.7 years, who were admitted consecutively during a 6-month period. Diet supplied a minimum of 2.7 gm/m2 of calcium, 0.3 gm/m2 of magnesium, and 2.2 gm/m2 phosphate. Blood specimens were obtained daily for 10 +/- 5 days for the following tests: (1) simultaneous analysis for ionized calcium, magnesium, and intact parathyroid hormone (group A); (2) two of these children, randomly selected, had serial 2-hour determinations on a single day (group B); (3) a modified Ellsworth-Howard test, consisting of a 10-minute infusion of synthetic parathyroid hormone 18 +/- 10 days post-burn and associated changes in urinary cyclic adenosine monophosphate excretion and renal threshold phosphate concentration (group C). Three of these children, when normomagnesemic, also received a standard magnesium infusion to determine magnesium retention (group D). Data were analyzed with chi-square, regression analysis, and non-parametric testing as appropriate. RESULTS: All patients showed sustained hypocalcemia and hypomagnesemia; intact parathyroid hormone response was inappropriately low and response to synthetic parathyroid hormone infusion was blunted. Lowest ionized calcium levels were associated with hypomagnesemia. CONCLUSION: Hypoparathyroidism and blunted renal response to parathyroid hormone suggest that magnesium depletion may contribute to their pathogenesis. Magnesium repletion and monitoring are recommended.

Latent hypoparathyroidism in children with conotruncal cardiac defects.

BACKGROUND: DiGeorge anomaly is characterized by hypoplasia or atresia of the thymus and parathyroid glands resulting in T cell-mediated deficiency, hypocalcemic hypoparathyroidism, and conotruncal cardiac defects. It usually is associated with deletions of chromosomal region 22q11. We hypothesized that the stimulated (secretory reserve) but not the constitutive secretion of parathyroid hormone would be reduced in normocalcemic children with conotruncal cardiac defects but no overt immune deficiency and would be related to the presence of a deletion in the DiGeorge chromosomal region of 22q11. METHODS AND RESULTS: Blood-ionized calcium and serum-intact parathyroid hormone were measured at baseline and seven more times during hypocalcemia induced during cardiopulmonary bypass in 22 patients and 10 control subjects with an atrial septal defect. Chromosomal deletions were detected by fluorescent in situ hybridization and DNA dosage analysis. There were no differences in basal calcium and parathyroid hormone levels between patients and control subjects. All had increased parathyroid hormone in response to hypocalcemia; despite lower calcium levels, parathyroid hormone levels were lower in patients. The parathyroid hormone secretory reserve in 14 of 22 patients was reduced compared with control subjects; 4 of the 14 had deletions. CONCLUSIONS: A significant number of children with conotruncal cardiac defects have normocalcemia and a normal constitutive level of parathyroid hormone but deficient parathyroid hormone secretory reserve; about 30% also have 22q11 deletions. Such children may be at risk for the later development of hypocalcemic hypoparathyroidism.