James C. Huhta

Indomethacin in the treatment of premature labor. Effects on the fetal ductus arteriosus.

Indomethacin is a potent agent in the treatment of premature labor, but its use has been limited because of concern about its constrictive effects on the fetal ductus arteriosus. To study these effects we used serial fetal echocardiography in 13 pregnant women in premature labor who received indomethacin according to three different dose schedules, ranging from 100 to 175 mg per day, for a maximum of 72 hours. The gestational ages of the fetuses ranged from 26.5 to 31.0 weeks. The detection of ductal constriction in 7 of the 14 fetuses by echocardiography led to the discontinuation of indomethacin. Three fetuses also had tricuspid regurgitation. There was no statistically significant difference between the mean (+/- SEM) gestational age of the fetuses with ductal constriction and that of those without constriction (29.3 +/- 0.59 and 28.4 +/- 0.52, respectively). There was no relation between serum indomethacin levels in the mothers and ductal constriction. In all seven fetuses affected, ductal constriction had resolved by the time they were restudied 24 hours after the discontinuation of indomethacin. Persistent fetal circulation was not detected in any of the 11 neonates studied after delivery. Indomethacin used to treat premature labor appears to cause transient constriction of the ductus arteriosus in some fetuses, even after short-term use.

Diagnosis and Treatment of Fetal Cardiac Disease A Scientific Statement From the American Heart Association

Background— The goal of this statement is to review available literature and to put forth a scientific statement on the current practice of fetal cardiac medicine, including the diagnosis and management of fetal cardiovascular disease. Methods and Results— A writing group appointed by the American Heart Association reviewed the available literature pertaining to topics relevant to fetal cardiac medicine, including the diagnosis of congenital heart disease and arrhythmias, assessment of cardiac function and the cardiovascular system, and available treatment options. The American College of Cardiology/American Heart Association classification of recommendations and level of evidence for practice guidelines were applied to the current practice of fetal cardiac medicine. Recommendations relating to the specifics of fetal diagnosis, including the timing of referral for study, indications for referral, and experience suggested for performance and interpretation of studies, are presented. The components of a fetal echocardiogram are described in detail, including descriptions of the assessment of cardiac anatomy, cardiac function, and rhythm. Complementary modalities for fetal cardiac assessment are reviewed, including the use of advanced ultrasound techniques, fetal magnetic resonance imaging, and fetal magnetocardiography and electrocardiography for rhythm assessment. Models for parental counseling and a discussion of parental stress and depression assessments are reviewed. Available fetal therapies, including medical management for arrhythmias or heart failure and closed or open intervention for diseases affecting the cardiovascular system such as twin–twin transfusion syndrome, lung masses, and vascular tumors, are highlighted. Catheter-based intervention strategies to prevent the progression of disease in utero are also discussed. Recommendations for delivery planning strategies for fetuses with congenital heart disease including models based on classification of disease severity and delivery room treatment will be highlighted. Outcome assessment is reviewed to show the benefit of prenatal diagnosis and management as they affect outcome for babies with congenital heart disease. Conclusions— Fetal cardiac medicine has evolved considerably over the past 2 decades, predominantly in response to advances in imaging technology and innovations in therapies. The diagnosis of cardiac disease in the fetus is mostly made with ultrasound; however, new technologies, including 3- and 4-dimensional echocardiography, magnetic resonance imaging, and fetal electrocardiography and magnetocardiography, are available. Medical and interventional treatments for select diseases and strategies for delivery room care enable stabilization of high-risk fetuses and contribute to improved outcomes. This statement highlights what is currently known and recommended on the basis of evidence and experience in the rapidly advancing and highly specialized field of fetal cardiac care.

Detection and quantitation of constriction of the fetal ductus arteriosus by Doppler echocardiography.

Pulmonary hypertension may occur in the fetus in the presence of constriction of the ductus arteriosus. The feasibility of detection and quantitation of fetal ductal constriction by Doppler echocardiography was assessed in an animal preparation in which ductal constriction was created in the fetal lamb with a variable ligature causing varying degrees of fetal pulmonary hypertension (fetal pulmonary arterial systolic pressure 57 to 97 mm Hg and ductal gradient 9 to 42 mm Hg). Comparison of blinded, continuous-wave peak Doppler velocity (V) measurements of the ductal gradient with the modified Bernoulli assumption (gradient = 4V2) compared well with direct catheter measurements of instantaneous peak systolic gradient (r = .99, catheter = 0.95 X Doppler + 0.6), peak-to-peak gradient (r = .97), and mid-diastolic gradient (r = .85). Ductal constriction was characterized by an increase in the peak systolic and diastolic velocities. The normal human fetal ductus arteriosus blood flow velocity pattern was assessed by pulsed Doppler techniques in 25 normal human fetuses after 20 weeks gestation. The peak systolic flow velocity in the ductus arteriosus measured by image-directed pulsed Doppler echocardiography ranged from 50 to 141 cm/sec (mean 80 cm/sec) and increased with gestational age (r = .50). Diastolic velocity in the ductus arteriosus was consistently directed toward the descending aorta and ranged from 6 to 30 cm/sec. The ductal systolic velocities were the highest blood flow velocities in the fetal cardiovascular system. Application of these techniques to fetuses whose mothers were receiving indomethacin for treatment of premature labor at 30 to 31 weeks gestation confirmed this method to be sensitive for detection of fetal ductal constriction, which developed in three fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

Doppler Echocardiography of Normal and Abnormal Embryonic Mouse Heart

To evaluate normal embryonic mouse heart development using Doppler echocardiography and to quantify changes in normal embryonic mouse cardiac function with increasing gestational age from the time of cardiac septation, a new method was applied using Doppler echocardiography. Trisomic embryos were screened to evaluate a model of abnormal cardiac anatomy. The development of the embryonic heart in mice has been well studied anatomically, but there are limited physiologic studies. A new method has been developed to assess the mouse fetal heart in a similar fashion to the current use of echocardiography in the chick embryo and the human fetus. This method was applied to normal mouse embryos known to survive and to abnormal trisomy embryos that die during gestation and have cardiac failure. To analyze early normal embryonic heart hemodynamics, Doppler echocardiograms were performed on n = 129 C57B1/6J mouse embryos from d 10 through 19 of gestation and 20 embryos with trisomy 16 (gestational d 11-14). The maximal blood velocities recorded at the inflow and outflow of the embryonic heart were analyzed for heart rate, peak early and peak late inflow and outflow velocities, and measurements were made of systolic ejection, filling, and other time intervals normalized for heart rate. A high velocity holosystolic or diastolic velocity with altered time intervals was identified as atrioventricular or semilunar valvular regurgitation, respectively. Inflow and outflow velocities increased with increasing gestational age. The time period of isovolemic contraction time was present before and undetectable after gestational d 17, whereas the total filling time increased. Ejection time and isovolemic relaxation time had no significant change. No valvular regurgitation was detected in normal embryos. These echocardiographic patterns are similar to those observed for human embryos. Abnormal Doppler findings were present (inflow or outflow valvular regurgitation) in 55% of trisomy 16 embryos. Echocardiographic data can now be obtained beginning at d 11 in the mouse embryo for analyses relating to abnormal heart development. A noninvasive technique may be invaluable to monitor the physiologic condition of embryos within a litter and to detect and monitor those embryos where heart defects may be expected. Qualitative markers of embryonic congestive heart failure such as valvular regurgitation may be present and detectable with structural valvular abnormalities or failing cardiac physiology. The mouse embryo is an appropriate animal model to analyze normal and abnormal mammalian heart development and function.

Venous Doppler ultrasonography in the fetus with nonimmune hydrops

Eighteen pregnancies with nonimmune hydrops fetalis were referred for fetal echocardiography to rule out congenital heart disease. In 14 of these cases, pulsating blood velocities were recorded in the umbilical vein, which in a normal population had a nonpulsatile blood velocity pattern. The four cases without pulsations in the umbilical vein were found to have intrauterine viral infections. In the last 10 cases examined, the umbilical venous pulsations were found to reflect abnormal central venous pulsations during atrial systole suggesting increased fetal central venous pressure. Right ventricular shortening fraction was significantly decreased in the group with umbilical venous pulsations compared with those without (0.18 versus 0.32, p less than 0.05). All the fetuses without venous pulsations survived, but only four of the 14 with pulsations survived (p less than 0.05). The results suggest that blood velocity recordings in the umbilical and central veins of the fetus can give valuable clinical information with regard to the presence of fetal congestive heart failure and differentiate between this physiologic state and other causes of nonimmune hydrops fetalis. This may have implications for fetal diagnostic work-up and prognosis.

A cardiovascular profile score in the surveillance of fetal hydrops

Objective. To assess the value of a cardiovascular profile score in the surveillance of fetal hydrops. Methods. In a retrospective study, 102 hydropic fetuses were examined between 15 and 37 completed weeks of gestation with ultrasonographic assessment of hydrops, heart size, and cardiac function, and arterial umbilical and venous Doppler sonography of the ductus venosus (DV) and the umbilical vein (UV). A cardiovascular profile score (CVPS) was constructed by attributing 2 points for normal and taking away 1 or 2 points for abnormal findings in each category. The score of the final examination prior to treatment, delivery, or fetal demise was compared to the fetal outcome in these 102 fetuses after exclusion of terminated pregnancies. The scores of the first and last examinations were compared in 40 fetuses and the relationship between these scores and the evolution of fetal hydrops and fetal outcome was assessed. Results. Twenty-one pregnancies were terminated (21%). Fifty-four of the remaining 81 hydropic fetuses survived (67%) and perinatal death (PNM) occurred in 27 fetuses (33%). The median CVPS was 6.0 (IQR 4.75–8.00) for all fetuses, with a median of 6.0 (IQR 5.00–6.00) in fetuses who died in the perinatal period compared to a median of 7.0 (IQR 4.00–8.00) in those who survived (p < 0.035). All fetuses in this study had a ‘severe’ form of hydrops with skin edema. The best predictor for adverse outcome was the venous Doppler sonography of UV and DV, in particular umbilical venous pulsations. Among fetuses included in the longitudinal arm of the study, the survival rate was 40% and the PNM was 60%, after exclusion of terminated pregnancies. CVPS increased by a median of 1 (IQR 0.00–2.00) point in the last exam for those fetuses that lived, whereas among those fetuses that died, the CVPS decreased by a median 1.5 (IQR 0.25–2.75) points (p < 0.001). Conclusions. The fetal cardiovascular profile score can be used in the surveillance of hydropic fetuses for prediction of the presence of congestive heart failure and as an aid for predicting fetal outcome.

Fetal congestive heart failure: correlation of Tei-index and Cardiovascular-score.

Abstract Introduction: Congestive heart failure (CHF) may be present in fetuses with hydrops fetalis (HF) and the severity is difficult to quantitate. Differential ventricular dysfunction may be present in the fetus with CHF. A non-geometric measure of ventricular function that is not afterload dependent would be useful to measure the severity of myocardial dysfunction. Methods: Tei-index (isovolumetric time/ejection time) was measured prenatally in 23 normals (24–34 weeks gestational age-GA) and in 7 with HF (24–34 weeks GA). Prenatal CHF severity was graded by a 10 point cardiovascular (CV) score (2 points each for absence of hydrops, normal venous Doppler, heart function, arterial Doppler, and heart size, and 10/10 = normal). A paired student t-test was used to compare RV and LV and nonpaired t-test compared HF and normals. Tei-index and CV score were correlated. Results: Tei-index normals were 0.38 ± 0.04 in the right ventricle (RV) and 0.41 ± 0.05 in the left ventricle (LV) and there were no significant RV-LV or gestational age (GA) differences. Among HF fetuses, RV and LV Tei-indices were both significantly increased (0.54 and 0.92) and not significantly different. CV score ranged from 2 to 8 (mean 5.43 out of 10) and correlated inversely with Tei-index (r = −0.52, r = −0.68). Conclusion: Hydrops fetalis is associated with biventricular dysfunction and congestive heart failure. Tei-index correlates with CV score obtained within two weeks of delivery or intrauterine death. Tei-index may be useful in the serial assessment of myocardial dysfunction in the fetus with hydrops.

Hemodynamic profile of severe pregnancy-induced hypertension

Cases of severe pregnancy-induced hypertension or eclampsia were studied in forty-five women by catheterization of the right side of the heart to define the presenting hemodynamic profile associated with this disorder. These women could not be easily categorized into one specific hemodynamic pattern. Most patients had high-normal to elevated systemic vascular resistance indices (mean 2726 +/- 120 dynes.sec.cm-5.m2). The mean cardiac index was 4.14 +/- 0.13 L.min-1.m2. The severity of hypertension was largely attributable to a disproportionate rise in the systolic component (mean 193 +/- 3 mm Hg) compared with diastolic blood pressure (mean 110 +/- 3 mm Hg). Women with eclampsia had significantly lower arterial blood pressure and systemic vascular resistance indices when compared with those of the rest of the study group. Analysis of Starling curves indicated that all patients had normal or hyperdynamic left ventricular function. A modest correlation was observed between central venous pressure and pulmonary capillary wedge pressure (r = 0.59). This disparity most likely results from the maintenance of normal to high cardiac output in the presence of an increased left ventricular afterload. The majority of patients with severe pregnancy-induced hypertension do have normal to high cardiac indices and pulmonary capillary wedge pressures accompanied by normal or hyperdynamic left ventricular function. This is true despite the presence of severe hypertension.

Guidelines for the Evaluation of Heart Failure in the Fetus With or Without Hydrops

Fetal echocardiography has progressed to be able to diagnose many forms of congenital heart disease and to assess the prognosis of cardiac lesions based on their anatomy and presentation in utero. However, the presence of signs of fetal heart failure, such as hydrops or valvular regurgitation, makes the assessment of prognosis difficult. This article outlines a straightforward method for the rapid evaluation of the fetus who may have congestive heart failure. The differentiation of the prehydropic state from normal is illustrated.

Two-dimensional echocardiographic assessment of the aorta in infants and children with congenital heart disease.

To determine the accuracy of two-dimensional echocardiography in the identification of congenital anomalies of the aorta, we compared two-dimensional echocardiographic with angiographic results in 261 consecutive infants and children with congenital heart disease (age 1 day to 20 years, mean 3.3 years). Two-dimensional echocardiography was performed and interpreted without knowledge of angiographic results. Complete visualization of the ascending and descending aorta and aortic arch branches was possible by two-dimensional echocardiographic examination in suprasternal, parasternal, and subcostal views of 255 patients (98%). Identification of the esophagus during swallowing aided the diagnosis of anatomic characteristics of aortic arch. One or more significant aortic arch anomalies were present on angiograms of 116 of 255 patients (46%) and were detected by two-dimensional echocardiography in 110 (sensitivity 95%, 99% specificity). Anomalies detected by two-dimensional echocardiography/angiography were ascending aorta hypoplasia in four/four, truncus arteriosus three/three, right aortic arch 31/31, anomalous subclavian artery 11/16, coarctation 27/29, and patent ductus arteriosus 53/57. We conclude that two-dimensional echocardiography can be used to determine the anatomy of the aorta in most infants and children. In selected patients, two-dimensional echocardiography may eliminate the need for angiographic examination before surgery for congenital heart disease.