Anita Krishnan

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.

Human Cardiac Development in the First Trimester A High-Resolution Magnetic Resonance Imaging and Episcopic Fluorescence Image Capture Atlas

With rapid advances in medical imaging, fetal diagnosis of human CHD is now technically feasible in the first trimester. Although the first human embryologic studies were recorded by Hippocrates in 300–400 BC, present day knowledge of normal human cardiac development in the first trimester is still limited. In 1886, two papers by Dr His described development of the heart based on dissections of young human embryos. Free hand wax models were made that illustrated the external developmental anatomy. These wax plate reconstruction methods were used by many other investigators until the early 1900s1. Subsequently serial histological sections of human embryos have been used to further investigate human cardiac development2–6. Based on analysis of histological sections and scaled reproductions of human embryos, Grant showed a large cushion in the developing heart at 6 6/7 weeks (CS 14) and separate AV valves at 9 1/7 weeks (CS 22)2. At the end of the 8th week (CS 8), separate aortic and pulmonary outflows were observed. Orts-Llorca used three dimensional reconstructions of transverse sections of human embryos to define development of the truncus arteriosus and described completion of septation of the truncus arteriosus in 14–16mm embryos, equivalent to EGA 8 weeks (CS18)5. n nGiven the complex tissue remodeling associated with cardiac chamber formation and inflow/outflow tract and valvular morphogenesis, the plane of sectioning often limited the information that can be gathered on developing structures in the embryonic heart. These technical limitations in conjunction with limited access to human embryo specimens have meant that much of our understanding of early cardiac development in the human embryo is largely extrapolated from studies in model organisms7–10. With possible species differences in developmental timing and variation in cardiovascular anatomy, characterization of normal cardiac development in human embryos is necessary for clinical evaluation and diagnosis of CHD in the first trimester. This will be increasingly important, as improvements in medical technology allow earlier access to first trimester human fetal cardiac imaging and in utero intervention. n nRecent studies have shown the feasibility of using magnetic resonance imaging (MRI) to obtain information on human embryo tissue structure11, 12. MRI imaging data can be digitally resectioned for viewing of the specimen in any orientation, and three-dimensional (3D) renderings can be obtained with ease. Similarly, episcopic fluorescence image capture (EFIC), a novel histological imaging technique, provides registered two-dimensional (2D) image stacks that can be resectioned in arbitrary planes and also rapidly 3D rendered10. With EFIC imaging, tissue is embedded in paraffin and cut with a sledge microtome. Tissue autofluorescence at the block face is captured and used to generate registered serial 2D images of the specimen with image resolution better than MRI. Data obtained by MRI or EFIC imaging can be easily resectioned digitally or reconstructed in 3D to facilitate the analysis of complex morphological changes in the developing embryonic heart. In this manner, the developing heart in every embryo can be analyzed in it entirety with no loss of information due to the plane of sectioning. n nUsing MRI and EFIC imaging, we conducted a systematic analysis of human cardiovascular development in the first trimester. 2D image stacks and 3D volumes were generated from 52 human embryos from 6 4/7 to 9 3/7 weeks estimated gestational age (EGA), equivalent to Carnegie stages (CS) 13–23. These stages encompass the developmental window during which all of the major milestones of cardiac morphogenesis can be observed. Using the MRI and EFIC imaging data, we constructed a digital atlas of human heart development. Data from our atlas were used to generate charts summarizing the major milestones of normal human heart development through the first trimester. MRI and EFIC images obtained as part of this study can be viewed as part of an online Human Embryo Atlas. To view the Human Embryo Atlas content, visit http://apps.nhlbi.nih.gov/HumanAtlas/home/login.aspx?ReturnUrl=%2fhumanatlas%2fDefault.aspx.

Neurobehavioral Abnormalities in Newborns with Congenital Heart Disease Requiring Open-Heart Surgery

In a prospective study, we evaluated the perioperative application of the Neonatal Intensive Care Unit Network Neurobehavioral Scale in a cohort of newborns with congenital heart disease (CHD). Infants with CHD were found to have suboptimal neurobehavioral performance compared with healthy infants without CHD, with particular vulnerability in the Regulation and Stress subscales.

A detailed comparison of mouse and human cardiac development

Background:Mouse mutants are used to model human congenital cardiovascular disease. Few studies exist comparing normal cardiovascular development in mice vs. humans. We carried out a systematic comparative analysis of mouse and human fetal cardiovascular development.Methods:Episcopic fluorescence image capture (EFIC) was performed on 66 wild-type mouse embryos from embryonic day (E) 9.5 to birth; 2-dimensional and 3-dimensional datasets were compared with EFIC and magnetic resonance images from a study of 52 human fetuses (Carnegie stage 13–23).Results:Time course of atrial, ventricular, and outflow septation were outlined and followed a similar sequence in both species. Bilateral venae cavae and prominent atrial appendages were seen in the mouse fetus; in human fetuses, atrial appendages were small, and a single right superior vena cava was present. In contrast to humans with separate pulmonary vein orifices, a pulmonary venous confluence with one orifice enters the left atrium in mice.Conclusion:The cardiac developmental sequences observed in mouse and human fetuses are comparable, with minor differences in atrial and venous morphology. These comparisons of mouse and human cardiac development strongly support that mouse morphogenesis is a good model for human development.

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 ⩽24u2009h. 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.

Human Cardiac Development in the First Trimester

With rapid advances in medical imaging, fetal diagnosis of human CHD is now technically feasible in the first trimester. Although the first human embryologic studies were recorded by Hippocrates in 300–400 BC, present day knowledge of normal human cardiac development in the first trimester is still limited. In 1886, two papers by Dr His described development of the heart based on dissections of young human embryos. Free hand wax models were made that illustrated the external developmental anatomy. These wax plate reconstruction methods were used by many other investigators until the early 1900s1. Subsequently serial histological sections of human embryos have been used to further investigate human cardiac development2–6. Based on analysis of histological sections and scaled reproductions of human embryos, Grant showed a large cushion in the developing heart at 6 6/7 weeks (CS 14) and separate AV valves at 9 1/7 weeks (CS 22)2. At the end of the 8th week (CS 8), separate aortic and pulmonary outflows were observed. Orts-Llorca used three dimensional reconstructions of transverse sections of human embryos to define development of the truncus arteriosus and described completion of septation of the truncus arteriosus in 14–16mm embryos, equivalent to EGA 8 weeks (CS18)5. n nGiven the complex tissue remodeling associated with cardiac chamber formation and inflow/outflow tract and valvular morphogenesis, the plane of sectioning often limited the information that can be gathered on developing structures in the embryonic heart. These technical limitations in conjunction with limited access to human embryo specimens have meant that much of our understanding of early cardiac development in the human embryo is largely extrapolated from studies in model organisms7–10. With possible species differences in developmental timing and variation in cardiovascular anatomy, characterization of normal cardiac development in human embryos is necessary for clinical evaluation and diagnosis of CHD in the first trimester. This will be increasingly important, as improvements in medical technology allow earlier access to first trimester human fetal cardiac imaging and in utero intervention. n nRecent studies have shown the feasibility of using magnetic resonance imaging (MRI) to obtain information on human embryo tissue structure11, 12. MRI imaging data can be digitally resectioned for viewing of the specimen in any orientation, and three-dimensional (3D) renderings can be obtained with ease. Similarly, episcopic fluorescence image capture (EFIC), a novel histological imaging technique, provides registered two-dimensional (2D) image stacks that can be resectioned in arbitrary planes and also rapidly 3D rendered10. With EFIC imaging, tissue is embedded in paraffin and cut with a sledge microtome. Tissue autofluorescence at the block face is captured and used to generate registered serial 2D images of the specimen with image resolution better than MRI. Data obtained by MRI or EFIC imaging can be easily resectioned digitally or reconstructed in 3D to facilitate the analysis of complex morphological changes in the developing embryonic heart. In this manner, the developing heart in every embryo can be analyzed in it entirety with no loss of information due to the plane of sectioning. n nUsing MRI and EFIC imaging, we conducted a systematic analysis of human cardiovascular development in the first trimester. 2D image stacks and 3D volumes were generated from 52 human embryos from 6 4/7 to 9 3/7 weeks estimated gestational age (EGA), equivalent to Carnegie stages (CS) 13–23. These stages encompass the developmental window during which all of the major milestones of cardiac morphogenesis can be observed. Using the MRI and EFIC imaging data, we constructed a digital atlas of human heart development. Data from our atlas were used to generate charts summarizing the major milestones of normal human heart development through the first trimester. MRI and EFIC images obtained as part of this study can be viewed as part of an online Human Embryo Atlas. To view the Human Embryo Atlas content, visit http://apps.nhlbi.nih.gov/HumanAtlas/home/login.aspx?ReturnUrl=%2fhumanatlas%2fDefault.aspx.

Prenatal Evaluation of Congenital Heart Defects and Fetal Intervention

The majority of congenital heart defects (CHD) can be detected prenatally, although many patients still go undetected until after birth. The main goal of prenatal diagnosis is to improve the physical condition of the fetus and the outcome for the neonate. The ability to identify patients with cardiac lesions prenatally leads to the potential for identification of associated extracardiac abnormalities and underlying genetic etiologies. Similarly, the prenatal detection of extracardiac abnormalities or genetic derangements may provoke a fetal cardiac evaluation. The most common reason for fetal cardiac evaluation is the suspicion of a structural heart abnormality on obstetric ultrasound screening, with a rate of diagnosis of CHD as high as 70%. Fetal evaluation should also include an assessment of extracardiac abnormalities, which are seen in an estimated 37-45% of fetuses with CHD. The field of fetal intervention for CHD is still relatively young. Fetal therapies include maternal medication administration, ultrasound-guided and other minimally invasive techniques, and invasive open uterine fetal surgery.

Human Cardiac Development in the First Trimester: A High Resolution MRI and Episcopic Fluorescence Image Capture Atlas

With rapid advances in medical imaging, fetal diagnosis of human CHD is now technically feasible in the first trimester. Although the first human embryologic studies were recorded by Hippocrates in 300–400 BC, present day knowledge of normal human cardiac development in the first trimester is still limited. In 1886, two papers by Dr His described development of the heart based on dissections of young human embryos. Free hand wax models were made that illustrated the external developmental anatomy. These wax plate reconstruction methods were used by many other investigators until the early 1900s1. Subsequently serial histological sections of human embryos have been used to further investigate human cardiac development2–6. Based on analysis of histological sections and scaled reproductions of human embryos, Grant showed a large cushion in the developing heart at 6 6/7 weeks (CS 14) and separate AV valves at 9 1/7 weeks (CS 22)2. At the end of the 8th week (CS 8), separate aortic and pulmonary outflows were observed. Orts-Llorca used three dimensional reconstructions of transverse sections of human embryos to define development of the truncus arteriosus and described completion of septation of the truncus arteriosus in 14–16mm embryos, equivalent to EGA 8 weeks (CS18)5. n nGiven the complex tissue remodeling associated with cardiac chamber formation and inflow/outflow tract and valvular morphogenesis, the plane of sectioning often limited the information that can be gathered on developing structures in the embryonic heart. These technical limitations in conjunction with limited access to human embryo specimens have meant that much of our understanding of early cardiac development in the human embryo is largely extrapolated from studies in model organisms7–10. With possible species differences in developmental timing and variation in cardiovascular anatomy, characterization of normal cardiac development in human embryos is necessary for clinical evaluation and diagnosis of CHD in the first trimester. This will be increasingly important, as improvements in medical technology allow earlier access to first trimester human fetal cardiac imaging and in utero intervention. n nRecent studies have shown the feasibility of using magnetic resonance imaging (MRI) to obtain information on human embryo tissue structure11, 12. MRI imaging data can be digitally resectioned for viewing of the specimen in any orientation, and three-dimensional (3D) renderings can be obtained with ease. Similarly, episcopic fluorescence image capture (EFIC), a novel histological imaging technique, provides registered two-dimensional (2D) image stacks that can be resectioned in arbitrary planes and also rapidly 3D rendered10. With EFIC imaging, tissue is embedded in paraffin and cut with a sledge microtome. Tissue autofluorescence at the block face is captured and used to generate registered serial 2D images of the specimen with image resolution better than MRI. Data obtained by MRI or EFIC imaging can be easily resectioned digitally or reconstructed in 3D to facilitate the analysis of complex morphological changes in the developing embryonic heart. In this manner, the developing heart in every embryo can be analyzed in it entirety with no loss of information due to the plane of sectioning. n nUsing MRI and EFIC imaging, we conducted a systematic analysis of human cardiovascular development in the first trimester. 2D image stacks and 3D volumes were generated from 52 human embryos from 6 4/7 to 9 3/7 weeks estimated gestational age (EGA), equivalent to Carnegie stages (CS) 13–23. These stages encompass the developmental window during which all of the major milestones of cardiac morphogenesis can be observed. Using the MRI and EFIC imaging data, we constructed a digital atlas of human heart development. Data from our atlas were used to generate charts summarizing the major milestones of normal human heart development through the first trimester. MRI and EFIC images obtained as part of this study can be viewed as part of an online Human Embryo Atlas. To view the Human Embryo Atlas content, visit http://apps.nhlbi.nih.gov/HumanAtlas/home/login.aspx?ReturnUrl=%2fhumanatlas%2fDefault.aspx.