The Heart

The heart

Gross lesions:

Pericardial and pleural effusions:

            After opening the chest, the volume of pericardial and pleural effusions can be measured or estimated. A 20 ml Toomey syringe will be successful. The pericardial fluid can be removed using a sharp needle on the syringe. Prenatal ultrasound has identified some normal fetal pericardial fluid1,2, but an abnormal effusion leaves visibly distends the pericardial sac (Fig 1a,1b).

Fig 1. The pericardium is intact and the arrow points to a collection of fluid at the apex.
The stillborn infant had heart failure with nonimmune fetal hydrops from familial polyvalvular dysplasia. 
Fig 2. The pericardial sac shows fluid between it and the heart in this 39 week gestation infant with 24-48 hours of postmortem retention and evidence of both mild heart failure and acute asphyxia. 

The fluid may be clear, or with the leakage of hemoglobin into tissue as part of autolysis, the fluid may be deep red, but still without solid components. This is still a serous effusion, not a hemorrhage. Old blood or pus is murkier from protein and dead cells. 

Heart size:

            The size of the heart can be judged to some degree by how much it fills the chest cavity.  (Fig 3).

Fig 3. The heart fills the chest cavity in this 31 weeks of gestation, stillborn infant with 24 to 48 hours of postmortem retention. The cardiomegaly was the result of complex heart malformation. The heart to brain weight ratio was 0.11, approximately twice the normal size. 

The diagnosis of cardiomegaly is ultimately determined by the heart weight. The mean heart: brain weight ratio is .053. To avoid adding the weight of lumen blood, the heart is weighed after the complete dissection which will have removed any luminal blood. Heavy, but normally formed, hearts are a common finding in infants of diabetic mothers (Fig 4). Such infants typically are macrosomic and show increased subcutaneous adipose tissue. The heart: body weight ratio in these macrosomic infants may exceed .005. 

Fig 4: This heart fills the chest in this 40 weeks of gestation, intrapartum stillbirth from a diabetic mother. There is prominent pericardial adipose tissue. The heart brain weight ratio was 0.14, and the heart:body weight ratio was .01 with a autopsy body weight of 4670 grams.

            The “size” of the heart on inspection is also a function of the dilation of the chambers. The degree of distention of the atria and of the ventricles can be documented by a digital image best taken after the thymus has been removed. Normally a small portion of the left ventricle can be seen when the chest is opened. With ventricular dilatation the left ventricle appears to bulge beyond the usual contour (Fig 5a-5d). With atrial dilatation, the atrial appendage is often distended with blood.

Fig 5a: The left ventricle is visible to the left of the left descending artery (LAD) which externally demarcates the septum. This is a normal, non-dilated appearance. This term stillborn infant with 4-12 hours of postmortem retention demonstrated chorioamnionitis/funisitis, pulmonary neutrophils adrenal hemorrhages, and general organ congestion which are all features consistent with death from septic shock. 
 
Fig 5b: The left ventricle is visible beyond the septum, but not excessively. The right atrial appendage is less distended than in Fig 5a. The heart and lungs demonstrate petechiae evidence of acute asphyxia. The 36 week gestation infant had approximately 4-12 hours of postmortem retention.
Fig 5c: This heart shows a bulging left ventricular profile (*) and the right atrial appendage is also distended. This 30 weeks of gestation infant survived for one hour and had nonimmune fetal hydrops and Noonan syndrome. The arrow points to a post stenotic dilatation of the pulmonary artery.
Fig 5d: This heart demonstrates a large dilated left ventricle as evidence of heart failure. There are also numerous epicardial and pleural petechiae, as well as extensive vernix aspiration that were evidence of acute asphyxia. This infant was 41 weeks of gestation with 24 to 48 hours of postmortem retention, and no anatomic cause of death or asphyxia. The arrow points to pleural petechiae.

External examination of the heart:

            Of heart malformations, stillbirth is most often associated with lesions that elevate right sided heart resistance, and lead to right sided heart failure and anasarca (non-immune fetal hydrops). The cause underlying this association is likely due to the elevated pressure on umbilical venous return. Some outflow lesions may also be associated with disruption of nodal pathways that can lead to tachyarrhythmias and high out put cardiac failure. Many congenital heart malformations, such as hypoplastic left heart, VSD, or transposition, do not compromise cardiac function until after birth and transition from the fetal to the permanent circulatory pattern. Other cardiac lesions may be associated with syndromes that have an increased risk of stillbirth, such as common atrio-ventricular canal in trisomy 21. A systematic examination of the heart during the autopsy of a stillborn infant is critical to detecting the wide array of congenital heart anomalies. The pathologist can note the normal and document the abnormal, often with digital images. The intent of this manual is to guide the autopsy of fetal and peripartum death, and it cannot cover these malformations in depth. There are many excellent textbooks and monographs that present cardiac malformations.

            The external heart examination begins with noting the situs and direction that the apex points. The removal of the thymus exposes the innominate vein crossing from the left subclavian vein to the right superior vena cava. If this is absent, then there is likley a left superior vena cava entering the coronary sinus that may warn of possible other venous or lymphatic abnormalities. (Fig 6a, 6b).

Fig 6a: The arrows point to a left and right superior vena cava. This  32 weeks of gestation infant lived 4 hours but died from massive effusions from lymphatic / thoracic duct malformation.
 
Fig 6b: This is the same heart as in Fig 6a, but the pericardium has been opened and the apex lifted out of the chest to expose the left superior vena cava entering the left atrium in the vicinity of the coronary sinus. This was connection was demonstrated subsequently with a probe. The hemostat is on the right superior vena cave. 

After the pericardium is completely removed, the color of the heart should be noted. It may be pale from anemia, red stained from hemolysis of postmortem retention, mottled from lipid deposition, or dotted with petechiae (Fig7a, 7b).

Fig 7a: The entire chest and heart are pale, consistent with exsanguination in a 20 weeks of gestation fetus after days to 1 week of postmortem retention.
 
Fig 7b: The heart and chest organs are stained red from autolytic hemolysis in this 19 week gestation fetus with a similar postmortem retention interval. 

The position of the atria can be determined by identification of the pyramidal right atrial appendage and the chicken wing like left atrial appendage. The right atrium normally lies superficial to the left. The anterior surface of the heart facing the pathologist should normally show the right ventricle with a conus leading up to the pulmonary artery. The pulmonary artery should be superficial to the aorta and directed to the left, while the aorta should be deep, and directed to the right of the infant. These two great arteries should be of equal diameter. If one is narrower, it is evidence of an underlying malformation interfering with cardiac outflow (Fig 8).

Fig 8: The pulmonary artery is narrower than the aorta. The left heart is also prominent (note the left “chicken wing” atrial appendage. The aorta appears shifted to the right. There was no VSD, as there would be in Tetralogy of Fallot. The heart demonstrated a marked pulmonic valve stenosis. The fetus had isolated cranial edema associated with a tightly wrapped nuchal umbilical cord. The heart lesion may have been unrelated to the fetal death. The fetus was 16 weeks of gestation with postmortem retention of more than 1 week. 

The left anterior descending artery defines the ventricular septum. The right ventricle is positioned more anteriorly, but both ventricles are normally of approximately the same size. The aorta normally arises from the left ventricle and sweep first right, then left to follow left of the vertebral column to the diaphragm. An aorta that runs along the right of the vertebral column may form a vascular ring that the junction with the ductus arteriosus can compress the esophagus and impede fetal swallowing (Fig 9). This can result in polyhydramnios. The heart next is lifted outward and the four pulmonary veins visualized. 

Fig 9: This posterior view demonstrates the ductus arteriosus from the left meeting the right sided aorta, creating a vascular ring that compressed the esophagus. This infant was a post-delivery, term, neonatal death from lethal osteogenesis imperfecta. 

The ductus arteriosus and aortic isthmus

            The left lung can be lifted out of the chest (a piece of gauze may make gripping the lung easier). Then, peeling back the pleura over the descending aorta, will provide a clear view of the ductus arteriosus and aortic isthmus. The ductus is a continuation of the pulmonary artery between takeoff of the right and left pulmonary arteries to the junction with the aorta. The aortic isthmus starts at the left subclavian artery and continues until the junction of the ductus with the descending aorta. As over the anterior heart, the relative diameters of these two vessels reflects relative flow. The aortic isthmus is often narrower than the ductus. If it is more than 50% narrower, this is likely to reflect an abnormality. The narrow isthmus is a common finding in some cases of hydrops particularly with early jugular lymphatic obstruction sequence (Fig 10a, Fig 10b).

Fig 10a: The arrow points to the narrow aortic isthmus. The ductus is the same diameter as the normal pulmonary artery. This 19 weeks of gestation infant with an intrapartum death had hydrops associated with early jugular lymphatic obstruction sequence associated with monosomy X. A possible inference is that lowered oncotic pressure resulted in chronically decreased umbilical venous return to the left side of the heart, although it is unclear why this would not equally effect the superior and remaining inferior vena caval return to the right ventricle.  
Fig 10b: The area labeled AI in this image appears to be a narrow segment of the aortic arch even proximal to the isthmus starting after the left carotid. The 22 week infant had between 24-48 hours of postmortem retention, and had early jugular lymphatic obstruction sequence of unknown etiology. 

The dynamics of such disturbed fetal blood flow and its relationship to the development of aortic coarctation is unclear. If the ductus arteriosus is narrow, this may be from decreased flow usually in early gestation (Fig 11a, 11b)

Fig 11a: The arrow points to a narrow ductus arteriosus with the left pulmonary artery along the left of the arrow and the descending aorta to the right of the arrow. The diameter of the ductus is substantially less than that of the aortic isthmus. There was no anatomic evidence of ductal constriction. This 22 week gestation infant with 24 to 48 hours of postmortem retention, demonstrated an abnormally long umbilical cord and fetal obstructive vasculopathy. A speculative interpretation is that chronic hypoxia induced decreased resistance in the pulmonary vascular bed in effect shunting blood from the right to the left heart. 
Fig 11b: The arrow points to the narrow ductus arteriosus in a 23 weeks of  gestation infant with 24-48 hours of postmortem retention. No anatomic cause of death was found. 

or from ductal contraction in later gestation (Fig 12a-c).

Fig 12a: The arrow points to the ductus arteriosus which is not obviously narrowed, however on opening from the pulmonary artery the scissors were stopped by a luminal narrowing at the junction with the ductus. This 38 weeks of gestation stillbirth with 12-24 hours of postmortem retention, died as the result of a premature separation of the placenta with underlying retroplacental hematoma of 75% of the placental area. (Formalin fixed tissue)
Fig 12b. From the same specimen as in Fig 12a, the ductus has been opened with a left pin marking the pulmonary artery – ductal junction and the right pin marking the ductal-descending aorta junction (DA). The cut wall of the ductus is thicker than that of the pulmonary artery or aorta and its intima is wrinkled in comparison to the smooth surface of the pulmonary artery and aorta. The exit of the right and left pulmonary arteries are labeled R,L PA and the entry of the aortic isthmus at the junction of the ductus and aorta is labeled AI. (Formalin fixed tissue)
Fig 12c: This is another ductus that was grossly closed and on opening had a thickened wall with intimal wrinkling. This 42 weeks of gestation infant with more than 3 days of postmortem retention had a large amounts of aspirated meconium. The mother had a history of headaches but only recalled taking Tylenol.  

As with a narrow isthmus, the hemodynamics creating a narrow, uncontracted ductus in younger gestation fetuses is not understood. In older gestation fetuses the ductus responds to oxygen and prostaglandins as it must after birth to close the fetal circulation.  Indomethacin is commonly used to close a patent ductus arteriosus in neonates. Indomethacin used to treat preterm labor has resulted in fetal ductal constriction/closure3,4. Whether other NSAIDS can contract the ductus in utero is unclear. The consequences of ductal closure in utero would block outflow from the right ventricle5,6.

            An unexplained but common autopsy finding in stillborn infants is a small adventitial hemorrhage of the ductus arteriosus. This may be an effect of ductal contraction (Fig 13a-c).

Fig 13a: The arrow points to the ductal adventitial hemorrhage. Compared to the pulmonary artery (PA), the ductus may be slightly. This appropriate weight for gestation infant was 40 weeks of gestation, with 12-24 hours of postmortem retention. The only other finding was petechiae on the pleura.  
Fig 13b: The arrow points to a large adventitial hemorrhage over the ductus arteriosus. This infant was 35 weeks of gestation was of appropriate birth weight and had 24 to 48 hours of intrauterine retention. After opening the ductus was wall appeared to be thickened.
Fig 13c: This microscopic image of the same ductus (DA) in Fig 13b demonstrates the increased wall thickness compared to the pulmonary artery (PA). There is no adventitial hemorrhage in the section, but there is a small hemorrhage at the junction of the intima and media of the ductus. 

The heart dissection:

            Dissecting the small hearts of stillborn infants in situ maintains the relationships to vessels and other organs prior to removal of the heart.  One technique is to open the right atrium from the superior vena cava into the inferior vena cava in the plane parallel to the chest. This will expose both the atrial septum and the tricuspid valve. The extent of coverage of the septum secundum over the foramen ovale can be observed, and normal right to left probe patency can be demonstrated. The tricuspid valve can be observed for its position, normal valve leaflets, and possible vegetations. Then under direct observation, the lateral margin of the right ventricle can be opened, then scissors turned toward the base and cut following the ventricular septum into the anterior surface of the pulmonary artery. After the conal bands and the semilunar valves have been observed, the cut can continue through the ductus arteriosus into the descending aorta. With this opening, the entry of the isthmus is exposed and can be probed to identify coarctation. Then the left atrium can be entered from the appendage and a cut made along the lateral atrial and ventricular margins which will visualize the mitral valve. The cut can then be continued into the left ventricle, and as on the right side, the scissors can be turned toward the cardiac base and by cutting parallel to the septum and slipping the top blade of the scissor beneath the pulmonary artery the aorta can be opened, likely through the non-coronary cusp. The semilunar valve leaflets and coronary ostia can be seen, and the main arterial branches identified.

            Cardiac malformations, if present, need to be accurately described. Some lesions can lead to right heart failure and result in non-immune fetal hydrops (anasarca). These lesions include absent or dysmorphic tricuspid valves (Fig 14), pulmonic stenosis (Fig 15), or lack of right ventricular volume such as Eisenmenger anomaly.

Fig 14: The arrows point to the abnormal thickened tricuspid valve. The asterisks are on areas of endocardial thickening on the atrial wall from regurgitation. This heart was from an infant with familial polyvalvular dysplasia.
Fig 15: The black arrow points to the dysplastic, thicken semilunar pulmonary valve. The white arrow points to the outward curve of the pulmonary trunk from post stenotic dilatation from blood flow forced at higher pressure. This 30 weeks of gestation infant with Noonan syndrome survived for 1 hour. 

A vascular ring of the great vessels can be a cause of polyhydramnios if it interferes with the swallowing of amniotic fluid. An unusual cause of fetal hydrops in a cardiac rhabdomyoma, usually associated with tuberous sclerosis, protruding into the right ventricle (Fig 16).

Fig 16: The mass (arrow) is protruding from the septum into the right atrium and ventricle. The 19 weeks of gestation infant was hydropic and had a family history of tuberous sclerosis.

Rarely, there is iatrogenic trauma. Some outflow lesions may also be associated with disruption of nodal pathways that can lead to tachyarrhythmias and high output cardiac failure. Some cardiac lesions may be associated with syndromes that have an increased risk of stillbirth, such as common atrio-ventricular canal in trisomy 21. Many congenital heart malformations, such as hypoplastic left heart, VSD, or transposition, do not compromise cardiac function until after birth and transition from the fetal to the permanent circulatory pattern. Knowing the clinical history and following a systematic examination of the heart during the autopsy is critical to detecting the wide array of congenital heart anomalies. The autopsy report can then note the normal and document the abnormal, often with digital images. Abnormalities may be photographed in situ and/or after heart removal including endocardial thickening and valve lesions, as well as malformations (Fig 17). There are many excellent textbooks and monographs that present cardiac malformations. 

Fig 17: The heart shows a typical membranous VSD that was an incidental finding and created no external findings because the pressure in the right and left ventricle are similar within the fetal circulation, preventing significant blood shunting across the VSD. This 36 weeks of gestation infant died at 3 hours of age due to extensive pneumonitis. The postmortem lung culture grew enterococcus.

            The heart, either after dissecting or after the removal of the organ block, can be separated at the great vessels. The heart weighed at this point in the dissection should have all luminal blood removed. The valve circumferences can be measured, as well the ventricular chamber diameters midway to the apex, and the thickness of free wall measured at the same location. One approach to histological sampling of a normally formed heart is to sample both ventricles with a longitudinal slice from near the apex, including papillary muscle, and extending through the atrio-ventricular valve. In very small hearts, appropriate sampling can document some malformations (Fig 18).

Fig 18: The asterisk is on the septal defect at the level of the triscuspid and mitral valves creating a complete atrioventricular canal defect (endocardial cushion defect). The infant was 14 weeks of gestation with an intrapartum death. The lesion is frequent in trisomy 21. (4x, H&E)

Microscopic findings

Postmortem retention: 

The findings of Dr. Genest and colleagues were that the inner third of the myocardium has lost basophilia after 24 hours and the outer third after 48 hours of postmortem retention7 (Fig 19). (Loss of basophilia is defined by at least 1% of nuclei entirely devoid of basophilic staining).

Fig 19: This section is from the epicardial surface of the heart showing preserved nuclear basophilia in the subendocardial cells but loss deeper to that. Often the extent of inner myocardial loss of basophilia is shallower. The heart is from a 33 weeks of gestation infant who had premature separation of the placenta and retroplacental hematoma of approximately 50% of the placental surface. The estimated postmortem retention was 24 to 48 hours.  (20x, H&E)

Epicardial surface: 

The microscopic sections should confirm the location of petechial hemorrhages and the size of confluence of hemorrhages. There is often congestion of venules and capillaries (Fig 20). A small hemorrhage is often deep to the surface coronary arteries (Fig 21a, b).

Fig 20: The small hemorrhage is apparent in the connective tissue adjacent to the superficial myocardium. Within the myocardium small vessels and capillaries are dilated. The 38 weeks of gestation infant was an intrapartum death due to premature placental separation. (20x, H&E)
Fig 21a: A small hemorrhage is seen beneath a coronary artery. The infant was 40 weeks of gestation with 4 to 12 hours of postmortem retention and a 90% premature placental separation. There were petechiae over the thymus, pleura and epicardium. (4x, H&E)
Fig 21b: This is another example of a small hemorrhage deep to a coronary artery. This 28 weeks of gestation infant had 12-24 hours of postmortem retention. The infant was small for gestation with multiple placental infarctions, and thymic atrophy. There was an acute premature placental separation of 40% of the placental area. (4x, H&E)

The significance of these petechiae is presented in the section on thymus. The parietal pericardium/epicardium may demonstrate acute inflammation from infection, although this inflammation is often difficult to distinguish from ectopic myelopoiesis (Fig 22a, b). The pericardium is a characteristic site of infection in horses with the blood borne bacterial infection from colonic ulcers (due to swallowed tent caterpillars) in Mare Reproductive Loss Syndrome8. 

Fig 22a: There are numerous inflammatory cells in the epicardium. There is cardiac muscle visible in bundles on the right side of the image. The cells were a mix of neutrophils and less mature myeloid cells making it difficult to distinguish myelopoiesis from acute inflammation. This small for gestation term infant had 12-24 hours of postmortem retention, petechiae of thymus, pleura and epicardium, and a history of maternal SLE. (H&E)
Fig 22b: This is a higher power magnification of a pericardial infiltration with most of the cells staining positive with the Leder stain (chloracetate esterase) identifying them as neutrophils. This 39 weeks of gestation infant could not be resuscitated at delivery because of pulmonary hypoplasia from akinesia and from large amounts of aspirated meconium in the lung. This patient was reported because of  some similarities to cases of Mare Reproductive Loss Syndrome.(40x, Leder)

Endocardial surface:

            Any notable subendocardial fibrosis is abnormal. This can be related to abnormal flow and pressure patterns in malformations, and also occurs in the recipient heart in twin-to-twin transfusion syndrome, presumably due to hypertension.

Heart valves:

            Vegetations on the tricuspid valve from marantic (non-bacterial) endocarditis occur rarely in infants of a diabetic mother (Fig 23). Another valve abnormality is formation of loose connective tissue forming globules in inherited polyvalvular dysplasia9 and in one form of a Noonan related syndrome10 (Fig 24).

Fig 23: This large tricuspid valve vegetation was from a 39 week gestation infant of a diabetic mother who survived one day. There are blood cells on the surface but no neutrophils or bacteria, only loose fibrin. The infant had pulmonary emboli and shock lesions. (H&E)
Fig 24: The loose connective tissue is forming globules rather than the loose portion of the valve leaflet above the compact portion of the leaflet. The infant was 30 weeks of gestation with a Noonan like phenotype who survived one hour. (4x, H&E)

Subendocardial and papillary muscle: 

            The papillary muscle and the subendocardial region have the most distant blood supply starting from the entrance of surface coronary arteries making these areas vulnerable to ischemia. Infants dying in cardiovascular shock from untreated hypoplastic left heart show infarctions in subendocardial tissue and papillary muscles11 (Fig 25a, b). The implication is not only that these areas became infarcted from lack of blood flow, but that the heart had continued to pump, and the infant survived long enough for the lesions to become histologically discernable , which in the classic Mallory White timing of adult myocardial infarctions is 3-5 hours12.

Fig 25a: At low magnification the papillary muscle demonstrates a slight eosinophilia (arrow). This term infant was delivered because of bradycardia and resuscitation was unsuccessful. (H&E)
Fig 25b: At higher magnification of the same area, the cytoplasmic eosinophilia and the pyknosis of cardiomyocyte nuclei is clearer. These are the features of coagulation necrosis. Some of the nuclei (arrows) have nuclear karyorrhexis, a feature of apoptosis. (H&E)

These infarctions can calcify and have been observed radiologically and histologically in neonates13. These subendocardial/papillary muscle infarctions can be seen in stillborn infants. In some cases, they are acute and are evidence consistent with hours of severe shock. They may also be scarred and calcified, indicating likely fetal recovery from a previous episode of shock (Fig 26).

Fig 26: A portion of the papillary muscle is calcified consistent with a remote low flow state. The infant was 14 weeks of gestation with prolonged postmortem retention who had early jugular lymphatic obstruction sequence. (4x H&E)

Myocardium:

            The fetal heart can suffer from viral myocarditis, particularly from Coxsackie B and echoviruses. The lesions may cause heart failure/hydrops. These lesions may also calcify, and this calcification be visible even is completely autolyzed hearts (Fig 27).

Fig 27: This very autolytic myocardium demonstrates calcifications and cellular infiltration. The infant was hydropic and weighed 125 grams. No attempt was made to identify a virus in this case from more than 40 years ago.  (4x, H&E)

            At least in theory, the heart muscle in a distended failing heart should have a different microscopic appearance from that of a heart that succumbs rapidly to asphyxia. There does sometimes appear to be more capillary congestion in an acute failing heart compared to sudden asphyxia seen in comparing stillbirth from large versus smaller extents of premature placental separation (Fig 28a, b). However, this observation is subjective and has not been tested rigorously. There is a study on wavy cardiac fibers in stillborn infants, but this has not been duplicated. As a research technique, staining for atrial natriuretic protein, or brain natriuretic protein in the ventricles, might show unique patterns between the brief heart failure from acute asphyxia and more prolonged heart failure, but such a study has not been reported in stillborn infants14,15.

Fig 28a: The myocardium does not demonstrate capillary congestion in this term stillborn infant with 4-12 hours of intrauterine retention, and a 90% placental separation. (10x, H&E)
Fig 28b: The myocardium has prominent capillary congestion in this term infant with an early resolved episode of bradycardia, and then a second episode immediately before delivery. The infant could not be resuscitated at birth, and the autopsy showed early shock lesions. (20x, H&E)

            The myocardium may demonstrate myocardiocyte hypertrophy or storage disease. There is a potential pitfall in the latter in that young gestation hearts tend to have increased glycogen and mitochondria creating a histologically clear myocyte cytoplasm in routine microscopic sections. 

References:

1.         Jeanty P, Romero R, Hobbins JC. Fetal pericardial fluid: a normal finding of the second half of gestation. Am J Obstet Gynecol 1984;149:529-32.

2.         Dizon-Townson DS, Dildy GA, Clark SL. A prospective evaluation of fetal pericardial fluid in 506 second-trimester low-risk pregnancies. Obstet Gynecol 1997;90:958-61.

3.         J R, P J. Fetal cardiac function and ductus arteriosus during indomethacin and sulindac therapy for threatened preterm labor: A randomized study. Am J Obstet Gynecol 1995;173:20-5.

4.         Moise KJ, Jr., Huhta JC, Sharif DS, et al. Indomethacin in the treatment of premature labor. Effects on the fetal ductus arteriosus. N Engl J Med 1988;319:327-31.

5.         Kohler HG. Premature closure of the ductus arteriosus (P.C.D.A.): a possible cause of intrauterine circulatory failure. Early Hum Develop 1978;2:15-23.

6.         Heymann MA, Rudolph AM. Effects of acetylsalicylic acid on the ductus arteriosus and circulation in fetal lambs in utero. Circ Res 1976;38:418-22.

7.         Genest DR, Williams MA, Greene MF. Estimating the time of death in stillborn fetuses: I. Histologic evaluation of fetal organs; an autopsy study of 150 stillborns. Obstet Gynecol 1992;80:575-84.

8.         Bendon R, Sebastian M. Chorioamnionitis in the human with some comparison to the horse in mare reproductive loss syndrome. In: Powell DG, Furry D, Hale G, editors. Proceedings of a workshop on the equine placenta; 2003; Maxwell H. Gluck Equine Research Center: University of Kentucky. p. 116-8.

9.         Bendon RW, Siddiqi T, de Courten-Myers G, Dignan P. Recurrent developmental anomalies: 1. Syndrome of hydranencephaly with renal aplastic dysplasia; 2. Polyvalvular developmental heart defect. Am J Med Genet Suppl 1987;3:357-65.

10.       Bendon R, Asamoah A. Perinatal autopsy findings in three cases of jugular lymphatic obstruction sequence and cardiac polyvalvular dysplasia. Pediatr Dev Pathol 2007:1.

11.       Coen R, McAdams AJ. Visceral manifestation of shock in congenital heart disease. Am J Dis Child 1970;119:383-9.

12.       Mallory G, White P, Salcedo-Salgar J. The speed of healing of myocardial infarction A study of pathological anatomy in seventy-two cases. Am Heart J 1939;18:647-71.

13.       Setzer E, Ermocilla R, Tonkin I, John E, Sansa M, Cassady G. Papillary muscle necrosis in a neonatal autopsy population: Incidence and associated clinical manifestations. J Pediatr 1980;96:289-94.

14.       Das BB, Raj S, Solinger R. Natriuretic peptides in cardiovascular diseases of fetus, infants and children. Cardiovasc Hematol Agents Med Chem 2009;7:43-51.

15.       Doyama K, Fukumoto M, Takemura G, et al. Expression and distribution of brain natriuretic peptide in human right atria. J Am Coll Cardiol 1998;32:1832-8.

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