The normal closure of the ventricular septum

The normal

closure

of the ventricular

septum

Shiela C. Mitchell, M.D., M.P.H.* Heinz W. Berendes, M.D.** William M. Clark, Jr., M.D.*** Bethesda, Md.

A

lthough experimental proof is lacking, it has generally been conceded that membranous ventricular septal defects are due either to failure of the right and left bulbar ridges to fuse with each other or with the endocardial cushions at horizon XVII (approximately 35 days after conception) ,lm4or to a minor degree of lack of torsion of the primitive cardiac tube at approximately horizon X (some 22 days after conception). lr5t6 Muscular defects are presumably due to excessive trabeculation during formation of the ventricles or to aberrations in the coalescence of the myocardial shells which normally contribute to the formation of the interventricular septum.’ In 1960, Evans, Rowe and Keith7 documented by repeat cardiac catheterization the first case of postnatal closure of an isolated ventricular septal defect. By 1963, From

13 such cases had been recorded.* Since all of these patients survived, the mechanism of closure in them can only be surmised. Three patientsgJO without clinical documentation of closure were found to have a membranous ventricular septal defect sealed off by fibrous adhesion of the medial leaflet of the tricuspid valve. Without autopsy proof, closure by fibrous tissue or hypertrophy of muscle bundles has been postulated.3J1 In 1965, Hoffman and Rudolph,” reporting on 62 infants with isolated ventricular septal defects, described the case of a 1,250-gram infant with a clinically typical ventricular septal defect at 51 days of age who at 12 weeks of age showed a small ventricular septal defect by cineangiography, and at 15 weeks an entirely normal heart by autopsy. The patient died at home of undetermined cause. Although this in-

the P&natal Research Branch, Kational Institute of Neurological Diseases and Blindness, National Institutes of Health, Bethesda, Md. The Collaborative Study of Cerebral Palsy, Mental Retardation and Other Neurological and Sensory Disorders of Infancy and Childhood is supported by the National Institute of Neurological Diseases and Blindness. The following institutions participate: Boston Lying-In Hospital; Brown University; Charity Hospital, New Orleans; Children’s Hospital of Buffalo; Children’s Hospital of Philadelphia; *Children’s Medical Center, Boston; Columbia University; Johns Hopkins University; Medical College of Virginia; New York Medical College; Pennsylvania Hospital; University of Minnesota; University of Oregon; University of Tennessee; Yale University; and the P&natal Research Branch. N.I.N.D.B. (*Babies born at Boston Lying-In Hospital are followed-up at Children’s Medical Center of Boston, and these are treated as one institution; the same rule applies to Pennsylvania Hospital and Children’s Hospital of Philadelphia.) Received for publication May 6, 1966. *Collaborative Studies Program Area. Geographic Pathology Section, National Heart Institute, National Institutes of Health. Address: National Heart Institute, National Institutes of Health, Bldg. 31, Room 5-A-08, Bethesda, Md., 20014. **P&natal Research Branch, National Institute of Neurological Diseases and Blindness, National Institutes of Hsaltb. ***Department of Pediatrics, University of Oregon Medical School, Portland, Ore.

334

Normcll

fant \vas premature, the authors did not find, among their 13 patients with conplete closure a disproportionate number of premature infants. However, one third of their cases of ventricular septal defects \vere in infants with birth weights under 2,500 grams, and their estimated incidence of ventricular septal defects among premature infants n-as 4.5 per 1,000 live births in contrast to 0.95 per 1,000 for full-term liveI)orn infants. They attributed this increased incidence to a general increase in congenital lesions in premature infants and to a more complete case ascertainment among small infants \\-ho routinelyreceive extensive evaluation and care. In the present stud>- the methods are different, but again one finds an excess of ventricular septal defects among premature infants. .I new h>-pothesis of the etiology of these findings is detailed. Materials

and

methods

Since 1959, the Collaborative Study on Cerebral Palsy and Mental Retardation has prospectively studied pregnant women at 13 collaborating institutions in order to evaluate the effects of perinatal events on the outcome of pregnancy. By 1965, some 50,000 Ijirths had occurred to lvomen enrolled in this study. Among the study offspring who weighed lnore than 400 grams ;\t IJirth, 64 cases of isolated ventricular septal defects have heen found. (Products of conception weighing less than 400 grams have been defined as abortions.) Xscertainment of almormalities among the dead infants is not a problem since the autops\rate is better than 90 per cent. .kcertninment among the living presents a number of difficulties; hence, the figures here presented are not to be construed as definitive incidence data. All of the 43 living infants have lIeen examined 11y a pediatric cardiologist; 8 have undergone catheter and/or angiocardiographic studies. The others have not required this adjunct to therapy. Thus, although in all cases there was a definitive cardiologic diagnosis, consideration has not I)een restricted to those in which the lesions were severe. The 43 living patients reflect the complete clinical spectrum of isolated ventricular septal defects from spontaneous closure and maladie de Roger to pulmonary hypertension and

Fig. test.

closure

I. Frecluenc>~

qf’ ventriclrlilr

distribution

.wptum

of birth

weights.

335

See

cardiac failure due to a large left-to-right shunt. Forty-two per cent of the 64 patients with ventricular septal defects are Negro; 47 per cent of the entire study population are Negro. Birth weights were known for 60 of the 64 infants with isolated ventricular septal defects. The average weight for infants with ventricular septal defects was 2,590 f 77 grams, nhereas the average IGrth weight for the core group of infants was 3,170 + 4 grams. The frequency distribution of these birth weights is shown in Fig. 1. The infants with ventricular septal defects Ivere also gestationally younger than the core group. Their average gestational age was 37 + 0.7 lveeks, whereas the average gestational age of the core group \vas 39 It 0.1 weeks. The frequency distribution of the gestational ages is given in Fig. 2. The differences between the group \vith ventricular septal defects and the core group for birth weight and gestational age are both significant with p < O.OOl.* Fig. 3 shows that infants with isolated ventricular scptal defects are young and small, not mature small infants whose intrauterine growth has I)een stunted. The line dra\vn *For

these comparisons tile Y test has been used. tests the ratio oi the difference between standard error oi that difference. The if ratller than the “t” test (where variance since a prehminarg assessment uf variance different groupings. including the cow group 16,000 patients, showed the variance to tx

This statistic means to the test was used is estimated). within the of mow than homopeneous.

336

Mitchell,

Fig. 2. I;requency See test.

distribution

Fig. 3. Comparison age in patients defects.

on this squares

clnd Clurk

IJerendes,

of gestational

of birth weight and gestational with isolated ventricular septal

figure has the property with the formula:

v = u+ x

ages.

Z??iYi

ZXi’

- ZXiZYi/N - (ZXi)‘/N

of least

and infants of diabetic mothers have been deleted from these and subsequent tables. Clearly, the infants with cardiac defects other than ventricular septal defects are heavier than the infants with isolated ventricular septal defects or than those without cardiac abnormalities. The infants with ventricular septal defects are not significantly different in weight from those without heart disease who died in the neonatal period. In Table II, the group of living infants with ventricular septal defects are compared with the core group (essentially all of whom survived). Here it can be seen that the infants with ventricular septal defects are smaller than those of the core group. It does not appear to be the presence of associated malformations in the infants with ventricular septal defects which precipitates delivery or impairs growth, since 30 per cent of the infants with isolated ventricular septal defects had extracardiac malformations, whereas 43 per cent of the infants with other cardiac defects had associated abnormalities. Nor when allowance is made for birth weight do the patients with ventricular septal defects show an unusual predisposition to hyaline mernbrane disease. It would appear, therefore, as though prematurity had revealed rather than caused, or been caused by, the defect. The data suggest that, had these infants gone to term, many would not have presented with this defect. Clearly, this can happen only if the ventricular septum continues to develop and close throughout pregnancy. Hoffman’s” data suggest also that it continues to close throughout the first year of life. Discussion

(X-2)

When the cases of ventricular septal defect are separated into deaths and survivors, the following facts emerge. Table I shows all neonatal deaths of liveborn inflints in 3 groups, those without heart disease (identified through October, 1963), those with isolated ventricular septal defects, and those with all other types of cardiac defects. Because of the known relationship to birth weight, cases of twins

The hypothesis is proposed that the normal time of ventricular septal closure may not be limited to the fourth and fifth postconceptive weeks, but rather may extend, for a minority of patients, throughout pregnancy and into the postpartum period. Such a hypothesis would explain the excess number of isolated ventricular septal defects among premature infants, and the lack of any abnormal autopsy findings in patients with spontaneously closed ventricular scptal defects. It would also

Ttlbl~ 1. Neon&l

dearths in livehorn ifzfants Infants

without congrnitczl heart defects

Hirt A weight (Gw.)

I i

Number soo-2,500 > 2,500

In/(znts wntriczrlar

Per cent

378 163

~ I

NzLn’bei

70 .ZO

541

with isolated se&&z1 dtferts

I

Per c-ent

7 1

100

1

87 1.1

8

100

flfanf: c mgrnztnl

with (111 other heavt defects

Lvlinmbci

Per cent

19 34

36 64

53

100

s:! = 26.01. ,> = < 0.005.

I’uble II. Comparison

of birth weights in living infants I

Core group”

Hirth weight (Gfl.)

_ Cases

! 2,001-2,500 2,501-3,000 3,001-3,500 > 3,501

*Core GroupFirst s2 = 11.21. p = < 0.025.

Study

pregnancy,

single

Grozzp

with

isolated

-__ I

Per cent

I

Ca se.7

/

I’SD _--.~

-

Per cent

1,418 4,654 7,521 5,060

8 25 40 27

7 9 15 3

21 26 44 9

18,653

100

34

100

births

explain the disproportionate lack of ventricular septal defects among the autopsied adult population as compared to the living pediatric clinic population.‘” This concept of continued growth of normal structure within the heart is not without precedent. For example, at birth, the septum primum, which by the XVII horizon (approximately 35 days after conception) has appeared, developed, degenerated, and grown into essentially the natal relationship with the septum secundum, still has not fused with this secondary septum.” Only by postnatal proliferation of the subendothelial connective tissue b) some 600 to 700 per cent does the foramen ovale beconle oljliterated sometime after the third month and usually I)efore the end of childhood.18 Since lack of closure is not

usually a functional handicap, the exact time of closure has received scant attention. Similarly, through intimal proliferation, the ductus arteriosus becomes anatomically sealed sometime between the second and eighth postnatal weeks. Normally, the earliest phases of this process are recognizable during the third trimester, and are accelerated after biAh.13 Striking changes also occur after birth in the histologic appearance of the sinoatrial and atrioventricular nodes, although these are readily identifiable from the sixth intrauterine week onward .5 Clearly then, the heart is far from structurally complete at birth. There is, of course, no precedent for organogenesis per se Iqrond the first part of the first trimester. Rut that is not I\-hat is proposed.

What is proposed is that, although the right and left bulhar ridges, the endocardial cushions, and the muscular portions of the ventricular septum appear and develop during the fourth to the sixth intrauterine weeks, their growth may not be limited to this period but may continue throughout pregnancy and into the first few years of life. Data are lacking on the precise location of ventricular septal defects which subsequently close spontaneously. With this information at hand, it would be possible to determine whether, in fact, closure is effected by hypertrophy of muscle bundles by scarring, or bv normal growth of tissue. The implications of normal closure throughout pregnancy and the postpartum period are many. Teratogenesis need not be limited to the first trimester. Studies of incidence and inheritance cannot ignore the implications of birth weight. Case ascertainment throughout infancy becomes essential, and the importance of pathology to etiology is underscored. Summary

From the Prospective Collaborative Study on Cerebral Palsy and Mental Retardation, 64 cases of isolated ventricular septal defects have been identified. In these there has been a significantly lower mean birth weight and gestational age than in infants without heart disease, as well as in those with cardiac defects other than ventricular septal defects. The hypothesis is proposed that this is due to an essentially normal phenomenon whereby the right and left bulbar ridges and the endocardial cushions apparent in the heart since horizon XVI continue to grow throughout pregnancy and the postpartum period, effecting closure either during the second or third trimester or the first few years of life. The

rationale for and consequences of hypothesis are discussed. We gratefully acknowledge the assistance nlax Halperin and l>r. Maureen Henderson analyses of these data.

this of Dr. in the

REFERENCES 1. Streeter, G. I>. : Contributions to embryology, No. 211, in 1)evelopmental horizons in human embryos, age groups XI to XXIII, Washington, D.C., 1948, Carnegie Institution of Washington, pp. 144 and 170. 2. Hamilton, IV. J., Boyd, J. D., and Mossman, H. W.: Absorption of the sinus venosus into the right atrium, ix Hamilton, \V. J., editor: Human embryology, Baltimore, 1962, Williams & Wilkins Company, pp. 172 and 174. J, E.: Malformations of the ventricu3. Edwards, lar septal complex, ix Gould, S. E., editor: Pathology of the heart, Springfield, Ill., 1960, Charles C Thomas, p. 316. 4. Morris, E. W. T.: Embryology of some congenital cardiac anomalies, Thorax 20:158, 1965. 5. Keith, J. D., Rowe, R. D., and Vlad, P.: Heart disease in infancy and childhood, New York, 1958, The Macmillan Company. Embryology of rongellital heart disease (p. 1271, and ventricular septal defect (p. 216). G. I..: Cont,ributions to embrl ology, 6. Streeter, SO. 197, if2 Developmental Horizons in Human Embryos, ;1ge Groups XI to XXIII, Washington, D.C., 1942, Carnegie Institution of Washington, p. 217. 7. Evans, J. I~., RON-e, 12. L)., and Keith, J. D.: Spontaneous closure of ventricular septal defects, Circulation 22:1044, 1960. 8. \Vnde, G., and \Vright, J. I’.: Spontaneous closure of ventricular septnl defects, The Lancet 1:737, 196.1. 9. Majka, \I., Ryan, J., and Bandy, D. C.: SPOIItaneous repair of a ventricular septal defect, Canad. M. A. J. 82:317, 1960. 10. Miller, W. I>., and Kovachevich, R.: Self-sealing ventricular septal defects of the heart, hu. HEAI