CONGENITAL
MALFORMATIONS
AND
PEDIATRICS
By Josef Warkany, M.D.
Children’s Hospital Research Foundation and the Department of Pediatrics, College of Medicine, University of Cincinnati
C
ONGENITAL MALFORMATIONS are of in-terest to the pediatrician because theycontribute greatly to children’s mortality and morbidity.
When pediatrics emerged as a new medi-cal specialty around the turn of the century it was dominated by interest in nutritional and infectious diseases, which were in
those days the most urgent problems con-fronting our predecessors. The two genera-tions of pediatricians who worked before ours were incredibly successful; they re-duced the mortality and morbidity of in-fants and children to an extent considered impossible by the founders of the specialty. Although much credit must be given to fin-proved sanitation, to improved social and
economic conditions and to other sciences, pediatrics can claim a share in the success, because it recognized the problems, di-rected the reforms and applied and devised medical treatment. However, children are still subject to illness or death and our hos-pitals are overcrowded. It is generally recognized that a shift has taken place in
the spectrum of the causes of death and
disease.1 The fetal and neonatal mortality
rates have not fallen so rapidly as have those of older age groups.1’5 While some of
the causes of early death yield to medical measures, others persist and assume
in-creased relative importance. Congenital
malformations are among the persistent of-fenders. They show a relative increase in neonatal life and throughout early child-hood (Figs. 1 and 2).
It is of interest to compare the trends of mortality from diseases which were in the
center of pediatric attention with those
from the neglected congenital
malforma-tions. In Figure 3 are plotted the
per-centage contribution of deaths under 1 year
of age from enteritis against deaths from congenital malformations, as reported by
the U.S. Vital Statistics between 1910 and
1952.6 While deaths from enteritis decrease
steadily, those from malformations show a
ADDRESS: Elland and Bethesda, CincInnati 29, Ohio.
725
relative increase. Congenital malformations account now for about 14% of all infant deaths in the United States. In New Zea-land, where infant death rates are lower than in the United States, congenital mal-formations at the present time contribute 20% to the general infant mortality.7 It can
be expected that in the United States fin-proved infant care will lead to similar re-sults and that within a short time 20% of all
deaths under 1 year will be due to congeni-tal malformations.
Early pediatrics was greatly concerned
with contagious diseases of children. In the Nineteenth Century diphtheria and scarlet fever were the main threats to the young, and in recent years poliomyelitis has taken their place. In Table I five contagious dis-eases are listed and compared with
con-genital malformations as causes of death.
The incidence of four of these contagious
diseases has been reduced to such an extent
that malformations have become of greater
importance as a cause of death than the five combined.8
In these statistics congenital
malforma-tions show not only a relative but also an absolute increase as a cause of death. This
increase may be due chiefly to improved diagnostic knowledge. Progress in roent-genology, pathology and surgery has shown that internal malformations are at the root
of many diseases which previously had been considered as the principal illness. In the
past many children who are now considered the victims of well-defined congenital mal-formations lived or died with diagnoses
such as pneumonia, gastroenteritis, chronic nephritis, etc. Although statistical analyses based on death certificates are of definite value,8’9 necropsies5’10’4 reveal additional
malformations of internal organs which may not appear in general statistical records. The
incidence and the importance of congenital malformations cannot be established by
(Decrease In total rate 24%)
Premature
birth
Deaths
under
I mo.
per
1,000 live
births
29.3
25
-20
$5
10
-5’
0-S..
‘S S.
S.. ‘S
-22%
-23%
+9%
+8%
.41%
--.,
--_tw /
- ,
/ /
Injury at birth
22.2
20
$5
Deaths
under
I mo.
per
10 1,000
live
births
.5
0 Premature
birth
Injury
at
birth
Congenital
malform ations
Asphyxia
a
at electas is
Pneum.& influ.
Other
specified
causes
Congenital
malformations
Asphyxia
a
a felectasis Pneumonia &
infl .*ri
Other specified
causes
ill-defined unkn.
Ill-defined-and unknown
NEONATAL
MORTALITY
(Birth
to age 1 month)
939 1948
Children’s
Bureau.
/950
FIG. 1. From U. S. Children’s Bureau: Changes in infant, childhood, and maternal mortality over the
Accidents
(Decrease in total rate 50%)
Pneumonia
a
influenza
Congen. Molform.
Cancer & leukemia
4 main contagious dIseases
300
-200
-Death
rate
per
100,000
children
aged
1-4
$00
0-Fic. 2. From U.
Diarrhea, enter itis,
etc.
S.
‘S ‘S
-21% S.
S.
‘S S
‘S S.
S.
‘S
Accidents
‘S
-66% ‘S
Pneumonia
a
influenza
S.
‘t’7t ‘-,.. Congen. Molform.
Cancer 6 leukemia
4 main contog.dls.
Diarrhea, enterltis
-80% _.“
-- /
- /
_r49%-.- ,
/ /
-49%
,;
I, I,
// I,
I,
1
;57%
‘I I,
/
158.7
$00 Death
rate
per
$00,000
children
aged
1-4
-0
Tuberculosis
Tuberculosis
Other
specified
causes
Other speclf led
causes
Ill-defIned &unkn.
Children’s
Bureau
S. Children’s Bureau: Changes in infant, ChildhOOd, and maternal mortality over the
decade, 1939-1948. Statistical series No. 6, Washington, D.C., 1950.
318.3
CONFERENCE ON TERATOLOGY
PRESCHOOL
MORTALITY
$939
(Ages 1-4 years)
30 DEATHS FROM:
25
-S.
- S.,’
S.
z 20 - DIARRHEA AND
- “S ENTERITIS
V)
IS
/\
I:
- CONGENITAL MALFORMATIONS
_LLIIIIIIIIIIIIIIIIIIIIIIIIIIIII liii 111111 Il
191012 14 168202224262830323436384042 44 4648 50 52
1910-1953
FIG. 3. Comparison of trends of deaths from diarrhea and enteritis with deaths from congenital
malformations (expressed as per cent of all deaths in U.S.A. under 1 year of age).
TABLE I
* From reference No. 6.
Such children may remain well for many
years but develop illness later in life.
The incidence of congenital malforma-tions in living children cannot be estab-lished easily. It must be remembered that
only a few malformations can be seen by
external inspection. Medical diagnostic pro-cedures such as auscultation, roentgeno-graphic examination, uroscopy or
ophthal-moscopy can reveal additional internal mal-formations, but these often remain unrecog-nized until illness leads to special
examina-tions. As illness from malformations may
begin at birth, at any time during postnatal
life or never, estimates vary greatly. In
medical classifications or statistics, con-genital malformations are not always listed as such, but appear in many heterogeneous
categories. If they are fatal at an early age they may be listed as abortions,
miscar-riages, stillbirths, or neonatal deaths. If they are compatible with life they may be classified as cases of blindness, deafness,
mental deficiency, endocrine disease or others. In medical practice they are often
listed according to the complications they
VITAL STATISTICS OF THE U.S.A.6
CAUSE OF DEATH
1939 194.e 1946 1953
Whooping Cough
Measles
Diphtheria
Scarlet Fever
Poliomyelitis
3,026
1,997
1,174
858
778
2,586
1,802
1,273
561
447
1,241
1,310
1,259
198
1,845
270
462
156
79
1 ,577
Total 7,823 6,119 5,853 2,544
From reference No. 22.
cause, whereby their teratologic nature is overlooked. Terms such as pyelitis, cystitis, vomiting, malnutrition, hypothyroidism and many others may conceal a variety of con-genital defects. The borderlines of
con-genital malformations, fetal diseases and metabolic errors are ill defined. It is
under-standable, therefore, that estimates of the incidence of congenital malformations are unreliable. Differences among statistical statements are remarkable. Estimates ob-tained from official records in large areas show that only about 1% of liveborn chil-dren are reported as being congenitally de-formed.15_17 Most estimates of congenital malformations from obstetrical clinics vary between 0.5 and 3 per 100 births.18’19 Such estimates are of course too low since many defects, though present at birth, are not recognizable at birth. In a recent inter-departmental study at Columbia University of almost 6,000 pregnancies, congenital mal-formations were recognized in 7% of live-born infants by the time these children were 1 year old.2#{176}It is interesting, though not surprising, that less than one-half of these malformations had been suspected at birth.
This demonstrates that even a team of ex-perts is unable to discover at birth more
than a fraction of the malformations oc-curring in a group of infants. It is certain that the percentage of recognized malfor-mations increased appreciably in this group
as the children grew older.
It would be valuable to know the role played by congenital malformations in the general morbidity of children. A quantita-tive estimate of this role is extremely diffi-cult to obtain. Many congenital malforma-tions represent merely points of reduced re-sistance which cause disease only when postnatal pathogenic factors intervene. A deformity of the ureter or a congenital
structural anomaly of bone may be
con-verted into disease by minor infections or trauma. In such cases it is difficult to
evalu-ate the importance of prenatal and postnatal factors. Another obstacle to such estimates is presented by the vagne borderlines of congenital malformations and congenital
microscopic or functional disturbances. Al-though congenital metabolic errors or microscopic malformations are closely re-lated etiologically to gross malformations,
they are usually classified differently in
medical usage.
Anybody working in an infants’ ward of
a children’s hospital will be impressed by
the number of children found there because
of congenital defects. Dr. B. B. Monroe is now conducting a survey of the incidence of congenital malformations and anomalies
in the infants’ ward population of the
Chil-dren’s Hospital in Cincinnati. During a period of 5 months he found that 36.5% of
the children were on the ward because of
structural congenital malformations.
In wards of older children one finds many
patients who are hospitalized for repair of orthopedic, surgical or urologic disorders
which arise because of congenital defects.
The contribution of such defects to crip-pling of children is hardly realized by the medical profession and the public.2’ Table
II shows an estimate of the contributions
made to disability by five categories item-ized in a list of causes of crippling of chil-dren on State Registers. Although con-genital heart disease and other disorders are not included, the five items listed are of greater numerical importance than
polio-myelitis, the best known and most feared
crippler of childhood.22
Congenital malformations and other pre-natal disorders closely related to them are responsible for many chronic disorders of childhood.2 As they are often masked by
medical terms, which do not take into ac-count the origin of the chronic disorder, it
may be worth while to illustrate this point by a few examples.
TABLE II
CONTRIBUTION OF Soam CONGENITAL ANOMALIES TO TOTAL CASES OF DIs.nmrry*
Anomaly
%
Cleftliporpalate Clubfoot
Congen. dislocation of hip
Spina bifida
Other congen. defects
- 4.1
7.4
2.4
1.1
5.7
20.7
It has been estimated that about 30% of
the orthopedic conditions of handicapped children in state programs are congenital malformations.2 Some of these, such as clubfoot or congenital dislocation of the
hip, though limited to one joint, are im-portant because of the high incidence
(Table II). Other malformations are sys-temic and cause orthopedic problems in
many areas. Arthrogryposis, arachnodactyly, the chondrodystrophies, osteogenesis im-perfecta and many others could be men-tioned here.
Cardiac disorders of children are
receiv-ing much attention at the present time, be-cause new forms of treatment have become available. In spite of this interest, it is still difficult to obtain statistical data on the
in-cidence of cardiac defects in children.
Causes of heart disease in children vary according to age group and locality. Some years ago about one-half of the cases of heart disease occurring in school children
were considered to be congenital.25’26 However, there has been a strildng decrease in the incidence of rheumatic heart disease27
in recent years and the congenital cardiac
disorders thus come to the foreground.
The separation of prenatal and postnatal
factors responsible for deafness is admit-tedly difficult. Trauma or infection may be
superimposed on developmental defects of
the ear and be considered the cause of the
hearing defect. Impressions as to causation
are distorted because many parents dislike
to admit that a child was born deaf and
prefer to relate deafness to trauma or dis-ease. A study of the causes of deafness in institutions and schools for the deaf, made in the Chicago area in 1930, showed that about 61% of these children were congeni-tally deaf.28 In 1943 Best29 considered 41.5% of the deaf in the United States as con-genital cases. Modern treatment of ear
infections is now responsible for a marked
change in the percentage distribution of causative factors. As deafness due to
in-fections becomes rarer, congenital anoma-lies of the ear assume increased importance.
The role of congenital malformations of the visual apparatus is well appreciated.
Many congenital defects of the eye are ex-ternally visible and internal anomalies can
often be detected with the ophthalmoscope in early life. As ophthalmia neonatorum, syphilis and other infections become rarer as causes of blindness, the role of congenital visual disturbances becomes more obvious. In 1948 Kerby3#{176} estimated that in schools for the blind in the United States 58% of
the pupils are afflicted by blindness of pre-natal origin. More recently Sorsby3’ stated that today children blinded by infections
are seen only rarely and that, in the greatly
reduced numbers of schools for the blind, congenital malformations and genetic dis-orders now predominate.
Mental retardation is one of the big chal-lenges to present-day medicine. Conserva-tive estimates place the incidence of mental deficiency at 1%. There are more than a
million and a half mentally defective per-sons in the United States.32 It is difficult to evaluate the etiologic factors responsible for mentally defective persons at large;
better information can be obtained in
insti-tutions, where patients and their families can be investigated. Yannet33 found that in over 90% of 2,000 patients admitted to the Southbury Training School, the deficiency
could be attributed to etiologic agents operative during the prenatal period. In only 3% could injuries during birth be
im-plicated, and in 6%, postnatal factors such as infections or trauma. It is true that not all prenatal injurious factors result in mal-formations. Yet, in a study of the neuro-pathology of 543 necropsies of mental
de-fectives, Malamud34 classified 400 (74%) of the brains examined as congenitally mal-formed.
Congenital malformations of the urogeni-tal tract are among the most common
anomalies of the human body. Although some of these anomalies are compatible with good health, pediatricians encounter many cases of chronic illness attributed to malformations of the urinary tract. In former times such malformations went fre-quently undiagnosed and the symptoms elicited by them were mistaken for the dis-ease proper. Chronic pyelitis, cystitis, nephritis, anorexia, malnutrition, appendi-citis, anemia and many other diagnoses
destruc-CONFERENCE ON TERATOLOGY
tion of the renal tissues. At a time when medical attention was focused on infections and nutrition, infectious or nutritional com-plications were in the center of interest while the basic anomalies were neglected.35 Owing to improved diagnostic methods many malformations of the urinary tract are now recognized and some repaired in early life. But it seems likely that we still
overestimate secondary pathogenic agents and underestimate prenatal factors in the etiology of chronic renal disorders.
The role played by congenital malforma-tions in chronic diseases of children could be further illustrated by examples of pre-natal anomalies of the gastrointestinal and respiratory tracts, of the glands of internal secretion, of the skin and of other organs.23 It will be understandable by now why the estimates of congenital malformations by obstetricians and pediatricians differ so widely. Most of the malformations men-tioned as causes of chronic illness are not visible externally and not manifest at the time of birth. It may take many years be-fore an internal congenital malformation causes symptoms or illness. An example will illustrate the different views obtained by obstetricians and pediatricians. In 1955 Hendricksle reported an incidence of 0.74%
of liveborn, congenitally malformed infants
in Ohio. In the same year a pediatric group36 found a rate of 0.83% in a large series of unselected infants of cardiovascular mal-formations alone.
The pediatrician’s functions are limited in dealing with malformations. He can aid in the nutrition and care of afflicted chil-dren, he can treat infectious complications with antibiotics and relieve endocrine de-ficiencies with glandular preparations. He can call upon his surgical colleagues (plas-tic surgeons, neurosurgeons, thoracosur-geons, orthopedists or urologists) to repair the damage done before the child came under pediatric care. Thus the pediatrician’s role is not an enviable one, and it is under-standable that children affected by congeni-tal malformations are of great concern to him. It is clear that children damaged be-fore birth must receive the best of care, that they must be helped to live a life as normal as possible and that their defects
must be corrected. But it is equally clear that prevention and not repair must be our
aim.
What can the pediatrician do in the pre-vention of congenital malformations? He can emphasize that prenatal developmental defects represent a large practical problem which deserves the interest and the support
of those responsible for the reduction of children’s mortality and morbidity. He can
adjust pediatric thinking and teaching to the unsolved questions of his specialty and he can make some contributions in the search for the causes of congenital anoma-lies. Pediatricians are becoming aware of the fact that many children’s diseases have their root in prenatal life and that much can be learned from the history of the family and of the mother. Pediatricians can do experimental work and aid in the elucida-tion of fundamental questions of teratology. Teratologic experiments can now be per-formed in mammals, a step forward not thought possible 20 years ago. But the pediatrician cannot observe or treat the child and his environment before birth. He is confronted with a difficult situation, as
during the most critical months of develop-ment the unborn is not under his care. It is not yet clear whose task it is to investigate, prevent, and treat prenatal diseases. So long as it was thought that a mother who appears healthy guarantees complete pro-tection of the child in utero, obstetrical care was considered adequate for the fetus. But since there is increasing evidence that the unborn child can be injured by agents well tolerated by the mother, this old belief can-not be upheld. Today the field of prenatal pathology is a no man’s land between ob-stetrics and pediatrics in which progress
has not been adequate. Communications must be improved between research
Tera-tology will change the situation, but it can contribute to a solution by pointing out the need for exploration of the wide and empty spaces which lie between obstetrics and pediatrics.
REFERENCES
1. Collins, S. D., Trantham, K. S., and
Leh-mann,
J.
L.: Illness and MortalityAmong Infants During the First Year of
Life. Washington, D.C. Pub. Health
Monogr. No. 31, 1955.
2. Children’s Bureau Statistical Series No. 6: Changes in infant, childhood, and ma-ternal mortality over the decade, 1939-1948. Washington, D.C., 1950.
3. Potter, E. L.: The trend of changes in causes of perinatal mortality. J.A.M.A. 156:1471, 1954.
4. Dunham, E. C.: Premature Infants, 2d Ed. New York, Harper, 1955.
5. Bundesen, H. N., Dulak, F. A., and Mul-lady, W. F.: Progress in the prevention of needless neonatal deaths. Reprinted
from Annual Report of Health
Depart-ment, City of Chicago, 1951. 6. U. S. National Office of Vital Statistics:
Vital Statistics of the United States. Washington, D.C., 1910 to 1953. 7. Leitch, I.: Statistics on infant mortality.
Proc. Nutr. Soc., 1:247, 1944 (cited by
Record and McKeown9).
8. Murphy, D. P.: Congenital Malformations:
A Study of Parental Characteristics With Special Reference to the Repro-ductive Process, 2d Ed. Philadelphia, Lippincott, 1947.
9. Record, R. G., and McKeown, T.: Con-genital malformations of the central nervous system; a survey of 930 cases.
Brit.
J.
Social Med., 3:183, 1949.10. Potter, E. L., and Adair, F. L.: Factors associated with fetal and neonatal deaths; analysis of 773 such deaths oc-curring in 17,728 deliveries at Chicago
Lying-in Hospital. J.A.M.A., 112:1549, 1939.
11. Gruenwald, P.: Survey of congenital
anomalies as found in 1131 necropsies. Illinois M.
J.,
79:55, 1941.12. Arey,
J.
B.: Pathologic findings in theneonatal period.
J.
Pediat., 34:44, 1949.13. Potter, E. L., and Adair, F. L.: Fetal and
Neonatal Death: A Survey of the
Inci-dence, Etiology, and Anatomic
Manifes-tations of the Conditions Producing Death of the Fetus in Utero and the
In-fant in the Early Days of Life, 2d Ed. Chicago, Univ. Chicago Press, 1949.
14. Miller, H. C.: Analysis of fetal and
neo-natal deaths in 4,117 consecutive births.
PimiAmIcs 5:184, 1950.
15. Wallace, H. M., Baumgartner, L., and Rich, H.: Congenital malformations and birth injuries in New York City.
PEDIA-mics, 12:525, 1953.
16. Hendricks, C. H.: Congenital malforma-tions. Analysis of 1953 Ohio records.
Obst. & Gynec., 6:592, 1955.
17. DePorte,
J.
V., and Pankhurst, E.:Con-genital malformations and birth injuries
among the children born in New York
State, outside of New York City, in
1940-1942. New York State
J.
Med.,45:1097, 1945.
18. Ehrat, Regula: Die Missbildungen der
Neugeborenen an der
Universit#{228}tsfrau-enklinik Zurich, 1921-1944. Zurich, Vii-liger, 1948.
19. Worcester,
J.,
Stevenson, S. S., and Rice,R. G.: Six hundred and seventy-seven
congenitally malformed infants and as-sociated gestational characteristics; par-ental factors. PErIAmics, 6:208, 1950.
20. McIntosh, R., Merritt, K. K., Richards,
M. R., Samuels, M. H., and Bellows, M. T.: The incidence of congenital
mal-formations: A study of 5,964
pregnan-cies. Pwriucs, 14:505, 1954.
21. Lesser, A.
J.,
and Hunt, E. P.: The na-tion’s handicapped children. Am.J.
Pub. Health, 44:166, 1954.
22. U. S. Children’s Bureau: Number of
Crip-pled Children on State Registers, Dec.
31, 1940, by Diagnosis. Washington,
1942.
23. Warkany,
J.:
The role of congenital anom-alies in the etiology of chronic dis-eases.J.
Chron. Dis., 3:46, 1956. 24. Shands, A. R., Jr.: The care and treatmentof crippled children in the United
States.
J.
Bone & Joint Surg., 35-A:237,1953.
25. Rauh, L. W.: The incidence of organic
heart disease in school children. Am. Heart
J.,
18:705, 1939.26. Keith,
J.
D.: Congenital heart disease, in Modem Trends in Pediatrics, edited by Parsons, L. C. New York, Hoeber, 1951,p. 75.
27. Apley,
J.,
and Perry, C. B.: A six-yearsurvey of the cases seen at a school
cardiac clinic. Arch. Dis. Childhood,
29:317, 1954.
28. Bakwin, R. M.: The deaf child.
J.
Pediat.,36:668, 1950.
29. Best, H.: Deafness and the Deaf in the
CONFERENCE ON TERATOLOGY
Relation to Those Sometimes More or
Less Erroneously Known as
“Deaf-Mutes.” New York, Macmillan, 1943.
30. Kerby, C. E.: What causes blindness in
children? Sight-Saving Rev., 18:21,
1948.
31. Sorsby, A.: Clinical Genetics. London,
Butterworth, 1953.
82. Tarjan, C., and Wright, S. W.: Mental
deficiency-a challenge to medicine. Am.
J.
Ment. Deficiency, 58:316, 1953. 33. Yannet, H.: Symposium on congenitalanomalies; mental deficiency due to
pre-natally determined factors. PanATiucs,
5:328, 1950.
34. Malamud, N.: Recent trends in
classffica-tion of neuropathological findings in
mental deficiency. Am.
J.
Ment. De-ficiency, 58:438, 1954.35. Campbell, M.: Clinical Pediatric Urology. Philadelphia, Saunders, 1951.
36. Richards, M. R., Merritt, K. K., Samuels,
M. H., and Langmann, A. C.: Congeni-tal malformations of the cardiovascular system in a series of 6,053 infants.