Reprinted by permission of
American Association for Maternal
and Infant Health

TKE B~L~I~ OF ~TE~ ANLl
INFANT HF.ALTH Vol. VII,
No. 2~18-23, 1960

Ih. Vitgtnin Afigar is a member of the Deparlarriit of
Itesearch of the National Foundation (March of Ihmrs).
lbrmerly she was Professor of Anrslhcstology at Columbia
Univcrsi& and active in itre field of perinatal research.

Congenital anomalies always will be
present in the human race. They are an
integral part of every living species.
That they need to be present to the ex-
tent to which they are now found is by
110 means a foregone conclusion.  Some
methods are presently at hand to de-
crease the frequency of certain anoma-
lies, while other factors, if uncontrolled,
will cause a theoretical increase. The ap
parently relentless increase of population
throughout the world will result in more
apomalous children who will ne-ed diag-
nosis, treatment and care, but it is not
a necessary corollary that the rate of mu-
tations will also increase.

What is the present incidence of con-
genital anomalies?  The answer to this
question involves so many factors that
no true answer is possible. What is
meant by "congenital anomalies"? The
derivation of the word "congenital" sug-
gests that its use be confined to the time
of generation or fertilization of the egg.
This interpretation places great stress on
genetic factors and little on environment,
except for the biocliemical and physical

18

Congen ita I

Anomalies,

1960

environment of the oocyte, spermatozoa,
and fallopian tubes. Common usage dic-
tates that the term "congenital" refers
to "the time of birth."  What is meant
by "anomaly"? A dictionary definition,
which represents the opinion of a cross-
section of intelligent people, suggests
"a departure from the normal."  Thus,
a caput succedaneum, or a fractured clav-
icle, at birth, is, strictly speaking, a con-
genital anomaly, The term "malforma-
tion" denotes a morphological anomaly
and in this decade is too limited. Al-
though chromosomal aberrations would
now be included under this morpholog-
ical term, the biochemical anomalies of
enzyme systems, hemoglobin chains, hap-
toglobins and other proteins would nec-
essarily be omitted.

At what period of life is the incidence
figure desired? Almost nothing is known
in human beings, as to the survival of
every fertilized egg. The data of Hertig
and Rock' are the best at present regard-
ing the recovery of the product of con-
ception after a known date of possible
fertilization. Their figure of 30 per cent,
for successful recovery of embryos two
weeks after coitus in women undergoing
hysterectomy, agrees well with other
mammalian data.  In another 30 per
cent, the zygote or early embryo was ap-
parently not viable. Abortion specimens
should be examined with at least the
same care as that expended on autopsies
of neonatal deaths. The published data
for morphological anoillalies accompany-
ing stillbirths of viable age or weight

seem quite low: 10.1 per cent according
to Potter.2 No published investigation
has been made of biocliemical or chro-
mosomal anomalies in human stillbirths,
a fertile field for research.
The series of almost GO00 infants and
children reported by McIntosh et UP in
1954 affords the first clue to incidence of
morphological anomalies found in an
urban American population. They re-
port that 43.2 per cent of the anomalies
evident after six years of follow-up
visits were diagnosed at birth. By the
end of the first year, a total of 97.3 per
cent of malformations had been diag-
nosed. In the study of Wallace et al,4
their data show that 84 per cent of the
anomalies occurring in 629 children who
had died with congenital malformations,
were diagnosed by the end of the first
year. Many more studies of this type
are needed, with the denominator popu-
lation clearly defined.

For what population is the incidence
of congenital anomalies being described?
In Japan, Nee1 and Schull6 ran into dif-
ficulties in determining the effect of
acute radiation from the Hiroshima and
Nagasaki experience because the base-
line incidence of congenital anomalies
in the Japanese people was unknown.
They were surprised to find that this
incidence in their control group was dis-
tinctly higher than in the United States.
Careful epidemiological investigations
by Penrose,6 Stevenson,? Record and
Edwards8 and others in Great Britain
and Ireland seem to indicate an especial-
ly high incidence of anencephaly in Ire-
land and of congenital dislocation of the
hips in Birmingham. In another British
study, the biochemical anomaly result-
ing in phenylketonuria has been found
to stem from grandparents born in Ire-
land.@ There are no data for the vast
majority of population groups.
What degree of anomaly should be in-
cluded? The slightly webbed toes of the
Dionne quintuplets were of no signifi-
cance to them but are singularly impor-
tant to the geneticist. This leads to
other questions.  For whom or what dis-
cipline is the incidence figure requested?
What time in an individual's life is
being considered? How serious an effect

is produced by the anomaly? What is
the source of information regarding in-
cidence?

The anatoniic classifications of anom-
alies have long been existent and have
been useful to a certain degree.  Below
are listed many other factors to be con-
sidered in classifying anomalies and re-
lating them to estimates of incidence:
Effect of Anomaly

Fatal
Seriously disabling
Moderately disabling
Of little consequence
Of no consequence

Time in Life of Individual
1st trimester of pregnancy

zygote
embryo
fetus

2nd trimester of pregnancy
3rd trimester of pregnancy
Neonatal period (0-28 days)
Infancy (28 days to 1 year)
Childhood (1 year to 12 years)
Adolescence (12 to 18 years)
Adulthood (18 years and older)

Observer
Patient
Relatives of patient
General practitioner
Medical specialist

General Pediatric internist

surgeon   Pediatric surgeon
Gynecologist  Physiatrist
Metabolic   Psychiatrist

Neurologist Public health
Obstetrician officer
Pathologist

specialist Plastic surgeon

Anatomist
Biochemist
Dental specialist
Geneticist
Government organizations

National Office of Vital Statistics
U. S. Public Health Service
War Department

Psychologist
Public Health nurse
Rehabilitation workers
Social service workers
Statisticians
Veterinary specialist
Voluntary health organizations

19

Source of Information

Autopsy
Clinical record

Hospital
Outpatient clinic
Private practice record

Patient
Patient's family
et cetera
Available incidence figures indicate

that severely disabling anomalies which
are often fatal are present in 0.9 to 3.1
per cent of live births,lO, 11 that there is
approximately a 7.0 per cent incidence
of anomalies of significance to the pedia-
trician in the first six years of life,3 and
if minor dermal, dental and skeletal
anomalies are included, almost half the
population have anomalies.
The causes for congenital anomalies
are much more elusive than figures for
incidence. The extremely complicated
interrelation of genetics and environ-
ment impatiently awaits further inter-
est, and further skills of able people
with a background in genetics, medicine,
epidemiology, biochemistry, radio bio 1-
ogy and even unnamed specialties. With
present knowledge, it has been suggest-
ed that genetic influence is mainly re-
sponsible for congenital anomalies in 20
per cent of patients.l2 As suggested by
Runner,l3 every anomaly involves a
"genetically permissive" individual, and
an environment which is "permissive."
There can be no complete separation of
environmental and genetic effects.
Neell2 has indicated that another 10 per
cent or so of congenital anomalies in
human beings are related to antenatal
viral infections of the mother.

There is definite evidence of effects
of rubella infection especially in the first
eight weeks of pregnancy, which results
in cataracts, deafness, or congenital heart
lesions in the infant, depending on the
week of infection.  There is some evi-
dence for fetal death following polio-
myelitis in early pregnancy, but none to
date for the production of congenital
anomalies. Mumps also is under sus-
picion as being related to the production
of human malformations. Data on the
effect of the influenza virus are conflict-
ing. While it is logical to associate

20

viremia in the mother with adverse ef-
fects on the fetus, it is possible that toxic
by-products of virus infection may be
responsible for anomalies, even without
proven viremia. At any rate, it is most
likely that anomalies resulting from
virus infection of the mother during
early pregnancy are not heritable, and
should be classified as environmental
effects, with no stigma of possible future
anomalies in siblings, nor in the next
generation.
There is a remainder of 70 per cent
of congenital anomalies for which a
proper cause is not known. Chromosome
aberrations and enzyme deficiencies may
account for another ten per cent, but
such investigations are only recently un-
der way.
What can be done about serious anom-
alies found at birth, today?  The first
line of attack is to expect them, in cer-
tain conditions. A thorough prenatal
history should reveal the presence of
anomalies in pr e v i o u s pregnancies,
while in many instances, such as viral
infections early during the previous preg-
nancy, these anomalies have no known
relation to an abnormal second preg-
nancy; other anomalies do have a small,
but definite relation to their occurrence
in subsequent pregnancies. Their chance
of doing so depends on the type of in-
heritance, if it is known, Le., dominant,
sex-linked recessive gene.14 Although
nothing definitive can be done for these
conditions in the immediate postnatal
period, a somewhat guarded prognosis
on the part of the obstetrician and pedia-
trician before delivery may spare the
parents the shock of a second abnormal
pregnancy. A few conditions which are
operable at birth have been reported in
more than one child, i.e., tracheo-
esophageal fistula. The pediatrician,
knowing of a previous anomaly in the
family, will look especially for the anom-
aly in the next child, and institute prop-
er therapy promptly.  There is on rec-
ordl6 a report of a woman, who herself
had a congenital heart lesion of the cya-
notic type, and who had had two anen-
cephalic children. Surgical repair of her
heart lesion resulted in normal oxygena-
tion. Her next cliild was entirely nor-

mal. Altliougli iioi coiidiisive, this rc-
port fits in with cxpcrimental data oL'
Ingalls and others.'"

If polyhydramnios is present in tllc
mother, anomalous children also shou Id
be expected.  The high association of
this condition with anomalies in the off-
spring has been known for years.  Esti-
mates of the association range from 4 to
59.5 per cent.". 18 The anomalies which
are found, following pregnancv with
polyhydramnios are associated with in-
terruption of the normal circulation of
amniotic fluid during the last trimester.
A variable, but appreciable amount of
amniotic fluid is actively swallowed by
the fetus, absorbed from its upper intes-
tinal tract, and returned to the placenta
by the mesenteric and umbilical circula-
tion. Any interruption of this flow may
lead to polyhydramnios. Several defi-
cienciq in the central nervous system
have been cited by Prindle as a cause.19
All infants with anencephaly involving
a functionally absent medulla are de-
livered from mothers having polyhy-
dramnios, while the mothers of those
with an occipital bone, or remnants
thereof, which have a minimally func-
tioning medulla do not have polyhy-
dramnios since the fetus can swallow
amniotic fluid. Many of the mothers of
infants with tracheo-esophageal fistula
and esophageal atresia have polyhydram-
nios.20 Indeed, the diameter of the fis-
tula can be predicted from this symptom.
All mothers of infants with complete in-
testinal obstruct ion, whether from
atresia, volvulus, constriction by an an-
nular pancreas, or peritoneal bands have
polyhydramnios.  One mother of an in-
fant who had suffered antepartum per-
foration of the ileum with tremendous
hydroperitoneum had polyhydramnios.21
It is indeed true that in many cases of
polyhydramnios, anomalies are not
found in the infants at birth, but they
are often missed because of inadequate
examination. In pediatric teaching, em-
phasis should be placed on the impor-
tance of questioning whether there was
excessive amniotic fluid in the mother,
when a newborn child is admitted as an
emergency, or an excessive gain of

wciglit (over 25 pinds). If the mother
is not ;I\ ailablc, die lather accompany-
ing he child olten knows the correct
answer, or better yet, a conversation with
the obstetrician will reveal polyhy-
dramnios in the mother before delivery.
Thus, the diagnosis of the anomaly in
the infant can quickly be narrowed to
those in wliich reparative surgery will
be lifesaving.
The second line of attack is to ex-
amine all newborn infants routinely in
the first fifteen minutes for anomalies.
Aside from the obvious gross malforma-
tions, many hidden anomalies can be
diagnosed with nothing more than a
stethoscope, a flashlight or laryngoscope
and a catheter, by an inquisitive physi-
cian or nurse. The catheter is used to
rule out choanal, esophageal, anal, and
rectal atresia, and to measure the con
tents of the stomach. Over 25 cc should
suggest partial or complete intestinal ob-
struction. Observation for appearance
of bowel sounds, and rectal swab exami-
nation for squamous cells should lead to
a definitive diagnosis. The stethosocpe
is used to rule out the presence of dia-
phragmatic hernia, which causes a shift
of the heart sounds away from the
hernia, and absent respiratory sounds
over the site of the hernia. The light is
used to rule out cleft palate due to bony
or soft tissue defects.

Surgery, as soon as the infant has re-
covered from tlie normal birth asphyxia,
and possible additional antenatal as-
phyxia, is indicated in tlie following con-
ditions: tracheo-esophageal atresia, per-
foration of the stomach, intestinal
obstruction, anorectal atresia, omphalo-
coele, and diaphragmatic hernia.
Auscultation of the various heart
sounds will not yield diagnostic infor-
mation unless their site of maximum in-
tensity is distinctly misplaced. Murmurs
and abnormal sounds are not diagnostic.
Angiocardiography and phonocar d iog-
raphy from within the paracardial
blood vessels may give useful informa-
tion, but at the present, these are tech-
nics demanding highly trained person-
nel. It is now known that tliere may be
a flow of blood in either direction, or

21

both, for some days or weeks after birth
through the dwtus, without abnormal-
ity. Persistence of flow may be associ-
ated with other cardiac lesions. In some,
maintenance of Bow through the ductus
is lifesaving. Ligation is fatal. A pedi-
atric cardiorespiratory team is the best
hope for this group of patients.

In a few newborn infants, surgery is
imperative to prevent death. Tracheos-
tomy for complete laryngeal stenosis or
for choana1 atresia is occasionally indi-
cated. The latter condition may be treat-
ed successfully by inserting an infant
pharyngeal airway, or pulling the tongue
away from the posterior pharyngeal wall
with a suture through the midline near
the tip. Operations on the bony atresia
itself are being developed.22
A third line of attack is presented by
exciting new diagnostic opportunities
during the first week of life. These are
concerned with biochemical abnormali-
ties. The mental deficiency accompany-
ing phenylketonuria can be completely
prevented by early diagnosis and appro-
priate therapy.  The same is true for
galactosemia, Rh incompatibility is the
anomaly of blood groups most widely
recognized and treated, but many others
exist. Abnormal amounts of fetal hemo-
globin, abnormal hemoglobin chains, ab-
normal haptoglobins and other serum
proteins can be diagnosed by new metii-
ods of protein analysis.  Routine blood
grouping of the infant for the common
AB0 groups may point out incompati-
bilities with the parents so that kernic-
terus may be avoided by exchange trans-
fusion, or even newer therapeutic
methods.

Practical human genetics is in its in-
fancy. The mapping of gene loci on
human chromosomes is just beginning,
while in mouse chromosomes, it is far
advanced. The discovery of three poly-
morphic loci on human chromosomes
may lead to unexpected diagnoses and
thus appropriate treatment: (1) The
Lutheran blood group and the AB0
secretor loci, (2) the Rh locus and that
for elliptocytosis, and (3) the AB0 locus
and that for the nail-patella syndrome,
in which the finger and toenails are var-

iously deformed, the patellae are abnor-
mal, the iliac crest shows unusually bony
growth and the radius and ulna are fre-
quently fused at the proximal end.**
In the last four years, technics. to de-
termine chromosome abnormalities have
been developed. Over 35 different con-
ditions have already been identified in
human beings. Many of these involve
diagnosis of sex. It is not surprising that
human populations appear to have as
many intersex variations as other mam-
mals. A smear of the buccal mucosa,
suitably stained, can be used to identify
the presence or absence of sex chroma-
tin, or the diagnosis of double sex chro-
matin.  Tissue cultures of minute sam-
ples of skin or bone marrow can be
harvested, and the infant's karyotype
defined in detail. Certain entities are
already apparent. All mongols have
chromatin material equivalent to '47
chromosomes. However, not all persons
with 47 chromosomes are mongols.  In
general, individuals with any number of
chromosomes other than the usual 46,
are not normal. Most are mentally de-
ficient.

What are the prospects for the future?
To date, there is no suggestion as to
what can be done about abnormal chro-

mosomes.  It is not known whether the
extra chromosome in mongolism con-
tains normal nucleic acid, or an abnor-
mal type.  Most individuals with such
abnormal chromosomes are not fertile,
but the record of seven marriages involv-
ing one or both partners who were mon-
gols shows that 50 per cent of the off-
spring were mongols.z* Cytologists at
present are advancing knowledge of
heredity by surgery of the cell, micrurgy.
In lower forms of life, nuclei are being
t~~planted from one cell to another.
The next step will be to transplant or
delete chromosomes and observe the ef-
fect on the organism. Following this,
anatomy and chemistry of genes and
gene particles will have been defined,
and their transpiantatio~ may  be ef-
fected.

For several years, mammalian eggs
after fertilization have been transferred
to foster mothers (rabbits) and the rela-

22

tive etfect of heredity and environment  persons trained in these special methods,
noted.25 Many more such experiments  and able to discover new metliods are
in niany species are needed to properly  needed. Ten years from now, many of
interpret the results.           the current problems will be solved and

Only recently, it has been reported36  new and different problems will present
that it is possible to distinguish from.  themselves, only to be met by better-
each other spermatozoa wl&h carry the  trained, more experienced investigators.
male, and those which carry the female  Pessimism is impe~issible.
chromosomes. So far, it has not been
possible to separate these two types of
spermatozoa, but such a time is not
far off.

All these seemingly tinrefated experi-
merits have a bearing on human abnor-

            BlBLlOGRAPHY

1.  Hertig, A. T. and Rock. J. Series of potentially abor-

tiye ova recovered from fertile women prior to first mid

2. Potter. E. L. and Adair. F. L. Fetal and Neouatal

3. McIntosh, R.. Merritt. K. K.. Richarda, M. It.. spmucfi.

M. H. and Bellows, M. T. The incidence of congenital
malformations: A rtudy of 5,964 pregnancies.  Pediatrics J4:
505-522, November, 1954.
4. Wallace. H. and Sanders. D. Mortality experiena in
children with congenital anomalies.  J.Pediat. 5f: 801-808,
June, 1959.
5. Schull, W. J. and Ned. J- V.  Atomic bomb explooion
aud the pregnancies of biologicaIly related parents.  Amer.

                               6. Pen-. L. S Genetics of anencephaly. J.Ment.Dcf.Ra
                                   I: 4-15. 1957.
chance for transmission, First cousins 7. Stevenson, A. C. The load of hemxitary defec~ in hu-
                                   man populations.  Radiat.Res. Suppl. 1: 306-325, 1959.
                              fluences related to the etiology of congenital dirloation Of

menstrual wid. A=r.J.Ol=teLGyncc. 558: 96s. 1949.

tkath.     154. Thtr University of Chicago prar. ~9.

Even more* the

                      of
a true social conscience among human

ture generations, is within    reach

bein@, and a real desire to improve fu-

~~OZU.'~ The few, well-proven genetically

quenTe should not be permitted the

should not consider reproduction unless

their genetic history is marked by ab-
sence of expression OE delterious genes.
Young married women should not have
eIective x-rays for diagnosis in the pelvic

determined diseases of serious conse- J.Pnb~.Hlth. 19: 1621-1629, December, 1959.

8. Record. R. G. and Fdwardq J. H. Environmental in-

ihe hip. Brit.J.prev.m.Med. 12: 8-22. January. 1958.
9- genetics. University c- of Utah. May, on methodofogy 1960.

                            in humvl
~it~~~~o~a~~~~ ~~m~~~~~j~~~ $;$yFk zy:
Pediatrics 12: 525, 1953.

                                11. Tholen, A.. cited by Logan. W. P. D.  Incidence of
regions, except in the first two weeks  congenital malformations and their relation to vim infm-
after menstmation, for the very early  tions during pregnancy. Brit.med.J. 2: 641. 1951-
                              12. Neel. J. V. International Medical Congress on Congcn-
embryo is especially sensitive to radia-   ita1 Malformations. London. July. 1960.
                               13. Runner, M. Course in Medical Chetia. Bar Harbor,

tion. Young married males, who have M~I~.  st, 1960.
had accidental doses of radiation to their ~~a~~~~ 6~~U~v~~~~~~~~~o~~~g~et~
testes, should not consider attempts at   15. Olim. C B. and Turner, H. 8. Anenccphafy in fanam

                                 of a mother with tetralogy of Fallot. J.Amer.med.As8. 119:
fertilization for at least two months. Re-  932, July 5, 195%
                             16. In& T. H. and Philbrook. F. R. Monaroritia in-
covery of spermatozoa from radiation  duced by hypo& New Ewl.J.Med. 259: 558.564, seprrm.
damage occupies about that period of

               2 t&:58&. H. Dircus*w of cw: repoRl by I)r. E. E.
time, but at least it is known that B;nzeI. Aker.J.Obuet.Gynec. 21: 784-786, November. 19%.
                             Giud by Moya F Am V Jam- L. S. and Bemen. C.
spermatozoa can recover born such an  Hydrasmnios ah '&gcn:tal ';-alkh J.A==.A

assault. 18. Polck, E. LIL expectancy with hydramniok Mrhr.
                               Gebunrch.GynUk. 63: 203-210. July. 1933. Cited by Mwa,
Although chemotherapeutic control of  F.. et d.
                             19. Prindle, R. A., Ingalls, T. H. and Kirkwmd, S. B.

viral infections has been relatively un-  Materod hydnunniol. and congenital momalien of antd
successful thus far, there is considerable  zy w-*
Chance for SUCCeS along this line.  pm-   20.

                                 Humphw8, G. H.. Hasp. B. M. and F-r, J-  Coa-
                            genital atda of esophagus. J.ThoraC.Surg. 32: 539-3M.
sibly, the intentional exposure of young   1s.
                               21. Penonai Communication. C. Marshal Lee. Jr. cfndn-

women of high school age to various  nati,Ohio. 1954.
                                22. &infield. H. H. Wayr and meam to      h-t
                              mortality due to suffocation. J.Anu?r.mcd.Aa. 170: 647450.
                                June 6, 1959.
                               23. Penroae. L. S. Outline of Human Genetkr Pp. 79-81,

infections during early pregnancy.
There is a new awakening of interest  JO~U wilcy and Sow. NM York. 1959.
                                24. Lebmann. 0. and Forsunan. 8. Chmmomme compk-
in the future of human beings. There is  mutt in a moogdoid mather, b chiid ond the child's
                                    father. Lvlar 1/71% 498. Febniaq M, 1960.

thought as to the improvement in their  25. Chang M-C, Transplantation d feailired rpbbit ova.
mental and physical attributes. Means p&f&,Ts* ~&~~~~~b,w rd ,prrmoto-
are at hand to diagnose and study defi-
ciencies in these attributes. Many more

173: 1552-1556. AU~US~ 6. 1960-

Engl.J-Med. z12: 555-561D AprU

viruses may lead to diminution of such

265f54;:g6=; ;yknetic change.

American seientiu 47: 551-562. December. 1959.

23