Fetal Growth with Congenital Syphilis:
A Quantitative Study
RICHARD L. NAEYE,
Department
M.D.
of Pathology, Pennsylvania State University
Hershey, Pennsylvania 17033
College of
Medicine,
ABSTRACT
Naeye, Richard L.: Fetal growth with congenital syphilis: A quantitative
study. Amer. J. Clin. Path. 55: 228-231, 1971. Although fetal infection is one
of the commonly recognized causes of fetal growth retardation, the effects of
congenital syphilis on antenatal growth have not been published. A quantitative, morphologic study of 36 stillborn and newborn infants with congenital
syphilis was undertaken. Despite considerable evidence of tissue destruction,
body growth, organ growth, and cellular growth were near normal in the
infants as a group.
is a recognized cause of
antenatal growth retardation. Mechanisms
most often involved in this retarded growth
include cellular destruction and inhibition
of cellular multiplication. 2 " 4 The relative
importance of each of these mechanisms in
individual types of infection is unknown.
Also unknown is whether late gestational
infections have the same influence on
growth as those incurred in early gestation.
Congenital syphilis provides a model for
examination of some of these questions. It
is usually incurred after midgestation and
is associated with prominent tissue necrosis.
The present study provides a quantitative
morphologic analysis of organs and cell
structure in infants with congenital syphilis. The effects of the infection on fetal
growth are surprisingly small.
FETAL INFECTION
Case Material
Autopsy material from 36 newborn infants with congenital syphilis who had well
preserved tissues was examined. The 13 inReceived April 20, 1970; accepted for publication
May 5, 1970.
228
fants who were liveborn survived less than
72 hours each. In every case, the diagnosis
was established by histologic demonstration
of Treponema pallidum in the tissues using
Levaditi's stain. The 36 infants had gestational ages ranging from 25 to 40 weeks,
as calculated from the mothers' statements
of their last menstrual periods, the mean
value being 33.5 weeks. All infants died
before 1945. Serologic tests for syphilis
(STS) or Wasserman tests of cord blood
samples from nine infants were done; all
results were positive. Twenty-three of the
infants were Negro; the rest were classified
as Caucasian. No cases in which nonsyphilitic fetal or maternal disorders might have
affected fetal growth were included. Fetal
conditions that led to exclusion included
congenital malformations, chromosomal
disorders, erythroblastosis fetalis, and multiple births. Maternal factors that led to
exclusion were hypertension or other manifestations of toxemia, diabetes mellitus,
cardiac disease, and certain placental abnormalities, such as large infarcts or prolonged partial separation.
February
1971
229
FETAL G R O W T H W I T H CONGENITAL SYPHILIS
The infected infants were compared with
36 noninfected control infants, matched
for gestational age, who had body weights
within 10% of mean normal values for gestational age.8 In the control infants, deaths
were due to pulmonary hemorrhage, cerebral hemorrhage, hyaline membrane disease, fetal or intrapartum hypoxia.
Table 1. Group Measurements in Newborn Infants
with Congenital Syphilis in Percentages of
Control Values
Body weight
Body length
Heart weight
Lungs weight
Liver weight
Spleen weight
Adrenals weight
Kidneys weight
Pancreas weight
Thymus weight
Methods
Organ weights and body measurements
were obtained from autopsy protocols. In
each case, weights and measurements were
calculated as percentages of mean values
for control infants of the same gestational
age as published by Schulz and associates.6
A mean percentage of Schulz's control values was calculated for each organ or body
measurement in the infected infants. Mean
values for the control group were within a
few percentage points of Schulz's published
figures.
The percentages of fetal and permanent
zones of the adrenal cortex were determined
by using a planimeter on camera lucida
drawings of cross sections of the gland. The
93.9%
98.4%
97.0%
93.8%
128.7%*
189.0%t
98.2%
118.2%
90.1%
70.9%
*p< 0.05.
f p < 0.01 by comparison with controls.
same technic was used to determine the
relative proportions of the cortical and
medullary zones comprising the thymus.
The method of line sampling was used to
quantitate individual components in the
various organs. 1 ' 7 In this method, random
microscopic fields are projected onto measured lines with a camera lucida. Each tissue component to be analyzed (i.e., cell,
cell component, or larger structure) is measured along the line at those points where
it intersects the line. By this means, the
CONGENITAL
SYPHILIS
Number of cells or organ structures
HEART
120
100
LIVER
ADRENALS
PANCREAS
KIDNEYS
-
80
60
-
40
-
20
MYOCARDIAL
FIBERS
HEPATIC
CELLS
FETAL
ZONE
CELLS
PERMANENT
ZONE
CELLS
EXOCRINE ENDOCRINE
CELLS
CELLS
GLOMERULI
FIG. 1. Visceral organs in newborn infants with congenital syphilis have a normal or near-normal
number of their usual parenchymal cells by comparison with noninfected control infants.
230
A.J.C.P.—Vol.
NAEYE
Table 2. Group Cellular and Other Organ Measurements
in Newborn Infants with Congenital Syphilis
in % of Control Values*
weights, cellular dimensions, and cell numbers.
Results
Heart
Mean diameter of myocardial nuclei
Cytoplasm per myocardial fiber
92.0%
102.3%
Liver
Mean diameter of hepatic cell nuclei
Cytoplasm per hepatic cell
87.7%
110.0%
Pancreas
A. Exocrine Gland
Mean diameter of glandular cell nuclei
Cytoplasm per glandular cell
92.5%
87.2%
B. Endocrine Gland
Mean diameter of glandular cell nuclei
Cytoplasm per glandular cell
86.4%
97.7%
Adrenal Glands
A. Permanent Cortex
Mean diameter of glandular cell nuclei
Cytoplasm per glandular cell
96.7%
104,5%
B. Fetal Cortex
Mean diameter of glandular cell nuclei
Cytoplasm per glandular cell
85.3%
97.8%
Thymus
Mean diameter of epithelial islands
88.8%
Kidneys
Mean diameter of glomeruli
55
The organs showed the histologic abnormalities often reported with congenital
syphilis. These included interstitial fibrosis
of the liver and pancreas in a number of
cases. Foci of necrosis were most common in
the liver but often were also found in other
organs, such as the adrenal glands. Inflammatory cells were evident in many organs,
being most prominent in the liver and
lungs. The spirochetes were usually demonstrated in the liver and less often in
lungs and adrenal glands.
Most body and organ measurements in
the infected infants as a group were near
normal values; the spleen and liver were
overweight (Table 1). Despite the aforementioned inflammation and necrosis, all
organs studied had near-normal numbers
of their usual parenchymal cells (Fig. 1).
Cellular dimensions were also normal in
all of the organs examined (Table 2). Hepatic enlargement was due almost entirely
to increased mass of hematopoietic tissue,
96.7%
* p values for the infants with syphilis are all greater
than 0.05 by comparison with controls
140 r
120 -
approximate percentages of various components comprising a tissue can be determined. In addition, relative sizes and numbers of cells and cellular components can
be calculated. In most instances, multiple
sections of each organ were examined using
this technic.
After determining the number of individual components in individual cases,
mean values for each component for infected and control cases were calculated.
The numbers of components in the two
groups were compared. Details of calculations using these methods have been published.1' 7 Student's t test was used to determine the significance of abnormal organ
100
£ 80
^
Interstitium & other tissues
UJ
o
tr
y so
\ Hematopoietic Tissue
:':£•&' Hepatic Cell Cytoplasm
^
40
Hepatic Cell Nuclei
20
CONTROLS
CONGENITAL
SYPHILIS
tic 2. T h e total lengths of the columns represent the relative volumes of individual components
of the liver. T h e column labeled interstitium also
includes inflammatory cells, edema fluid, and connective tissue. T h e enlargement of the livers in the
infants with syphilis is due almost entirely to increased mass of hematopoietic tissue, inflammatory
cells, connective tissue, and edema.
February
1971
231
FETAL G R O W T H W I T H CONCEN1TAL SYPHILIS
inflammatory cells, connective tissue, and
edema (Fig. 2). The masses of lymphoid
centers actually were somewhat subnormal
in the spleens of the infected infants, the
organs being enlarged mostly by increased
masses of hematopoietic tissue and erythrocytes (Fig. 3).
SPLEEN
200
160
140
Discussion
In the present study congenital syphilis
was found not to have a significant effect
on antenatal body and organ growth. In
this regard it resembles congenital toxoplasmosis and is quite unlike congenital
rubella and cytomegalovirus infections,
which often retard antenatal growth. 2-4 Necrosis cannot always induce growth retardation, because it is more common with syphilis than with rubella, yet the latter is often
associated with severe growth retardation.
Necrosis also correlates poorly with fetal
growth in individual cases of all four of
the infectious disorders. 2 ' 3
The duration or time of onset of an infection may be an important factor in its
ability to retard growth. Fetal infection by
Treponema pallidum before the eighteenth
gestational week has not been reported. 8 In
virtually every instance where rubella is
responsible for retarded growth, the infection starts in the first trimester.8 The same
may be true for cytomegalovirus infections,
but it is usually impossible to establish the
time of onset of the latter. 2 Cells destroyed
in early gestation or even within a few
weeks of birth probably disappear in most
instances without residual necrosis or connective tissue replacement. Fetal organs
have a remarkable capacity for repair and
reconstruction, an ability which is progressively lost after birth.
In cases of rubella, there is evidence that
antenatal growth may be retarded through
an inhibition of cellular multiplication. 3
T o date there is no evidence that Treponema pallidum has a similar capacity. It
is of interest that most newborn infants
o 100
80
I
I Remaining Tissue
IIIIII'IIII Lymphoid Centers
CONTROLS
CONGENITAL
SYPHILIS
FIG. 3. T h e spleens are enlarged in the infants
with congenital syphilis. T h e masses of lymphoid
centers actually are somewhat subnormal in the
spleens of the infected infants, the organs being
enlarged mostly by increased masses of hematopoietic tissue and erythrocytes.
with syphilis show no morphologic evidence of undernutrition.' 1 The severe placental abnormalities induced by the infection seem to have no major influence on
nutrient transfer.
Acknowledgment.
Doctor Robert Heptinstall of
Johns Hopkins Hospital in Baltimore permitted us
to study many of the cases in this report.
References
1. Naeye RL: Organ and cellular development in
mice growing at simulated high latitude. Lab
Invest 15:700-706, 1966
2. Naeye RL: Cytomegalovirus disease, the fetal
disorder. Amer J Clin Path 47:738-744, 1967
3. Naeye RL, Blanc WA: Pathogenesis of congenital rubella. JAMA 194:1277-1283, 1965
4. Naeye RL, Kelly JA: Judgment of fetal age. III.
T h e pathologist's evaluation. Pediat Clin N
Amer 13:849-862, 1966
5. Morison JE: Foetal and Neonatal Pathology.
London, Butterworths, 1963, p 507
6. Schulz DM, Giordano DA, Schulz DH: Weights
of organs of fetuses and infants. Arch Path
74:244-250, 1962
7. Uotila U, Kaunas O: Quantitative histological
method of determining proportions of principal
components of thyroid tissue. Acta Endocrin
11:49-60, 1952