TERATOLOGY 62:36 – 41 (2000)
Risk Factors for Congenital Hypothyroidism:
An Investigation of Infant’s Birth Weight,
Ethnicity, and Gender in California,
1990 –1998
D. KIM WALLER,1* JAMES L. ANDERSON,1 FRED LOREY,2 AND
GEORGE C. CUNNINGHAM2
1
University of Texas, Houston Health Science Center, School of Public Health, Houston, Texas 77225
2
California Newborn Screening Program, Genetic Disease Branch, California Department of Health
Services, Berkeley, California 94704
ABSTRACT
Background: Approximately 85% of primary congen-
ital hypothyroidism (CH) is sporadic and due to malfor-
mations of the thyroid gland. Past studies have re-
ported an increased birth weight among infants with
CH. We have attempted to replicate and expand these
observations, examining the association between dif-
ferent birth weight categories and CH stratified by
infant’s sex. We have also examined the prevalence of
CH by mother’s age and infant’s ethnicity, gender, and
year of birth.
Methods: A cross-sectional study was conducted on
5,049,185 infants screened by the statewide Califor-
nia Newborn Screening Program between 1990 and
1998, an estimated 98.6% of all newborns in the state.
Dried blood spots from a heel stick were assayed for
thyroxine (T4), and presumptive positives had follow-up
assays of thyroid-stimulating hormone (TSH) to deter-
mine definite positives.
Results: A total of 1,806 cases of CH were identified.
The following findings are unlikely to be due to chance.
Compared with infants with birth weights of 3,000 –
3,499 g, infants weighing ⬍2,000 g and those weigh-
ing ⱖ4,500 g had a twofold or greater increase in the
prevalence of CH. This was not explained as a result of
confounding by the infant’s ethnicity or gender. Com-
pared with whites, elevated prevalence rates were
found in most ethnic groups, which include the follow-
ing: Hispanics, Chinese, Vietnamese, Asian Indians,
Filipinos, Middle Easterners, and Hawaiians. As re-
ported previously, black infants had about one-third the
prevalence rate of whites. We also observed the fre-
quently described female preponderance of CH. The
female excess was maintained at all birth weights,
however it varied by infant’s ethnicity. Trends in the
prevalence of CH were not associated with mother’s
age or with the time interval between 1990 and 1998.
Conclusions: We observed an increased risk of CH in
both low-birth-weight (⬍2,000-g) and macrosomic
(ⱖ4,500-g) infants. This U-shaped association has not
© 2000 WILEY-LISS, INC.
been described in past studies. We have also ex-
panded the previously described ethnic differences in
CH risk to include ethnic groups not previously studied.
The unique pattern of CH occurrence suggests that
further studies to define modifiable risk factors may be
useful.
Teratology 62:36 – 41, 2000. © 2000 Wiley-Liss, Inc.
INTRODUCTION
Primary congenital hypothyroidism (CH) occurs in
about 1 of every 3,000 – 4,000 live births and results in
mental retardation if thyroid hormone replacement is
not initiated promptly. The initial report that thyroid
replacement markedly decreased the occurrence of
mental retardation in these children was made by
Smith et al. (’57). During the early 1970s, screening
programs for congenital hypothyroidism and other pre-
ventable causes of mental retardation in newborns
were initiated in the United States (Fisher et al., ’79)
and are now required in all states (Roberts et al., ’97).
As a result of these screening programs, virtually all
cases of congenital hypothyroidism in the United
States are now identified.
To date, newborn screening programs have reported
that, compared with whites, the birth prevalence of CH
is lower in blacks and higher in Asians and Hispanics
(Brown et al., ’81; Sobel and Saenger, ’89; Lorey et al.,
’92; Ray et al., ’97; Roberts et al., ’97; Seeherunvong
and Sunchai, ’98). These and other studies have con-
sistently reported that females have about twice the
prevalence of males.
We conducted an analysis of risk factors for CH,
using cross-sectional data from the California State-
wide Newborn Screening Program for 1990 –1998. A
primary goal of this study was to examine the associ-
*Correspondence to: Kim Waller, University of Texas, Houston
Health Science Center, School of Public Health, P.O. Box 20186,
Houston, TX 77225. E-mail: kwaller@utsph.sph.uth.tmc.edu
Received 30 September 1999; Accepted 31 December 1999
 RISK FACTORS FOR CONGENITAL HYPOTHYROIDISM
ation between birth weight and CH. There is a large
excess of low birth weight among infants with most
types of malformations. Since the 1950s, studies have
observed that infants with CH are more likely to have
increased birth weights compared with unaffected in-
fants (Childs et al., ’54; Andersen, ’61; Maenpaa, ’72;
Smith et al., ’75; Grant et al., ’92; Law et al., ’98). Based
on these observations, we hypothesized a U-shaped
relationship between birth weight and the prevalence
of CH. We have also examined the birth weight and CH
association stratified by infant’s sex and ethnicity,
which past studies have not done.
In addition, we sought to characterize the relation-
ship between ethnicity and CH more accurately by
examining the prevalence of CH for 13 different ethnic
groups, most of which have not been examined previ-
ously. We also sought to determine if there were differ-
ences in the prevalence of CH by maternal age or
whether the prevalence of CH was changing between
1990 and 1998.
MATERIALS AND METHODS
From January 1, 1990 to December 31, 1998, a total
of 5,049,185 infants, or greater than 98.6% of the total
live births in the state, were screened for congenital
hypothyroidism by the California Newborn Screening
Program of the California Department of Health Ser-
vices.
The case definition for this study included only con-
firmed cases of primary CH. In primary CH, the defect
in the production of thyroxine occurs at the level of the
thyroid gland. Approximately 85–90% of these cases
are due to structural malformations of the thyroid
gland (Sobel and Saenger, ’89; Virtanen et al., ’89). The
remaining cases of primary CH are hereditary and
attributed to autosomal recessive mutations affecting
the synthesis of thyroxine. Similar to previous studies
of risk factors for CH, this study did not have the
necessary information to determine the etiology of the
primary CH. Screening programs are designed to de-
tect primary CH, but not the underlying cause or eti-
ology. Because testing to determine the underlying eti-
ology is complex and does not alter management, some
clinicians consider it optional (LaFranchi, ’99).
Although the California Newborn Screening Pro-
gram is designed to detect primary CH, some cases of
secondary and tertiary CH are also detected. These
cases are rare and have conditions that indirectly affect
the production of thyroxine through effects on the pro-
duction of hormones in the pituitary (secondary CH)
and the hypothalamus (tertiary CH) (Sobel and
Saenger, ’89; De Vijlder et al., ’97). A total of 74 sec-
ondary and tertiary cases was ascertained by the Cal-
ifornia Newborn Screening Program over the study
period and is excluded from our analysis.
A heel-stick blood sample spotted onto a preprinted
collection form was used for screening. Infant’s ethnic-
ity and gender, mother’s date of birth, infant’s date of
birth, date of screening, and infant’s birth weight were
37
collected on this form before testing for CH. All infor-
mation for this study came from the computerized
records of these collection forms maintained by the
California Newborn Screening Program.
The collection form had checkboxes for the following
categories of infant’s ethnicity: white, Hispanic, black,
Chinese, Japanese, Korean, Cambodian, Laotian, Viet-
namese, Filipino, Native American, Middle Eastern,
Asian Indian, Hawaiian, Guamanian, Samoan, and
other. Data from the collection form indicated that 14%
of the infants included in this study belonged to two or
more ethnic groups. Almost all of these infants belonged
to only two ethnic groups, one of which was white. We
assigned these infants to their nonwhite ethnic group.
Instances of overlap between nonwhite ethnic groups
(e.g., Chinese and black or Chinese and Korean) were
very rare and were handled by giving preference to the
smaller ethnic group. All infants indicated to be Native
American or Hawaiian were assigned to those ethnic
groups, irrespective of the presence of other nonwhite
ethnic groups. Infants indicated to be both black and
Hispanic were assigned to a separate group. The sam-
ple size for Guamanians, Samoans, Cambodians, and
Laotians was too small for meaningful analysis. There-
fore, infants from these ethnic groups were included
with infants from other unspecified ethnic groups and
infants whose ethnicity was unknown.
The mother’s age at delivery was calculated from the
time elapsed between the mother’s date of birth and
the infant’s date of birth. Birth weights of ⬍250 g or
⬎7,500 g were considered improbable and were reas-
signed as missing.
From January 1990 through October 1997, heel-stick
samples of dried blood spots from all screened infants
were assayed for thyroxine (T4). Values of ⱕ9.0 mg/dl
were considered presumptively positive. In addition,
the lowest 5% of the values in each tray of samples
were also considered presumptively positive. Presump-
tive positives were assayed for thyroid-stimulating hor-
mone (TSH). Values of ⱖ25 ␮U/ml were considered
definitely positive. Infants with positive results were
referred to a pediatric endocrinologist for further diag-
nostic testing. In November 1997, The California New-
born Screening Program implemented new CH screen-
ing procedures. Since that time, all infant blood
samples have been assayed initially for TSH blood lev-
els and values of 25–100 ␮U/ml are considered pre-
sumptively positive. These infants receive a second
assay; if the TSH is still ⬎25 ␮U/ml, they are consid-
ered definitely positive. Initial assays of TSH above 100
␮U/ml are considered definitively positive.
Prevalences were compared using prevalence ratios
rather than prevalence odds ratios. Strata frequencies,
relative risks, confidence intervals, and logistic regres-
sion were calculated using the SAS data analysis pro-
gram.
RESULTS
The distribution of the infant’s ethnicity in our study
population was 45.6% Hispanic, 33.0% white, 7.5%
38 WALLER ET AL.

TABLE 1. Prevalence of primary congenital hypothyroidism by infant’s race and

infant’s sex: 1990 –1998, California per 100,000 live births
Female:male
Prevalence Prevalence ratio prevalence ratio
Race (cases/births) (95% CI) (95% CI)c
White 28.3 (47 1,666,721) 1.0 2.0 (1.7–2.5)
Hispanic 45.1 (1,038/ 2,301,768) 1.6 (1.4–1.8) 2.4 (2.1–2.7)
Black 8.7 (33/ 379,309) 0.3 (0.2–0.4) 1.0 (0.5–1.9)
Blk/Hisp 24.1 (7/ 29,005) 0.9 (0.4–1.8) –
Filipino 35.6 (41/ 115,271) 1.3 (0.9–1.7) 2.3 (1.2–4.4)
Chinese 43.7 (36/ 82,294) 1.5 (1.1–2.2) 1.9 (1.0–3.7)
Vietnamese 41.6 (21/ 50,435) 1.5 (1.0–2.3) 1.0 (0.4–2.3)
Japanese 11.7 (3/ 25,579) 0.4 (0.1–1.2) —
Korean 27.3 (7/ 25,625) 1.0 (0.5–2.0) —
NAa 33.2 (10/ 30,131) 1.2 (0.6–2.2) —
M Eastern 46.3 (17/ 36,695) 1.6 (1.0–2.6) 1.6 (0.6–4.1)
Asian Indian 82.5 (22/ 26,661) 2.9 (1.9–4.4) 0.7 (0.3–1.7)
Hawaiian 72.8 (4/ 5,496) 2.6 (1.0–6.6) –
Unspecifiedb 35.0 (96/ 274,195) 1.2 (1.0–1.5) 1.7 (1.1–2.5)
Total: 35.8 (1,806/ 5,049,185) — 2.1 (1.9–2.3)
a
Native American.
b
Includes unknown and unspecified ethnicity, Samoan, Guamanian, Laotian, and Cambo-
dian.
c
Sex ratio not included for ethnic groups with 10 cases or less.

black, and 13.9% other ethnic groups combined. Over
the study period of 1990 –1998, the proportion of all
newborns that were Hispanic increased steadily from
40.9% in 1990 to 49.9% in 1998. The proportion of
infants from all other ethnic groups decreased slightly
over the same period.
The prevalence of primary CH for the total study
population was 35.8 per 100,000 live births (1 per
2,793) and varied according to the infant’s ethnicity
(Table 1). Compared with whites, most of the ethnic
groups we examined had elevated prevalence rates,
including Hispanics, Chinese, Filipinos, Vietnamese,
Middle Easterners, Asian Indians, and Hawaiians. The
increase we observed for Filipinos was not significant
statistically. However, the 95% confidence interval
(95% CI) indicates that that an elevation in this group
is very likely. Prevalence rates for white and Hispanic
infants were the most stable, and there was a 1.6-fold
increased prevalence of CH among Hispanic infants
compared with white infants (prevalence ratio 1.6, 95%
CI ⫽ 1.4 –1.8). Asian Indians had particularly high
rates of CH compared with whites (prevalence ratio
2.9, 95% CI ⫽ 1.9 – 4.4). Black infants had the lowest
CH prevalence, at 8.7 per 100,000 births. This was
one-third the CH prevalence of white infants (preva-
lence ratio 0.3, 95% CI ⫽ 0.2– 0.4). Infants who were
Japanese or Korean and those indicated to be both
black and Hispanic had prevalence rates that were
similar to, or slightly less than, those of whites. How-
ever, the rates for these groups are based on small
sample sizes and the 95% CI values suggest that they
are not stable.
Table 1 gives the ratio of prevalence rates for females
compared with males separately, on the basis of infant
ethnicity. The female-to-male prevalence ratio was 2.1
overall and varied considerably by infant ethnicity.
Hispanics had the highest excess of female cases of CH
with a female to male prevalence ratio of 2.4. Whites
and Filipinos also had a clear preponderance of female
cases, with prevalence ratios of 2.0 and 2.3, respec-
tively. Most of the remaining ethnic groups showed a
lower preponderance of female cases, although small
numbers make these less precise and more likely due to
chance. Among black, Vietnamese, and Asian Indian
infants, the prevalence ratio in females compared with
males was less than or equal to 1.0. However, because
of the small numbers, the 95% CI values suggest that
these estimates are not stable.
Table 2 gives the prevalence of CH separately by
year of birth from 1990 through 1998. Although not
statistically significant (P ⫽ 0.18), there is a slight
increase in prevalence for the total population over the
study period. However, when this secular trend was
examined separately for four major ethnic groups, eval-
uation for linear trend by logistic regression showed no
significant trend for any of these ethnic groups.
Table 3 shows the prevalence of CH separately for
different categories of birth weight. Since, on average,
male infants are larger than female infants (Alexander
et al., ’96), the data are stratified by infant sex. Both
low- and high-birth-weight infants had an increased
prevalence of CH (Table 3, Fig. 1). Infants weighing
ⱕ2,000 g had a twofold or greater increase in the risk
of CH compared with the referent infants who weighed
3,000 –3,499 g. We examined prevalence ratios for
three weight categories of infants weighing ⱖ3,500 g
and found a modest trend of increasing risk of CH with
increasing birth weight, especially among female in-
fants. For infants weighing ⱖ4,500 g, there was a 2.4-
fold increase in the risk of CH among females infants
and a 2.3-fold increase in the risk of CH among males
infants compared with the sex-specific referent groups
of 3,000 –3,499 g (Table 3).
 RISK FACTORS FOR CONGENITAL HYPOTHYROIDISM 39

TABLE 2. Prevalence of primary congenital hypothyroidism by infant’s race and year of birth, 1990 –1998,
California per 100,000 live births†
Infant’s
race 1990 1991 1992 1993 1994 1995 1996 1997 1998 P-value*
White 26.1 31.4 28.0 25.7 26.3 36.8 30.2 28.8 22.9 0.93
Black 8.9a 11.0a 13.3a 6.7a 11.5a 9.8a 5.1a 10.6a —a 0.18
Hispanic 41.7 42.9 43.0 49.6 46.2 45.3 42.0 43.3 52.8 0.24
Other 35.2 44.6 39.4 35.5 33.6 30.1 33.1 51.2 37.9 0.84
Total: 32.3 36.5 35.1 36.5 35.2 37.5 34.5 37.8 37.9 0.18
†
Observations missing due to missing variables: 13,618 (0.3% of total births), no cases missing.
a
Less than 10 cases.
*Tested for linear trend using logistic regression.

TABLE 3. Primary congenital hypothyroidism: 1990 –1998 prevalence by infant’s sex and birth weight per
100,000 live births*
Females Males
Prevalence Prevalence
Weight (g) Prevalence Cases ratio 95% CI Prevalence Cases ratio 95% CI
⬍2,000 83.8 47 2.0 1.5–2.7 51.0 29 2.4 1.6–3.5
2,000–2,499 50.2 51 1.2 0.9–1.6 23.4 21 1.1 0.7–1.7
2,500–2,999 41.8 178 1.0 0.8–1.2 19.5 66 0.9 0.7–1.2
3,000–3,499a 41.9 404 1.0 a
21.3 189 1.0 a

3,500–3,999 54.1 365 1.3 1.1–1.5 22.8 187 1.1 0.9–1.3

4,000–4,499 67.1 119 1.6 1.3–2.0 24.0 69 1.1 0.9–1.5
ⱖ4,500 102.0 31 2.4 1.7–3.5 49.9 30 2.3 1.6–3.4
*Birth weights of ⬍250 g or ⬎7,500 g were considered improbable and were excluded from analysis. A total of 76,822 births
(1.5% of total births), including 20 cases (1.1% of cases), were excluded from this analysis because of missing birth weight or
infant sex.
a
Referent.

We examined the prevalence of CH for five categories

of mother’s age: ⱕ18, 19 –24, 25–29, 30 –34, and ⱖ35
years (results not shown). To control for differences in
the age distribution of births among different ethnic
groups, this analysis was stratified by four groups of
infant’s ethnicity: white, black, Hispanic, and all other
ethnic groups. Testing for linear trend by logistic re-
gression revealed no significant trends by age in any of
the groups or for total births (P ⫽ 0.39). The ratio of
female to male cases did not differ across these catego-
ries of maternal age.

Fig. 1. Primary congenital hypothyroidism prevalence by gender and
birth weight in 1,786 cases. California, 1990 –1998.
The distribution of birth weight varies by ethnic
group with blacks tending to be smaller than whites
and Hispanics. To determine whether the U-shaped
relationship observed between prevalence of CH and
birth weight was confounded by infant’s ethnicity we
examined the prevalence ratios for these birth weight
categories separately for white, Hispanic, and black
infants (results not shown). In each of these ethnic
groups, there was an increased prevalence of CH both
among infants weighing ⱕ2,000 g and among infants
weighing ⱖ4,500 g, compared with the referent weight
group. We also noted that the ratio of female to male
cases did not vary across these birth weight categories.
DISCUSSION
We observed a U-shaped association between the
prevalence of CH and birth weight that has not been
previously described. It is well known that infants with
congenital malformations have a large excess of low
birth weight due to growth retardation that often ac-
companies the malformation. Thus, it was not surpris-
ing to observe an excess of low birth weight among
infants with CH. However, except for CH and rare
genetic syndromes in which infants are born with mac-
rosomia (Jones, ’97), previous studies have not noted
an association between macrosomia and congenital
malformations (Milli et al., ’91).
Although, a female excess has been reported for neu-
ral tube defects (NTDs) and some types of cardiac mal-
formations (Seller, ’87; Pradat, ’92; Samanek, ’94;
Shaw et al., ’94), these excesses are neither as consis-
40 WALLER ET AL.
tent nor as large as the female excess associated with
CH. Thus, the female excess is a particularly interest-
ing feature of the epidemiology of primary CH. It is
unclear, however, whether females are more suscepti-
ble to developing CH or whether females with CH have
increased in utero survival compared with males with
CH. The observation of thyroxine in the cord serum of
fetuses with CH suggests that levels of fetal thyroxine
are maintained by transfer of maternal thyroxine to
the fetus and that CH may not be deleterious to the
fetus before birth (Vulsma et al., ’89). Also, Dussault et
al. (’80) reported that the ratio of female to male cases
among hereditary cases of CH was approximately 1.0.
Among the 74 cases of secondary and tertiary CH that
we excluded from this study, the ratio of females to
males was 0.8 (33 females to 41 males), compared with
the ratio of 2.0 (1,210 females to 596 males) observed
among our cases of primary CH, P ⬍0.001. These ob-
servations suggest that fetal hypothyroidism alone
does not cause differential survival of females com-
pared with males and that the preponderance of female
cases may be confined to the 85–90% CH which are due
to malformations of the thyroid gland. It also follows
that there may be a true increase in the number of
female infants in whom malformations of the thyroid
gland develop.
Our study is consistent with previous studies in ob-
serving that Hispanics and Asians have an increased
and blacks a decreased prevalence of CH compared
with whites (Brown et al., ’81; Sobel and Saenger, ’89;
Lorey et al., ’92; Toublanc, ’92; Ray et al., ’97; Roberts
et al., ’97; Seeherunvong and Sunchai, ’98). The epide-
miology of CH among black infants is strikingly differ-
ent from that of other ethnic groups. They have a very
low prevalence of CH and an equal ratio of the females
to males. Although our observation of a female to male
ratio of 1.0 for cases of CH in blacks is not statistically
significant, it is consistent with a similar finding re-
ported by Lorey and Cunningham (’92).
The increased prevalence of CH that we observed
among infants with macrosomia and infants from spe-
cific ethnic groups might be explained by an increased
prevalence of CH among mothers with diabetes.
Women with insulin-dependent diabetes (IDDM) and
gestational diabetes are at greater risk of having mac-
rosomic infants and of having infants with a variety of
congenital anomalies (Ramos-Arroyo et al., ’92; Becerra
et al., ’95). Compared with white women, increased
diabetes has been reported among pregnant women in
Hispanics, Native Americans, Chinese Americans,
Asian Indians, and Middle Easterners (Kieffer, ’98).
We also observed an increased prevalence of CH among
infants belonging to these same ethnic groups. How-
ever, we could not directly test the hypothesis of an
increased risk of CH associated with maternal diabetes
because our study data do not include information on
diabetes in the mothers.
Some investigators have suggested that infants with
CH have a tendency to prolonged gestation, although
only a few have presented data on gestational age
(Maenpaa, ’72; Smith et al., ’75; Grant et al., ’92).
Larger and more refined analyses are needed in order
to determine whether the association between macro-
somia and CH is independent of gestational age. That
is, do infants with CH tend to be large for their gesta-
tional age?
Primary CH is a relatively common condition with
almost complete ascertainment in developed countries.
Thus, an excellent sampling frame exists to conduct
population-based studies of these infants. To date,
most studies of risk factors for CH have been based on
existing databases and did not distinguish between the
different subtypes of primary CH. Future studies of
primary CH should attempt to distinguish between
hereditary cases and malformations of the thyroid,
which can be further classified into dysgenesis and
agenesis of the thyroid. It appears that the female
excess of primary CH probably varies across these sub-
types. An analysis by sub-types might also shed light
on the epidemiology of CH among black infants.
The prevention of mental retardation due to CH,
through the use of thyroxine replacement therapy, is
an important public health success story. However,
little work has been done to identify modifiable risk
factors with the potential to prevent CH. Knowledge of
such risk factors could decrease the number of infants
who need lifetime thyroid hormone replacement ther-
apy.
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