Declines in sex ratio at birth and fetal deaths in Japan, and in U.S. whites but not African Americans.
ABSTRACT The expected ratio of male to female births is generally believed to be 1.05, also described as the male proportion of 0.515.
We describe trends in sex ratio at birth and in fetal deaths in the United States, in African Americans and in whites, and in Japan, two industrial countries with well-characterized health data infrastructures, and we speculate about possible explanations.
Public health records from national statistical agencies were assembled to create information on sex ratio at birth and in fetal deaths in the United States (1970-2002) and Japan (1970-1999), using SPSS.
Sex ratio at birth has declined significantly in Japan and in U.S. whites, but not for African Americans, for whom sex ratio remains significantly lower than that of whites. The male proportion of fetal death has increased overall in Japan and in the United States.
Sex ratio declines are equivalent to a shift from male to female births of 135,000 white males in the United States and 127,000 males in Japan. Known and hypothesized risk factors for reduced sex ratio at birth and in fetal deaths cannot account fully for recent trends or racial or national differences. Whether avoidable environmental or other factors--such as widespread exposure to metalloestrogens or other known or suspected endocrine-disrupting materials, changes in parental age, obesity, assisted reproduction, or nutrition--may account for some of these patterns is a matter that merits serious concern.
- SourceAvailable from: oxfordjournals.org[show abstract] [hide abstract]
ABSTRACT: We investigated the possible association between the Kobe earthquake (January 1995) and the sex ratio among live-born infants after the catastrophe. A significant decline in the sex ratio (0.501) of Hyogo Prefecture in October 1995 was observed 9 months after the Kobe earthquake as compared with an expected value of 0.516 in the period from January 1993 to January 1996 (P = 0.04; one-tailed). Simultaneously, a reduction in fertility of approximately 6% was also observed, compared with the month of October 2 years previously. Thus, the acute stress resulting from a great natural catastrophe can be a cause of a low sex ratio at birth 9 months later.Human Reproduction 09/1998; 13(8):2321-2. · 4.67 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Researchers from seven European nations and the United States have published reports of increasing rates of hypospadias during the 1960s, 1970s, and 1980s. Reports of increasing rates of cryptorchidism have come primarily from England. In recent years, these reports have become one focus of the debate over endocrine disruption. This study examines more recent data from a larger number of countries participating in the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS) to address the questions of whether such increases are worldwide and continuing and whether there are geographic patterns to any observed increases. The ICBDMS headquarters and individual systems provided the data. Systems were categorized into five groups based on gross domestic product in 1984. Hypospadias increases were most marked in two American systems and in Scandinavia and Japan. The increases leveled off in many systems after 1985. Increases were not seen in less affluent nations. Cryptorchidism rates were available for 10 systems. Clear increases in this anomaly were seen in two U.S. systems and in the South American system, but not elsewhere. Since 1985, rates declined in most systems. Numerous artifacts may contribute to or cause upward trends in hypospadias. Possible "real" causes include demographic changes and endocrine disruption, among others.Environmental Health Perspectives 05/1999; 107(4):297-302. · 7.26 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Once- or twice-weekly consumption of fish (or a small amount of fish intake) reduces the risk of coronary heart disease and sudden cardiac death in Western countries. It is uncertain whether a high frequency or large amount of fish intake, as is the case in Japan, further reduces the risk. To examine an association between high intake of fish and n3 polyunsaturated fatty acids and the risk of coronary heart disease, a total of 41,578 Japanese men and women aged 40 to 59 years who were free of prior diagnosis of cardiovascular disease and cancer and who completed a food frequency questionnaire were followed up from 1990-1992 to 2001. After 477,325 person-years of follow-up, 258 incident cases of coronary heart disease (198 definite and 23 probable myocardial infarctions and 37 sudden cardiac deaths) were documented, comprising 196 nonfatal and 62 fatal coronary events. The multivariable hazard ratios (HRs) and 95% confidence intervals in the highest (8 times per week, or median intake=180 g/d) versus lowest (once a week, or median intake=23 g/d) quintiles of fish intake were 0.63 (0.38 to 1.04) for total coronary heart disease, 0.44 (0.24 to 0.81) for definite myocardial infarction, and 1.14 (0.36 to 3.63) for sudden cardiac death. The reduced risk was primarily observed for nonfatal coronary events (HR=0.43 [0.23 to 0.81]) but not for fatal coronary events (HR=1.08 [0.42 to 2.76]). Strong inverse associations existed between dietary intake of n3 fatty acids and risk of definite myocardial infarction (HR=0.35 [0.18 to 0.66]) and nonfatal coronary events (HR=0.33 [0.17 to 0.63]). Compared with a modest fish intake of once a week or &20 g/d, a higher intake was associated with substantially reduced risk of coronary heart disease, primarily nonfatal cardiac events, among middle-aged persons.Circulation 01/2006; 113(2):195-202. · 15.20 Impact Factor
In modern nations today, the proportion of
couples reporting difficulties with reproduc-
tion ranges from one of every five to one in
four. The survival of any population depends
on the capacity of individuals to reproduce
successfully if and when they chose to do so.
It is increasingly clear that exposures to for-
eign substances in either parent before con-
ception can have a broad range of teratogenic
effects, including reproductive failure, struc-
tural or functional defects or altered expres-
sion of sex at birth (James 1987, 1998a,
1998b). It is well known that various nutri-
tional, physical, and chemical exposures of
pregnant females can affect reproductive suc-
cess and the health of offspring. Moreover,
evidence has mounted that paternal nutrition
and a number of behavioral, environmental,
and workplace factors affect the DNA of
sperm produced (Somers 2004) as well as the
tendency to father children with birth defects
(Garry et al. 1996; Ryan et al. 2002).
Within any population, the determina-
tion of sex at birth is understood to be the
result of complex paternal and maternal fac-
tors. For any single pregnancy, the SRY (sex-
determining region Y) gene located on the Y
chromosome determines the sex of a fertilized
egg. But events occurring after conception
may differentially affect the viability of a male
conceptus. There is a normalized rate of the
proportion of male and female births: Most
often, for every 100 female births, 105 male
births typically occur (United Nations 2004),
which can also be expressed as the male pro-
portion of 0.515. Deviations from this nor-
malized rate and trends in sex ratio overall
can provide clues about underlying shifts in
population-wide factors that affect the proba-
bility that a male conceptus will survive preg-
nancy. As with many population-wide effects,
when it comes to what determines sex ratio at
birth, timing of exposure may be more criti-
cal than the total dose or rate of exposure
(Davis et al. 1998).
To assess recent trends in sex ratio, we
expanded work previously published on pat-
terns of recorded sex at birth in Japan and the
United States from 1970, including data for
white and African-American U.S. subpopula-
tions. These two countries were chosen
because they are industrial nations with well-
established systems for collecting such data
and relatively complete ascertainment of sex
at birth. We also examined trends in the sex
ratio of fetal deaths in these countries. Given
these findings, we explored theoretical expla-
nations for these recent trends in light of
studies of highly exposed populations of male
workers and propose further studies.
Along with parental age, birth order of
child, maternal illness, parental hormone
levels, stress, and natural disaster and war, sex
ratio has also been shown to vary by racial/
ethnic origin of mother (e.g., Mathews and
Hamilton 2005). The numerous studies on
the topic present highly varied and sometimes
conflicting results (Catalano 2003; Gutierrez-
Adan et al. 2000; James 1987; Misao et al.
1998; Parazzini et al. 1998). Marcus et al.
(1998) found that patterns of sex ratio differed
between U.S. whites and African Americans,
with the latter showing a slight increase. They
noted that differences in estrogen and testos-
terone levels between African-American and
white women may contribute to differences in
the sex ratio of their offspring. A recent study
of the Aamjiwnaang First Nation community
in Canada reported that sex ratios have
dropped from an expected 0.55–0.54 range to
0.45 for the late 1990s, to 0.35 for the
1999–2003 period (Mackenzie et al. 2005).
To our knowledge, this is a more significantly
reduced sex ratio and greater rate of change
than has been reported previously anywhere,
and strongly suggests that sex ratio may prove
to be an environmentally sensitive indicator.
Paternal exposures before conception have
been found to affect the sex of offspring. Men
exposed to dibromochloropropane, certain
pesticides, alcohol, lead, and solvents, as well
as men employed in the aluminum industry
and in saw mills, father fewer sons than
expected (Davis et al. 1998). Mocarelli et al.
(2000) observed a decreased sex ratio in the
offspring of men exposed to dioxin from an
industrial accident in Seveso, Italy, in 1976.
Environmental Health Perspectives • VOLUME 115 | NUMBER 6 | June 2007
Address correspondence to D.L. Davis, 5150 Centre
Ave., Suite 432, Pittsburgh, PA 15232 USA.
Telephone: (412) 623-1172. Fax: (412) 623-1382.
E. Reitano, J. Kuo, and Y.-Y. Han provided
research assistance in final preparation of this manu-
script. A. Ilaqua assisted in the retrieval of data
sources, as did J. Lee and T. Suzuki. Constructive
comments also were received from F. Mudagno,
R. Ness, E. Talbott, and K. Burns.
Funding was provided by The Heinz Endowments,
the University of Pittsburgh Cancer Institute, DSF
Charitable Trust, the U.S. Centers for Disease
Control and Prevention, and the W. Alton Jones
The authors declare they have no competing
Received 21 July 2006; accepted 1 March 2007.
Declines in Sex Ratio at Birth and Fetal Deaths in Japan, and in U.S. Whites
but Not African Americans
Devra Lee Davis,1Pamela Webster,1Hillary Stainthorpe,2Janice Chilton,3Lovell Jones,3and Rikuo Doi4
1Center for Environmental Oncology, University of Pittsburgh Cancer Institute and Department of Epidemiology, Graduate School of
Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; 2Feinberg School of Medicine, Northwestern University,
Evanston, Illinois, USA; 3Center for Research on Minority Health, University of Texas M.D. Anderson Cancer Center, Houston, Texas,
USA; 4Yokohama City University, School of Medicine, Yokohama, Japan
BACKGROUND: The expected ratio of male to female births is generally believed to be 1.05, also
described as the male proportion of 0.515.
OBJECTIVES: We describe trends in sex ratio at birth and in fetal deaths in the United States, in
African Americans and in whites, and in Japan, two industrial countries with well-characterized
health data infrastructures, and we speculate about possible explanations.
METHODS: Public health records from national statistical agencies were assembled to create infor-
mation on sex ratio at birth and in fetal deaths in the United States (1970–2002) and Japan
(1970–1999), using SPSS.
RESULTS: Sex ratio at birth has declined significantly in Japan and in U.S. whites, but not for
African Americans, for whom sex ratio remains significantly lower than that of whites. The male
proportion of fetal death has increased overall in Japan and in the United States.
CONCLUSIONS: Sex ratio declines are equivalent to a shift from male to female births of 135,000
white males in the United States and 127,000 males in Japan. Known and hypothesized risk factors
for reduced sex ratio at birth and in fetal deaths cannot account fully for recent trends or racial or
national differences. Whether avoidable environmental or other factors—such as widespread expo-
sure to metalloestrogens or other known or suspected endocrine-disrupting materials, changes in
parental age, obesity, assisted reproduction, or nutrition—may account for some of these patterns is
a matter that merits serious concern.
KEY WORDS: African Americans, environment, fetal deaths, Japan, race, sex ratio, trends. Environ
Health Perspect 115:941–946 (2007). doi:10.1289/ehp.9540 available via http://dx.doi.org/ [Online
9 April 2007]
In the first decade after a chemical plant
explosion caused unusually high exposures to
dioxin, of the children born to those with the
highest exposures, all were female. In another
study, Egeland et al. (1994) showed that men
who were occupationally exposed to dioxin
had altered gonadotrophin and testosterone
levels; the researchers hypothesized that altered
paternal hormone levels might affect the via-
bility of Y-bearing sperm or the fetuses con-
ceived by them. A follow-up study failed to
find significant changes in sex ratio of off-
spring or fetal death rates in this small sample
population (Schnorr et al. 2001). A recent
study of men and women working in a
Russian plant that manufactured the herbicide
2,4,5-trichlorophenoxyacetic acid found that
only 38% of the children fathered by these
exposed workers were male, whereas exposed
mothers produced a normal 51% males (Ryan
et al. 2002). An investigation of the effect of a
variety of chemicals on the sex ratio of chemi-
cal industry workers in Japan was, in some
ways, inconclusive (Okubo et al. 2000):
Although researchers found that exposure to
chemical materials may have affected the sex
ratio of the offspring of the workers, they
could not indicate with certainty which chem-
ical materials may have been responsible. The
workers’ exposure to heat, they hypothesized,
may have been a co-contributor.
Maternal exposure can also be an important
determinant of sex ratio. Maternal serum
exposure to polychlorinated biphenyls (PCBs)
from the consumption of contaminated Great
Lakes fish resulted in decreased sex ratio of off-
spring (Weisskopf et al. 2003). The odds of
having a male child decreased by 46% for
every unit increase in the natural log of serum
PCB concentration. This observation adds to
the growing body of evidence that exposure to
certain chemicals can alter sex ratio at birth.
Moreover, an increased risk of cryptorchidism
among sons of female gardeners has been
reported in Denmark, suggesting an association
with prenatal exposure to chemicals used in
farming and gardening (Weidner et al. 1998).
There is some evidence that dose and combi-
nations of exposures can have differing
impacts on sex ratio (Axelrod et al. 2001).
One small study found that mothers with the
highest levels of exposure to PCBs gave birth
to proportionally more males than females,
whereas those with the lowest exposure did
not (Sharpe and Skakkebaeke 1993).
Materials and Methods
We conducted separate analyses for the
United States and Japan. For Japan, we exam-
ined sex ratio at births and of fetal deaths
from 1949 to 1999. We relied on national
statistics provided by the Japanese Vital
Statistics Bureau (Japan Statistical Yearbook
2000), which are published yearly, but are not
available for the postwar years 1944–1946.
For the United States, we examined trends
in sex ratio overall, for African Americans, and
for whites, from vital statistics data (Martin
et al. 2003) from 1970 to 2002. Last, we cal-
culated the U.S. sex ratio of all fetal deaths,
using fetal death data files for 1983–1995
(National Center for Health Statistics 2003).
We examined trends in the male proportion of
live births, and from these we calculated sim-
ple linear regressions. We calculated the male
proportion of fetal deaths by dividing the
number of male fetal deaths by the sum of
male and female fetal deaths. Summing male
and female fetal deaths should provide a more
accurate estimate of male proportion than
using total fetal deaths, because total fetal
deaths include fetuses of unknown sex.
Data for the United States were taken
from vital statistics published by the National
Center for Health Statistics (Martin et al.
2003). Data to examine the U.S. sex ratio of
fetal deaths were obtained from the National
Center for Health Statistics (2003). For every
year from 1983 to 1995 a fetal death data file
was released for public use, and from these we
obtained figures to calculate the male propor-
tion of fetal deaths. We examined only deaths
after 20 weeks gestation because most deaths
before that time are of unknown sex. Where
sex was unknown, that case was excluded
from analysis. Mother’s race was used to cal-
culate proportions by race.
Our data show distinct and unexplained
trends in sex ratio in Japan and in the United
States. Since 1970, sex ratio (SR) has declined
significantly in U.S. whites and Japanese. But
in African Americans, SR has increased mod-
estly over time, while remaining lower than
that of whites.
Figure 1 shows the male proportion of live
births in Japan from 1949 to 1999. In years
before 1970, sex ratio fluctuated greatly from
year to year, but since 1970 sex ratio has
declined fairly steadily with less yearly fluctua-
tion. For 1970–1999, the regression coeffi-
cient is –9.91 × 10–5 with an R2of 0.70. Over
the study period of 1970–1999, SR for Japan
declined significantly (p < 0.01) from 0.5172
to 0.5135. This is equivalent to a decline of 37
males per 10,000 births. If the 1970 male pro-
portion had remained constant, this would
correspond to a shift from male to female
births of approximately 127,000 over these
In Japan, fetal death rates are typically
more than twice those of the United States,
and range to as much as five times as large. For
example, in 1999 Japan reported 31.6 deaths
per 1,000, whereas the 1999 U.S. fetal mortal-
ity rate for all races was 6.7 per 1,000. Figure 2
shows the male proportion of fetal deaths. For
1972–1999, the rate of increase is 4.27 × 10–3,
nearly seven times greater than that of the pro-
ceeding 72 years. The proportion of fetal
deaths that are male has gone from just over
half to nearly two-thirds, a figure that held
throughout the 1990s. Male fetuses in Japan,
then, are clearly at greater risk of dying than
are female fetuses. Although fetal death rates
have generally fallen, from around 100 per
1,000 in 1960 to 32 per 1,000 in 1999, the
proportion of fetal deaths that are male has
Davis et al.
VOLUME 115 | NUMBER 6 | June 2007 • Environmental Health Perspectives
Figure 1. Proportion of male live births, Japan, 1949–1999.
1949 1959 1969 197919891999
Figure 2. Proportion of male fetal deaths, Japan, 1949–1999.
1954 196419741984 1994
continued to increase, from 56% of fetal
deaths in 1960 to 67.7% in 1999.
Next consider data for the United States,
shown in Figure 3. For all races in the United
States, the sex ratio decreased from 105.5 in
1970 to a low of 104.6 in 2001. This can be
expressed as a decline from 0.5134 in 1970 to
0.5117 in 2002, equivalent to a drop of 17
males per 10,000 births. This trend has a
regression coefficient of –0.022 (p < 0.001)
(or –5.27 × 10–5if expressed as the propor-
tion of births that are male). When U.S. non-
Hispanic whites and U.S. African Americans
are examined separately, distinct differences
are apparent. For U.S. whites, the sex ratio
decreased from 105.9 to 105.0 between 1970
and 2002 (and was as low as 104.7 in 2001).
This can be expressed as a decline from
0.5143 to 0.5122, equivalent to a drop of 21
males per 10,000 births. This trend for whites
has a regression coefficient of –0.029 (p <
0.001); that is, the trend for whites was for
the sex ratio to drop –0.029 annually since
1970. Assuming that the 1970 sex ratio for all
births in the United States had remained con-
stant over these three decades, this is equiva-
lent to a shift from male to female births of
For U.S. African Americans, however, the
sex ratio increased from 103.1 to 103.2
(expressed as male proportion, 0.5076 to
0.5079), and remained well below that of U.S.
whites. This trend has a regression coefficient
of 0.013 (p < 0.01). In sum, the data show a
reduction in the sex ratio for non-Hispanic
whites, but no comparable decline for African
Americans, whose rates are significantly lower.
Figure 4 shows the 1983–1995 U.S. trend
in the proportion of fetal deaths that are male,
separately by race. The male proportion of
fetal death has increased most for U.S. African
Americans, going from about 0.535 to 0.545
in a decade. The trend for U.S. whites is also
slightly upward, with an increase of < 0.005 in
the proportion of fetal deaths that are male.
Fetal death rates have declined for all races
since 1970, falling roughly in half from 14 to
6.6 per 1,000 in 2000. Although all races have
experienced declines in fetal mortality, there
are racial disparities in levels of infant mortal-
ity. For all years, U.S. African Americans have
a higher fetal mortality rate and a higher male
proportion of fetal deaths than U.S. whites.
In 2000, the fetal mortality rate for African-
American mothers was 12.4 per 1,000,
compared with a rate for white mothers of
5.6 deaths per 1,000 (Minino et al. 2002).
Previous reports have indicated that in several
industrial countries, including the Netherlands,
Denmark, Finland (Moller 1996; Vartiainen
et al. 1999), Canada (Allan et al. 1997), and
the United States, the proportion of males
born declined significantly from 1970 to
1990, ranging from an annual drop of 0.001
for the United States (Davis et al. 1998) to
0.003 for the Netherlands (Van Der Pal-de
Bruin et al. 1997). In some Latin American
countries (Feitosa and Krieger 1992), the
male proportion has fallen by about one male
birth per 1,000 live births since the 1970s.
Such declining patterns are not evident in
some longer term trends. An independent
joinpoint analysis by the U.S. Centers for
Disease Control and Prevention reported that
the trend for whites and Mexicans mirrored
the overall downward trend for the last
30 years, but trends for African-American and
Chinese mothers rose, and trends for other
groups were stable (Mathews and Hamilton
2005) One analysis in Finland (Vartiainen et
al. 1999) found that male proportion had
increased from 1751 to 1920, and decreased
afterward, except for peaks during and after
World War I and World War II. Another
analysis found parallels between the postwar
secular decline of the male:female ratio at
birth and the decline of perinatal morbidity
and mortality, congenital anomalies, and
various constitutional diseases (Jongbloet
et al. 2001). Not paternal nor maternal age,
nor difference in age of parents, nor birth
order can explain these varying time trends
(Vartiainen et al. 1999).
The continuing trends in declining sex
ratio for U.S. whites and for Japanese that we
report here are consistent with those reported
recently in other industrial countries, and
remain unexplained. Among the explanations
suggested for these declines in sex ratio are
prenatal exposures to endocrine-disrupting
environmental pollutants at a critical stage of
sexual differentiation. Researchers theorize
that the same chemicals that reduce the sex
ratio in the offspring of male workers
(Jongbloet et al. 2001) may cause similar
effects in populations that are chronically
exposed to low levels of these same pollutants.
Not only are fewer males born to some
highly exposed cohorts of workers, but surviv-
ing male fetuses also appear more susceptible
to detrimental effects of toxic exposures than
females (Del Rio Gomez et al. 2002; James
1998b; Toppari et al. 1996). Garry et al.
(1996) have shown that both reduced SR and
higher rates of male birth defects are associ-
ated with paternal occupation as a pesticide
How workplace exposures may contribute
to reduced sex ratio in offspring has yet to be
explained. Fetal development of male character-
istics is a complex process largely determined by
the hormonal cascade controlled by the SRY
gene. Without the proper hormonal cues, even
genetically male fetuses will develop along the
default female pathway. Sex ratios at birth may
be an “important tool” for the investigation of
endocrine disruption and a marker of endocrine
disruption of one or both parents at the time of
conception (Sharpe and Skaakebaeke 1993).
A growing body of evidence indicates that
several exogenous factors may be functioning
to impair male development. Male reproduc-
tive disorders including reduced sperm count
Declines in sex ratio at birth in Japan and the United States
Environmental Health Perspectives • VOLUME 115 | NUMBER 6 | June 2007
Figure 3. Proportion of male live births, United States, 1940–2002.
1940 1950196019701980 1990
Figure 4. Proportion of male fetal deaths, United States, 1983–1995.
and quality, testicular cancer, cryptorchidism
(undescended testes), and hypospadias (dis-
placement of the urinary opening toward the
scrotum) have been increasing in industrial
countries (Del Rio Gomez et al. 2002;
Toppari et al. 1996; Weidner et al. 1998).
Each of these disorders represents a mild
degree of feminization and may have a shared
etiologic origin in prenatal exposure to xenoe-
strogenic endocrine disruptors. Thus, declin-
ing sex ratio may be a manifestation of further
increased phenotypic feminization of XY
fetuses. Evidence that changes in sex ratio
could represent a complete phenotypic femi-
nization of genetically male fetuses is pro-
vided by observations in animal populations
and should be explored further in humans.
Whatever their causes, trends in the sex
ratio of fetal death can have important impacts
on trends in SR. With respect to the different
sex ratio trends in U.S. African Americans and
whites, it is important to consider that fetal
loss is more common with male fetuses, as
indicated by the male dominance in sex ratio
of fetal deaths in all populations studied.
Improvements in obstetric care for the general
population may account for increases in SR
that occurred before 1970 in many countries.
If fetal deaths in Japan are recorded at 12
weeks and in the United States at 20 weeks,
this could account for why the death rates dif-
fer so much. But the increasing proportion of
males in fetal deaths in the United States and
Japan is noteworthy.
In the United States, quality of and access
to prenatal obstetric care for African Americans
historically has lagged behind those of whites.
To the extent that improvements in obstetric
care lead to reductions in fetal deaths that
occur disproportionately in African-American
males, then these advances in care could affect
sex ratio at birth. It is possible that improve-
ments in prenatal care may reduce male fetal
death rates, with a time lag in the African-
American population, as advances have
reached this population at a later point in time.
The effect of any exposure causing a decline in
SR would be more clearly reflected in the
white population than the African-American
population, because for African Americans
recent changes in SR are subject to the con-
founding effect of drops in the male fetal death
rate, as a result of improved prenatal care. As
male fetal loss rates decline because of better
obstetric care for U.S. African Americans,
more male fetuses are expected to survive to
birth, leading to an increase in SR. For all
years, U.S. African Americans have a lower SR
than U.S. whites. Both worldwide and within
the United States, sex ratios vary by a few
males per 100 females when one examines
different racial and ethnic groups. In the
United States, this difference could be partly
the result of differences in fetal death rates
combined with sex ratio of fetal deaths.
African Americans have a higher fetal death
rate and a higher male proportion of fetal
deaths. Combined, these factors could
account for reductions in SR for U.S. African
Americans compared with U.S. whites by
eliminating a larger proportion of male
fetuses between conception and birth. Thus,
the slight increase in SR for U.S. African
Americans since 1970 may be the result of
relatively recent advances in prenatal care.
Racial differences in sex ratio in the
United States may seem puzzling, though it is
possible that what is “normative” varies
slightly among groups of different racial her-
itage. Among the reasons why sex ratio in
African Americans could be consistently lower
than that of whites are factors that contribute
to parental hormonal differences. Some stud-
ies have found that greater rates of early onset
puberty and premature menarche in young
African-American women (e.g., James 2006)
whereas others have reported greater expo-
sures to hair care and other personal care
products that are contaminated with hor-
mones (e.g., Paulozzi 1999). Whether these
factors contribute to a more estrogenic prena-
tal environment and thereby to a lower pro-
portion of male births, and to greater rates of
breast cancer in young African-American
women < 35 years of age, are topics that merit
One other possibility deserves mention.
Among African-American young women,
obesity is nearly 50% higher than among
their white counterparts. Among non-
Hispanic white adults 20–74 years of age,
46.8% of women are overweight or obese
(body mass index ≥ 25.0). Among non-
Hispanic African Americans in the same age
group the percentage is 68.3 (Herman-
Giddens et al. 1997). In the United States,
several observers have speculated that the rise
of obesity, while reflecting suburban sprawl,
increasing television watching, and inactivity
patterns of children, may also be attributed to
increased consumption of growth-stimulating
and endocrine-disrupting agents in the food
supply (Tiwary 1998).
Many developed countries where sex ratio
has declined have also seen substantial
increases in average body weight and obesity
(Centers for Disease Control and Prevention
2002). Moreover, it appears that increased
body weight is correlated with a lower sex
ratio. At least one study in Africa found that
obesity was independently related to a low sex
ratio at birth (Andersson and Bergstrom
1998). A declining sex ratio for a population
has generally been diagnosed as an indicator
of worsening female advantage (Jayaraj and
Subramanian 2004). Additional research
regarding the role of societal factors in the
alteration of sex ratio is needed.
One particular aspect of Japanese culture
that may be involved in earlier changes in sex
ratio in Japan we do not analyze here.
According to one widely held superstition,
called Hinoe-uma, females born in certain
years are believed to be stronger than males
and will ultimately kill their husbands. Based
on this belief, every 60 years when Hinoe-
uma occurs, female babies have been killed by
midwives or sometimes even by their family
immediately after birth. This is believed to
have resulted in a rise in sex ratio in 1906 and
again in 1966 (Itoh and Brando 1987).
Regarding changes in SR in Japan, Mizuno
(2000) hypothesized that the increase in sex
ratio of fetal death in Japan may be affecting
the overall rate. Our data suggest that the
steady decline in Japanese fetal death rates may
be mitigating the impact of Japan’s greatly ele-
vated sex ratio of fetal deaths on SR. Had fetal
death rates remained constant, it is likely that
SR would have declined even further than it
has. Why the sex ratio of fetal deaths in Japan
has risen so dramatically since 1970 requires
explanation. One possibility we believe merits
evaluation is the body burden of mercury or
other metalloestrogens, to which male fetuses
may be more susceptible. Bioaccumulation of
methylmercury can occur in tuna, haddock,
and other large fish, an important part of the
Japanese diet (Iso et al. 2006). Recent research
suggests that a host of prenatal effects occur at
intake levels 5–10 times lower than that of
adults (Iso et al. 2006). Past research has docu-
mented that when severe and widespread
methylmercury pollution was experienced in
Minamata City, Japan, there was an extreme
reduction in the sex ratio at birth of fetal
Minamata disease patients, especially in the
period of worst pollution and at the worst pol-
luted area (Doi et al. 1987, 2001). The authors
also noted that a characteristic seasonal pattern
of the birth of male and female fatal Minamata
disease patients coincides with the seasonal pat-
terns of the fish catch in Minamata and the
outbreak of Minamata disease patients. Lately,
Sakamoto et al. (2001) confirmed this inde-
pendently of Doi et al. (1987, 2001) with the
same data, and they also described an increase
in male stillborn fetuses.
Strikingly, the severity of birth defects and
impairment of sex ratio in Minamata was
increased most in those with the highest levels
of mercury (Sakamoto et al. 2001).
We hypothesize that the decline in sex
ratio in industrial countries may be caused
partly by prenatal exposure to metalloestrogens
and other endocrine-disrupting chemicals at a
critical stage of prenatal development, or
paternal exposures that take place before con-
ception that select against expression of the Y
chromosome, or some combination of these
factors that selectively increase male fetal death
rates. Workplace studies and experimental
Davis et al.
VOLUME 115 | NUMBER 6 | June 2007 • Environmental Health Perspectives
Declines in sex ratio at birth in Japan and the United States
Environmental Health Perspectives • VOLUME 115 | NUMBER 6 | June 2007
findings support this hypothesis. Recent
research in mice offers a fascinating indication
that altered gene expression can be affected by
chemical factors. Chemically mediated alter-
ation of expression of Stra8 (stimulated by
retinoic acid gene 8) differentially affects the
timing of meiosis in the ovary and testes and
could influence sex. Stra8 effects occur during
embryogenesis in the female, but occur only
after birth in the male (Koubava et al. 2006).
In mammals, meiosis occurs at different
time points in males and females, although the
mechanism accounting for this is unknown.
Although female germ cells begin meiosis dur-
ing embryogenesis, male embryonic germ cells
do not; males undergo G0/G1mitotic cell
cycle arrest. Only after birth does meiosis
begin in the testes. The Stra8 has been shown
to be required for both male and female germ
cells to transition into meiosis. Without
retinoic acid (RA), an active derivative of vita-
min A, meiotic initiation will not occur. RA is
sufficient to induce Stra8 expression in embry-
onic testes and in vitamin A–deficient adult
testes in vivo. Cytochrome P450 (CYP)-medi-
ated RA metabolism prevents premature Stra8
expression in embryonic testes. Treatment
with an inhibitor of RA-metabolizing enzymes
shows that a CYP from the 26 family
(CYP26) delays Stra8 expression in embryonic
testes. Sex-specific regulation of RA signaling
thus plays an essential role in meiotic initia-
tion in embryonic ovaries and precludes its
occurrence in embryonic testes.
Other explanations may also be relevant.
Some studies suggest that psychological stress
can lead to a reduction in the sex ratio at
birth. A study examining changes associated
with a 10-day war in Slovenia documented
both a decrease in the sex ratio at birth 6–9
months later, as well as significantly reduced
sperm motility among 38 subjects (p = 0.01)
(Zorn et al. 2002). Similarly, a decline in the
sex ratio was documented after the Kobe
earthquake in Japan, along with a general
reduction in fertility and a lower sex ratio at
birth 9 months later (Fukuda et al. 1998).
Others have noted a tendency for the sex ratio
to decline as socioeconomic development pro-
ceeds. The potential roles of delays in first
pregnancy, older age of parents, and other
factors remain to be further elucidated.
Although the percentage declines in SR
reported here are small, because they have
occurred in populations of > 400 million,
they represent large numbers with consider-
able public health implications. Declines in
the proportion of males born in Japan from
1970 through 1999 and for whites in the
United States from 1970 through 2002 are
equivalent to a shift from male to female
births of 127,000 and 135,000 births, respec-
tively. Fetal death rates are five times higher
in Japan than in whites in the United States.
Disturbances in SR may provide a sentinel
indicator of larger ecologic patterns that can
only be corroborated by detailed studies of
smaller, more defined cohorts, with specified
exposures and well-characterized information
on socioeconomic, cultural, and racial factors.
While noting that sex ratio has declined in
many regions, one of the foremost authorities
on the topic questions whether environmen-
tally prevalent endocrine disrupters could ever
be demonstrated to account for such broad
patterns (James 1998b). He adds that it is not
possible to determine what sex ratios would
have been doing absent current pollution pat-
terns or current increasing trends in age of
parents. We agree. Sex ratio in a population is
the result of multiple determinants that can be
identified only through detailed studies of
selected subpopulations with unusual expo-
sures or conditions. For example, the health
survey underway in Sarnia, Ontario, Canada,
to further investigate the pronounced decrease
in sex ratio in a First Nation community may
shed light on this topic (Mackenzie et al.
2005). In addition, in the data examined here,
the possibility that there could be systematic
differences in the ascertainment of sex at death
cannot be ruled out. If this proves to be the
case, it could account for the observed differ-
ences in male fetal deaths rates in the United
States and Japan. As it stands, the falling sex
ratio coupled with the disproportionately male
fetal deaths supports the hypothesis that males
are being culled in some systematic fashion. In
addition, the fact that boys are disproportion-
ately represented in miscarriages (< 20 weeks),
indicates that the trends here are underesti-
mates of the true patterns of fetal deaths, as we
have restricted our analysis to those that occur
after 20 weeks.
Although population-wide trends in sex
ratio cannot be attributed to any single set of
risk factors, given the importance of reproduc-
tion for the health of any species, the continu-
ing trends in reduced births of males in U.S.
whites and Japan reported here are matters that
merit concern. Efforts should proceed to exam-
ine sex ratio in smaller groups with defined
exposures as a potential indicator of environ-
mental contamination, and to develop geo-
graphic and temporal analyses of patterns in
sex ratio as a means of generating hypotheses
about avoidable or controllable factors that
may account for the trends reported here.
Allan BB, Brant R, Seidel JE, Jarrell JF. 1997. Declining sex
ratios in Canada. CMAJ 156:37–41.
Andersson R, Bergstrom S. 1998. Is maternal malnutrition
associated with a low sex ratio at birth? Hum Biol
Catalano RA. 2003. Sex ratios in the two Germanies: a test of the
economic stress hypothesis. Hum Reprod 18(9):1972–1975.
Centers for Disease Control and Prevention. 2002. Prevalence
of Overweight and Obesity among Adults: United States,
1999–2002. Available: http://www.cdc.gov/nchs/products/
pubs/pubd/hestats/obese/obse99.htm [accessed 4 May
Davis DL, Axelrod D, Jones LA, Hajek RA. 2001. It’s time to
rethink dose: the case for combining cancer and birth and
developmental defects [Editorial]. Environ Health Perspect
Davis DL, Gottlieb MB, Stampnitzky JR. 1998. Reduced ratio of
male to female births in several industrial countries.
Del Rio Gomez I, Marshall T, Tsai P, Shao Y-S, Guo YL. 2002.
Number of boys born to men exposed to polychlorinated
biphenyls. Lancet 360:143–44.
Doi R, Ohno H, Davis DL, Harada M. 2001. Altered sex ratio at
birth in fetal Minamata disease patients [Abstract]. 6th
International Conference on Mercury as a Global
Pollutant, Minamata, Japan, 15–19 October 2001, 227.
Doi R, Ohno H, Yamashita K, Harada M. 1987. Seasonal
changes in the birth of fetal Minamata disease patients.
Progr Biometeorol 5:139–144.
Egeland GM, Sweeney MH, Fingerhut MA, Wille KK, Schnorr
TM, Halperin WE. 1994. Total serum testosterone and
gonadotropins in workers exposed to dioxin. Am J
Feitosa MF, Krieger H. 1992. Demography of the human sex
ratio in some Latin American countries, 1967–1986. Hum
Fukuda M, Fukuda K, Shimizu T, Moller H. 1998. Decline in sex
ratio at birth after the Kobe earthquake. Hum Reprod
Garry VF, Schreinemachers D, Harkins ME, Griffith J. 1996.
Pesticide appliers, biocides, and birth defects in rural
Minnesota. Environ Health Perspect 104:394–399.
Gutierrez-Adan A, Pintado B, de la Fuente J. 2000. Demographic
and behavioral determinants of male-to-female birth ratio
in Spain from 1981 to 1997. Hum Biol 72:891–898.
Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ,
Bhapkar MV, Koch GG, et al. 1997. Secondary sexual char-
acteristics and menses in young girls seen in office prac-
tice: a study from the pediatric research in office settings
network. Pediatrics 99(4):505–512.
Iso H, Kobayashi M, Ishihara J, Sasaki S, Okada K, Kita Y, et al.
2006. Intake of fish and n3 fatty acids and risk of coronary
heart disease among Japanese: the Japan public health
center-based (JPHC) study cohort I. Circulation 113(2):
Itoh T, Brando R. 1987. Fertility change of the year of “Hinoe-
uma.” Jinko Mondai Kenkyu (181):31–43.
James WH. 1987. The human sex ratio, part 1: a review of the
literature. Hum Biol 59:721–752.
James WH. 1998a. Hypothesis on mammalian sex ratio at birth.
J Theor Biol 192:113–116.
James WH. 1998b. Re: The use of offspring sex ratios in the
search for endocrine disruptors [Letter]. Environ Health
James WH. 2006. Offspring sex ratios at birth as markers of
paternal endocrine disruption. Environ Res 100(1):77–85
Japan Statistical Yearbook. 2000. Japan Statistical Yearbook.
Tokyo:Japanese Statistics Bureau, Ministry of Internal
Affairs and Communications.
Jayaraj D, Subramanian S. 2004. Women’s wellbeing and the
sex ratio at birth: some suggestive evidence from India.
J Dev Stud 40(5):91–119.
Jongbloet PH, Zielhuis GA, Groenewoud HM, Pasker-De Jong
PC. 2001. The secular trends in male:female ratio at birth in
postwar industrialized countries. Environ Health Perspect
Koubava J, Menke DB, Zhou Q, Capel B, Griswold MD, Page DC.
2006. Retinoic acid regulates sex-specific timing of meiotic
initiation in mice. Proc Natl Acad Sci USA 103(8):2474–2479.
Mackenzie CA, Lockridge A, Keith M. 2005. Declining sex ratio
in a First Nation community. Environ Health Perspect
Marcus M, Kiely J, Xu F, McGeehin M, Jackson R, Sinks T.
1998. Changing sex ratio in the United States 1969–1995.
Fertil Steril 70(2):270–273.
Martin JA, Hamilton BE, Sutton PD, Ventura MA, Menacker F,
Munson MS. 2003. Births: final data for 2002, Natl Vital Stat
Mathews TJ, Hamilton BE. 2005. Trend analysis of the sex ratio
at birth in the United States. Natl Vital Stat Rep 53(20):1–18.
Minino AM, Arias E, Kochanek KD, Murphy SL, Smith BL. 2002.
Deaths: final data for 2000. Natl Vital Stat Rep 50(15):1–119.
Misao F, Kyomi F, Shimizu T, Moller H. 1998. Decline in sex
ratio at birth after Kobe earthquake. Hum Reprod
Mizuno R. 2000. The male/female ratio of fetal deaths and
births in Japan. Lancet 356:738–739.
Mocarelli P, Gerthoux PM, Ferrari E, Patterson DG Jr, Kieszak
SM, Brambilla P, et al. 2000. Paternal concentrations of
dioxin and sex ratio of offspring. Lancet 355:1858–1863.
Moller H. 1996. Change in male:female ratio among newborn
infants in Denmark. Lancet 348:828–829.
National Center for Health Statistics. 2003. Fetal Death Data CD-
ROM, 1983–1995. Springfield, VA:National Technical
Okubo Y, Suwazono Y, Kobayashi E, Nogawa K. 2000. Altered
sex ratio of offspring in chemical industry workers.
J Occup Health 42:147–148
Parazzini F, La Vecchia C, Levi F, Franceschi S. 1998. Trends in
male:female ratio among newborn infants in 29 countries
from five continents. Hum Reprod 13:1394–1396.
Paulozzi LJ. 1999. International trends in rates of hypospadias
and cryptorchidism. Environ Health Perspect 107:297–302.
Ryan JJ, Amirova Z, Carrier G. 2002. Sex ratios of children of
Russian pesticide producers exposed to dioxin. Environ
Health Perspect 110:A699–A701.
Sakamoto M, Nakano A, Akagi H. 2001. Declining Minamata male
birth ratio associated with increased male fetal death due to
heavy methylmercury pollution. Environ Res 87(2):92–98.
Schnorr TM, Lawson CC, Whelan EA, Dankovic DA, Deddens JA,
Piacitelli LA, et al. 2001. Spontaneous abortion, sex ratio, and
paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo-
p-dioxin. Environ Health Perspect 109:1127–1132.
Sharpe RM, Skakkebaeke NE. 1993. Are oestrogens involved in
falling sperm counts and disorders of the male reproduc-
tive tract? Lancet 341:1392–1395.
Somers CM, McCarry BE, Malek F, Quinn J. 2004. Air pollution
lowers the risk of heritable mutations in mice. Science
Tiwary CM. 1998. Premature sexual development in children
following the use of estrogen- or placenta-containing hair
products. Clin Pediatr (Phila) 37:733–740.
Toppari J, Larsen JC, Christiansen P, Giwercman A, Grandjean
P, Guillette LJ Jr, et al. 1996. Male reproductive health and
environmental xenoestrogens. Environ Health Perspect
United Nations. 2004. Live births by age of mother, sex of the child
and urban/rural residence: latest available year, 1995–2004.
Table 10. In: Demographic Yearbook. Available: http://
Table10.pdf [accessed 27 February 2007].
Van Der Pal-de Bruin KM, Verloove-Vanhorick SP, Roeleveld N.
1997. Change in male:female ratio among newborn babies in
Netherlands. Lancet 349:62.
Vartiainen T, Kartovaara L, Tuomisto J. 1999. Environmental
chemicals and changes in sex ratio: analysis over 250
years in Finland. Environ Health Perspect 107:813–815.
Weidner IS, Moller H, Jensen TK, Skakkebaek NE. 1998.
Cryptorchidism and hypospadias in sons of gardeners and
farmers. Environ Health Perspect 106:793–796.
Weisskopf MG, Anderson HA, Hanrahan LP, and the Great
Lakes Consortium. 2003. Decreased sex ratio following
maternal exposure to polychlorinated biphenyls from cont-
aminated Great Lakes sport-caught fish: a retrospective
cohort study. Environ Health 2(1):2.
Zorn B, Sucur V, Stare J, Meden-Vrtovec H. 2002. Decline in
sex ratio at birth after 10-day war in Slovenia: brief com-
munication. Hum Reprod 17(12):3173–3177.
Davis et al.
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