American Journal of Epidemiology
Copyright ª 2005 by the Johns Hopkins Bloomberg School of Public Health
All rights reserved; printed in U.S.A.
Vol. 162, No. 8
DOI: 10.1093/aje/kwi276
Advance Access publication August 24, 2005
Original Contribution
Association of DDT and DDE with Birth Weight and Length of Gestation in the
Child Health and Development Studies, 1959–1967
Lili Farhang1,2, June M. Weintraub1, Myrto Petreas3, Brenda Eskenazi4, and Rajiv Bhatia1,2
1
San Francisco Department of Public Health, San Francisco, CA.
Public Health Institute, Oakland, CA.
3
Hazardous Materials Laboratory, Department of Toxic Substances Control, California Environmental Protection Agency,
Berkeley, CA.
4
Center for Children’s Environmental Health Research, School of Public Health, University of California at Berkeley,
Berkeley, CA.
2
Received for publication January 21, 2005; accepted for publication April 13, 2005.
The pesticide p,p#-dichlorodiphenyltrichloroethane (DDT) and its persistent metabolite p,p#-dichlorodiphenyldichloroethylene (DDE) are associated with negative reproductive outcomes in animals. In humans, however, the
findings are inconsistent. Using data from the Child Health and Development Studies, a longitudinal study of
20,754 pregnancies among San Francisco Bay Area women from 1959 to 1967, the authors examined the effects
of maternal serum DDT and DDE concentrations on preterm birth, small-for-gestational-age birth, birth weight, and
gestational age in 420 male subjects. Data were analyzed using multivariate logistic regression for preterm and
small-for-gestational-age birth and linear regression for birth weight and gestational age. Median serum concentrations of DDE were 43 lg/liter (interquartile range: 32–57; range: 7–153) and of DDT were 11 lg/liter (interquartile
range: 8–16; range: 3–72), several times higher than current US concentrations. The adjusted odds ratio for
preterm birth was 1.28 (95% confidence interval (CI): 0.73, 2.23) for DDE and 0.94 (95% CI: 0.50, 1.78) for
DDT. For small-for-gestational-age birth, the adjusted odds ratio was 0.75 (95% CI: 0.44, 1.26) for DDE and
0.69 (95% CI: 0.73, 1.27) for DDT; none of the study results achieved statistical significance. Given the persistence
of DDT in the environment and its continuing role in malaria control, studies using more robust data should continue
to assess this relation.
birth weight; DDT; dichlorodiphenyl dichloroethylene; gestational age; hydrocarbons, chlorinated; infant, small for
gestational age; preterm birth; serum
Abbreviations: CHDS, Child Health and Development Studies; CI, confidence interval; DDE, p,p#-dichlorodiphenyldichloroethylene; DDT, p,p#-dichlorodiphenyltrichloroethane; OR, odds ratio; PCB, polychlorinated biphenyl; SE, standard error.
Preterm birth and low-birth-weight birth are associated
with infant mortality and a range of infant and childhood
morbidities, including respiratory illness, infections, neurologic impairment, and developmental delays (1–9). In the
United States, neonatal mortality is more than twice as likely
in infants born preterm (10). Risk factors associated with
preterm birth and low birth weight include socioeconomic
status, race/ethnicity, and smoking (1, 2, 11). Some suggest
that environmental contaminants such as organochlorine
pesticides may also adversely impact fetal development (12).
The United States banned the organochlorine pesticide
dichlorodiphenyltrichloroethane (technical DDT) in 1972.
Correspondence to Lili Farhang, Environmental Health Section, San Francisco Department of Public Health, 1390 Market Street, Suite 910,
San Francisco, CA 94102 (e-mail: [email protected]).
717
Am J Epidemiol 2005;162:717–725
718 Farhang et al.
However, human health concerns continue because of its
ongoing use in vector control and malaria prevention, its
persistence in the environment, its accumulation in the
human food chain, its long half-life in human tissues, and
its resistance to metabolism (13–16). Developing fetuses
are exposed to p,p#-dichlorodiphenyltrichloroethane (DDT)
and its metabolites through in utero placental transfer (17,
18). Concerns regarding exposure to these chemicals stem
from their potential role in endocrine disruption. DDT can
mimic estrogen action; its major metabolite p,p#-dichlorodiphenyldichloroethylene (DDE) can interfere with androgens (19).
Environmental exposure to organochlorine pesticides has
been associated with adverse reproductive outcomes in animals (20–23). Findings regarding the relation of DDT and
DDE to human reproductive outcomes are inconsistent.
Some studies report that increased levels of DDT and
DDE are not significantly associated with infant birth
weight (24–29) or preterm birth (12, 30–32). Others report
associations with preterm birth (12, 29, 30, 33, 34), lowered
birth weight (35), small-for-gestational-age birth (12), and
intrauterine growth retardation (36).
In this study, we examine the association of serum levels
of DDT and DDE with the birth weight and gestational age
of male infants in a population of women during a period of
high nationwide organochlorine pesticide usage.
MATERIALS AND METHODS
Study participants
Data for this study come from the Child Health and Development Studies (CHDS), a longitudinal cohort study of
20,754 women, their pregnancies, and children born from
those pregnancies in the San Francisco Bay Area during
1959–1967. Participants were members of the prepaid Kaiser Foundation Health Plan, reflecting a diverse metropolitan population with at least one employed household
member. The study enrolled women when they first contacted participating facilities regarding a confirmed or possible pregnancy. Nearly 92 percent of all women with
eligible pregnancies who were invited to participate were
included in the cohort. Pregnant women who enrolled in the
CHDS were interviewed after recruitment and later during
their pregnancy (37), and multiple maternal serum samples
were taken during pregnancy and postpartum. At least one
sample was obtained for 89 percent of all CHDS pregnancies. Serum samples were subsequently divided into a package of four 2-ml vials and stored at 20C at the National
Institutes of Health. Maternal and pediatric medical records
were abstracted throughout the follow-up period. The
CHDS observed 89.4 percent of liveborn children until 5
years of age (37).
The 420 subjects included in this analysis were originally
selected for a study of maternal serum concentrations of
organochlorine contaminants and the risk of genital anomalies in male offspring. The original study included 155
male infants with hypospadias or cryptorchidism who survived for 2 years and 265 randomly selected male controls
(38). As Bhatia et al. (38) did not find an association be-
tween maternal DDT and DDE levels and the development
of hypospadias or cryptorchidism, cases and controls were
combined in this analysis to assess the association of organochlorine pesticides and other adverse birth outcomes.
Laboratory assays
Laboratory methods have been described elsewhere (38).
Briefly, serum conservators from the CHDS selected which
serum sample would be provided. The majority of our samples were drawn in the postpartum period (n ¼ 334), and
the rest were drawn during the second (n ¼ 32) and third
(n ¼ 54) trimesters. Given the long half-life of DDT and
DDE and the high correlation among DDE levels measured at different times during gestation (39), these serum
samples should accurately reflect body burdens over the
entire pregnancy.
The requested samples were shipped on dry ice from the
National Cancer Institute (Frederick, Maryland) to the Hazardous Materials Laboratory of the state of California in
Berkeley, California, where they were stored at below
20C until laboratory analysis. One ml of thawed serum
was extracted with hexane/dichloromethane, cleaned
through Florisil (U.S. Silica Company, Berkeley Springs,
West Virginia), and eluted with hexane followed by hexane/dichloromethane. Analysis was performed by gas chromatography with electron-capture detection equipped with
60-m DB-XLB (Agilent Technologies, Palo Alto, California) and Rtx-5ms (Resick Corporation, Bellefonte, Pennsylvania) capillary columns. Standard quality assurance
procedures included rigorous calibration procedures, traceability of all standards, and internal review and audit. In
addition to DDT and DDE, several other organochlorines
were measured (38, 40). Total cholesterol and triglycerides
were determined enzymatically in small aliquots of serum.
Target analytes, which measured above detection limits in
more than 90 percent of our samples, included p,p#-DDE,
p,p#-DDT, b-hexachlorocyclohexane, hexachlorobenzene,
oxychlordane, trans-nonachlor, polychlorinated biphenyl
(PCB) 74, PCB 99, PCB 118, PCB 138, PCB 153, PCB
170, PCB 180, PCB 187, PCB 194, and PCB 203.
Each batch included nine samples, one method blank, one
laboratory control (bovine serum fortified with target analytes), and one standard reference material (SRM 1589,
a human serum from the National Institute of Standards
and Technology, Gaithersburg, Maryland). An analyte was
quantitated when its signal in a sample was at least three
times its signal in the method blank. Laboratory controls and
standard reference materials were used to evaluate background contamination, precision, accuracy, and analyte
recovery.
Based on external quality control samples, within-batch
precision (expressed as the intrabatch coefficient of variation) was 2.7 percent for DDT and 3.0 percent for DDE. The
interbatch coefficient of variation was 10.0 percent for DDT
and 9.1 percent for DDE. Recoveries of internal standards
were used to gauge overall data quality across all serum
samples. Recoveries were 93 percent for DDT and 91 percent for DDE, and no corrections were made to the data.
Am J Epidemiol 2005;162:717–725
DDT, DDE, and Birth Weight and Gestational Age
Outcome measures
Four outcomes were assessed in this analysis: 1) preterm
birth, defined as birth at less than 37 completed weeks of
gestation; 2) small-for-gestational-age birth, defined as birth
weight at less than the 10th percentile at each week of gestation, with a sample of 9,744 CHDS male livebirths as the
standard; 3) birth weight, measured continuously in grams;
and 4) gestational age, measured continuously in weeks.
Birth weight was extracted by CHDS staff from clinical birth
records and included in the CHDS data set. Gestational age
was constructed from the number of completed weeks between the self-reported date of last menstrual period and
birth. The date of the last menstrual period was obtained
through CHDS interviews with mothers during pregnancy.
TABLE 1. Demographic characteristics of the study sample
from the US Child Health and Development Studies cohort,
1959–1967
Overall (n ¼ 420)
No.
We examined the relation of DDT and DDE serum concentrations to birth outcomes using logistic regression for
preterm birth and small-for-gestational-age birth and linear
regression for birth weight and gestational age. DDE and
DDT serum concentrations were modeled as both continuous and categorical variables. To increase the interpretability
of results in models using continuous chemical measures,
subjects’ serum levels (lg/liter) were divided by the interquartile distance for DDT and DDE, and coefficients are
reported per interquartile distance change in DDT and
DDE. In models using categorical chemical measures, subjects were divided into four categories based on the quartile
distribution of each chemical measure among the study population. Trend tests were constructed by modeling categorical variables as ordinal variables in these models.
Because of small numbers, African-American, Hispanic,
Asian, and multiple/other race/ethnicity subjects were combined into a non-White category. Observations on maternal
height or prepregnancy weight were missing for 25 percent
of subjects. To address this, we imputed prepregnancy body
mass index for those women who were missing only prepregnancy weight by calculating the median weight gained
during pregnancy for women in each body mass index category and applied this weight change to the women whose
weight was measured at the same point during their pregnancy. Body mass index was calculated as weight in kilograms divided by height in meters squared.
A ‘‘base’’ model was developed for each chemical and
outcome that included serum cholesterol and triglycerides
as continuous variables (grams/liter), as these are correlated
with DDE and DDT concentrations. To control for the role
of case-control status from the original study with our
outcomes of interest, base models also included a term for
case-control status, based on their designation in the initial
genital anomalies study, and an additional interaction term
for case-control status and chemical measure. In addition to
all the variables in base models, demographic and behavioral
variables were selected as covariates for further adjustment
based on associations reported in the literature. Covariates
were included in ‘‘full’’ multivariate models if the addition of
each variable to base models changed the coefficient of the
serum level by 10 percent or more. The covariates examined
Am J Epidemiol 2005;162:717–725
%
Age
Median age, years
(interquartile range)
Missing
Race
26 (22–31)
5
1.2
White
267
63.6
Non-White*
148
35.2
5
1.2
Missing
Education
<12th grade
Statistical analysis
719
High school graduate
College/trade school graduate
Missing
76
18.1
236
56.2
59
49
14.0
11.7
325
77.4
Marital status
Married
Unmarried
27
6.4
Missing
68
16.2
189
45.0
33
7.9
127
30.2
71
16.9
Occupation
Housewife
Factory/household worker
Secretary/clerical/professional/
teacher/student
Missing
Place of birth
California
137
32.6
Southeast US state
Other US state
87
108
20.7
25.7
Foreign born
39
9.3
Missing
49
11.7
Current smoking status
Smoker
128
30.5
Nonsmoker
218
51.9
74
17.6
Missing
Body mass index
18
19–24
41
9.8
233
55.5
25
56
13.3
Missing
90
21.4
Parity
0
146
34.8
1–2
184
43.8
88
2
21.0
0.5
3
Missing
* Non-White includes Hispanic, Asian, and other race/ethnicity.
included maternal age, race, education, marital status, place
of birth, occupation, smoking status, body mass index, and
parity (table 1). All covariates changed either the DDT or
DDE effect estimates for each of the four outcomes and,
720 Farhang et al.
consequently, we decided to apply a uniform model that
included all covariates for comparability across models.
Finally, because of high percentages of missing values for
many of the demographic and behavioral covariates, we
included terms for missing values in each of the models
where greater than 5 percent of values were missing (education, marital status, place of birth, occupation, smoking
status, and body mass index). All analyses were conducted
using the SPSS, version 11.5, statistical program (SPSS, Inc.,
Chicago, Illinois).
RESULTS
Sociodemographic characteristics of the participants are
described in table 1. The majority of women were multiparous, were White, and had completed high school. Over
three fourths were married, and nearly one half were housewives. Almost a third reported smoking during their CHDS
pregnancy.
Of 420 births in this population, 7.9 percent (n ¼ 33) were
born preterm, and 9.8 percent (n ¼ 41) were born small for
gestational age. The mean birth weight in grams was 3,350.7
(standard deviation: 527.0), and the mean duration of gestation was 39.5 (standard deviation: 2.2) weeks.
The median unadjusted serum concentrations of DDE
were 43 lg/liter (interquartile range: 32–57; range: 7–153).
For DDT, the median unadjusted serum concentration was
11 lg/liter (interquartile range: 8–16; range: 3–72). The
interquartile distance for DDE measured 26 lg/liter and
for DDT measured 8 lg/liter. The median concentrations
of cholesterol and triglycerides were 3 g/liter and 2 g/liter,
respectively. With recovery levels of 93 percent for DDT
and 91 percent for DDE, recovery-adjusted results did not
differ substantially from those not adjusted for recovery.
Overall, no statistically significant relations or trends
were observed between serum measurements of DDT or
DDE and birth weight or length of gestation. In the base
model for preterm birth, the odds of preterm birth were 6
percent higher per interquartile distance increase in DDE
(odds ratio (OR) ¼ 1.06, 95 percent confidence interval
(CI): 0.66, 1.70) and, with further adjustment, the odds of
preterm birth increased by 28 percent (OR ¼ 1.28, 95 percent CI: 0.73, 2.23). When assessing increasing DDT levels
and preterm birth, we found inverse but nonsignificant associations per interquartile distance increase in both base
(OR ¼ 0.87, 95 percent CI: 0.51, 1.48) and full (OR ¼
0.94, 95 percent CI: 0.50, 1.78) models (table 2).
The odds of a small-for-gestational-age birth were 4 percent lower (OR ¼ 0.96, 95 percent CI: 0.61, 1.51) in base
models and 25 percent lower (OR ¼ 0.75, 95 percent CI:
0.44, 1.26) in full models per interquartile distance increase
in DDE. The odds of a small-for-gestational-age birth were
24 percent lower per interquartile distance increase in DDT
(OR ¼ 0.76, 95 percent CI: 0.48, 1.20); further adjustment
did not materially change these results (table 2).
The results of analyses for birth weight and gestational
age were also not statistically significant. An interquartile
distance increase in DDE was associated with a decrease
in infant birth weight of 34 g (standard error (SE): 36;
p ¼ 0.34) in the base model, and further adjustment reduced
the decrease to 17 g (SE: 37; p ¼ 0.65). An interquartile
distance increase in DDT was associated with an increase in
infant birth weight of 21 g (SE: 35; p ¼ 0.55) and, after
further adjustment, was associated with an increase of 32 g
(SE: 37; p ¼ 0.38). For gestational age, no significant associations were revealed (table 2).
In the analysis of the associations between outcomes and
serum levels measured in quartiles, no statistically significant associations were found (table 2). For preterm birth,
women whose serum levels were in the fourth quartile
(57.5 lg/liter) had a 54 percent increased odds compared
with women in the lowest quartile (31.6 lg/liter) after
adjustment for covariates in the full model (OR ¼ 1.54,
95 percent CI: 0.45, 5.34; ptrend ¼ 0.89). There were decreased odds of preterm birth in all DDT categories when
compared with the lowest referent category (8.1 lg/liter);
however, none were statistically significant.
We also found no statistically significant association between small-for-gestational-age births and either serum
DDT or DDE levels. Women in the highest DDE quartile
had 9 percent decreased odds of a small-for-gestational-age
birth in the base model (OR ¼ 0.91, 95 percent CI: 0.32,
2.60; ptrend ¼ 0.98); odds decreased upon further adjustment
but were still not statistically significant (OR ¼ 0.64, 95
percent CI: 0.18, 2.29; ptrend ¼ 0.58) (table 2).
For the birth weight analysis by quartiles, none of the
relations or trends were statistically significant, and the
point estimates were very unstable. For example, there
was an increase in birth weight in the second DDT quartile
in the base model (b ¼ 128 g, SE: 74), which decreased by
almost one third after adjustment in the full model (b ¼ 90 g,
SE: 75) (table 2).
Similarly, the gestational age analysis did not reveal any
statistically significant relations. There was a decrease in
gestational age in the highest DDE quartile of the base model
(b ¼ 0.22 weeks, SE: 0.35; ptrend ¼ 0.81) when compared
with the lowest, though the drop was smaller after adjustment for the covariates in the full model (b ¼ 0.10 weeks,
SE: 0.38; ptrend ¼ 0.90). In the full model for gestational age
and DDT, the coefficients for the second and third quartiles
were similar (second quartile b ¼ 0.36 weeks, SE: 0.33; third
quartile b ¼ 0.41 weeks, SE: 0.33); there was no significant
difference between the highest DDT quartile and the lowest
(b ¼ 0.08 weeks, SE: 0.36; ptrend ¼ 0.77).
Several covariates were adversely and significantly associated with our outcomes, including being unmarried, current smoking, body mass index of less than or equal to 18,
history of no previous pregnancies, non-White race/ethnicity, and being born outside California or outside a southeast
US state. We did not see any statistically significant effects
of hypospadias and cryptorchidism on any of our outcomes.
There were also no statistically significant associations
between the DDE:DDT ratio and any of the outcomes. All
findings remained unchanged when we restricted the analyses to controls from the original genital anomalies study,
when we restricted all analyses to subjects who had complete data on all covariates, and when we examined birth
weight, gestational age, and small-for-gestational-age births
in term infants only (data not shown).
Am J Epidemiol 2005;162:717–725
Am J Epidemiol 2005;162:717–725
TABLE 2. Adjusted odds ratios and beta coefficients for maternal serum DDE* and DDT* and preterm birth, small-for-gestational-age birth, birth weight, and gestational age
for participants in the US Child Health and Development Studies cohort, 1959–1967
Preterm delivery
Basey
OR*
95% CI*
Small for gestational age
Fullz
OR
95% CI
Basey
OR
95% CI
Birth weight (g)
Fullz
OR
95% CI
Basey
Gestational age (weeks)
Fullz
Basey
b
p
b
p
b
coefficient SE* value coefficient SE value coefficient
SE
Fullz
p
b
value coefficient
SE
p
value
DDE§
1.06
0.66, 1.70
1.28
0.73, 2.23
0.96
0.61, 1.51
0.75
0.44, 1.26
34
36
0.34
17
37
0.65
0.14
0.15
0.35
0.08
0.16
0.61
DDT§
0.87
0.51, 1.48
0.94
0.50, 1.78
0.76
0.48, 1.20
0.69
0.37, 1.27
21
35
0.55
32
37
0.38
0.13
0.18
0.39
0.08
0.16
0.60
DDE (lg/liter)
Q*1 (31.6)
Referent
Referent
Referent
Referent
Referent
Referent
Referent
Referent
Q2 (31.7–42.5)
1.13
0.43, 2.95
1.24
0.40, 3.91
0.83
0.33, 2.14
0.92
0.31, 2.71
41
74
40
75
0.16
0.31
0.18
Q3 (42.6–57.4)
0.30
0.08, 1.18
0.35
0.08, 1.57
1.04
0.42, 2.62
1.02
0.35, 2.99
23
76
12
79
0.17
0.32
0.22
0.33
Q4 (57.5)
1.06
0.37, 3.07
1.54
0.45, 5.34
0.91
0.32, 2.60
0.64
0.18, 2.29
22
85
10
88
0.22
0.35
0.10
0.38
ptrend
0.61
0.89
0.98
0.58
0.78
0.99
0.32
0.90
0.81
DDT (lg/liter)
Referent
Referent
Referent
Referent
Referent
Referent
Referent
Referent
Q2 (8.2–11.0)
0.46
0.16, 1.31
0.44
0.14, 1.42
0.60
0.22, 1.61
0.78
0.26, 2.36
128
74
90
75
0.29
0.31
0.36
0.33
Q3 (11.1–16.2)
0.43
0.15, 1.22
0.25
0.07, 0.87
1.14
0.48, 2.72
1.27
0.46, 3.53
102
75
105
76
0.16
0.31
0.41
0.33
0.60
0.22, 1.65
0.58
0.17, 2.01
0.74
0.27, 1.99
0.93
0.30, 2.97
66
79
70
84
0.14
0.33
0.08
0.36
Q4 (16.3)
ptrend
0.28
0.19
0.87
0.87
0.50
0.39
0.60
0.77
* DDE, p,p#-dichlorodiphenyldichloroethylene; DDT, p,p#-dichlorodiphenyltrichloroethane; OR, odds ratio; CI, confidence interval; SE, standard error; Q, quartile.
y The covariates adjusted for include cholesterol (g/liter), triglycerides (g/liter), case-control status, and chemical 3 case-control status.
z The covariates adjusted for include cholesterol (g/liter), triglycerides (g/liter), case-control status, chemical 3 case-control status, age (years), race, education, marital status, place of birth, occupation, current
smoker, body mass index, and parity.
§ The coefficients reported per interquartile distance change in DDT and DDE. The interquartile distance for DDE measured 26 lg/liter and for DDT measured 8 lg/liter.
DDT, DDE, and Birth Weight and Gestational Age
Q1 (8.1)
721
Authors, year
(reference no.)
Location of
population
Year
specimen
collected
No.y
Type of specimen
O’Leary et al.,
1970 (35)
United States/
Florida
Not provided
67
Fetal whole blood
Saxena et al.,
1980 (33)
India/Lucknow
Not provided
40
Maternal serum
Procianoy and
Schvartsman,
1981 (30)
Brazil/Sao Paulo
Not provided
54
Maternal serum
Cord blood
Wasserman et al.,
1982 (34)
Israel
Not provided
Am J Epidemiol 2005;162:717–725
27
Maternal serum
Rogan et al.,
1986 (28)
United States/
North Carolina
1978–1982
912
Maternal milk fat
Dewailly et al.,
1993 (25)
Berkowitz et al.,
1996 (32)
Canada/Quebec
1989–1991
94
Maternal milk
United States/
New York City
1990–1993
40
Maternal serum
Bjerregaard and
Hansen, 2000 (24)
Greenland/
Disko Bay
1994–1996
160
Longnecker et al.,
2001 (12)
United States/
11 cities
1959–1966
2,380
Ribas-Fito et al.,
2002 (29)
Spain/Flix
1997–1999
70
Gladen et al.,
2003 (26)
Ukraine/Kyiv and
Dniprodzerzhinsk
1993–1994
197
Cord blood
Maternal serum
Cord blood
Maternal milk
Level of chemical(s)
reported
DDE (ppb) median (minimum, maximum)
White cases: 21 (18.7, 26.8)
White controls: 5 (2, 13)
Black cases: 17 (6.6, 34.3)
Black controls: 5 (3, 12)
DDE (ppb) median (minimum, maximum)
20.79 (3.8, 324.49)
DDT (ppb) median (minimum, maximum)
12.32 (1.58, 432.78)
DDE (lg/liter) mean (SE*)
Cases: 18.75 (9.48)
Controls: 20 (13.63)
DDT (lg/liter) mean (SE)
Cases: 9.71 (4.84)
Controls: 10.52 (10.63)
DDT (ppb) mean (SE)
Cases: 12.9 (10)
Controls: 2.9 (3.0)
DDE (ppb) mean (SE)
Cases: 18.1 (7.3)
Controls: 10.7 (6.1)
DDE (ppm in milk fat) (minimum, maximum)
(0, >6)
Not given
DDE (ng/ml) median (minimum, maximum)
Cases: 1.30 (0.50, 17.90)
Controls: 1.35 (0.60, 4.00)
Plasma (lg/liter wet weight) mean (SE)
DDE
4.8 (4.0)
DDT
0.2 (0.2)
DDE (lg/liter) median (minimum, maximum)
25 (3, 178)
DDE (ng/ml) (25%, 50%, 75% cutpoints)
(0.49, 0.85, 1.69)
DDE (ng/g of milk fat) median (minimum, maximum)
2,457 (328, 17,412)
DDT (ng/g of milk fat) median (minimum, maximum)
336 (not detectable, 3,150)
Outcomes
under study
Resultsz
DDE
DDT
Low birth weight
þ
Preterm delivery
þ
þ
Preterm delivery
NS*
NS
Preterm delivery
þ
þ
Preterm delivery
þ
þ
Birth weight
NS
Birth weight
NS
Preterm delivery
NS
Birth weight
Gestational age
NS
NS
NS
NS
Preterm delivery
Small for gestational age
Birth weight
Small for gestational age
Preterm delivery
Birth weight
þ
þ
NS
NS
þ
NS
NS
NS
NS
722 Farhang et al.
TABLE 3. Characteristics of studies examining DDT* and DDE* with birth weight and length of gestation
þ
NS
NS
NS
NS
NS
Intrauterine growth
retardation
Birth weight
Preterm birth
Small for gestational age
Birth weight
Gestational age
Maternal serum
420
United States/
northern California
Farhang et al., 2005
(present study)
1959–1967
Maternal serum
168
United States/
Michigan
Karmaus and Zhu,
2004 (27)
1979–1991
Maternal serum
54
Not provided
India/Lucknow
Siddiqui et al.,
2003 (36)
Am J Epidemiol 2005;162:717–725
* DDT, p,p#-dichlorodiphenyltrichloroethane; DDE, p,p#-dichlorodiphenyldichloroethylene; SE, standard error; NS, not significant.
y Number of specimens on which reported or estimated DDT and DDE levels were based, which may not reflect the total number of participants in the study.
z A blank space indicates that the chemical was not examined in the study, and a plus sign (þ) indicates a significant association.
NS
Mexico/Mexico City
Torres-Arreola et al.,
2003 (31)
1995
233
Maternal serum
DDE (ng/g of fat) median
Cases: 189.45
Controls: 152.78
DDE (lg/liter) mean (SE)
Cases: 8.79 (4.19)
Controls: 6.32 (2.95)
DDT (lg/liter) mean (SE)
Cases: 0.55 (1.75)
Controls: 0.26 (1.25)
DDE (lg/liter) (minimum, maximum)
(<5, >25 )
DDE (lg/liter) median (minimum, maximum)
7 (43, 153)
DDT (lg/liter) median (minimum, maximum)
11 (3, 72)
Preterm delivery
NS
NS
NS
NS
NS
DDT, DDE, and Birth Weight and Gestational Age
723
Our study’s laboratory analysis included measures of several other organochlorine chemicals and PCBs in maternal
serum including b-hexachlorocyclohexane, hexachlorobenzene, oxychlordane, trans-nonachlor, PCB 74, PCB 99,
PCB 118, PCB 138, PCB 153, PCB 170, PCB 180, PCB
187, PCB 194, and PCB 203. We assessed the role of confounding by these chemicals by including them in full models examining DDT or DDE and each of the four outcomes.
The sum of 10 PCB congeners (tetra- to octa-chlorinated)
was used as the measure of PCBs. We did not find evidence
of confounding when we added these chemicals to our models (data not shown).
DISCUSSION
Neither maternal serum levels of DDT nor levels of its
major metabolite DDE were significantly associated with
preterm birth, small for gestational age, birth weight, or
gestational age in male infants in this study of women participating in the Child Health and Development Studies
from 1959 to 1967. These results cannot be generalized to
female infants.
There is much variation in studies reporting on these relations (table 3). While our results are consistent with findings
reported in a number of US and international studies examining birth weight (24–29) and preterm birth (30–32), others
have illustrated divergent findings (29, 30, 33–36). Many of
these studies reporting no association were smaller than our
study, and the majority had lower exposure levels than ours
did (24, 26–32). In some of these contrasting studies, researchers did not control for potential confounding factors
such as occupation, age, and race/ethnicity (33–35). In addition, while some studies do not provide enough information
to allow comparisons between chemical levels (25, 33, 34),
for all other studies our concentrations of DDT and DDE
were higher. For example, the recovery-adjusted median
DDE level in the CHDS (47 lg/liter after adjusting for 91
percent recovery) was somewhat higher than that found
in another prospective study conducted in the same time
period (1959–1966), the US Collaborative Perinatal Project
(36 lg/liter after adjusting for 70 percent recovery) (12).
The Collaborative Perinatal Project was comparable in
study design and time period to the CHDS but, unlike our
study, found increasing odds of preterm and small-forgestational-age birth associated with higher serum DDE
concentrations. Infants whose mothers had serum DDE
levels in the highest category (60.0 lg/liter) had adjusted
odds ratios of 3.1 (95 percent CI: 1.80, 5.40) for preterm
birth and 2.6 (95 percent CI: 1.30, 5.20) for small-forgestational-age birth (12). Longnecker et al. (12) illustrated
a linear exposure-response relation between DDE categories, while our study had no such appearance of linearity.
Like our study, they found no association of DDT or the
DDT:DDE ratio with preterm and small-for-gestationalage birth. DDT and DDE, while related, may affect humans
via different physiologic mechanisms.
A possible explanation for the contrasting findings for
DDE between the Collaborative Perinatal Project and the
CHDS is that the population from the former was drawn from
724 Farhang et al.
12 university-based centers across the country, whereas the
CHDS population was drawn from managed health-care facilities in northern California. Populations seeking health care
from teaching hospitals may be different from populations
covered through health insurance, the former representing
primarily low-income populations and the latter representing
employed persons and their partners. Differences in social
position may influence results if social position indicates sensitivity to chemical effects, correlates with other environmental exposures that act synergistically with DDE, or confounds
the association with DDE in unexpected ways.
Our study faced several limitations. We may lack power
to detect an effect on preterm and small-for-gestational-age
births because of our small sample size, though we had
adequate power to detect an effect in continuous models
assessing birth weight and gestational age. For instance, in
the fully adjusted interquartile distance model assessing preterm birth, the odds ratio was 1.28 (95 percent CI: 0.73,
2.23) per interquartile distance increase in DDE, and in
the preterm categorical model, the comparison of quartile
4 with quartile 1 provided an odds ratio of 1.54 (95 percent
CI: 0.45, 5.34) for the effect of DDE. Although the confidence intervals were wide, the point estimates may suggest
a modest effect of higher DDE levels on the risk of preterm
birth. With only 33 preterm births, it is likely that our lack of
power limited our ability to detect a significant effect.
Our study undersampled adverse birth outcomes. Data for
this study were originally used in a case-control analysis of
cryptorchidism and hypospadias (38). To meet case inclusion
criteria for that study, a diagnosis of cryptorchidism and/or
hypospadias must have been present at 2 years of age. All
randomly selected controls were also required to have been
alive at 2 years of age. Therefore, the study population excluded all infants who died during the neonatal and postneonatal periods, when preterm birth and birth weight have the
largest role in causing infant death. With the elimination of
infant deaths, the proportion of preterm and low-birth-weight
births in our sample was reduced when compared with the
underlying cohort (7.9 percent in our study population were
preterm vs. 10.4 percent in the underlying cohort of 9,927;
9.8 percent were small for gestational age vs. 10.5 percent in
the underlying cohort; 4.5 percent were low birth weight vs.
7.3 percent in the underlying cohort). If DDT and DDE are
harmful enough to cause preterm and low-birth-weight birth,
we could have missed an association because our results
were biased toward the null by excluding those infants who
died in the first and second years of life. It is noteworthy that,
in the Collaborative Perinatal Project, study researchers also
undersampled adverse outcomes, and they hypothesized that
the number of undersampled birth outcomes was likely too
small to bear any effect on the analysis (12).
We managed missing values on demographic and behavioral covariates by including ‘‘missing’’ terms for the variables of interest in our adjusted multivariate models. To
further assess the potential effect of these missing values,
we repeated all analyses, imputing missing values by use of
the Schafer stand-alone NORM program, version 2.02, for
Windows (http://www.stat.psu.edu/~jls/misoftwa.html). In
these findings, the role of confounding and our overall findings were unchanged.
It is possible that unmeasured confounding masked an
exposure-outcome relation. For example, we had no information on diet, and if diet is associated with DDT exposure
as well as better birth outcomes, failure to include diet in our
analyses would obscure an association.
Our study has several strengths. We sampled a population
from a large prospective cohort study with consistent procedures for recording infant birth outcomes. The CHDS
enrolled subjects at a time of high domestic use of organochlorine insecticides (14), and chemicals were measured
directly through maternal serum samples. Our results are
comparable to measures of DDE from another analysis of
CHDS-archived maternal serum (41) and also to those found
in an analysis of archived serum collected between 1964 and
1971 in northern California (42). Detailed comparisons with
these and other populations are made elsewhere (38, 43).
In our sample, maternal characteristics such as non-White
race/ethnicity, low body mass index, history of no previous
pregnancy, current smoking, and being unmarried were associated with adverse birth outcomes, findings that are in
agreement with the reproductive health literature (1, 2, 7,
44). This consistency adds to our confidence in these data
and strengthens our assessment that our sample properly
represents known relations in the data.
In summary, while we cannot exclude the possibility of
modest effects, our study does not provide epidemiologic
support for a strong causal relation between DDT or DDE
and adverse male infant birth outcomes. Given, however,
ongoing use of DDT for malaria prevention, environmental
persistence, documented adverse reproductive effects in animals, and inconsistent findings across human studies, continued investigation of the human impacts of DDT and DDE
remains appropriate.
ACKNOWLEDGMENTS
This study was funded by grant R29 ES09042 from the
National Institute of Environmental Health Sciences.
The authors thank Drs. Bea van den Berg and Barbara
Cohn for making CHDS specimens available for this study
and Roberta Christianson for sharing her wealth of
knowledge about the CHDS database. They also thank
Rita Shiau for her input in the early phase of this work.
Conflict of interest: none declared.
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