American Journal of Epidemiology
Copyright O 1997 by The Johns Hopkins University School of Hygiene and Public Health
All rights reserved
Vol. 145, No. 6
Printed In U.SJL
Is There an Association between Preconception Paternal X-ray Exposure
and Birth Outcome?
Katharine M. Shea,1 Ruth E. Little,2 and the ALSPAC Study Team3
Diagnostic x-rays are performed commonly on men of reproductive age, yet little is known about the
potential effects of these x-rays on the future unborn children of such men. This study examines the possibility
that preconception diagnostic x-ray studies of fathers may adversely effect their newboms. The authors used
prospectively collected data from the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC) for
7,678 birth records for women who gave birth in the County of Avon, England, in 1991-1992. Birth weight,
gestational age, and fetal growth of infants whose fathers received diagnostic x-ray examinations likely to
deliver significant gonadal doses within one year prior to conception were compared with infants whose
fathers did not receive such x-rays. The mean birth weight of babies of exposed fathers was 3,358 g compared
with a mean of 3,437 g in the unexposed group (p = 0.055). A similar difference was noted for intrauterine
growth, 3,374 g exposed versus 3,437 g unexposed (p = 0.078). The downward trend in birth weight and fetal
growth (birth weight adjusted for gestational age) persisted despite control for infants' sex and important
parental variables such as age, height, race, education, occupational exposure, parity, and maternal smoking.
Because medical x-rays are the largest controllable source of man-made ionizing radiation, more detailed
study of the potential effect of paternal x-irradiation on progeny seems justified. Am J Epidemiol 1997;145:
546-51.
birth weight; paternal exposure; prospective studies; radiography; x-rays
Ionizing radiation is known to have detrimental effects on the reproductive systems of both males and
females (1). In the United Kingdom, 12 percent of all
exposure to ionizing radiation comes from man-made
sources, 94 percent of which are medical radiologic
procedures. It is estimated that 21 million radiologic
examinations are performed in Britain each year (2).
These radiologic examinations are evenly distributed
among age groups, including those encompassing the
major reproductive years (3). Fluoroscopic examinations account for approximately 6 percent of all x-rays,
and such examinations contribute gTeatly to the genetically significant radiation dose received by the population (4).
The danger to the embryo and fetus of intrauterine
ionizing radiation exposure is well documented (5).
Atomic bomb studies show that children exposed to
ionizing radiation in utero exhibit a linear dose-effect
relation between exposure and several neurodevelopmental and growth abnormalities depending on the
gestational age at exposure (6). Diagnostic x-rays are
no longer performed routinely during pregnancy because of the risk of damage during critical periods of
organogenesis (7). The effect on the fetus of preconception x-irradiation is less well described. Some studies of humans show an increased incidence of chromosomal abnormalities in offspring of mothers who
received preconception diagnostic x-rays (8). Other
studies suggest an association between preconception
paternal exposure to diagnostic x-rays and infant leukemia (9).
Work in the past decade has increasingly suggested
the potential importance of preconception paternal exposures to fetal growth and development. Mechanisms
by which the father may contribute to birth outcomes
include genetic and epigenetic phenomena (10). An
important epigenetic phenomenon is genomic (gametic) imprinting, where the expression of a gene depends
on whether it was transmitted by the mother or father.
This parent-of-origin effect means there must be dif-
Received for publication March 7, 1996, and accepted for publication October 22, 1996.
Abbreviations: ALSPAC, Avon Longitudinal Study of Pregnancy
and Childhood; DNA, deoxyribonucleic acid; IGF2, insulin-like
growth factor 2.
1
General Clinical Research Center, UNC-NIEHS Program, UNC
Hospitals, Chapel Hill, NC.
2
Epidemiology Branch, NIEHS, Research Triangle Park, NC.
3
Department of Child Health, Royal Hospital for Sick Children,
St. Michael's Hill, Bristol, Avon, England.
Reprint requests to Dr. Katherine M. Shea, NIEHS, P.O, Box
12233, Bkjg. 101, MD A3-05, 111 T. W. Alexander Drive, Research
Triangle Park, NC 27709.
546
Preconception Paternal X-ray Exposure and Birth Outcome
ferential (non-mutational) modification of deoxyribonucleic acid (DNA) at gametogenesis. There is evidence in the mouse (11, 12) that the imprint is
differential methylation of DNA that occurs before or
during gametogenesis and is erased between generations. Of particular interest in the present context is the
fact that the insulin-like growth factor 2 (IGF2) gene is
imprinted in both mouse and human, with only the
paternally derived allele being active during fetal life
(13, 14). IGF2 stimulates fetal growth. Fetal mice
without the active paternal IGF2 allele are born small
(13) and removal of the maternal silencing imprint by
a nearby H19 deletion causes mice to be born large
(15). Another gene of interest is the negative regulator
of cell proliferation, p57AyA>2, which is imprinted, but
here, the paternally derived allele is the silent one (16).
One effect of DNA damage by x-rays is to trigger
cell "protection'Vtumor suppressor responses such as
increased p53 production that can suppress growth
(17). This growth suppression by p53 may be effected
through various mechanisms including transcriptional
down-regulation of a number of genes. In somatic
cells, at least, transcriptional regulators can induce
sequence-specific demethylation (18). Perhaps in the
germline, increases in p53 induced by x-rays might
modify the imprint setting/DNA methylation of IGF2,
p57 2, or other imprinted genes involved in regulating growth. Kirk and Lyon (19) were able to induce
dwarfism and several congenital anomalies in offspring of male mice irradiated with large doses of
x-rays immediately prior to conception.
Ionizing radiation is capable of inducing a wide
spectrum of cellular, molecular, biochemical, and hormonal abnormalities. It is therefore reasonable to examine the potential effect of ionizing radiation on fetal
growth mediated through the father. In this study, we
investigated the association between paternal diagnostic medical x-ray exposure prior to conception and
subsequent fetal growth. Because medical x-rays represent the bulk of controllable man-made exposure to
ionizing radiation, the identification of possible detrimental effects on fetal growth from paternal exposures
could have important influence on decisions involving
elective radiologic procedures in men and family planning.
MATERIALS AND METHODS
The sample for this study is drawn from the Avon
Longitudinal Study of Pregnancy and Childhood
(ALSPAC), which has been previously described (20).
Briefly, ALSPAC is a prospective, longitudinal study
of a geographic cohort of children beginning during
pregnancy and continuing to age 7 years. The study
was designed to identify environmental, social, psyAm J Epidemiol
Vol. 145, No. 6, 1997
547
chologic, and genetic factors associated with fetal,
infant, and child health. Extensive self-administered
questionnaires, abstracted medical records, biologic
samples, and direct examination of children provide a
unique body of health information for analysis.
Participants in ALSPAC were recruited from among
all pregnant women who lived in three health districts
of the County of Avon, England, and whose expected
dates of delivery fell between April 1, 1991 and December 31, 1992. Over 80 percent of eligible women
chose to participate, resulting in 14,893 pregnancies
initially enrolled. Women were approached at booking. If they enrolled in the study, they were encouraged to invite their partners to participate as well. Each
woman was sent two questionnaires that inquired
about diagnostic x-ray exposure: one questionnaire for
the woman to complete and the other for her partner to
complete. Of these questionnaires, 12,471 were returned by women who were still pregnant, and 8,650
were returned by the partners. From the latter returned
questionnaires, we excluded partners who did not answer any of the questions on x-ray exposure and
partners who were not the father of the infant by
maternal report. The cohort was further restricted to
singleton live births, leaving 7,678 birth records for
analysis.
The exposure variable was generated from an item
on the partner's questionnaire asking about specific
medical x-ray studies performed any time within 12
months preceding conception. Dates of examination
were not requested, so it was not possible to determine
the precise timing of procedures within the 12-month
interval with respect to the time of conception. Only
those procedures with a high likelihood of gonadal
exposure were chosen for analysis. These included
abdominal x-rays, barium studies of the upper and
lower gastrointestinal tract, intravenous pyelograms,
and pelvis and hip x-rays. Head and neck films, limb
films, and chest films were not considered likely to
result in significant gonadal exposures. Lumbar spine
films were not differentiated in the questionnaire from
other back films and were included with the studies
without significant gonadal exposure.
Estimates of gonadal x-ray dose received from these
procedures vary from a mean of 4.40 mGy (0.44 rad)
for hip or pelvis studies to 0.07 mGy (0.007 rad) for
lumbar spine studies (21). The actual dose received by
individual patients may, however, vary by up to three
orders of magnitude depending on differences in radiographic technique, individual body habitus, and
equipment type (2). Thus, actual individual doses cannot be determined from historical data. For this reason,
exposures were combined into a single categorical
variable of "exposed" versus "nonexposed." The non-
548
Shea et a).
exposed category consisted of the group of fathers
who received no x-rays within one year prior to conception and fathers who received only x-rays distal to
the gonads. The exposed group was all fathers who
had studies of the abdominal or pelvic areas.
Potential maternal and paternal self-reported occupational exposures to ionizing radiation were captured
from additional questionnaire items. Occupational exposures considered for mothers and fathers included
medical, dental, scientific, and laboratory-related exposures, as well as nuclear power production exposures. Paternal exposures were grouped as either total
lifetime exposures or exposures within one year of
conception of the birth under study. Maternal occupational exposures were grouped only as total lifetime
exposures.
The main outcome variables were birth weight, gestational age, and fetal growth (birth weight adjusted
for gestational age). Birth weight was collected from
the mothers and recorded in grams. Gestational age
was calculated from the estimated date of confinement
and the actual birth date. Sex ratio of infants and rates
of preterm delivery (delivery before 37 weeks gestation) were also examined. Secondary independent
variables were included in the analysis based on their
potential impact on these outcome measures. Maternal
and paternal height in centimeters, and maternal and
paternal age at birth were treated as continuous variables. Maternal and paternal race (white vs. nonwhite),
along with maternal parity and gravidity, maternal
smoking during pregnancy, and maternal alcohol use
during pregnancy were considered and treated as dichotomous variables. Maternal and paternal educational status were analyzed using a four-level categorical variable consistent with the British educational
system. Sex of the infant was also included. Variables
which failed to reduce variance in birth weight residuals by a minimum p value of 0.15 were dropped from
the analysis.
The effect of exposure on birth weight was first
examined using means of the unadjusted data. The
difference in the means was evaluated by a standard
two-tailed t test (22). Using multivariate models including other independent variables known to predict
birth weight, an analysis of x-ray exposure was performed in multivariate linear regression (22). In such a
model, the estimated effect of x-ray exposure can be
interpreted as the difference between means adjusted
for these other factors. Subgroup analyses were performed adjusting for educational status, parental race,
and occupational exposure, but these variables were
not required in the final regression. A similar procedure was used for intrauterine growth by including
linear and squared gestational age in the multivariate
regression model, and for gestational age in days. Sex
ratios of exposed versus nonexposed infants as well as
frequency of preterm delivery in exposed versus nonexposed babies were also examined using the chisquare test (22). The effect of paternal exposure to
chest x-ray studies without other studies likely to
deliver significant gonadal doses during the year prior
to pregnancy was used as an additional control. Finally, x-ray examinations preceding the one year prior
to the pregnancy under consideration were examined
in similar fashion for effect on birth outcome.
In all analyses, a statistically significant finding is
one for which the appropriate statistic has a two-sided
p value of 0.05 or less (22).
RESULTS
Table 1 shows the characteristics of the mothers and
fathers by father's exposure category. There were no
notable differences likely to confound the results of
the analysis. Mean unadjusted birth weight of infants
born to unexposed fathers was 3,437 g compared with
a mean of 3,358 g for infants born to exposed fathers.
This difference of 79 g decreased slightly after controlling for sex of infant, maternal parity, maternal and
paternal height, and maternal smoking during pregnancy, and remained statistically nonsignificant (table
2). The difference in mean birth weight between infants of exposed and nonexposed fathers lessened
when nonwhite parents were excluded from the analysis, but the nonsignificant trend toward lower birth
weight remained evident. Further subgroup analysis
excluding maternal and paternal medical occupational
exposure as well as occupational radiation exposure
showed persistent but smaller differences in mean
adjusted birth weights in infants of exposed fathers.
Fetal growth, defined as birth weight adjusted for
gestational age, showed a similar decrease in infants of
x-ray-exposed fathers (3,374 g) compared with nonexposed fathers (3,437 g). This decrease persisted after
adjustment for infants' sex, maternal parity, maternal
and paternal height, and maternal smoking during
pregnancy. It also remained evident after excluding
nonwhite parents and various occupational exposures
of both the mother and the father, and controlling for
parental education level. All differences failed to meet
the statistical significance criterion used here.
Mean gestational age was found to be 280 days in
infants of unexposed fathers compared with 279 days
in infants of exposed fathers. This slight nonsignificant difference remained after adjustment for maternal
age and sex of the infant, both with and without
nonwhite parents. No difference was found in the rate
of preterm delivery in infants born to exposed vs.
nonexposed fathers, though only ten of the 172 babies
Am J Epidemiol Vol. 145, No. 6, 1997
Preconception Paternal X-ray Exposure and Birth Outcome 5 4 9
TABLE 1. Comparison of descriptive parental characteristics by exposure of father to preconception
diagnostic x-rays: Avon Longitudlnai Study of Pregnancy and Childhood, County of Avon, England,
1991-1992*
Unexposed fathers
OilalaClDinDC
Exposed fathers
%
Frequency
Frequency
%
Maternal characteristics
Smoking status
Nonsmoker
Smoker
Parity
Primiparous
Muttiparous
Age (yeans) at birth
<18
18-24
25-34
35-45
Height (inches)t
<60
60-63
64-68
£68
Race
White
Nonwhite
5,649
1,483
80
20
127
42
75
25
3,518
3,916
47
78
91
46
54
31
<1
16
<1
71
12
1
33
115
33
19
67
13
2
32
52
13
4
61
79
26
36
46
15
98
2
152
5
97
3
0
11
117
36
6
0
6
69
21
3
19
91
11
54
56
33
154
1
99
<1
53
1,210
5,363
937
138
2,386
3,882
1,000
6,989
138
2
Paternal characteristics
Age (years) at birth
<18
18-24
25-34
35-44
45-66
Height (inches)t
<64
64-68
69-71
272
Race
White
Nonwhite
8
648
4,983
1,661
173
<1
9
67
22
2
78
953
3,790
2,572
51
35
6,848
157
98
2
1
13
4
2
• None of the parental characteristics differed significantly between exposed and unexposed fathers by the
chi-square test
1 1 inch = 0.0254 m.
of x-ray-exposed fathers in the analysis cohort were
premature. Sex ratios were the same in infants born to
x-ray-exposed fathers compared with nonexposed fathers. No reduction or significant difference in birth
weight or intrauterine growth was found in infants
born to fathers who had only chest x-rays during the
year prior to pregnancy (n = 288, mean unadjusted
birth weight = 3,474 g) compared with infants born to
fathers who received neither chest x-rays nor x-rays
with gonadal exposure prior to pregnancy (n = 7,266,
mean unadjusted birth weight = 3,435 g). Finally, no
significant reduction in birth weight, intrauterine
growth, or gestational age was found in infants born to
fathers exposed to diagnostic x-rays any time before
one year prior to conception (n = 1,190, mean unadAm J Epidemiol
Vol. 145, No. 6, 1997
justed birth weight = 3,394 g) compared with infants
born to nonexposed fathers {n = 6,004, mean unadjusted birth weight = 3,424 g).
DISCUSSION
We did not find a statistically significant difference
in any of three major birth outcomes between infants
of x-ray-exposed fathers and x-ray nonexposed fathers. The fact that the decreases in birth weight,
gestational age, and fetal growth were robust in the
face of controlling for a number of confounders is,
however, a provocative finding. If the exposure variable had been more precise, it is possible that reductions in birth weight and fetal growth would have been
550
Shea et al.
TABLE 2. Mean birth weight and Intrauterlne growth by exposure of father to preconception diagnostic
x-rays: Avon Longitudinal Study of Pregnancy and Childhood, County of Avon, England, 1991-1992
Outcome category
Unadjusted birth weight
No.
Mean (g) (SEt)
Adjusted birth weight*
No
Mean (g) (SE)
Intrauterine growth§
No.
Mean (g) (SE)
Adjusted intrauterine growthU
No.
Mean (g) (SE)
Exposed
fathers
172
3,358 (40)
164
3,315 (39)
172
3,374 (34)
164
3,334 (34)
Unexposed
fathers
Difference*
in means
P
value
7,546
3,437 (6)
79
0.055
7,146
3,388 (7)
73
0.064
7,546
3,437 (5)
63
0.078
7,146
3,387 (6)
53
0.120
• Mean birth weight of infants of unexposed fathers less mean birth weight of infants of exposed fathers.
t SE, standard error.
i Birth weight adjusted for infant's sex, maternal smoking during pregnancy, parity, and maternal and paternal
height
§ Birth weight adjusted using linear and quadratic terms for gestation in days.
H Birth weight adjusted for gestationai age and infant's sax, maternal smoking during pregnancy, parity, and
maternal and paternal height.
more substantial or would have followed a dose response curve. For example, the birth weights of infants
whose fathers had x-rays more than one year prior to
conception were no different from birth weights of
infants of unexposed fathers. This suggests that the
important exposure interval may be immediately prior
to conception within a single cycle of spermatogenesis. Documenting precise individual doses and time
within 3 months of conception might demonstrate a
significant relation. Even if this were the case, it would
be important to question whether the suggestive association might be due to x-ray exposure per se or to
some difference in paternal health for which x-ray
exposure might be a surrogate. The failure to find a
birth weight decrement in infants of fathers who underwent chest x-ray in the year prior to conception,
suggesting illness or cigarette smoking, argues against
this and further strengthens the hypothesis that x-ray
exposure to the father's gonads specifically represents
a risk to his offspring.
The persistence of slightly reduced birth weights
with paternal x-ray exposure adds support to the growing literature that suggests that preconception paternal
health and exposure status may have measurable impact on pregnancy outcome. Because diagnostic x-rays
will continue to be widely utilized, knowledge of
possible detrimental effects on reproductive outcomes
is of practical importance. For years, mothers have
been routinely cautioned about the dangers of x-ray
exposure during pregnancy. This standard of practice
evolved over time as the dangers of low dose xirradiation were defined. For example, several studies
(23-26) that demonstrated an increase in childhood
leukemia in offspring exposed to prenatal diagnostic
x-ray were required to supplant the older conclusion of
no additional risk based on finding of no excess leukemia in infants exposed in utero to the atomic bomb
blast (27). Perhaps fathers should also be concerned
about the dangers of x-ray prior to attempts to conceive, but several careful positive studies are required.
This is a questionnaire study and is therefore subject
to response bias. The ALSPAC study is unusual in its
broad scope and projected time frame. Over 80 percent
of mothers in the geographic cohort and almost 70
percent of their partners responded to the questionnaires that generated the data for this study. We were
unable to find any effect of maternal or paternal education, a good surrogate for social class, on our main
results. Further, because we failed to find a difference
in the group of infants whose fathers had chest x-rays
versus infants of nonexposed fathers, this argues
against the small decrement in birth weight in infants
of exposed fathers being the result of reporting bias
alone. Nonetheless, studies designed to examine this
question specifically would be necessary to determine
whether paternal preconception x-ray exposure does
affect birth weight, fetal growth, or gestationai age.
Additional work to investigate the effects of paternal x-rays on birth outcomes could be based on more
detailed questionnaires of prospective fathers in family
planning and obstetric clinics. Important information
to gather would include precise timing of x-ray exposure prior to conception, medical indication for diagnostic x-ray, results of x-ray procedures, number of
films taken, and duration of fluoroscopy. This would
refine the exposure variables by permitting precise
Am J Epidemiol
Vol. 145, No. 6, 1997
Preconception Paternal X-ray Exposure and Birth Outcome
definition of the timing of x-rays with respect to the
period of spermatogenesis prior to conception, identification of potential health conditions that might confound results, and determination of more precise individual dose information. The potential public health
impact of this issue and the suggestive results of our
study seem to justify more detailed study of this hypothesis.
8.
9.
10.
11.
ACKNOWLEDGMENTS
This study could not have been undertaken without the
financial support of the Wellcome Trust, the Department of
Health, the Department of the Environment, British Gas,
and other companies including British Nuclear Fuels. The
ALSPAC study is part of the World Health Organizationinitiated European Longitudinal Study of Pregnancy and
Childhood. This project has been funded in whole or in part
with federal funds from the National Institute of Environmental Health Sciences, National Institutes of Health, contract no. NO1-ES-35356.
We thank the midwives for their cooperation and help in
recruitment. The ALSPAC study team comprises interviewers, computer technicians, laboratory technicians, clerical
workers, research scientists, volunteers, and managers who
continue to make the study possible. Special thanks to Prof.
Marcus Pembrey for his valuable contributions to this paper.
We would also like to thank Prof. Jean Golding, Dr. Allen
Wilcox, Dr. Clarice Weinberg, and Prof. Alan Preece for
their comments on earlier versions of this manuscript.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
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