To our knowledge, this is the first epidemiological study to ascertain the association of

reproductive and hormonal factors in the incidence of thyroid cancer in the Middle East. Since
the establishment of population-based cancer registry in the late 1970s, thyroid cancer has
consistently been the second most commonly recorded neoplasm among Kuwaiti women.1, 21
Similarly high relative frequency and incidence of the disease has also been observed in other
countries in the Gulf region.1719 Concerning the reproductive factors, these countries also have
relatively high birth and total fertility rates. For example, in 1998, the total fertility rate (i.e.,
number of children per women) in Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the United
Arab Emirates was 3.4, 5.2, 6.5, 5.1, 5.0 and 4.9, respectively.22 Other reproductive health
patterns include relatively high prevalence of consanguinity, young age at first marriage and
childbearing, short birth intervals and older ages at last birth.23 All of the above factors result in
a relatively long reproductive life span. The Kuwaiti women in our study showed this
reproductive pattern (see Tables IV,V).

A number of case-control studies, mostly from western Europe and USA and 2 from Asia (China
and Japan) have examined the influence of reproductive factors in thyroid cancer. The data are
limited, however, and the findings have been inconsistent, partly because of the relatively small
number of cases in some of the studies. A meta-analysis by a consortium2 showed that parity,
spontaneous or induced abortion and history of infertility were not associated with the risk of
thyroid cancer. The OR was above unity for women who had their first birth at ages 30 years
(OR = 1.3; 95% CI: 1.01.8). It was concluded that associations of menstrual and reproductive
factors with thyroid cancer were generally weak, but seemed stronger among women diagnosed
with the disease at younger ages (35 years).3 A similar conclusion was reached concerning the
role of exogenous female hormones: there was no evidence of a persistent excess risk of thyroid
cancer after use of oral contraceptives and hormone replacement therapy.4 It is also noteworthy
that all the studies in the combined analysis have been conducted in countries with relatively
much lower birth and fertility rates than Kuwait. Moreover, the mean age at diagnosis of thyroid
cancer (about 35 years) among women in our study was relatively much lower than that reported
in other series (4554 years).7

Case-control studies are subject to a variety of biases. These may include issues of case and
control ascertainment, misclassification, representativeness and participation rates; recall and
information bias between cases and controls and survival bias. The free and easy access to heath
care, KCCC being the only cancer hospital in the country and the weekly thyroid cancer clinic,
provided equal opportunity to all thyroid cancer patients, resident in the country, to visit the
KCCC during the 14-month study period. Patients who were living abroad or had emigrated
(particularly non-Kuwaitis), those with incomplete or unavailable case-notes or invalid telephone
contact had no opportunity to be included in the study. Nevertheless, the age, gender and
histological distribution of cases included in our study (see Table II) is similar to the population-
based data from the cancer registry.

Sociodemographic differences in the characteristics of women who did or did not agree to
participate in the study may influence our results; as may errors in recall of various aspects of
reproductive life and events, particularly for cases diagnosed in the 1980s. The possibility of
recall bias is always a potential problem in case-control studies. Based on our experience with
other studies conducted in Kuwait, certain reproductive variables, particularly parity, ages at
births and miscarriage, are unlikely to be greatly affected by recall or information bias. It is
noteworthy that the total fertility rate among women in our study was similar to the national rate;
and the reproductive patterns and events among our cases and controls (see Table IV) are
consistent with the findings of a large population-based survey conducted by the Ministry of
Health.22, 23 Furthermore, the distinctive network of primary care clinics in Kuwait, with free
and easy access to a variety of services, provided equal opportunity to all women, with varying
reproductive or other characteristics, to be selected as control subjects.

Among all cancers, thyroid cancer has one of most favorable prognosis with all-stage relative 5-
year survival rate of around 95% for women.7 The study included cases diagnosed over an
extended period; 66 patients were known (in the records of the cancer registry) to have died by
the time our study was started. Some other patients may have died abroad or from causes other
than thyroid cancer. The exclusion of these cases from the study might influence the results if
some reproductive or hormonal exposure is associated with relatively worse prognosis of thyroid
cancer. Furthermore, there have also been changes in histological classification and diagnostic
criteria of thyroid cancer over this period.5, 24 Data from our cancer registry show that over 97%
of all thyroid cancers diagnosed in Kuwait were histologically verified. Variation between
pathologists in classification of histological subtypes, however, is likely to have led to some
misclassification by histology.

In our study, age at pregnancy seemed to be significantly related to the risk of thyroid cancer.
Women who started childbearing at a young age had a substantially reduced risk of thyroid
cancer. Women who had their last pregnancy at ages 30 years were at about 2 times increased
risk. There was also a significant trend in risk with increasing age at last pregnancy. Considering
that the reproductive life (ages 1545 years) of women can be divided approximately into 2
equal halves, these findings (along with recency of diagnosis in the second and third year after a
birth and the mean age at diagnosis of about 35 years) suggest that childbearing during the first
half of reproductive life offers some protective effect; whereas, having a large number of
children during the latter half substantially increases the risk of thyroid cancer. These findings
are biologically plausible and are consistent with the hypothesis concerning the possible role of
thyroid stimulating hormone in thyroid cancer.

Only 3 other case-control studies have examined the effect of age at pregnancy in some detail.
An increased risk of similar magnitude was reported in a study from Italy (relative risk (RR) =
2.2; 95% CI: 1.33.7 for women aged 30 years at last birth);25 whereas, no association was
found in studies from Switzerland26 and Washington State in the US.27 In a nested case-control
study of a nation-wide Swedish cohort, there was a significant trend in excess risk among women
who had a live birth at ages 25 years (OR = 1.6; 95% CI: 1.12.5 for women aged 35 years at
last birth).28 A positive association, of similar magnitude, with late last birth (35 years) was
also demonstrated in a prospective cohort study of 63,090 women in Norway.29

Among the various reproductive factors, parity has received most attention. Most case-control
studies have demonstrated that women with thyroid cancer have had relatively more pregnancies
or live births than controls.25, 26, 28, 3036 These studies have shown modest increase in risk
with parity (varying approximately between 1.52.5 for parity 3 vs. >3). Some case-control
studies, however, did not show any association with parity.27, 3739 In a prospective birth
cohort study of 1.1 million Norwegian women of reproductive age, there was a progressive
increase in risk of thyroid cancer with parity (RR = 1.0, 1.13, 1.30, 1.39, 1.46 for women with 0,
1, 2, 3 and 4+ live births, respectively).40 The risk estimates for parity 2, 3 and 4+ were
statistically significant. Another cohort study of 63,090 Norwegian women with 124 cases of
thyroid cancer, however, did not find any increase in risk with parity.29 It is plausible that
pregnancy at young age induces some protective modification in risk and this threshold is
overwhelmed by prolonged and repeated hormonal (TSH, hCG and sex hormones) stimulation
due to large number of pregnancies and subsequent metabolic stress and hypertrophy of the
thyroid gland. It is also possible that thyroid gland of older women, who have also borne a
relatively large number of children, may become more susceptible to some of the carcinogenic
stimuli occurring during pregnancy. The relatively large number of children borne by the women
in our study population provided a unique opportunity to ascertain the role of age at pregnancy
and parity in thyroid cancer. In agreement with most studies, we also found a modest association
between high parity and the risk of thyroid cancer.

For history of spontaneous or induced abortion, the data are conflicting; with some reports of
increased risk of thyroid cancer with history of miscarriage or abortion, particularly as an
outcome of first pregnancy26, 3133, 37 and others of none.29, 38, 39, 41 Moreover, a
decreased risk was found in a study from Italy for women who had ever experienced an abortion
(RR = 0.6; 95% CI: 0.41.0).25 Our data showed an inverse relationship between miscarriage
and risk of thyroid cancer, particularly for women who had a miscarriage as outcome of first
pregnancy and for those who have had 3 miscarriages; there was also a significant trend in
decreasing risk with increasing number of miscarriages. It is possible that these findings could
well be due to chance, particularly when large number of associations are examined; differential
recall or information bias between cases and controls; or due to interaction with some indigenous
factor(s), the findings could be more relevant to our study population. It is plausible that early
termination of pregnancy may lower the risk of cancer as the thyroid gland is relieved of the
prolonged and recurrent stimulation by TSH and other hormones. As shown in the present and
most other studies, this would be consistent with the tendency toward increasing risk of thyroid
cancer in relation with increasing number of full-term pregnancies.

Only 3 epidemiological studies have examined the recency of diagnosis of thyroid cancer in
relation to time since last birth.27, 28, 40 All studies found higher risk with shorter time
intervals. In agreement with these studies, our data showed that women in the second and third
year after the last birth were at a substantially increased risk of being diagnosed with thyroid
cancer. Rossing et al.27 conducted a sub-analysis of their data to examine whether parity in the
last 5 years had any influence on incidence of thyroid cancer; they found that women with parity
2 had a significantly increased risk of thyroid cancer (OR = 4.2; 95% CI: 2.08.9). These
findings have led to the suggestion that hormonal, metabolic, or other biochemical changes
during both pregnancy and lactation may exert a transient influence on risk of thyroid cancer.

Women who had a history of post-partum thyroiditis were at about 10 times increased risk of
developing thyroid cancer. Numerous epidemiological studies have consistently demonstrated a
strong link between history of benign thyroid disease such as adenoma, nodule(s) or goitre and
thyroid cancer. In most case-control studies, the odds ratios for these conditions have varied
approximately between 2.530.0. Post-partum thyroiditis, is an often self-limiting and transient
episode of autoimmune thyroiditis that occurs in about 210% of women during the 28 months
after delivery.42 In 1025% of the women who had experienced 1 episode, the condition
recurred after subsequent delivery. In our study, 10.5% of ever-pregnant cases had a history of
post-partum thyroiditis. The possible link between this condition and thyroid cancer has not been
studied before. It can be argued that this finding could be due to differential recall or information
bias between cases and controls, as cases may have a better recollection of their history of
thyroid-related conditions. The magnitude of risk, however, is consistent with similarly high risk
reported for other benign thyroid conditions and could not be entirely attributed to possible
minor differences in recall between cases and controls. The findings of further similar studies,
showing consistent results, would finally permit more definite conclusions about the possible
link between post-partum thyroiditis and thyroid cancer.

Women on oral contraceptives have higher levels of TSH compared to women with normal
menstrual cycle. Among Kuwaiti women, there has been a decline in the use of oral
contraceptives over the last two decades: the prevalence of current use among married women
decreased from 79% in 1984 to 45% in 1999.43 In a recent household survey, about 62% of the
married Kuwaiti women had ever used oral contraceptives; and they were used more often for
spacing than limiting the number of children (Dr. Shah, personal communication). There has
been no report of the prevalence of use of hormone replacement therapy in Kuwait, which we
believe is relatively lower than the Western countries. In concordance with the majority of
epidemiological studies,44 we did not find any association between use of exogenous female
hormones and thyroid cancer.

A number of epidemiological studies have examined the association of thyroid cancer with
cigarette smoking and body size or weight gain. Most studies examining smoking have shown a
(usually non-significant) decrease in the risk of thyroid cancer among women.3538, 45 Based
on smoking status at the time of diagnosis/pseudo-diagnosis date, we found that women who had
ever smoked were at a non-significant increased risk of thyroid cancer compared to those who
had never smoked. In a recent cross-sectional survey, the prevalence of smoking among adult
Kuwaiti women, aged 1860 years, was around 2%.46 Most studies examining body size or
weight gain have shown a positive association with thyroid cancer among women. These factors
were not examined in the present study. It may be of interest, however, to note that compared to
other populations, Kuwaiti women have one of the highest reported prevalence of obesity. In a
cross-sectional survey, the prevalence of overweight (BMI >25) among adult Kuwaiti women
was about 73% and the prevalence of obesity (BMI >30) was 41%.47

In conclusion, the results of our study, conducted on a Middle Eastern population with relatively
high birth and fertility rates and incidence of thyroid cancer, support the hypothesis that
reproductive factors and patterns, particularly childbearing at older ages and high parity may
influence, or contribute to, the risk of developing thyroid cancer. On the contrary, miscarriage or
a woman's underlying biology that leads to miscarriage may confer some protective effect. The
results provide perhaps the first indication in the literature of a possible link between history of
post-partum thyroiditis and thyroid cancer. The findings of the study may also be relevant to
other countries in the Middle East, particularly those with similarly high fertility rates and
incidence of thyroid cancer.
Acknowledgements
We thank Professor V. Beral and Ms. A. Berrington for sharing their wisdom in helpful
discussions; Professor N. Shah and Dr. Y. Luqmani for comments on the manuscript; Dr. A. A.
Ali, Mr. V. David, Ms. L. Al-Kandari, Ms. M. Al-Khaldi, Ms. H. Habib and Ms. O. Zikrallah at
the Kuwait Cancer Registry for their help and support; and, most importantly, all the thyroid
cancer patients and control subjects who helped us with the study. The study was supported by a
grant from the Kuwait Foundation for the Advancement of Sciences (KFAS Project No. 96-07-
07) and administered by the Kuwait University Research Administration Department.