Parity, age at first birth and risk of death from kidney cancer: a population-based cohort study in Taiwan

Abstract

Background: This study was undertaken to examine whether there is an association between parity and age at first birth and risk of kidney cancer. Methods: The study cohort consisted of 1 292 462 women who had a first and singleton childbirth between 1 January 1978 and 31 December 1987. We tracked each woman from the time of her first childbirth to 31 December 2009, and their vital status was ascertained by linking records with the computerized mortality database. Cox proportional hazard regression models were used to estimate the hazard ratios (HRs) of death from kidney cancer associated with parity and age at first birth. Results: There were 95 kidney cancer deaths during 34 980 246 person-years of follow-up. The mortality rate of kidney cancer was 0.27 cases per 100 000 person-years. The adjusted HR was 1.88 [95% confidence interval (CI) 1.10–3.19] for women who gave birth between 24 and 26 years of age and 2.52 (95% CI 1.44–4.40) for women who gave birth after 26 years of age, when compared with women who gave birth when <23 years of age. A trend of increasing risk of kidney cancer was seen with increasing age at first birth. The adjusted HR was 0.88 (95% CI 0.49–1.59) for women who had two children and 0.89 (95% CI 0.47–1.67) for women with three or more births, when compared with women who had given birth to only one child. Conclusion: This study is the first to suggest that early age at first birth may confer a protective effect on the risk of kidney cancer.

Introduction

In Taiwan, kidney cancer is the 14th leading cause of cancer mortality for males and the 13th for females.¹ In 2008, the age-adjusted mortality rate for kidney cancer was 2.5 per 100 000 among males and 2.0 among females, with an incidence of 5.22 per 100 000 among males and 2.45 among females. There is substantial geographic variation in kidney cancer mortality within the country.

Renal cell cancer (RCC), the most common type of kidney cancer, represents approximately 80% of all kidney cancers.^2,3 Incidence rates of RCC have been increasing, both in Taiwan and globally,³ and RCC accounts for approximately 95% of all kidney cancer cases in Taiwan. However, little is known regarding the etiology of kidney cancer. Smoking, obesity and hypertension are the most consistently accepted causal risk factors for kidney cancer.⁴ These three risk factors explained half of the female RCC cases in the multiethnic cohort study,⁵ leaving a substantial proportion of this cancer still unexplained.⁶

Incidence rates among females are generally about half those among males,⁷ suggesting a possible role of reproductive or hormonal factors in kidney cancer.⁶ Animal studies have shown that estrogens can promote or induce kidney cancer development.^8,9 The influence of sex hormones on kidney cancer risk is supported by the presence of estrogen receptors in both normal and cancerous renal cell tissue in humans.¹⁰ Furthermore, obesity, which is a consistent risk factor for RCC, provides a major source of endogenous estrogen exposure in postmenopausal women.¹¹ These findings prompted the hormonal hypothesis that female reproductive and menstrual factors may be involved in the etiology of RCC.¹² However, findings regarding the association between estrogens exposure and kidney cancer risk is conflicting.⁶

The role of parity and age at first birth in the etiology of kidney cancer in women has received only limited attention in the literature, and the results have been inconsistent. Some studies reported positive associations between increasing parity and the risk of kidney cancer,^6,13–16 whereas others reported no association.^17–23 Likewise, reported associations between younger age at first birth and kidney cancer risk have been inconsistent, with some studies reporting an increased risk^{14–15,20,23} and others reporting no association.^{6,12,13,16,19,22}

The aforementioned epidemiologic studies have been conducted on high-incidence populations in Europe and North America, and study results have not been consistent. The present study was carried out because no studies have been conducted on low-incidence populations such as Asians. We studied a cohort of women who experienced a first and singleton childbirth between 1978 and 1987 to explore further the association between parity, age at first birth and the risk of kidney cancer in Taiwan.

Methods

Data source

Registration of births is required by law in Taiwan. It is the responsibility of the parents or the family to register infant births at a local household registration office within 15 days. The Birth Registration System, which is managed by the Department of Interior, released computerized data on live births since 1978. The registration form, which requests information on maternal age, education, parity, gestational age, date of delivery, infant gender and birth weight, is completed by the physician attending the delivery. Because most deliveries in Taiwan take place in either a hospital or clinic and the birth certificates are completed by physicians attending the delivery and it is mandatory to register all live births at local household registration offices, the birth registration data are considered complete, reliable and accurate. These data have been used in our previous study.²⁴

Study population

The study cohort consisted of all women with a record of a first and singleton childbirth in the Birth Register between 1 January 1978 and 31 December 1987. There were 1 333 312 first and singleton births in Taiwan between 1978 and 1987. Information on any subsequent births was also retrieved from the Birth Register. Of the 1 399 312 primiparous women, 106 850 subjects were excluded because data were missing on at least one variable, such as maternal age (n = 100 099), years of schooling (n = 382), marital status (n = 2665) or birth place (n = 4535). This exclusion left 1,292,462 women with complete information for the analysis. Their details have already been described in an earlier publication.²⁵

Follow-up

Each woman has her own unique personal identification number. Using this number, we tracked each woman from the time of her first childbirth to 31 December 2009, and their vital status was ascertained by linking records with the computerized mortality database, identifying the date of any deaths occurring in this cohort. Of the 1 292 462 women followed, none had a missing personal identification number; therefore, all cohort members were followed up. Because it is mandatory to register death certificates at local household registration offices, the mortality statistics in Taiwan were considered to be highly accurate and complete.²⁵

Statistics

The person-years of follow-up for each woman was calculated from the date of first childbirth to the date of death or 31 December 2009. Death rates were calculated by dividing the number of deaths from kidney cancer by the number of person-years of follow-up. Cox proportional hazard regression models were used to estimate the hazard ratios (HRs) of death from kidney cancer associated with parity (the number of children recorded in the last childbirth record of each woman registered during follow-up) and age at first childbirth. The 95% confidence intervals (CIs) for the HRs were also calculated. Kidney cancer is defined according to the International Classification of Disease, Injuries and Causes of Death (ninth revision) (ICD code 189.0). Age at first birth was categorized based on the tertile values derived from the entire cohort (≤23, 24–26 or >26). The variables in the final model included age at first childbirth, parity (1, 2, 3 or more), marital status (married, unmarried), years of schooling (≤9, >9 years) and birth place (hospital/clinic, home/other). The proportional hazards assumption was assessed for all aforementioned variables, and no violations were observed. To test for trends in risk with increasing levels of the exposures of interest, we assigned the categorical variables their ordinal number for parity and the category median for age at first birth and then fitted the assigned values for each risk factor as a continuous variable in the risk models. We then evaluated the statistical significance of the corresponding coefficient using the Wald test. Analyses were performed using the SAS statistical package (version 9.2, SAS Institute Inc., Cary, NC). All statistical tests were two-sided; P values <0.05 were considered to be statistically significant.

Results

Altogether 1 292 462 primiparous women with complete information were included in the analysis. A total of 34 980 246 person-years were observed during the follow-up period from the time of their first childbirth to 31 December 2009. There were 95 kidney cancer deaths, yielding a mortality rate of 0.27 cases per 100 000 person-years.

Table 1 gives the numbers of person-years of follow-up and kidney cancer deaths by age at recruitment (age at first birth), parity, marital status, years of schooling and birth place. The mortality rate was 0.36 among women who had given birth to one child, 0.29 among those with two children and 0.23 among those with three or more children.

Table 1

Demographic characteristics of the study cohort

Variables	No. of subjects	Follow-up person-years	No. of deaths from kidney cancer	Mortality rate (per 100 000 person-years)
Age at recruitment (first birth)
≤23	551 759	15 312 470.08	24	0.16
24–26	433 114	11 592 980.92	36	0.31
>26	307 589	8 074 795.00	35	0.43
Parity
1	157 207	4 170 772.33	15	0.36
2	564 727	15 124 112.33	44	0.29
3+	570 528	15 685 361.33	36	0.23
Marital status
Married	1 260 615	34 115 479.25	93	0.27
Not married	31 847	864 766.75	2	0.23
Years of schooling
≤9 years	722 518	19 850 938.17	41	0.21
>9 years	569 944	15 129 307.83	54	0.36
Birth place
Hospital/clinic	1 245 925	33 638 862.83	93	0.28
Home/other	46 537	1 341 383.17	2	0.15

The multivariate-adjusted HRs and 95% CIs are shown in table 2. An older age at first birth was associated with an increased kidney cancer risk. The adjusted HR was 1.88 (95% CI 1.10–3.19) for women who gave birth between 24 and 26 years and 2.52 (95% CI 1.44–4.40) for women who gave birth after 26 years, when compared with women who gave birth when younger than 23 years. A trend of increasing risk of kidney cancer was seen with increasing age at first birth (P for trend = 0.0011).

Table 2

Association between parity, age at first birth and hazard ratio of death from kidney cancer over a 32-year follow-up period

Variables	Crude HR (95% CI)	Multivariate-adjusted HRa (95% CI)
Age at recruitment (first birth)
≤23	1.00	1.00
24–26	2.06 (1.30–3.46)	1.88 (1.10–3.19)
>26	2.93 (1.74–4.93)	2.52 (1.44–4.40)
	P < 0.0001 for linear trend	P = 0.0011 for linear trend
Parity
1	1.00	1.00
2	0.81 (0.45–1.45)	0.88 (0.49–1.59)
3+	0.62 (0.34–1.14)	0.89 (0.47–1.67)
	P = 0.1008 for linear trend	P = 0.7648 for linear trend
Marital status
Married	1.00	1.00
Not married	0.85 (0.21–3.43)	0.92 (0.22–3.77)
Years of schooling
≤9 years	1.00	1.00
>9 years	1.78 (1.19–2.68)	1.39 (0.90–2.14)
Birth place
Hospital/clinic	1.00	1.00
Home/other	0.52 (0.13–2.10)	0.71 (0.17–2.90)

^aMutually adjusted.

After adjustment for age at first birth, marital status, years of schooling and birth place, the adjusted HR was 0.88 (95% CI 0.49–1.59) for women who had two children and 0.89 (95% CI 0.47–1.67) for women with three or more births, when compared with women who had given birth to only one child. Overall, we found no association between parity and kidney cancer risk.

Discussion

In this prospective cohort study, we found no association between parity and kidney cancer risk. Our finding is in agreement with previous studies,^17–23 but is not in agreement with other studies that reported a positive association between parity and kidney cancer risk.^6,13–16 Contrary to previous studies, in the present study, we found that risk of kidney cancer increased with increasing age at first birth after adjusting for parity.

This study has a number of strengths that deserve attention. First, in the event of a death in Taiwan, the decedent’s family is required to obtain a death certificate from the hospital or local community clinic, which then must be submitted to the household registration office. It is also mandatory to register all deaths at local household registration offices; therefore, the death registration is reliable and complete. Second, the complete population coverage and follow-up made possible by the national identification number has left the study without selection bias. Third, the number of study cohort is the largest published to date to examine the relationship between parity and age at first birth and kidney cancer risk.

Some potential limitations of this study need to be noted. First, Taiwan’s vital records and birth registration system cover only live births and excluded stillbirths and abortions. We were therefore unable to examine the possible role of gravidity on the kidney cancer risk. Second, by design, our study focused solely on mortality among parous women. We were unable to examine the possible role of nulliparity on the risk of kidney cancer. The generalizability of our findings is thus limited. Third, several studies have found that the use of oral contraceptives (OCs) was associated with a reduced risk of kidney cancer.^6,14,19 Other studies, however, have failed to find significant association between the use of OCs and kidney cancer.^12,16,22,23 Regarding hormone replacement therapy (HRT), previous studies have largely reported no association between HRT and kidney cancer risk^{6,12,14,16,20,23} We were unable to adjust for these two hormonal factors in the current study owing to the lack of available data. As the use of OC and HRT is low in Taiwan compared with Western countries,^24,25 the confounding effect resulting from these two factors should be small, if any exists at all. Fourth, smoking, obesity and hypertension are the most consistently accepted causal risk factors for kidney cancer.⁴ The prevalence rate of cigarette smoking is approximately 4.2% in Taiwanese women.²⁶ Given this low prevalence, the association between parity and age at first birth and kidney cancer in our study is unlikely to be affected remarkably by cigarette smoking. There is no information available on obesity for individual study subjects, and thus it could not be adjusted for in the analysis. However, obesity is common in women who have had several pregnancies. Hence, the actual risk reduction of kidney cancer in women with higher parity would have been larger than that shown if we had been able to adjust for obesity. There is no information available on hypertension for individual study subjects, and thus it could not be adjusted for in the analysis. However, there is no reason to believe that there would be any correlation between hypertension and parity and age at first birth. Nonetheless, the lack of information on obesity and hypertension should be regarded as a limitation of this study because obesity and hypertension are two major risk factors for kidney cancer. Finally, there is supporting evidence of an association between incidence of kidney cancer among workers exposed to degreasing agents and solvents (trichloroethylene) and to those in both iron and steel and dry cleaning and laundry work industries.^27,28 Asbestos has also been associated with elevated cancer mortality in those working with insulators and asbestos products.^29,30 Unfortunately, there is no information available on individual occupation, and thus it could not be adjusted for in the analysis. However, there is no reason to believe that there would be any correlation between this variable and age at first birth. Nevertheless, the problem of possible confounding from occupation should be evaluated. Age at first birth accounts for at least part of the socioeconomic differentials; age at first birth is considerably younger among those with lower levels of education. In this study, years of schooling was used as a proxy for socioeconomic status and was included as a control variable in the multivariate analysis. We therefore may have partially indirectly adjusted for the confounding effect resulting from occupational and environmental factors.

Pregnancy elevates serum estrogen levels approximately 100-fold.³¹ Increasing parity is associated with an overall increase in lifetime exposure of sex hormones (including estrogens). High doses of potent estrogens have been shown to induce renal cancers in the Syrian hamster.⁸ Estrogen and progesterone receptors have been found in normal and malignant renal cells.^10,11 Obesity, which provides a major source of estrogen in postmenopausal women,¹¹ has shown a stronger association with kidney cancer in females than in males.³² These findings support the pregnancy-associated hormonal changes, particularly high estrogen levels, may promote malignant changes by stimulating renal cell proliferation either directly or indirectly through paracrine growth factors.³³ However, the male predominance in incidence rates of kidney cancer and the observed reduction in risk in users of OCs in some studies^6,14,19 suggest that exposure to endogenous estrogen may be protective rather than a risk factor.⁶ Thus, if estrogens are associated with a reduced risk of kidney cancer, we would expect pregnancy to offer some protection from kidney cancer. As far as we know, ours is the only study to report that increased parity is associated with a tendency for decreased kidney cancer risk, but without statistical significance. The association between prolonged change in the estrogen and progesterone profile and RCC risk needs to be studied further.¹⁶

To our knowledge, this is the first study to find a significant positive association between age at first birth and kidney cancer risk. The reasons are unknown. It may be that a younger age at first birth played a protective role in kidney cancer risk through elevated levels of some hormones (including estrogen and progesterone) during pregnancy. Moreover, it has been found that age at menarche (and thus exposure to period estrogens’ stimulation) is related to age at which a woman delivers her first child.³⁴ Earlier exposure to regular menstrual cycles and the concomitant earlier increase in exposure to estrogens may protect against tumor initiation during this early life stage. Our finding of an increased risk of kidney cancer associated with older age at first birth may suggest that estrogen exposure is protective with respect to kidney cancer risk. However, because there is no evidence to date for a positive association between age at first birth and risk of death from kidney cancer, the possibility that this is a chance finding also needs to be considered. Clearly, more work will be needed before the influence of age at first birth on the risk of kidney cancer is understood.

To our knowledge, ours is the first prospective cohort study to report a protective effect of early age at first birth on the subsequent risk of death from kidney cancer. The reasons for these differences in findings are unknown. Only four prospective studies have examined the relationship between age at first birth and kidney cancer risk.^6,12,16,22 Most of previous studies used case–control designs.^{13–15,19,20,23} The main strength of this investigation is its prospective study design, which eliminates the possibility of recall bias. Also, the complete population coverage and follow-up made possible by the national identification number has left the study without selection bias. The mean age at baseline was 24.33 years in this study. Women included in our study tended to be younger than those in previous cohort studies (whose ages ranged from 30 to 69).^6,12,16,22 In addition, the number and type of potential confounders taken into account varied between studies. The relative risk estimate may therefore be different between studies. Also, information on exogenous hormone use (the use of OCs and HRT) and cumulative number of menstrual cycles (age at menarche and menopause) were not available in this study. Previous prospective cohort studies have included all different exposures in multivariate analyses. This analysis could help to better assess effect of each hormonal factor. Finally, age at first birth may be different in different countries and during different periods. The mean age at first birth was 24.33 in our cohort. This value was increased during the study period (ranged from 23.3 to 28.1 in 2006). Likewise, same temporal differences may exist for other countries.

Taiwan is a small island with a convenient communication network. It is believed that all kidney cancer cases had access to medical care. Mortality data rather than data on inpatient cases were used to assess the association between parity, age at first birth and kidney cancer in this study. The mortality of a disease is a function of its incidence and fatality. The 5-year survival rate over all stages for kidney cancer was 40–50%.³⁵ Deaths from kidney cancer may therefore be regarded as a reasonable indicator of the incidence of kidney cancer.

In conclusion, our study is the first to suggest that early age at first birth may confer a protective effect on the risk of kidney cancer. Despite substantial experimental evidence supporting the role of hormonal factors in the etiology of kidney cancer, the currently available epidemiologic evidence is inconsistent. More work will be needed to clarify the role of age at first birth in kidney cancer, and our finding warrants further study.

Funding

National Science Council, Executive Yuan, Taiwan (NSC-100-2314-B-037-023-MY2).

Conflicts of interest: None declared.

Key points

• Little is known about the etiology of kidney cancer. Although smoking, obesity and hypertension are accepted as risk factors, they can only explain half of the female cases of kidney cancer.

• Incidence rates of kidney cancer among females are generally about half of those among males; this may suggest a possible role of reproductive or hormonal factors in kidney cancer.

• Our study shows that risk of kidney cancer increases with increasing age at first birth; this finding suggests that reproductive factor may confer a protective effect on the risk of kidney cancer.