Parity and Oral Contraceptive Use in Relation to Ovarian Cancer Risk in Older Women

Abstract

Background

Several studies have suggested that the ovarian cancer risk reductions associated with parity and oral contraceptive use are weaker in postmenopausal than premenopausal women; yet little is known about the persistence of these reductions as women age. This question gains importance with the increasing numbers of older women in the population.

Methods

We addressed the question using data from three large US cohort studies involving 310,290 white women aged 50+ years at recruitment, of whom 1815 developed subsequent incident invasive epithelial ovarian cancer. We used Cox regression, stratified by cohort, to examine age-related trends in the hazard ratios per full-term pregnancy and per year of oral contraceptive use.

Results

The parity-associated risk reductions waned with age (P < 0.001 for trend in hazard ratio with increasing age), particularly among women aged 75 years or more, for whom we observed no association with parity. However we observed no such attenuation in the oral-contraceptive-associated risk reductions (P = 0.79 for trend in hazard ratio with increasing age).

Conclusion

These findings suggest that prior oral contraceptive use is important for ovarian cancer risk assessment among women of all ages, while the benefits of parity wane as women age.

Impact

This information, if duplicated in other studies, will be useful to preventive counseling and risk prediction, particularly for women at increased ovarian cancer risk due to a personal history of breast cancer or a family history of ovarian cancer.

INTRODUCTION

A large and consistent body of evidence indicates that increased parity and duration of oral contraceptive (OC) use are associated with reduced risk of invasive epithelial ovarian cancer (EOC), a malignancy with a 44% five-year survival rate in the US (1). Specifically, the data suggest that each full-term pregnancy (FTP) confers a risk reduction of approximately 19% (2), and risks among women with three or more years of OC use are 30–50% lower than those of women with little or no use (2, 3).

The available data also suggest that these associations are weaker in postmenopausal than premenopausal women (4–7). However this observation is based largely on women aged less than 65 years, and little is known about the longer-term effects of pregnancy and OC use among women as they age. This question has important clinical and public health significance, as more than 80% of all EOCs now occur after age 50 years (8), and this age group represents an increasing proportion of women in developed countries. Thus the burden of this highly fatal cancer will continue to grow as population distributions of women become more heavily skewed toward older ages, and accurate assessment of women’s risks is critical for development of cost-effective preventive strategies.

Here we assess the existence and extent of age-related trends in the effects of parity and OC use in older women, using data from three large US cohort studies involving 310,290 white women aged 50 years or more at recruitment, of whom 1815 developed subsequent incident invasive EOC. The three studies were the NIH-AARP Diet and Health Study (hereafter called the AARP study), the California Teachers Study (CTS), and the Women’s Health Initiative (WHI).

MATERIALS AND METHODS

Study population

The AARP Study, established in 1995–96, included 339,669 male and 222,732 female AARP members aged 50–71 years and residing in eight regions; California, Florida, Louisiana, New Jersey, North Carolina, Pennsylvania, and the metropolitan areas of Atlanta and Detroit. The CTS, established in 1995–96, included 133,479 female California public school professionals (active or retired) aged 22 years or more at recruitment. The WHI, established in 1993–98 and comprising longitudinal data from a randomized intervention trial and an observational study, includes 161,808 postmenopausal women aged 50–79 years, as identified by 40 US study sites. Details about the studies’ designs and characteristics have been described elsewhere (9–11).

Participants were potentially eligible for the current analysis if at recruitment they reported that they were white, aged 50 years or more, without prior invasive or noninvasive ovarian cancer diagnosis and without prior bilateral oophorectomy. A total of 318,709 participants met these criteria (155,636 from AARP, 50,772 from CTS, and 110,407 from the WHI trial and observational cohorts). Of these, 310,290 (154,045 from AARP, 47,365 from CTS and 108,880 from WHI) provided complete information on parity and duration of OC use, and were included in the analysis. Among the 108,880 eligible WHI subjects, 45,939 (42%) were trial participants. Of these, 16,208 participated in the Hormone Replacement Therapy (HRT) Trial and the remaining 29, 731 participated in one or both of the two diet trials (Diet Modification Trial and Calcium and Vitamin D Trial). Among the 16,208 HRT Trial participants, 10,373 also participated in one or both of the two dietary trials. We focused on parity and OC use because the three cohorts lacked comparable information on other covariates associated with ovarian cancer (e.g., tubal ligation, prior hysterectomy without bilateral oophorectomy, and duration of menopausal hormone therapy).

Ovarian cancer ascertainment

The AARP and CTS investigators identified incident ovarian cancer cases via linkages with cancer registries in the studies’ recruitment areas, while the WHI investigators did so using questionnaires mailed semi-annually during active intervention for clinical trial participants and annually otherwise. All three studies monitored participants’ vital statuses using the U.S. Social Security Administration Death Master File or the National Death Index. The present analysis includes invasive EOC’s diagnosed by December 31, 2006 (AARP), December 31, 2011 (CTS) and August 19, 2009 (WHI). EOC histology was available from the cancer registries for the AARP Study and CTS. In the WHI, all reported ovarian cancers were documented with medical records and pathology reports obtained at each clinic site and centrally reviewed and coded according to SEER standards (12).

Statistical methods

We performed left-truncated, right-censored survival analyses using Cox proportional hazards regression models stratified by cohort, with age as the underlying time variable. Each participant’s time-at-risk was left-truncated at the age she completed her baseline questionnaire, and right-censored at her age at first occurrence of the following events: last contact, death from any cause; diagnosis of any ovarian cancer (in-situ, low malignant potential, invasive epithelial, nonepithelial); bilateral oophorectomy subsequent to baseline questionnaire; and, for AARP and CTS, departure from the cohort catchment area (total US-SEER region for AARP and California for CTS).

All regressions included parity (coded as categorical or as ordinal variable), years of oral contraceptive use, (coded as categorical or as continuous variable) and year of birth (coded as continuous variable). We lacked data on recency of OC use. We used likelihood ratio statistics to evaluate age-related trends in the hazard-ratios (HRs) per full-term pregnancy and per 5-years of OC use. For example, we tested the null hypothesis of no age-related trend in parity-specific HRs by comparing the likelihood of the basic model that includes parity as ordinal variable (adjusted for OC use and birth year as continuous variables) with that of an expanded model that also includes terms for the product of parity and an ordinal variable for the three age-at-risk categories 50–64, 65–74 and 75+ years. We also used likelihood ratio statistics to evaluate age-related heterogeneity in EOC histology and cohort-heterogeneity in age-specific hazard ratios for parity and OC use. Analyses were implemented using SAS statistical software 9.4 (SAS Institute, Cary, NC). All tests of statistical significance are two-sided.

This research was approved by the Institutional Review Boards at the three study sites and at Stanford University School of Medicine.

RESULTS

Table 1 presents selected characteristics of the three cohorts, and the distributions of their eligible participants according to year of birth, age at recruitment, parity and years of OC use. Participants contributed, on average, 10.5 person-years at risk (PYRs) with overall standard deviation (SD) given by 3.3 PYRs. Corresponding cohort-specific values were 9.8 (SD = 2.2) for AARP, 13.0 (SD = 4.7) for CTS and 10.3 (SD = 3.3) for WHI, during which a total of 1815 EOCs were diagnosed. The crude incidence rates (CIRs) are higher than the US SEER rates for white women of similar ages, a difference that reflects the requirement here that time at risk of ovarian cancer be contributed only by participants with at least one intact ovary. (We checked this assertion by applying the SEER rates to the person-years at risk contributed by an expanded AARP cohort supplemented by women who reported a prior bilateral oophorectomy, and found that the expected number of cases was similar to the number observed in the cohort.) As expected, the CIRs decreased with increasing year of birth, increasing number of FTPs, increasing years of OC use, and decreasing age at recruitment.

Table 1.

Distribution of Participants, Person-years at Risk (PYR) and Invasive Epithelial Ovarian Cancers (EOCs), by Study Site

		AARP				CTS				WHI				Total
		N	PYRs	EOCs	CIRb	N	PYRs	EOCs	CIR	N	PYRs	EOCs	CIR	N	PYRs	EOCs	CIR
All participants		154,045	1,508,720	836	55.4	47,365	617,526	380	61.5	108,880	1,120,878	599	53.4	310,290	3,247,124	1815	55.9
Year of birth	<1930	44,444	427,330	305	71.4	17,614	204,446	171	83.6	40,341	394,481	227	57.5	102,399	1,026,261	703	68.5
	1930–39	80,326	789,177	406	51.5	15,102	207,323	125	60.3	47,158	494,275	285	57.7	142,586	1,490,773	816	54.7
	1940+	29,275	292,213	125	42.8	14,649	205,757	84	40.8	21,381	232,122	87	37.5	65,305	730,090	296	40.5
Age (yrs) at recruitment	50–64	100,651	995,395	473	47.5	28,384	394,815	192	48.6	61,277	651,837	323	49.6	190,312	2,042,047	988	48.4
	65–74	53,394	513,325	363	70.7	11,448	149,893	131	87.4	40,456	404,786	232	57.3	105,298	1,068,004	726	68.0
	75+	--	--	--		7,533	72,818	57	78.3	7,147	64,255	44	68.5	14,680	137,073	101	73.7
Number of FTPsa	0	23,838	233,185	162	69.5	9,775	125,271	92	73.4	12,369	127,660	77	60.3	45,982	486,116	331	68.1
	1–2	56,154	552,485	318	57.6	21,675	282,897	172	60.8	35,900	370,582	215	58.0	113,729	1,205,964	717	59.5
	3–4	57,500	562,992	292	51.9	13,895	182,942	108	59.0	44,318	457,568	230	50.3	115,713	1,203,502	630	52.4
	5+	16,553	160,058	64	40.0	2,020	26,416	8	30.3	16,293	165,068	77	46.7	34,866	351,542	149	42.4
Yrs OC use	<1	91,827	896,198	566	63.2	26,193	324,358	252	77.7	72,027	729,214	426	58.4	190,047	1,949,770	1244	63.8
	1–4	27,529	270,681	131	48.4	8,170	113,004	56	49.6	15,821	168,234	73	43.4	51,520	551,920	260	47.1
	5–9	19,536	192,573	89	46.2	7,085	98,058	39	39.8	10,752	114,780	58	50.5	37,373	405,410	186	45.9
	10+	15,153	149,268	50	33.5	5,917	82,106	33	40.2	10,280	108,650	42	38.7	31,350	340,024	125	36.8

^aFTP = full-term pregnancy

^bCIR = crude incidence rate (# EOCs per 100,000 PYRs)

Table 2 shows that most EOCs were classified as serous cancers (49.7% serous, versus 22.1% non-serous and 28.2% other/unspecified EOCs cancers). The proportion of serous EOCs among those of known histology did not vary significantly with age at risk (${\chi }_2^2=3.19$, P = 0.20) for test of heterogeneity among the three age groups (data not shown).

Table 2.

Distribution of epithelial ovarian cancer (EOC) cases according to histological subtype, by cohort

	AARP N=836		CTS n-380		WHI N=599		Total N=1815
	N	%	N	%	N	%	N	%
All cases	836	46.0	380	21.3	599	33.0	1815	100.0
Serous	436	52.2	169	44.5	297	49.6	902	49.7
Endometrioid	67	8.0	44	11.6	59	9.9	170	9.4
Mucinous	36	4.3	13	3.4	21	3.5	70	3.9
Clear Cell	26	3.1	20	5.3	30	5.0	76	4.2
Undifferentiated/Unclassified	271	32.4	134	35.2	192	32.0	597	32.8

Table 3 shows EOC hazard ratios corresponding to parity and OC duration, for three age-at-risk categories: 50–64, 65–74 and 75+ years. The table shows clear patterns of decreasing EOC risk with increasing parity for women aged less than 75 years, with statistically significant risk reductions of 12% per full-term pregnancy (FTP) among women aged < 65 years, and 8% per FTP among women aged 65–74 years. However these patterns are not evident among women aged 75+ years. Indeed there is no decrease in the EOC hazard ratio with increasing FTPs (P < 0.001 for interaction between parity and age at risk).

Table 3.

Parity and Oral Contraceptive (OC) Use in Relation to Invasive Epithelial Ovarian Cancer (EOCs) Incidence, by Age at Risk

	Age (years) at Risk
	50 – 64					65 – 74					75 +
	PYRsa	EOCs	CIRa	HRb	95% CI	PYRs	EOCs	CIR	HR	95% CI	PYRs	EOCs	CIR	HR	95% CI
FTPc			--	--	--			--	--	--			--	--	--
0	209428.3	116	55.39	1.00	REF	194582.2	154	79.14	1.00	REF	82104.3	61	74.30	1.00	REF
1–2	523337.8	206	39.36	0.93	0.75–1.16	485899.1	234	48.16	0.84	0.69–1.02	196728.6	100	50.83	1.01	0.75–1.37
3–4	391339.8	173	44.21	0.69	0.54–0.89	587899.6	367	62.43	0.74	0.61–0.89	224262.1	166	74.02	0.98	0.72–1.32
5+	82103.5	34	41.41	0.38	0.22–0.63	194164.4	135	69.53	0.56	0.43–0.73	75274.3	69	91.66	0.92	0.62–1.36
Trend per FTP				0.88	0.83–0.93				0.91	0.88–0.95				1.00	0.95–1.06
	Pinteraction = <0.001 d
Yrs OC Use
<1	508337.6	248	48.79	1.00	REF	963115.4	650	67.49	1.00	REF	478316.4	346	72.34	1.00	REF
1–4	302470.8	125	41.33	0.85	0.68–1.06	208348.1	116	55.68	0.87	0.71–1.06	41101.4	19	46.23	0.65	0.41–1.03
5–9	225398.2	94	41.70	0.86	0.67–1.09	151149.4	76	50.28	0.80	0.63–1.02	28862.5	16	55.44	0.77	0.46–1.27
10+	170002.8	62	55.39	0.73	0.55–0.97	139932.4	48	79.14	0.53	0.39–0.71	30089.0	15	74.30	0.70	0.42–1.18
Trend per 5 yrs use				0.88	0.80–0.98				0.82	0.74–0.91				0.85	0.71–1.02
	Pinteraction = 0.79e

^aPYRs = person-years at risk; CIR = crude incidence rate (# EOCs per 100,000 PRYs)

^bHR = hazard ratio from Cox regression with baseline hazard stratified by cohort. Parity HRs are adjusted for birth year and OC use, and OC HRs are adjusted for birth year and parity

^cFTP = full-term pregnancy

^dlikelihood ratio ${\chi }_2^2$ test of hypothesis that risk per FTP does not vary with age at risk

^elikelihood ratio ${\chi }_2^2$ test of hypothesis that risk per 5 years of OC use does not vary with age at risk

In contrast, the lower EOC risk associated with duration of OC use did not vary with attained age (P = 0.79 for interaction). The risk reductions per five years of OC use ranged from 12% to 18% in the three age groups, with no evidence for differences among the attained age groups, and with an overall reduction of 14% (95% confidence interval: 8–20%) among all ages combined. Indeed, even in the highest age group, despite the relatively few person-years contributed by women with a history of OC use, we nevertheless observed a statistically significant risk reduction among OC users relative to nonusers, with only 50 ovarian cancer cases observed among users compared to 72.4 cases expected (P < 0.004). Overall, increasing duration of OC use was associated with decreasing risk: a model involving four duration categories provided better fit (P = 0.01) than one involving just two categories (use for less than or more than one year). These findings were similar when we restricted analysis to serous and to nonserous EOCs (data not shown). Restriction of analysis to EOC cases with specific nonserous histologies was precluded by the sparsity of these cases, as seen in Table 2. Finally, we found no evidence for inter-cohort heterogeneity in the hazard ratios associated with parity (nulliparous vs. parous; P = 0.39) or duration of OC use (less than one year vs. one or more years; P = 0.71).

DISCUSSION

We used data from Caucasian participants of three large prospective cohort studies to examine how the risk reductions associated with parity and OC use change as women age. We found age-related differences in the protective effects of parity, with significantly reduced parity-associated hazard ratios among women less than 75 years, but no effect at later ages. In contrast, we did not find evidence that the risk reductions associated with OC use wane with age among older women.

Interpreting these findings and their implications for the etiology and pathogenesis of EOC is challenging. Since the lag between last exposure and age at risk is likely to be greater for pregnancy than for OC use (which may end only at menopause), the observed lack of age-related trend in the effects of OC use could reflect its recency relative to that of pregnancy. Another issue is that the HR associated with OC use may be attenuated among women aged 50–60 years by their use of menopausal hormone therapy, which is positively correlated with OC use (13).

The observed temporal waning of the effects of pregnancy is consistent with the hypothesis that anovulation reduces a woman’s ovarian cancer risk by reducing her burden of mutated epithelial cells at risk of conversion to malignancy. These mutations may reflect some ovulatory consequence (such as rupture of the ovarian epithelium or cellular exposure to follicular fluid or to hormonal fluctuations). The long-term benefits of anovulation (i.e, reducing the burden of premalignant cells) may be attenuated by the occurrence of additional somatic mutations occurring as part of normal ovarian tissue aging (14, 15). The attenuation may be greater for pregnancy than OC use because pregnancies occurred in the more distant past. Alternatively, the attenuation may be more obvious for pregnancy than OC use because a year of pregnancy-induced anovulation confers a greater risk reduction at all ages than one due to OC use, possibly due to transient hormonal changes during pregnancy that induce apoptosis of existing premalignant cells (16).

The present combined analysis of large prospective cohorts has several advantages. Unlike retrospective case-control studies comparing prior oral contraceptive use as recalled by EOC cases with those of disease-free controls, the cohort design ascertains reproductive history at cohort entry relatively soon after menopause and before the onset of disease, and thus avoids potential long-term recall bias. However the combined analysis of large cohorts has weaknesses. In the present study, for example, the questionnaire data was too limited to allow evaluation of such factors as recency of anovulatory exposures to age at risk. Another limitation is the sparsity of OC-users who subsequently developed EOC at ages 75+ years (n = 50). These limitations emphasize the need for replication of the current observations in other large cohorts of older women.

In summary, the current data suggest that the protective effects of OC use persist for decades after the menopause, while the protection afforded by increased parity wanes in older women, particularly those aged 75 years of more. This information, if duplicated in other studies, will be useful to preventive counseling and risk prediction, particularly for women at elevated ovarian cancer risk due to a personal history of breast cancer or a family history of ovarian cancer.

ABBREVIATIONS

AARP

American Association of Retired Persons

CI

confidence interval

CIR

crude incidence rate

CTS

California Teachers Study

EOC

epithelial ovarian cancer

FTP

full-term pregnancy

HR

hazard ratio

NIH

National Institutes of Health

OC

oral contraceptive

PYRs

person-years

WHI

Women’s Health Initiative