Abstract
Objective
Pregnancies reduce the risk of ovarian cancer and, among multiparous women, levels of circulating progesterone might be higher during pregnancies with wider birth spacing. We hypothesized that childbirth with wider birth spacing might reduce maternal risk of invasive epithelial ovarian cancer more than births with narrower spacing.
Methods
We conducted a case-control study nested in a nationwide cohort of Swedish women from 1961 to 2001. We selected five individually age-matched controls for each case of invasive epithelial ovarian cancer and analysis for the effect of birth spacing was performed for 5,341 cases and 29,047 controls. We applied unconditional logistic regression analyses adjusting for age, ages at childbirth, educational level, area of residence, and gender of offspring.
Results
Relative risk of invasive epithelial ovarian cancer associated with each one-year increase in average birth spacing is 1.00 (95% CI=0.98–1.01) among all women and 0.99 (0.98–1.01) among those born before 1935 and less likely to have used oral contraceptives. Further analyses on the biparous and triparous women did not find a consistent association between birth spacing and the risk of ovarian cancer.
Conclusions
Birth spacing is unlikely to be a major determinant underlying the protective effects of childbirth on ovarian cancer risk.
Keywords: Birth spacing, Invasive epithelial ovarian cancer, Progesterone
Introduction
Both case-control [1–10] and cohort [11] epidemiologic studies have revealed consistently that parous women are at a reduced risk of epithelial ovarian cancer compared with nulliparous women and the risk reduction magnifies with increasing parity. However, etiological mechanisms that underlie the protective effect of childbirth remain to be explored [2–4, 12].
Increased production of progesterone during pregnancy might contribute to the protective role of childbirth in epithelial ovarian carcinogenesis [13]. In experimental studies, progesterone inhibits cell proliferation and induces apoptosis in malignant human ovarian cells [14–16]. However, no epidemiologic study has yet directly evaluated the effect of pregnancy progesterone levels on epithelial ovarian cancer. Instead, the association with certain reproductive factors that reflect circulating levels of progesterone during pregnancy has been examined to lend indirect support and several epidemiologic studies have shown a greater risk reduction of epithelial ovarian cancer for the first birth than for subsequent births [2–5, 7–10]. These findings are compatible with the physiological observation that first-born infants have higher progesterone levels in umbilical cord blood than later-borns [17].
Maccoby et al [17] found that, among the later-born infants, progesterone levels in umbilical cord blood increased with wider birth spacing, and was closer to or even higher than first-borns. They also found that this phenomenon is more noticeable in later-born male offspring. There was a linear relation between birth spacing and progesterone levels among later-born male offspring: those with birth spacing of 5 years and longer had a 1.6-fold higher progesterone level (1.090±0.536 μg/ml) than those with a spacing of less than 2 years (0.681±0.220 μg/ml). To date, only one study has assessed the association between birth spacing and maternal ovarian cancer risk [5]. That study found no association between ovarian cancer risk and average birth spacing among women with two or more children.
Using a large population-based cohort in Sweden we reexamined the possible association between birth spacing and invasive epithelial ovarian cancer risk. We analyzed the time interval between consecutive childbirths separately for biparous and triparous women as well as the average spacing for women with two or more children.
Materials and methods
Study population
Members of the study cohort were identified in the Swedish Fertility Register, a nationwide population-based register including more than 3.4 million female resident citizens of Sweden. It contains information on number (including nulliparity), gender, and dates of live births for women who were born from 1925 and thereafter. In general, the quality of the information is considered high, though number of childbirths might be under- or over-reported for women born between 1925 and 1929 [18]. Information on date of birth for biological and adopted children born between 1943 and 1960 was collected retrospectively at the 1960 Census. From 1961 only biological children are included in the Fertility Register, to which all new births are annually added from vital statistics records. Vital and emigration status of women in the Fertility Register is updated annually by linkage of the National Population Register using the individually unique national registration number assigned to all individuals who reside in Sweden [18].
Case-control sampling
We used a nested case-control sampling design to allow more efficient analyses. Incident cases of ovarian cancer (International Classification of Diseases, seventh revision [ICD7], code 175.0) occurring from 1961 to 2001 were ascertained from the records of the Swedish National Cancer Register. Since 1958, the Cancer Register has received reports about all newly diagnosed malignant tumors from both the physician who made the diagnosis and the pathologist/cytologist who confirmed the diagnosis [19]. The completeness of reporting cancer to the Cancer Registry is close to 100% [19]. Each case is assigned a pathological anatomic diagnosis (PAD) code and information about the diagnostic basis. We included in the analysis only histologically verified invasive epithelial ovarian cancer (PAD codes 096 for adenocarcinoma, 196 for undifferentiated carcinoma, and 146 for squamous-cell tumor) [4].
For each case subject, five comparison control subjects were randomly selected from cohort members listed in the Fertility Register. Using incidence density sampling, control subjects were individually matched by birth year with the index case, were alive in Sweden at least to the date of the diagnosis for the index case, and had not been previously diagnosed with ovarian cancer before this date. For both case and control subjects, we included only pregnancies before the index case's date of diagnosis in the analyses. Compared with singleton birth pregnancy, multiple birth pregnancy is associated with a lower risk of epithelial ovarian cancer [20] as well as with higher production of progesterone [21]. Thus, women who had ever experienced a multiple birth and their corresponding cases and controls were excluded and 10,053 cases and 49,475 controls remained for the analysis.
Analysis for birth spacing was conducted for 34,388 women with two or more parities (5,341 cases and 29,047 controls), including 19,810 biparous (3,313 cases and 16,497 controls) and 9,871 triparous women (1,421 cases and 8,450 controls), who had information on date (year and month) of each childbirth.
Analyses
The exposure of interest is birth spacing among parous women who had two or more singleton births. Average birth spacing (months) was calculated by dividing spacing between the last and the first delivery by (number of pregnancies-1) [5]. For biparous and triparous women, spacing (months) between consecutive childbirths was calculated for each subject. We also grouped these women into six categories of spacing (<12 months, 12–17 months, 18–23 months, 24–47 months, 48–71 months, and 72 months or more).
The information on age at diagnosis or enrollment, parity, date (year and month) of each childbirth, educational level closest to age 40, area of residence closest to age 40, and gender of offspring was collected from the Fertility Register. Descriptive statistics on these characteristics of study cohort members were calculated. Unconditional logistic regression analysis was conducted to estimate a relative risk (odds ratio) of invasive epithelial ovarian cancer associated with the characteristics with its 95% confidence interval (CI). We presented relative risks for spacing categories using spacing of 24–47 months as a comparison group (reference) as well as for spacing in years as a continuous variable.
We examined the effect of average birth spacing and spacing between consecutive childbirths on the maternal risk of invasive epithelial ovarian cancer. For triparous women, we also assessed simultaneously the effect of birth spacing between the first and the second and that between the second and the third childbirth. To minimize the possible confounding effect of oral contraceptive use on the association between birth spacing and invasive epithelial ovarian cancer risk, we conducted further analyses with data restricting to women born before 1935 who were less likely to have used oral contraceptives than women born more recently. SAS procedures (SAS 9.1, SAS Institute, Cary, NC) were used to conduct the analyses.
Results
Table 1 presents the distribution of age, education, residence area, and childbirth between controls and cases of invasive epithelial ovarian cancer included in the analysis. Cases and controls had similar distributions on age, average birth spacing, and birth cohort, while cases tended to have lower parities, to have resided in rural area around age 40, and to have <9 years of education than the controls.
Table 1.
Characteristics of the study subjects (n=59,528).
| Variables | Cases (n=5,341) | Controls (n=29,047) |
|---|---|---|
| Age (years, mean±SD) | 52.7±10.1 | 52.2±10.3 |
| Parity (n, %) | ||
| 2 | 3,313 (62.0) | 16,497 (56.8) |
| 3 | 1,421 (26.6) | 8,450 (29.1) |
| 4 | 442 (8.3) | 2,793 (9.6) |
| 5 or more | 165 (3.1) | 1,307 (4.5) |
| Average birth spacing (years, mean±SD) | ||
| Women with two parities | 4.4±2.7 | 4.4±2.7 |
| Women with three parities | 4.3±1.8 | 4.3±1.9 |
| Women with four parities | 3.8±1.4 | 3.9±1.4 |
| Women with five or more parities | 3.2±1.0 | 3.2±1.0 |
| Education level (n, %) | ||
| <9 years | 2,655 (51.2) | 13,942 (48.9) |
| >=9 years | 2,527 (48.8) | 14,550 (51.1) |
| Area of residence (n, %) | ||
| Urban | 2,776 (52.0) | 15,660 (53.9) |
| Rural | 2,565 (48.0) | 13,387 (46.1) |
| Birth cohort (n, %) | ||
| <1935 | 2,524 (47.3) | 13,933 (48.0) |
| >=1935 | 2,817 (52.7) | 15,114 (52.0) |
Table 2 explores the relation between average birth spacing and risk of invasive epithelial ovarian cancer. A non-significant inverse association was present among women who were born before 1935; multivariate RRs (95% CI) of invasive epithelial ovarian cancer were 1.16 (0.51–2.68) for average birth spacing less than 12 months and 0.94 (0.83–1.06) for 72 months and longer compared with spacing between 24 and 47 months. Overall, no significant association with average birth spacing was observed (Table 2).
Table 2.
The association between average birth spacing and the risk of invasive epithelial ovarian cancer (n=34,388)1
| Birth year < 1935 |
||||
|---|---|---|---|---|
| Average birth spacing (months)2 | Cases/Controls | Crude RR (95% CI) | Adjusted RR3 (95% CI) | Adjusted RR3 (95% CI) |
| <12 | 12/59 | 1.12 (0.60–2.09) | 0.97 (0.52–1.80) | 1.16 (0.51–2.68) |
| 12–17 | 175/912 | 1.06 (0.90–1.25) | 0.98 (0.82–1.15) | 1.00 (0.78–1.29) |
| 18–23 | 357/2,067 | 0.95 (0.85–1.08) | 0.94 (0.83–1.06) | 0.85 (0.70–1.03) |
| 24–47 | 2,447/13,516 | 1.00 (reference) | 1.00 (reference) | 1.00 (reference) |
| 48–71 | 1,435/7,689 | 1.03 (0.96–1.11) | 1.00 (0.93–1.08) | 0.97 (0.87–1.08) |
| >=72 | 915/4,804 | 1.05 (0.97–1.14) | 0.96 (0.88–1.04) | 0.94 (0.83–1.06) |
| As a continuous variable 4 | 1.01 (0.99 – 1.02) | 1.00 (0.98 – 1.01) | 0.99 (0.98 – 1.01) |
Including subjects with parity >=2 and without missing data on any birth spacing.
(Age at last pregnancy – age at first pregnancy)/(number of pregnancies – 1)
Relative risk (RR) adjusted for age, number of pregnancies, age at first childbirth, education level, and area of residence.
Average spacing (in months) was fitted in the model as a continuous variable and its coefficient was multiplied by 12 before exponentiation to obtain RR associated with each one-year increase in birth spacing.
We next examined for biparous and triparous women separately the effect of birth spacing between consecutive childbirths on invasive epithelial ovarian cancer risk (Table 3). The analysis of 8,764 biparous women born before 1935 (1,493 cases and 7,271 controls) did not show a consistent association between birth spacing and the risk of ovarian cancer. Among triparous women born before 1935 (660 cases and 4,107 controls), a weak inverse association with spacing between the first and second childbirths was observed. However, analyses on the spacing between the second and third childbirths did not find a consistent association between birth spacing and the risk of ovarian cancer (Table 3).
Table 3.
The association between birth spacing and the risk of invasive epithelial ovarian cancer in biparous and triparous women
| Birth year < 1935 |
||||
|---|---|---|---|---|
| Birth spacing (months) | Cases/Controls | Crude RR (95% CI) | Adjusted RR (95% CI) | Adjusted RR (95% CI) |
| Biparous women (n=19,810)1 | ||||
| <12 | 12/59 | 1.00 (0.54–1.86) | 0.94 (0.51–1.76) | 1.10 (0.48–2.55) |
| 12–17 | 140/740 | 0.93 (0.77–1.12) | 0.91 (0.75–1.10) | 0.76 (0.56–1.03) |
| 18–23 | 257/1,368 | 0.92 (0.80–1.07) | 0.93 (0.80–1.07) | 0.81 (0.63–1.03) |
| 24–47 | 1,485/7,299 | 1.00 (Reference) | 1.00 (Reference) | 1.00 (Reference) |
| 48–71 | 782/3,915 | 0.98 (0.89–1.08) | 0.96 (0.87–1.05) | 0.92 (0.80–1.06) |
| >=72 | 637/3,116 | 1.01 (0.91–1.11) | 0.95 (0.85–1.05) | 0.90 (0.78–1.05) |
| As a continuous variable 3 | 1.00 (0.99 – 1.02) | 1.00 (0.98 – 1.01) | 0.99 (0.98 – 1.01) | |
| Triparous women (n=9,847)2 | ||||
| Interval between 1st and 2nd childbirth | ||||
| <12 | 8/75 | 0.64 (0.31–1.33) | 0.60 (0.29–1.26) | 1.48 (0.60–3.66) |
| 12–17 | 160/823 | 1.17 (0.97–1.41) | 1.15 (0.95–1.39) | 1.39 (1.07–1.80) |
| 18–23 | 198/1,244 | 0.95 (0.80–1.12) | 0.95 (0.80–1.13) | 0.95 (0.73–1.23) |
| 24–47 | 697/4,136 | 1.00 (Reference) | 1.00 (Reference) | 1.00(Reference) |
| 48–71 | 223/1,332 | 1.00 (0.85–1.18) | 0.97 (0.82–1.14) | 0.96 (0.76–1.21) |
| >=72 | 132/819 | 0.98 (0.80–1.19) | 0.93 (0.76–1.14) | 0.92 (0.69–1.23) |
| As a continuous variable 3 | 1.00 (0.97 – 1.02) | 0.99 (0.96 – 1.02) | 0.98 (0.94 – 1.02) | |
| Interval between 2nd and 3rd childbirth | ||||
| <12 | 2/28 | 0.43 (0.10–1.83) | 0.42 (0.10–1.78) | 1.37 (0.30–6.34) |
| 12–17 | 66/438 | 0.91 (0.69–1.20) | 0.91 (0.69–1.20) | 1.09 (0.74–1.61) |
| 18–23 | 94/697 | 0.81 (0.64–1.03) | 0.81 (0.64–1.03) | 0.84 (0.59–1.19) |
| 24–47 | 426/2,577 | 1.00 (Reference) | 1.00 (Reference) | 1.00(Reference) |
| 48–71 | 359/2,048 | 1.06 (0.91–1.24) | 1.05 (0.90–1.22) | 1.06 (0.84–1.34) |
| >=72 | 471/2,641 | 1.08 (0.94–1.24) | 1.04 (0.90–1.20) | 1.05 (0.85–1.29) |
| As a continuous variable 3 | 1.02 (1.00 – 1.03) | 1.01 (0.99 – 1.03) | 1.01 (0.98 – 1.04) | |
Relative risk (RR) adjusted for age, age at first childbirth, education level, area of residence, and gender of the 1st and 2nd infants.
RR adjusted for age, age at first childbirth, education level, area of residence, gender of the 1st, 2nd, and 3rd infants. The effect estimates for the interval between the 1st and 2nd childbirth and that between 2nd and 3rd childbirth were mutually adjusted for in the same model. 24 subjects had missing data on one or more variables included in the analysis.
Birth spacing (in years) was fitted in the model as a continuous variable and its coefficient was exponentiated to obtain RR associated with each one-year increase in birth spacing.
To explore whether year since delivery of the last child modifies the mostly null associations with birth spacing for the biparous and triparous women, analyses for Table 3 were repeated separately among those with less than 15 years since delivery of the last child and among those with 15 years or more. Patterns of the associations similar to that observed in Table 3 were found for the two subgroups (data not shown).
Discussion
Several hypotheses regarding the etiology of epithelial ovarian cancer have been suggested, but none provide a comprehensive explanation for all epidemiological observations on factors underlying the development of this tumor [23, 24]. According to the incessant ovulation hypothesis, ovulation causes chronically repeated traumas to ovarian epithelium leading to mutation and malignant transformation of epithelial cells [25]. Another prevailing hypothesis postulates that increased gonadotropin secretion increases estrogen production which stimulates epithelial proliferation and thus play a role in tumorigenesis [26]. To explain the protective mechanism of childbirth against ovarian cancer, the physiologic conditions of both hypotheses are suppressed during pregnancy and thus consequently childbirth appears to contribute to reducing epithelial ovarian cancer risk [23]. We have proposed that a pregnancy may clear pre-malignant epithelial cells of the ovary [4]. One potential mechanism of this clearance effect is the markedly increased synthesis of progesterone during gestation [5]. Findings on a reduced risk of ovarian cancer associated with twin pregnancies are considered more compatible with the clearance hypothesis and less consistent with the incessant ovulation and gonadotropin hypotheses [24].
Epidemiologic studies on the direct relation between endogenous progesterone levels during childbearing and subsequent occurrence of ovarian cancer are limited. However, different approaches have provided supportive evidence for a protective effect of progesterone on ovarian cancer. A case-control study found that women who used oral contraceptives containing high-potency progesterone were at a lower risk of ovarian cancer than those who used oral contraceptives of low progesterone potency [27]. Experimental studies have provided evidence of apoptotic effects of progesterone on ovarian epithelium as its underlying mechanism against cancer [14, 15, 28]. Based on findings indicating that levels of circulating progesterone increase with longer time between births, the present study tested whether the wider birth spacing for a given parity reduces the risk of ovarian cancer. With repeated pregnancies and close spacing between births, time may be too short for the recovery of certain maternal physiological processes involved in gestation and, as a result, the placenta may not be as active in producing progesterone [17].
Strengths of our study include the population-based nature of the study, the large sample size, and histologically verified cases. With the large number of subjects, analyses of data from this study have been able to identify the postpartum period when the risk of maternal ovarian cancer is at its lowest [18] and examine the effect of offspring gender on the risk of maternal ovarian cancer [29]. There are potential limitations. Information was unavailable in this study on the use of oral contraceptives and on the incomplete pregnancy outcomes such as abortions. Oral contraceptives may markedly reduce risk of ovarian cancer [30] and their use may be related to number of spacing of pregnancies. To minimize the potential confounding effect of oral contraceptives, we conducted separate analyses among women born before 1935 because oral contraceptive use was limited in the older cohort [30]. Since an incomplete pregnancy after the first birth does not influence epithelial ovarian cancer risk [22], the association between birth spacing and ovarian cancer among women with two or more infants would unlikely be confounded by incomplete pregnancies. Another limitation is that we could not separate mucinous and non-mucinous subtypes in cases. The proportion of epithelial ovarian cancers that are of the mucinous subtype has been estimated to be between 10 and 15 percent [6–9]. In the interpretation of our findings, thus, it needs to be taken into account that non-mucinous epithelial ovarian cancer is the great majority of cases.
In our study, the relative risk of invasive epithelial ovarian cancer associated with each one-year increase in average birth spacing was 0.99 (95% CI=0.98–1.01), which is similar to one earlier study [5]. It is possible that some of the biparous women who had a long interval between the first and the last pregnancy represented a subgroup of women who might have sub-fertile conditions that are associated with increased risk of ovarian cancer and obscure potential protective effect from progesterone [31]. However, analyses on the two birth spacings among the triparous women, who presumably have fewer sub-fertile conditions than biparous women, did not reveal a consistent association between birth spacing and the risk of ovarian cancer.
It is interesting to note that, among women with less than 15 years since delivery of the last child, no ovarian cases occurred among those with a very short birth spacing (<12 months), albeit with very small numbers of subjects. Although highly speculative, it might nonetheless be of interest to explore further the hormonal and other physiological characteristics underlying a substantially decreased risk of ovarian cancer among women who are able to conceive again within a short period after childbirth.
The present study tested the postulated association that wider spacing between childbirths reduces maternal risk of invasive epithelial ovarian cancer. The postulation is rooted in the findings that birth spacing increases with levels of circulating progesterone. However, the findings were based on only one study [17] that examined the relation between birth spacing and levels of progesterone in umbilical cord blood samples and it is possible that birth spacing may not represent an accurate measurement of maternal exposure to levels of progesterone during pregnancy. Another possibility is that a closer birth-spacing might be beneficial due to the sustained exposure to progesterone. Taken together, the present and previous findings [5] do not support that birth spacing is a major determinant underlying the protective effects of childbirth on ovarian cancer risk
Acknowledgements
We thank the reviewers for helpful comments. This research was supported by grant R01CA95112 from the National Institutes of Health, US Public Health Services.
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