8
Lactation and Breast Carcinoma Risk in a South African Population Patricia F. Coogan, Sc.D. 1 Lynn Rosenberg, Sc.D. 1 Samuel Shapiro, M.B. 1 Margaret Hoffman, M.B., Ch.B. 2 1 Slone Epidemiology Unit, Boston University School of Medicine, Brookline, Massachusetts. 2 Department of Community Health, University of Cape Town Medical School, Cape Town, South Africa. Presented as a poster at the Society for Epidemi- ologic Research Annual Meeting, Chicago, Illinois, June 24 –26, 1998. Supported by the National Cancer Institute (Grant R01 CA60954) and a grant from the Massachu- setts Department of Public Health. Address for reprints: Patricia F. Coogan, Sc.D., Slone Epidemiology Unit, Boston University School of Medicine, 1371 Beacon Street, Brookline, MA 02446. Received October 30, 1998; revision received Feb- ruary 11, 1999; accepted March 30, 1999. BACKGROUND. A number of epidemiologic studies have reported a reduced risk of breast carcinoma among women who have lactated but others have not. The current study presents data regarding lactation and breast carcinoma risk from a hospital-based case– control study of black and colored South African women. METHODS. Incident breast carcinoma cases treated between January 1994 and October 1997 (n 5 446) at 2 major hospitals in Cape Town and hospital patients admitted for conditions unrelated to breast carcinoma (controls, n 5 1471) were queried regarding the duration of breast-feeding each liveborn child and breast carcinoma risk factors. Multivariate logistic regression models were used to calcu- late odds ratios (ORs) for various categories of lactation compared with a reference category of never having breast-fed among women who had had at least one full term live birth. RESULTS. Approximately 83% of cases and 85% of controls had ever breast-fed (OR 5 0.9; 95% confidence interval [95% CI], 0.7–1.3). Among all subjects, the ORs for those who lactated for ,3 years were near or at unity. Beyond 3 years, ORs extending up to $7 years were less than unity, but the 95% CIs included 1.0 (OR for duration of $7 years 5 0.7; 95% CI, 0.4 –1.3). ORs did not vary by menopausal status. Breast carcinoma risk was not found to be related to the duration of breast-feeding the first child, the number of children breast-fed, or the patient’s age at first lactation. CONCLUSIONS. The results of the current study suggest lactation has little or no protective effect on breast carcinoma risk. Cancer 1999;86:982–9. © 1999 American Cancer Society. KEYWORDS: breast carcinoma, lactation, epidemiology, case– control studies. T he hypothesis that breast-feeding may prevent breast carcinoma was raised at least as early as the 1920s, 1 and several biologic mechanisms have been proposed. Lactation suppresses ovulation, and there may be a direct relation between the lifetime number of ovulatory cycles and breast carcinoma risk. 2 Thus, the total duration of lactation might be related inversely to breast carcinoma risk be- cause the duration of anovulation is correlated with the duration of lactation. However, anovulation does not last the full duration of lactation; prospective data suggest that the incidence of ovulation rises rapidly after the first 6 months postpartum among lactating women. 3 This suggests that the number of children breast-fed, espe- cially those breast-fed for at least 6 months (independent of total lifetime duration) may be related inversely to risk. Lactation changes the hormonal milieu of the breast. In one study, the milk of lactating women had lower levels of estrogen than did the breast fluid of pregnant or nonpregnant women and this 982 © 1999 American Cancer Society

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Page 1: Lactation and breast carcinoma risk in a South African population

Lactation and Breast Carcinoma Risk in a SouthAfrican Population

Patricia F. Coogan, Sc.D.1

Lynn Rosenberg, Sc.D.1

Samuel Shapiro, M.B.1

Margaret Hoffman, M.B., Ch.B.2

1 Slone Epidemiology Unit, Boston UniversitySchool of Medicine, Brookline, Massachusetts.

2 Department of Community Health, University ofCape Town Medical School, Cape Town, SouthAfrica.

Presented as a poster at the Society for Epidemi-ologic Research Annual Meeting, Chicago, Illinois,June 24–26, 1998.

Supported by the National Cancer Institute (GrantR01 CA60954) and a grant from the Massachu-setts Department of Public Health.

Address for reprints: Patricia F. Coogan, Sc.D.,Slone Epidemiology Unit, Boston University Schoolof Medicine, 1371 Beacon Street, Brookline, MA02446.

Received October 30, 1998; revision received Feb-ruary 11, 1999; accepted March 30, 1999.

BACKGROUND. A number of epidemiologic studies have reported a reduced

risk of breast carcinoma among women who have lactated but others have not.

The current study presents data regarding lactation and breast carcinoma risk

from a hospital-based case– control study of black and colored South African

women.

METHODS. Incident breast carcinoma cases treated between January 1994 and

October 1997 (n 5 446) at 2 major hospitals in Cape Town and hospital patients

admitted for conditions unrelated to breast carcinoma (controls, n 5 1471) were

queried regarding the duration of breast-feeding each liveborn child and breast

carcinoma risk factors. Multivariate logistic regression models were used to calcu-

late odds ratios (ORs) for various categories of lactation compared with a reference

category of never having breast-fed among women who had had at least one full

term live birth.

RESULTS. Approximately 83% of cases and 85% of controls had ever breast-fed

(OR 5 0.9; 95% confidence interval [95% CI], 0.7–1.3). Among all subjects, the ORs

for those who lactated for ,3 years were near or at unity. Beyond 3 years, ORs

extending up to $7 years were less than unity, but the 95% CIs included 1.0 (OR for

duration of $7 years 5 0.7; 95% CI, 0.4 –1.3). ORs did not vary by menopausal

status. Breast carcinoma risk was not found to be related to the duration of

breast-feeding the first child, the number of children breast-fed, or the patient’s

age at first lactation.

CONCLUSIONS. The results of the current study suggest lactation has little or no

protective effect on breast carcinoma risk. Cancer 1999;86:982–9.

© 1999 American Cancer Society.

KEYWORDS: breast carcinoma, lactation, epidemiology, case–control studies.

The hypothesis that breast-feeding may prevent breast carcinomawas raised at least as early as the 1920s,1 and several biologic

mechanisms have been proposed. Lactation suppresses ovulation,and there may be a direct relation between the lifetime number ofovulatory cycles and breast carcinoma risk.2 Thus, the total durationof lactation might be related inversely to breast carcinoma risk be-cause the duration of anovulation is correlated with the duration oflactation. However, anovulation does not last the full duration oflactation; prospective data suggest that the incidence of ovulationrises rapidly after the first 6 months postpartum among lactatingwomen.3 This suggests that the number of children breast-fed, espe-cially those breast-fed for at least 6 months (independent of totallifetime duration) may be related inversely to risk.

Lactation changes the hormonal milieu of the breast. In onestudy, the milk of lactating women had lower levels of estrogen thandid the breast fluid of pregnant or nonpregnant women and this

982

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reduction persisted after lactation had ceased.4 Lacta-tion also is a major excretion route for lipophilic com-pounds such as organochlorines, some of which (e.g.,dichlorodiphenyl trichloroethane and polychlorinatedbiphenyls) are estrogenic.5 These mechanisms predictthat breast carcinoma might be related inversely tototal duration of lactation.

Finally, lactation may confer some terminal dif-ferentiation of ductal epithelial cells that render themless susceptible to carcinogenic agents.6 If this is so,age at first lactation and perhaps duration of breast-feeding the first child might be the most importantaspects of lactation history.

A number of epidemiologic studies in developednations have reported reduced risks of breast carcinomaamong women who have lactated,7–15 but others havenot.16–26 Evidence from non-Westernized countries, inwhich women tend to breast-feed for longer durations,has supported a protective effect more consistently,27–32

although two large international studies found no oronly weak associations.33,34 Several studies found thatlactation reduced breast carcinoma risk only among pre-menopausal women, or that the effect was strongeramong these women.7–10,13,15,27

In the current study data regarding lactation andbreast carcinoma risk from a case– control study ofSouth African women are presented. Long durationsof lactation were common in this group of black(women of pure African ancestry) and colored women(women of mixed racial descent). Ethnic groups areclassified in this article according to terms used by theprevious apartheid government. The appropriatenessof using “race” as a variable in scientific researchcurrently is being debated, both in South Africa andinternationally.35,36 While the debate continues wehave felt obliged to use the old terms because therewere clear differences in breast carcinoma incidenceand covariates according to ethnic group. In doing so,we acknowledge that the system of apartheid resultedin disease patterns and in access to health care ac-cording to a racial classification that was not legiti-mate.

METHODSStudy BaseThis study was conducted for the primary purpose ofevaluating the use of injectable progestogen contra-ceptives and risk of breast carcinoma. White womenwere not included because the use of such contracep-tives was uncommon among this population. The sub-jects in the current study were women age ,55 yearswho lived within a defined geographic area within aradius of approximately 150 kilometers of Cape Town.Women were excluded if they had not lived in the

study area for at least 6 of the preceding 12 months orif they had a history of cancer at any site. The studywas approved by the institutional review boards ofeach participating institution.

CasesCases included all incident cases of invasive breastcarcinoma treated between January 1994 and October1997 at two hospitals (Groote Schuur and Tygerberg).All case diagnoses were confirmed by pathology re-port. Patients with carcinoma in situ were excluded.Until 1996, virtually all cases in the study region weretreated at the two hospitals. Thereafter, treatment be-came available elsewhere to women with comprehen-sive medical insurance (membership in a medical aidsociety). Thus a small number of cases may have beenmissed. There were 490 eligible cases, 3 of whom weretoo ill to be interviewed, and 3 subjects refused. Theremaining 484 cases were enrolled, 446 of whom hadhad at least 1 full term live birth.

ControlsControls were hospital patients admitted for condi-tions judged to be unrelated to contraceptive use orbreast carcinoma risk (e.g., trauma, acute infections,and orthopedic conditions). Discharge summarieswere reviewed to confirm control eligibility. Controlswere frequency-matched to the cases in a ratio of upto 5:1 for half-decade of age, ethnic group, and area ofresidence. For cases from the outlying areas, controlsreferred to the study hospitals from the same areaswere enrolled or they were recruited in hospitals lo-cated in those areas. There were 1627 controls, 2 ofwhom refused to participate. Of the eligible controls,1471 had had at least 1 full term live birth. The distri-bution of lifetime duration of breast-feeding was sim-ilar among the 3 major diagnostic groups that com-prised the controls (28.1%, 30.7%, and 30.8% ofpatients admitted for trauma, acute infections, andother conditions, respectively, had breast-fed $3years). The distribution of age at first lactation alsowas similar among the 3 groups (29.4%, 27.7%, and28.2% of patients admitted for trauma, acute infec-tions, and other conditions, respectively, were #18years of age at first lactation).

Data CollectionIn-person interviews were conducted in the hospitalin the patients’ preferred language (Afrikaans, English,or Xhosa) by nurse-interviewers. Informed consentwas obtained from all subjects prior to the interview.To maximize recall of reproductive events, the inter-viewers compiled a calendar of significant personalevents (age at menarche, births, etc.). Subjects were

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queried regarding the duration of breast-feeding foreach full term live birth and also were questionedregarding established and suspected breast carcinomarisk factors.

Statistical AnalysisThe current analysis was confined to women who hadat least one full term live birth. Logistic regressionmodels were used to calculate odds ratios (ORs) asestimates of the relative risk for various categories ofduration of lactation compared with a reference cate-gory of never having breast-fed.37 Multivariate ORswere adjusted for age in 5-year categories, age at firstbirth, parity, ethnicity, education, and whether thesubject belonged to a medical aid society (compre-hensive insurance) or sick fund (partial insurance) asindicators of socioeconomic status. Variables that hadlittle effect on the ORs were not included in the finalmodel (age at menarche, menopausal status, age atmenopause, body mass index, history of benign breastdisease, family history of breast carcinoma, alcoholconsumption, and duration of oral contraceptive useor injectable progestogen contraceptive use). Effectmodification was assessed by including an appropri-ate interaction term in the model.35 We evaluatedtrend in the ORs as total lifetime duration of breast-feeding increased, as duration of breast-feeding thefirst child increased, and as age at which subject firstlactated increased, among women who lactated byincluding a single continuous variable in the multivar-iate model.35

RESULTSThe majority of the cases and controls were coloredand ages 35– 49 years (Table 1). Cases had a higher ageat first birth and level of education than did controls.A higher proportion of cases than controls reported apositive history of benign breast disease or familyhistory of breast carcinoma and belonged to a medicalaid society. The distribution of parity, age at men-arche, and menopausal status was similar for casesand controls. Women who never breast-fed had fewerchildren, and were older at first birth than werewomen who had breast-fed; the distribution of othervariables was similar between women who did andthose who did not breast-feed (data not shown).

Three hundred and sixty-six cases (82%) and 1250controls (85%) had ever breast-fed, and the adjustedOR was 0.9 (95% confidence interval [95% CI], 0.7–1.3).The median total duration of breast-feeding was 16months among cases and 20 months among controls.Both cases and controls breast-fed an average of threechildren. The average duration of breast-feeding per

child was 10.7 months for cases and 11.9 months forcontrols.

Among all subjects, the ORs for those who lactatedfor ,3 years compared with those who never breast-fed were near or at unity. Beyond 3 years, ORs extend-ing up to $7 years were less than unity, but the 95%CIs included 1.0 (Table 2). Among women who lac-tated, a test for trend was not statistically significant(P 5 0.30). ORs among premenopausal and post-menopausal women were similar (Table 2), and againthe trend tests among women who lactated were notsignificant in either group.

ORs for the duration of the first episode of breast-feeding (whether the first child or not) compared withsubjects who never breast-fed were slightly below or atunity (Table 3). However, again all 95% CIs includedunity and the trend test was not significant (P 5 0.17).Results were not changed when 35 cases and 125controls who did not breast-feed their first child butdid breast-feed a subsequent child were excluded(data not shown). Breast carcinoma risk was not re-lated to the number of children breast-fed (Table 3).ORs for the duration of breast-feeding the first child ornumber of children breast-fed did not vary by meno-pausal status (data not shown).

Risks associated with age at which a subject firstlactated are shown in Table 4. With women who neverlactated as the reference group, the ORs amongwomen who first lactated at ,18 years of age was 0.7(95% CI, 0.5–1.1), and it rose to 1.2 (95% CI, 0.7–2.1) forfirst lactation at age $30 years (P value for trend 50.007). When subjects whose age at first lactation wasolder than the age at first birth were excluded, theresults did not change (data not shown). As expected,age at first lactation and age at first term birth werecorrelated closely (correlation coefficient 5 0.9). Forthat reason a term for age at first birth was not in-cluded in the regression model.

Table 5 displays the data from Table 4, this timewith women who never lactated omitted, and withcases and controls who first lactated at less than 18years of age as the reference category for the estima-tion of ORs. Corresponding ORs also are given for ageat first birth. The ORs increased as the age at firstlactation or age at first birth increased; in all categoriesof age at first lactation and age at first birth, the ORsvirtually were identical. Older age at first birth also wasassociated with breast carcinoma risk among nonlac-tators; compared with women whose age at first birthwas ,20 years, ORs for women ages 20 –24 years,25–29 and $30 years at first birth were 2.0 (95% CI,1.0 – 4.1), 1.5 (95% CI, 0.5– 4.0), and 1.5 (95% CI, 0.5–4.6). These ORs were based on only 77 cases and 218controls.

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In a recent analysis, lactation appeared to be as-sociated with a reduced risk only among women whohad one child.26 In our data, the ORs for ever havingbreast-fed were reduced slightly both among womenwho had 1 child (OR 5 0.6; 95% CI, 0.3–1.1) andamong those who had $5 children (OR 5 0.5; 95% CI,0.2–1.0), and were increased among women who had2 (OR 5 1.6; 95% CI, 0.8 –3.3), 3 (OR 5 1.4; 95% CI,0.7–2.9), or 4 (OR 5 1.4; 95% CI, 0.5– 4.1) children.There was no consistent effect of duration of lactationin any stratum of parity (data not shown).

DISCUSSIONIn the current study there was little evidence that longdurations of lactation for all children (or for the first

child) or repeated episodes of lactation reduced breastcarcinoma risk either among premenopausal or post-menopausal women. Although ORs for durations of$3 years were reduced by 20 –30%, there was no con-sistency in the risk reductions across strata, and all95% CIs included 1.0.

Of six previous studies that included appreciablenumbers of women with long durations of lactation,three found no relation between breast carcinoma riskand lactation duration.19,33,34 Three studies conductedin China reported risk reductions of 30 – 60% forwomen who breast-fed for $9 years.29 –31 When thesedata were pooled and augmented with additional datafrom one of the study sites (Tianjin) and reanalyzedwith adjustment for age at first birth, parity, and ed-

TABLE 1Characteristics of the 446 Cases and 1471 Controlsa

Cases Controls

No. (%)b No. (%)b

Ethnic groupc

Colored 384 (85.2) 1257 (85.5)Black 62 (14.8) 214 (14.5)

Age (yrs),30 17 (3.8) 124 (8.4)30–39 135 (30.3) 502 (34.1)40–49 199 (44.6) 622 (42.3)$50 95 (21.3) 223 (15.2)

Age at first birth (yrs),20 139 (30.8) 641 (43.6)20–24 213 (47.7) 612 (41.5)251 94 (21.5) 218 (15.0)

Parity1 81 (20.2) 234 (15.5)2 96 (22.3) 316 (21.0)3 100 (22.3) 334 (22.7)$4 169 (35.2) 587 (40.8)

Age at menarche (yrs)#12 95 (21.2) 295 (20.0)13–14 178 (39.2) 550 (37.4)$15 173 (39.6) 626 (42.6)

Education/trainingd

None–form 2 58 (12.5) 241 (16.8)Forms 3–8 309 (70.2) 1077 (73.9). form 8 70 (17.3) 139 (9.3)

Menopausal statusPremenopausal 346 (83.6) 1127 (77.1)Postmenopausal 81 (16.4) 315 (22.9)

Positive personal history of benign breast disease 43 (9.3) 99 (6.7)Positive family history of breast carcinoma 32 (7.0) 35 (2.4)Member of medical aid societye 70 (15.6) 81 (5.5)Member of sick fund 63 (14.7) 193 (13.1)

a Unknown values omitted.b Adjusted to age distribution of total study population.c “Black” refers to women of pure African ancestry and “colored” refers to women of mixed racial descent.d Form 8 is the equivalent of 12 years of education in the U. S.e A medical aid society member has comprehensive health insurance, whereas a sick fund member has only partial insurance.

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ucation, the ORs for lactating at least 9 years com-pared with women who never lactated among pre-menopausal and postmenopausal women were,respectively, 0.9 and 0.6 (no 95% CIs reported).38 Arecent Mexican study reported ORs of 0.33 (95% CI,0.18 – 0.62) and 0.31 (95% CI, 0.16 – 0.57), respectively,for women who breast-fed 3–5, and .5 years com-pared with women who never lactated. However, theORs was 0.47 (95% CI, 0.23– 0.95) for those who breast-fed only 1–3 months.32 The majority of other studieshave been conducted in societies in which a relativelysmall proportion of women had lifetime durations oflactation that exceeded 2 years. Several studies esti-mated risk reductions ranging from 30 – 60% for 1–$2years of lactation among premenopausal women,8,9 oramong both premenopausal and postmenopausalwomen.11,13 Some studies found that breast carci-noma risk was reduced only among premenopausal

women.8,9,14,15 Others found no relation betweenbreast carcinoma risk and lactation.16,17,20 –26

We found no evidence that the duration of breast-feeding the first child reduced breast carcinoma risk,which is consistent with several previous stud-ies.14,20,21 Byers et al.9 reported ORs of 0.65 for pre-menopausal women who breast-fed their first child7–11 months and 0.24 for those who did so for $12months compared with women who never breast-fed(no 95% CIs reported); however, the latter estimate

TABLE 2Total Duration of Lactation among Cases and Controls, Overall andby Menopausal Status

Total duration (yrs) Cases ControlsOdds ratioa (95%confidence interval)

All subjectsb

Never 77 218 1.0c—Ever 366 1250 0.9 (0.7–1.3),1 125 413 0.9 (0.6–1.3)1 67 195 1.1 (0.7–1.6)2 42 135 1.0 (0.6–1.5)3–4 38 179 0.8 (0.5–1.2)5–6 26 107 0.8 (0.5–1.4)$7 28 130 0.7 (0.4–1.3)P value for trend 0.3

Premenopausal subjectsNever 60 167 1.0c—Ever 284 958 1.0 (0.7–1.4),1 99 331 0.9 (0.6–1.3)1 53 143 1.2 (0.7–1.8)2 33 90 1.2 (0.7–2.1)3–4 27 141 0.7 (0.4–1.2)5–6 19 88 0.7 (0.4–1.4)$7 22 96 0.8 (0.4–1.4)P value for trend 0.2

Postmenopausal subjectsNever 15 48 1.0c—Ever 65 266 0.7 (0.4–1.5),1 22 72 1.2 (0.6–2.5)1–2 18 93 0.8 (0.3–1.8)3–4 9 35 0.5 (0.2–1.4)$5 11 47 1.0 (0.4–2.4)P value for trend 0.7

a Adjusted for age (5-year categories), age at first birth (years) (,20, 20 –,25, 25–,30, and $30), parity

(1, 2, 3, 4 –5, and $6), ethnicity (colored or black), education (no education–form 2, forms 3– 6, forms

7– 8, . form 8, and missing), and whether the subject belonged to a medical aid society or sick fund.b 43 cases and 94 controls with unknown duration were excluded from the analysis.c Reference category.

TABLE 3Total Duration of the First Episode of Breast-Feedinga and Numberof Children Breast-Fed among Cases and Controls

Cases ControlsOdds ratiob (95%confidence interval)

Duration (mos)Never 77 218 1.0c—,6 173 547 1.0 (0.7–1.3)6–11 68 181 1.1 (0.7–1.7)12–23 47 212 0.8 (0.5–1.2)24–35 33 141 0.8 (0.5–1.3)$36 27 116 0.8 (0.5–1.3)P value for trend 0.17

No. of children breast-fedNone 77 218 1.0c—1 80 260 0.9 (0.6–1.3)2 88 315 0.9 (0.6–1.3)3 79 286 1.0 (0.6–1.5)4 48 190 1.0 (0.6–1.6)5 36 105 1.3 (0.7–2.3)$6 25 83 1.1 (0.5–2.2)

a First child breast-fed, regardless of whether it was first full-term birth.b Adjusted for age (5-year categories), age at first birth (years) (,20, 20 –,25, 25–,30, and $30), parity

(1, 2, 3, 4 –5, and $6), ethnicity (colored or black), education (no education–form 2, forms 3– 6, forms

7– 8, .form 8, and missing), and whether the subject belonged to a medical aid society or sick fund.c Reference category.

TABLE 4Age at Which Subject First Breast-Fed among Cases and Controls

Age at firstlactation (yrs) Cases Controls

Odds ratioa (95%confidence interval)

Never 77 218 1.0b—#18 73 353 0.7 (0.5–1.1)19–20 79 309 0.8 (0.6–1.2)21–24 117 360 1.0 (0.7–1.4)25–29 66 162 1.1 (0.8–1.7)$30 28 55 1.2 (0.7–2.1)P value for trend 0.007c

a Adjusted for age (5-year categories), parity (1, 2, 3, 4 –5, and $6), ethnicity (colored or black),

education (no education–form 2, forms 3– 6, forms 7– 8, . form 8, and missing), and whether the subject

belonged to a medical aid society or sick fund.b Reference category.c Women who never lactated were omitted from the trend test.

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was based on only 2 cases and 8 controls. Romieu etal. reported relative risks of 0.62 (95% CI, 0.42– 0.91)for women who breast-fed for 4 –12 months and 0.28(95% CI, 0.17– 0.47) for those who breast-fed for $13months compared with women who never breast-fed.32 McTiernan and Thomas10 observed reductionsamong both premenopausal (3–5 months; 0.56 [95%CI, 0.27–1.1]; $6 months, 0.54 [95% CI, 0.27–1.1]) andpostmenopausal women ($6 months, 0.66 [95% CI,0.26 –1.7]) compared with women who never breast-fed. In the latter two studies, ORs for the duration ofbreast-feeding the first child were not adjusted for thetotal duration of breast-feeding, which in each studywas associated strongly with breast carcinoma risk. Ifthe duration of the first lactation was correlated withthe total duration of breast-feeding, as was the case inour data, these positive associations might reflect con-founding by the total duration of lactation. However,we noted that our results did not change when wecontrolled for the total duration of lactation.

Like Brinton et al.18 and Yoo et al.,27 we observedno association between breast carcinoma risk and thenumber of children breast-fed. Romieu et al.32 re-ported ORs of 0.57 (95% CI, 0.34 – 0.96), 0.52 (95% CI,0.31– 0.87), and 0.39 (95% CI, 0.21– 0.70) for breast-feeding 1–2, 3– 4, and 51 children, respectively, com-pared with women who never breast-fed (P value fortrend , 0.001). A U.K. study also found a significanttrend (P 5 0.02), although the risk reduction associ-ated with breast-feeding $3 children (OR, 0.8) was lessthan that associated with breast-feeding 2 children(0.7) (no 95% CIs reported).13

In our data there was a suggestion that early age atfirst lactation was related inversely to risk. However,the association could have been accounted for by itsclose correlation with early age at first birth, and thetwo factors could not be disentangled. In a U.K. study,there was no relation between age at first lactation andbreast carcinoma risk.13 Newcomb et al.8 reported an

OR of 0.54 (95% CI, 0.36 – 0.82) among premenopausalwomen who first breast-fed before age 20 yearswhereas Freudenheim et al.14 found a reduced OR(OR 5 0.67; 95% CI, 0.46 – 0.95) only among postmeno-pausal women who had first breast-fed before age 25years. In both studies the reference group was womenwho never lactated. Estimates from the latter twostudies were adjusted for age at first birth. In our data,ages at first birth and at first lactation were the samefor 90% of subjects who lactated. This correlation alsowas evident for 95% of Chinese subjects described byRoss and Yu.38 It is not clear that it is possible toinclude two such highly correlated variables in onemodel and obtain interpretable results. In our data,age at first birth was associated with increased breastcarcinoma risk among women who did not lactate,which suggests that age at first birth rather than atlactation may be the operative variable.

In our data lactation was related inversely tobreast carcinoma risk among women who had onechild or five or more children, but positively relatedamong women who had two, three, or four children.Thus there was no consistent pattern. None of theproposed mechanisms predicted that parity wouldmodify the effect of lactation, nor was there evidenceof effect modification by parity in previous stud-ies.8,11,16,34 One exception is the most recent assess-ment of lactation in the Nurses’ Health Study,26 inwhich ever (compared with never) breast-feeding ap-peared to confer a reduction in risk only amongwomen who had 1 child (OR, 0.68 [95% CI, 0.46 –1.00]among all women and 0.38 [95% CI, 0.14 –1.08] amongpremenopausal women).

The evidence thus far from numerous studies ofthe effect of lactation on breast carcinoma risk is con-tradictory. Several reasons have been proposed to ex-plain the different study results, such as methodologicdifferences and variation in breast-feeding practices,in terms of infant supplementation with other foods

TABLE 5Age at First Birth and First Lactation among Cases and Controls Who Lactated

Age at first lactation (yrs) Age at first birth (yrs)

Cases Controls Odds ratioa Cases Controls Odds ratioa

#18 73 353 1.0b 81 397 1.0b

19–20 79 309 1.2 86 320 1.221–24 117 360 1.4 128 364 1.525–29 66 162 1.5 55 134 1.5$30 28 55 1.8 19 38 1.7

a Adjusted for age (5-year categories), parity (1, 2, 3, 4 –5, and $6), ethnicity (colored or black), education (no education–form 2, forms 3– 6, forms 7– 8, . form 8, and missing), and whether the subject belonged

to a medical aid society or sick fund.b Reference category.

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and daily frequency of lactation. These latter variableshave been found to influence the likelihood of post-partum ovulation.3 If postponement of ovulation is infact the operative mechanism, then time to first post-partum ovulation might be more relevant than simpleduration of lactation or more complicated exposureschemes based on nursing frequency and supplemen-tation. However, in the one study of lactation thatexamined total duration of postpartum amenorrhea,amenorrhea was not associated significantly with therisk of breast carcinoma, although lactation was.13

It is unlikely that recall bias could have explainedthe findings in the current study because the ques-tions regarding lactation were part of a long interviewregarding all aspects of reproduction and other breastcarcinoma risk factors. Selection bias also is unlikely.Participation rates among cases and controls werevery high, and the lactation histories of the three di-agnostic groups comprising the controls were similar,suggesting valid selection of controls.

Parity, age at first birth, and education were con-founders in the current analyses. Other breast carci-noma risk factors had little effect on the estimates, andwe consider it unlikely that residual confoundingmasked an inverse association. It is more likely thatincomplete control for some covariates, particularlyage at first birth, contributed to the slight risk reduc-tions we observed for durations .3 years.

Our study was powerful enough to detect a stronginverse association of breast carcinoma risk with longterm lactation, had there been one. However, welacked information regarding details of breast-feedingpractice and time to first ovulation after birth. Never-theless, we believe that an inverse association, ifpresent, would have been evident among thosewomen who breast-fed $7 years. Our study failed tosupport the hypothesis that lactation reduces the riskof breast carcinoma. However, we note that breast-feeding has substantial benefits for infant health andtherefore should be encouraged.

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