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Menstrual and reproductive factors and the risk of myocardial infarction in women under fifty-five years of age
Menstrual and reproductive factors and the risk of myocardial infarction in women under fifty-five years of age Carlo La Vecchia, M.D., Adriano Decarli, Sc.D., Silvia Franceschi, M.D., Antonella Gentile, Ph.D., Eva Negri, Sc.D., and Fabio Parazzini, M.D.
Milan, Italy The relationship between menstrual and reproductive factors and subsequent risk of coronary heart disease was investigated in a hospital-based case-control study of 202 women with acute myocardial infarction and 374 control subjects admitted for a wide spectrum of acute conditions unrelated to any of the established risk factors for ischemic heart disease. No consistent association was observed with age at menarche or menopausal status, but women with a lifelong irregular menstrual cycle pattern were at significantly elevated risk of myocardial infarction (relative risk = 1.8, 95% confidence interval = 1.1 to 2.9). No clear trend in risk was evident with the number of livebirths, miscarriages, or induced abortions. However, women whose first pregnancy or livebirth occurred before age 20 years showed elevated risks of subsequent myocardial infarction compared with nulliparous ones (relative risks = 2.3; 95% confidence interval = 1.1 to 4.9), and there was a significant trend of increasing risk with earlier first birth. These associations were evident in both younger and middle-age women and were not explained by allowance for several identified potential confounding factors. (AM J OBSTET GYNECOL 1987;157:1108-12.)
Key words: Myocardial infarction, menstrual and reproductive factors, pregnancy
Evidence indicates that female hormones influence the risk of ischemic heart disease. The use of oral contraceptives increases the risk of myocardial infarction, 1 whereas it is still debated whether menopausal estrogen replacement treatment decreases the risk of cardiovascular disease. 2-4 Fewer data are available on the potential role of endogenous hormones and their correlates, that is, menstrual and reproductive factors. Although it is known that the advantage that women have over men in the incidence of coronary heart disease and death is confined to the premenopausal years (postmenopausal female rates rise to become comparable with those for elderly men 5 ), it is still uncertain whether early menopause increases the risk of myocardial infarction relative to premenopausal women of comparable age. 6 -8 With regard to reproductive history, a study based on the Mayo Clinic record linkage system showed elevated risks in women whose first pregnancy was below age
From the Istituto di Ricerche Farmacologiche Mario Negri, Istituto di Biometria e Statistica Medica, Universitil diM ilano, and /stituto Nazionale Tumori, lstituto di Statistica e Ricerca Operativa, Universitil di Trento, Centro di Riferimento Oncologico Aviano (Pordenone), and Consorzio /nteruniversitario Lombardo per l'Elaborazione Automatica. Conducted within the framework of the CNR (Italian National Research Council) Applied Project Preventive and Rehabilitative Medicine, Contracts Nos. 85.00487.56 and 85.00549.56. Received for publication july 22, 1986; revised june 24, 1987; accepted july 27, 1987. Reprint requests: Carlo La Vecchia, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea, 62, 20157 Milan, italy.
1108
25 years, 9 but the evidence was controversial in a large case-control study conducted in three geographic regions of North America. 8 In the present study, we have further considered the role of menstrual and reproductive factors in the risk of myocardial infarction with data from a case-control study conducted in Northern Italy where mortality rates from ischemic heart diseases are considerably lower than those in Northern European or American populations. 10
Subjects and methods Since January 1983, trained interviewers identified and questioned women below age 55 years admitted for acute myocardial infarction to the coronary care units of 30 hospitals in Lombardy and a few other areas in northern Italy (Turin, Genova, Verona, and Pisa). The general design of this investigation has already been described." Briefly, a regular liaison with cooperating hospitals was maintained at approximately fortnightly intervals. Less than 2% of the case or control subjects approached for interview refused to participate. A standard questionnaire was used to obtain information on sociodemographic factors, personal characteristics and habits (i.e., cigarette smoking, consumption of alcohol, coffee, and other methylxanthinecontaining beverages), a few selected dietary items, menstrual and reproductive factors (i.e., age at menarche, menopausal status, lifelong menstrual pattern, number of livebirths and abortions, and age at first pregnancy and at first and last birth), and history of
Menstrual and reproductive factors and risk of myocardial infarction
Volume 157 Number 5
11 09
Table I. Distribution of 202 cases of acute myocardial infarction and 374 control subjects according to selected risk factors, Northern Italy, 1983 to 1986 Myocardial infarction Risk factor
Age (yr) <40 40-49 50-54 Cigarette smoking Never Exsmoker Current Diabetes No Yes Hypertension No Yes Hyperlipidemia No Yes History of coronary heart disease in first degree relatives No Yes
I
Controls
I
(%)
No.
35 82 85
(17.3) (40.6) (42.1)
133 134 107
(35.6) (35.8) (28.6)
63 6 133
(31.2) (3.0) (65.8)
245 17 112
(65.5) (4.5) (29.9)
179 23
(88.6) (11.4)
358 16
(95.7) (4.3)
120 82
(59.4) (40.6)
339 35
(90.6) (9.4)
162 40
(80.2) (19.8)
348 26
(93.0) (7.0)
76 126
(37.6) (62.4)
208 166
(55.6) (44.4)
No.
lifetime use of oral contraceptives and female hormones for other indications. The cases studied included 202 women under 55 years of age with a diagnosis of acute myocardial infarction according to the standard World Health Organization criteria. An additional18 patients were considered unsuitable after review of the clinical records, chiefly because of recurrent infarction (n = 10) or uncertain diagnostic criteria (n = 8). The median age was 47 years, and 117 (58%) women were below age 50 years. The control subjects were patients under age 55 years admitted to the same hospitals where cases had been identified for acute diseases other than cardiovascular, malignant, metabolic, hormonal, or gynecologic, which were diagnosed within the year before interview. Further exclusion was made of all primary diagnoses potentially related to cigarette smoking (e.g., peptic ulcer or abdominal hernia) or alcohol consumption (e.g., liver diseases). A total of 374 women 24 to 54 years old were interviewed; the median age was 45 years, and 267 (71 %) were below age 50 years. Among them, 22% were admitted for traumatic conditions (mostly fractures or sprains), 22% had nontraumatic orthopedic disorders (mostly lower back pain and disc disorders), 25% were admitted for surgical conditions (including plastic surgery), and 31% had other illnesses, such as acute infections, skin, ear, nose and throat, or teeth disorders. The present analysis is based on data collected before February 1986. Data analysis. Since cases were older than the com-
(%)
parison group, relative risk estimates (together with their 95% approximate confidence intervals) 12 were derived from data stratified for quinquennia of age by means of the usual Mantel-Haenszel procedure. 13 The significance of the linear trends in risk, where appropriate, was assessed with the test described by Mantel. 14 The potential confounding effect of several factors (geographic area, marital status, education, social class, cigarette smoking, alcohol and coffee consumption, diabetes, hypertension, obesity, hyperlipidemia, family history of ischemic heart disease, oral contraceptive and other female hormone use) was controlled for by means of stratification and the Mantel-Haenszel procedure. 13 Second, identified potential distorting factors were simultaneously controlled for by multiple logistic regression, fitted by the method of maximum likelihood. 12 Included in the regression equations, in addition to the menstrual and reproductive factors considered in this article, were terms for age, geographic area, marital status, education, social class, cigarette smoking, alcohol consumption, diabetes, hypertension, obesity, hyperlipidemia, family history of ischemic heart disease, and oral contraceptive and other female hormone use. Relative risk estimates from multiple logistic models were not materially different from the age-adjusted Mantel-Haenszel estimates, and only the latter are presented in the tables. Results
The distribution of cases and control subjects according to age and risk factors showing significant as-
1110 La Vecchia et al.
November 1987 Am J Obstet Gynecol
Table II. Distribution of 202 women with acute myocardial infarction and 374 control subjects according to selected menstrual characteristics Myocardial infarction
Age at menarche (yr) <12 12-14
2:15
Unknown Menstrual cycle pattern Regular Irregular:j:
Controls
Table III. Distribution of 202 women with acute myocardial infarction and 374 control subjects according to number of livebirths and abortions
Relative risk estimates (95% Cl)*
Myocardial infarction
Controls
0 1-2
35 129
123 156
2:3
38
95
147 37
293 54
18
27
181 21
331 43
No. of livebirths 55
62 258
35 2
54
IIO
161 40
320 52
Unknown Menopausal status Before or during After natural
117 63
252 79
After surgical
22
43
2
It
0.49 (0.31-0.75) 0.61 (0.33-l.l2)
It
1.79 (l.l3-2.86)
It
0.77 (0.44-1.35) 0.69 (0.39-1.23)
CI = Confidence interval. *Mantel-Haenszel estimates adjusted for age m quinquennia. tReference category. :j:Defined as frequent occurrence of menstrual-like episodes less than 21 or more than 35 days apart.
sociation with the risk of myocardial infarction is shown in Table I. Women with myocardial infarction more frequently were smokers and reported a history of diabetes, hypertension, hyperlipidemia, and a family history of coronary heart disease. In Table II the relationship between selected menstrual characteristics and the risk of myocardial infarction is considered. Compared with women whose menarche occurred younger than 12 years, those with later menarche showed a reduced risk of infarction. However, there was no tendency for the risk to decrease with increasing age at menarche. Women with lifelong menstrual irregularities (simply defined as frequent occurrence of menstrual-like episodes less than 21 or more than 35 days apart) were at significantly elevated risk (relative risk = 1.8, 95% confidence interval = 1.1 to 2.9). In contrast, when age was allowed for, no significant relationship was evident between menopausal status and myocardial infarction risk. Allowance for major identified potential distorting factors by means of multiple logistic regression did not materially modify any of these estimates (i.e., multivariate relative risk for irregular menstrual cycle pattern = 2.1, 95% confidence interval = 1.2 to 3.3). There was no consistent pattern of risk according to
No. of miscarriages 0
I
2:2
No. of induced abortions 0 2:}
Relative risks estimates (95% Cl)*
It 1.85 (l.l5-2.96) 0.75 (0.40-1.39)
It
1.03 (0.69-l. 74) 1.08 (0.56-2.06)
It
0.96 (0.54-1.70)
CI = Confidence interval. *Mantel-Haenszel estimates adjusted for age in quinquennia. t Reference category.
the number of livebirths, since the point estimate was above unity for women with one or two children and below unity for those with three or more births compared with nulliparas (Table III). Likewise, there was no relationship between infarction risk and the number of miscarriages or induced abortions (Table III). Relative to women who had never been pregnant, the risk was significantly elevated (relative risk = 2.3, 95% confidence interval = 1.1 to 4.9) for those whose first pregnancy was below age 20 years, and the point estimate was above unity, although not significantly (relative risk = 1.5), for those women whose first pregnancy occurred above age 20 years (Table IV). The pattern of risk was similar with regard to age at first livebirth, and a significant trend of increasing risk with younger age at first livebirth was evident (Table IV). The relationship between early first birth was independent from the major identified potential distorting factors, since the multivariate relative risks were not materially different from the age-adjusted ones (relative risk for women before 20 years old at the first birth = 2.4 and 1.4 for those aged 20 to 24 years). Likewise, the risk of myocardial infarction was significantly elevated (relative risk = 2.1) in women whoselast birth occurred below age 25 years. However, the data are insufficient to allow separate analysis of the effects (and the interactions) of parity and age at first and last birth, which are, of course, strongly correlated. The influence of early births on subsequent myocar-
Volume 157 Number 5
Menstrual and reproductive factors and risk of myocardial infarction
dial infarction risk was long lasting, since the risk estimates were above unity for middle-aged (45 to 54 year) women, as well as for younger ones.
Table IV. Distribution of 202 women with acute myocardial infarction and 379 control subjects according to age at first pregnancy and at first and last livebirth
Comment
The findings of the present study indicate that several aspects of menstrual and reproductive history are related to the subsequent risk of acute myocardial infarction in younger and middle-aged women. The relative risk was significantly elevated for women with frequent irregularities in menstrual cycle and those with earliers pregnancies or births. No consistent association was evident for age at menarche, menopausal status, parity, and number of abortions. It is unlikely that the present findings are largely influenced by obvious bias. The control subjects were admitted for a wide spectrum of acute conditions requiring hospital treatment apparently unrelated to menstrual or reproductive events, and the participation rate was almost complete. Several variables considered (parity, age at first birth, or menopausal status) should not be influenced by recall or information bias, and also for variables whose recall may not be totally reliable (i.e., age at menarche or menstrual cycle pattern), there is little support for different recall by cases and control subjects having any considerable impact on the risk estimates. The potential influence of menstrual and reproductive factors on myocardial infarction risk, in fact, was not known to the interviewers and probably not to most patients either, and the major attention in this study was on the effects of other risk factors, such as exogenous female hormones or smoking. 11 With regard to confounding, the main findings of this study were not materially influenced by allowance for several identified potential distorting factors, including sociodemographic indicators and the major risk factors for myocardial infarction. Thus this study confirms the indication of a casecontrol study based on 169 incidences of coronary heart disease (angina, myocardial infarction, and sudden unexpected death) in women under age 60 years from Rochester, Minnesota, during 1960 to 1979, which showed a relative risk of 1.9 for women whose age at first pregnancy was under 20 years and 1.8 for those 20 to 24 years compared with never pregnant women and those with later first pregnancy. 9 The results of another large North American case-control study were more controversial and not statistically significant, although the point estimates for women whose first pregnancy was below age 25 years were also above unity in that study." A second interesting finding of this study was the elevated risk among women with lifelong irregular menstrual cycle pattern. Although the rather crude definition used for "menstrual irregularity" does not allow precise definition of the biologic correlates of this find-
1111
Myocardial infarction
Controls
24
28
20-24
76
132
2:25
73
106
Nulligravidas (trend)
29
108
21
23
20-24
71
117
2:25
75
Ill
Nulliparas
35
123
39
43
25-29
47
87
2:30
81
121
Nulliparas (trend)
35
123
Age at first pregnancy (yr) <20
x~
Age at first livebirth (yr) <20
xi (trend)
Age at last livebirth (yr) <25
X~
Relative risk estimates (95% Cl)*
2.31 (1.1 0-4.86) 1.52 (0.89-2.59) 1.55 (0.86-2.82) It 3.30 (p"' 0.07) 2.31 (1.1 0-4.87) 1.47 (0.89-2.44) 1.39 (0.80-2.41) It 3.99 (p"' 0.05) 2.14 ( 1.15-3.97) 1.09 (0.60-1. 98) 1.30 (0.75-2.24) It 4.15 (p"' 0.04)
CI "' Confidence interval. *Mantel-Haenszel estimates adjusted for age m quinquennia. tReference category. ing, it is likely that women with menstrual irregularities have more frequent anovular cycles and several steroid hormone imbalances (i.e., hyperandrogenemia). It is, however, still difficult to reconcile in unifying and widely accepted hormonal correlates the various findings of the present study, including the absence of association with menopausal status (which is in agreement with some but not all previous studies). 6 - 8 Likewise, other pathogenetic hypotheses put forward to explain the lower cardiovascular mortality rates in women based, for instance, on the suggestion that menses may provide a mechanism for the elimination of bloodborne factors that participate in atherogenesis 15 are partly (i.e., positive association with irregular menses) but not totally (i.e., absence of association with age at menopause) consistent with the findings of the present study. The influence of the major risk factors in the present
1112 La Vecchia et al.
study (irregular menstrual pattern and age at first pregnancy or birth) was still evident in middle-aged women, that is, after an interval of several years or decades. This suggests that these factors may influence the subsequent risk of myocardial infarction even after a considerable time, as previously indicated from data on the discontinuation of oral contraceptive use. 16 The negative relationship between age at first pregnancy or birth and the risk of ischemic heart disease, if confirmed, would have important public health implications, particularly if a similar relationship is not restricted to younger and middle-aged women analyzed in the present and previous"· 9 work but also applies to older age groups in whom there is a substantially greater incidence of coronary events. 5 • 10 Therefore it appears that the age at which a woman bears her first child is an important correlate of the subsequent history of several important diseases in terms of either direct (i.e., increased risk of breast cancer with increasing age at first livebirth) 17 or, possibly, inverse association (i.e., decreaseq risk of ischemic heart disease with older age at first livebirth). Data processing and analysis were performed at the computing facilities of the Inter-University Consortium of Lombardy for Automatic Data Processing (CILEA). We thank Ms. Laura Flores fof data management, and Ms. Judy Baggott, Ms. Gigliola Brambilla Pisani, and the G. A. Pfeiffer Memorial Library Staff for editorial assistance.
November 1987 Am J Obstet Gynecol
3.
4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
REFERE;NCES l. Stadel B V. Oral contraceptives and cardiovascular disease.
N Englj Med 1981;305:612-8, 672-7. 2. Wilson PWF, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular mor-
17.
bidity in women over 50. The Framingham study. N Eng! 1985;313:1038. Stampfer MJ, Willett WC, Colditz GA, Rosner B, Speizer FE, Hennekens CH. A prospective study of post menopausal estrogen therapy and coronary heart disease. N EnglJ Med 1985;313:1044. Bailar JC III. When research results are in conflict. . N EnglJ Med 1985;313:1080. Johansson S, Vedin A, Wilhelmsson C. Myocardial infarction in women. Epidemiol Rev 1983;5:67. Heller RF, Jacobs HS. Coronary heart disease in relation to age, sex, and the menopause. Br MedJ 1978;1:472. Gordon T, Kannel WB, Hjortland MC, McNamara PM. Menopause and coronary heart disease. The Framingham study. Ann Intern Med 1978;89: 157. Rosenberg L, Miller DR, Kaufman DW, et <1!. Myocardial infarction in women under 50 years of age. JAMA 1983;250:2801. Beard CM, Fuster V, Annegers JF. Reproductive history in women with coronary heart disease. A case-control study. Am] Epidemiol1984;120:108. LaVecchia C, Decarli A. Trends in ischemic heart disease mortality in Italy 1968-1978. Am J Public Health 1986;76:45. La Vecchia C, Franceschi S, Decarli A, Pampallona S, Tognoni G. Risk factors for myocardial infarction in young women. Am] Epidemiol1987;125:832. Breslow NE, Day NE. Statistical methods in cancer research. No. 32. Lyon: IARC Scientific Publication, 1980. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Nat! Cancer Inst 1959;22:719. Mantel N. Chi-square tests with one degree of freedom: extension of the Mantel-Haenszel procedure. J Am Stat Assoc 1963;58:690. Seely S. Possible reasons for the comparatively high resistance of women to heart disease. Am Heart J 1976; 91:275. Slone D, Shapiro S, Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD. Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. N EnglJ Med 1981;305:420. MacMahon B, Cole P, Lin TM, et a!. Age at first birth and breast cancer risk. Bull World Health Org 1970;43:209.
J Med
Milan, Italy The relationship between menstrual and reproductive factors and subsequent risk of coronary heart disease was investigated in a hospital-based case-control study of 202 women with acute myocardial infarction and 374 control subjects admitted for a wide spectrum of acute conditions unrelated to any of the established risk factors for ischemic heart disease. No consistent association was observed with age at menarche or menopausal status, but women with a lifelong irregular menstrual cycle pattern were at significantly elevated risk of myocardial infarction (relative risk = 1.8, 95% confidence interval = 1.1 to 2.9). No clear trend in risk was evident with the number of livebirths, miscarriages, or induced abortions. However, women whose first pregnancy or livebirth occurred before age 20 years showed elevated risks of subsequent myocardial infarction compared with nulliparous ones (relative risks = 2.3; 95% confidence interval = 1.1 to 4.9), and there was a significant trend of increasing risk with earlier first birth. These associations were evident in both younger and middle-age women and were not explained by allowance for several identified potential confounding factors. (AM J OBSTET GYNECOL 1987;157:1108-12.)
Key words: Myocardial infarction, menstrual and reproductive factors, pregnancy
Evidence indicates that female hormones influence the risk of ischemic heart disease. The use of oral contraceptives increases the risk of myocardial infarction, 1 whereas it is still debated whether menopausal estrogen replacement treatment decreases the risk of cardiovascular disease. 2-4 Fewer data are available on the potential role of endogenous hormones and their correlates, that is, menstrual and reproductive factors. Although it is known that the advantage that women have over men in the incidence of coronary heart disease and death is confined to the premenopausal years (postmenopausal female rates rise to become comparable with those for elderly men 5 ), it is still uncertain whether early menopause increases the risk of myocardial infarction relative to premenopausal women of comparable age. 6 -8 With regard to reproductive history, a study based on the Mayo Clinic record linkage system showed elevated risks in women whose first pregnancy was below age
From the Istituto di Ricerche Farmacologiche Mario Negri, Istituto di Biometria e Statistica Medica, Universitil diM ilano, and /stituto Nazionale Tumori, lstituto di Statistica e Ricerca Operativa, Universitil di Trento, Centro di Riferimento Oncologico Aviano (Pordenone), and Consorzio /nteruniversitario Lombardo per l'Elaborazione Automatica. Conducted within the framework of the CNR (Italian National Research Council) Applied Project Preventive and Rehabilitative Medicine, Contracts Nos. 85.00487.56 and 85.00549.56. Received for publication july 22, 1986; revised june 24, 1987; accepted july 27, 1987. Reprint requests: Carlo La Vecchia, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea, 62, 20157 Milan, italy.
1108
25 years, 9 but the evidence was controversial in a large case-control study conducted in three geographic regions of North America. 8 In the present study, we have further considered the role of menstrual and reproductive factors in the risk of myocardial infarction with data from a case-control study conducted in Northern Italy where mortality rates from ischemic heart diseases are considerably lower than those in Northern European or American populations. 10
Subjects and methods Since January 1983, trained interviewers identified and questioned women below age 55 years admitted for acute myocardial infarction to the coronary care units of 30 hospitals in Lombardy and a few other areas in northern Italy (Turin, Genova, Verona, and Pisa). The general design of this investigation has already been described." Briefly, a regular liaison with cooperating hospitals was maintained at approximately fortnightly intervals. Less than 2% of the case or control subjects approached for interview refused to participate. A standard questionnaire was used to obtain information on sociodemographic factors, personal characteristics and habits (i.e., cigarette smoking, consumption of alcohol, coffee, and other methylxanthinecontaining beverages), a few selected dietary items, menstrual and reproductive factors (i.e., age at menarche, menopausal status, lifelong menstrual pattern, number of livebirths and abortions, and age at first pregnancy and at first and last birth), and history of
Menstrual and reproductive factors and risk of myocardial infarction
Volume 157 Number 5
11 09
Table I. Distribution of 202 cases of acute myocardial infarction and 374 control subjects according to selected risk factors, Northern Italy, 1983 to 1986 Myocardial infarction Risk factor
Age (yr) <40 40-49 50-54 Cigarette smoking Never Exsmoker Current Diabetes No Yes Hypertension No Yes Hyperlipidemia No Yes History of coronary heart disease in first degree relatives No Yes
I
Controls
I
(%)
No.
35 82 85
(17.3) (40.6) (42.1)
133 134 107
(35.6) (35.8) (28.6)
63 6 133
(31.2) (3.0) (65.8)
245 17 112
(65.5) (4.5) (29.9)
179 23
(88.6) (11.4)
358 16
(95.7) (4.3)
120 82
(59.4) (40.6)
339 35
(90.6) (9.4)
162 40
(80.2) (19.8)
348 26
(93.0) (7.0)
76 126
(37.6) (62.4)
208 166
(55.6) (44.4)
No.
lifetime use of oral contraceptives and female hormones for other indications. The cases studied included 202 women under 55 years of age with a diagnosis of acute myocardial infarction according to the standard World Health Organization criteria. An additional18 patients were considered unsuitable after review of the clinical records, chiefly because of recurrent infarction (n = 10) or uncertain diagnostic criteria (n = 8). The median age was 47 years, and 117 (58%) women were below age 50 years. The control subjects were patients under age 55 years admitted to the same hospitals where cases had been identified for acute diseases other than cardiovascular, malignant, metabolic, hormonal, or gynecologic, which were diagnosed within the year before interview. Further exclusion was made of all primary diagnoses potentially related to cigarette smoking (e.g., peptic ulcer or abdominal hernia) or alcohol consumption (e.g., liver diseases). A total of 374 women 24 to 54 years old were interviewed; the median age was 45 years, and 267 (71 %) were below age 50 years. Among them, 22% were admitted for traumatic conditions (mostly fractures or sprains), 22% had nontraumatic orthopedic disorders (mostly lower back pain and disc disorders), 25% were admitted for surgical conditions (including plastic surgery), and 31% had other illnesses, such as acute infections, skin, ear, nose and throat, or teeth disorders. The present analysis is based on data collected before February 1986. Data analysis. Since cases were older than the com-
(%)
parison group, relative risk estimates (together with their 95% approximate confidence intervals) 12 were derived from data stratified for quinquennia of age by means of the usual Mantel-Haenszel procedure. 13 The significance of the linear trends in risk, where appropriate, was assessed with the test described by Mantel. 14 The potential confounding effect of several factors (geographic area, marital status, education, social class, cigarette smoking, alcohol and coffee consumption, diabetes, hypertension, obesity, hyperlipidemia, family history of ischemic heart disease, oral contraceptive and other female hormone use) was controlled for by means of stratification and the Mantel-Haenszel procedure. 13 Second, identified potential distorting factors were simultaneously controlled for by multiple logistic regression, fitted by the method of maximum likelihood. 12 Included in the regression equations, in addition to the menstrual and reproductive factors considered in this article, were terms for age, geographic area, marital status, education, social class, cigarette smoking, alcohol consumption, diabetes, hypertension, obesity, hyperlipidemia, family history of ischemic heart disease, and oral contraceptive and other female hormone use. Relative risk estimates from multiple logistic models were not materially different from the age-adjusted Mantel-Haenszel estimates, and only the latter are presented in the tables. Results
The distribution of cases and control subjects according to age and risk factors showing significant as-
1110 La Vecchia et al.
November 1987 Am J Obstet Gynecol
Table II. Distribution of 202 women with acute myocardial infarction and 374 control subjects according to selected menstrual characteristics Myocardial infarction
Age at menarche (yr) <12 12-14
2:15
Unknown Menstrual cycle pattern Regular Irregular:j:
Controls
Table III. Distribution of 202 women with acute myocardial infarction and 374 control subjects according to number of livebirths and abortions
Relative risk estimates (95% Cl)*
Myocardial infarction
Controls
0 1-2
35 129
123 156
2:3
38
95
147 37
293 54
18
27
181 21
331 43
No. of livebirths 55
62 258
35 2
54
IIO
161 40
320 52
Unknown Menopausal status Before or during After natural
117 63
252 79
After surgical
22
43
2
It
0.49 (0.31-0.75) 0.61 (0.33-l.l2)
It
1.79 (l.l3-2.86)
It
0.77 (0.44-1.35) 0.69 (0.39-1.23)
CI = Confidence interval. *Mantel-Haenszel estimates adjusted for age m quinquennia. tReference category. :j:Defined as frequent occurrence of menstrual-like episodes less than 21 or more than 35 days apart.
sociation with the risk of myocardial infarction is shown in Table I. Women with myocardial infarction more frequently were smokers and reported a history of diabetes, hypertension, hyperlipidemia, and a family history of coronary heart disease. In Table II the relationship between selected menstrual characteristics and the risk of myocardial infarction is considered. Compared with women whose menarche occurred younger than 12 years, those with later menarche showed a reduced risk of infarction. However, there was no tendency for the risk to decrease with increasing age at menarche. Women with lifelong menstrual irregularities (simply defined as frequent occurrence of menstrual-like episodes less than 21 or more than 35 days apart) were at significantly elevated risk (relative risk = 1.8, 95% confidence interval = 1.1 to 2.9). In contrast, when age was allowed for, no significant relationship was evident between menopausal status and myocardial infarction risk. Allowance for major identified potential distorting factors by means of multiple logistic regression did not materially modify any of these estimates (i.e., multivariate relative risk for irregular menstrual cycle pattern = 2.1, 95% confidence interval = 1.2 to 3.3). There was no consistent pattern of risk according to
No. of miscarriages 0
I
2:2
No. of induced abortions 0 2:}
Relative risks estimates (95% Cl)*
It 1.85 (l.l5-2.96) 0.75 (0.40-1.39)
It
1.03 (0.69-l. 74) 1.08 (0.56-2.06)
It
0.96 (0.54-1.70)
CI = Confidence interval. *Mantel-Haenszel estimates adjusted for age in quinquennia. t Reference category.
the number of livebirths, since the point estimate was above unity for women with one or two children and below unity for those with three or more births compared with nulliparas (Table III). Likewise, there was no relationship between infarction risk and the number of miscarriages or induced abortions (Table III). Relative to women who had never been pregnant, the risk was significantly elevated (relative risk = 2.3, 95% confidence interval = 1.1 to 4.9) for those whose first pregnancy was below age 20 years, and the point estimate was above unity, although not significantly (relative risk = 1.5), for those women whose first pregnancy occurred above age 20 years (Table IV). The pattern of risk was similar with regard to age at first livebirth, and a significant trend of increasing risk with younger age at first livebirth was evident (Table IV). The relationship between early first birth was independent from the major identified potential distorting factors, since the multivariate relative risks were not materially different from the age-adjusted ones (relative risk for women before 20 years old at the first birth = 2.4 and 1.4 for those aged 20 to 24 years). Likewise, the risk of myocardial infarction was significantly elevated (relative risk = 2.1) in women whoselast birth occurred below age 25 years. However, the data are insufficient to allow separate analysis of the effects (and the interactions) of parity and age at first and last birth, which are, of course, strongly correlated. The influence of early births on subsequent myocar-
Volume 157 Number 5
Menstrual and reproductive factors and risk of myocardial infarction
dial infarction risk was long lasting, since the risk estimates were above unity for middle-aged (45 to 54 year) women, as well as for younger ones.
Table IV. Distribution of 202 women with acute myocardial infarction and 379 control subjects according to age at first pregnancy and at first and last livebirth
Comment
The findings of the present study indicate that several aspects of menstrual and reproductive history are related to the subsequent risk of acute myocardial infarction in younger and middle-aged women. The relative risk was significantly elevated for women with frequent irregularities in menstrual cycle and those with earliers pregnancies or births. No consistent association was evident for age at menarche, menopausal status, parity, and number of abortions. It is unlikely that the present findings are largely influenced by obvious bias. The control subjects were admitted for a wide spectrum of acute conditions requiring hospital treatment apparently unrelated to menstrual or reproductive events, and the participation rate was almost complete. Several variables considered (parity, age at first birth, or menopausal status) should not be influenced by recall or information bias, and also for variables whose recall may not be totally reliable (i.e., age at menarche or menstrual cycle pattern), there is little support for different recall by cases and control subjects having any considerable impact on the risk estimates. The potential influence of menstrual and reproductive factors on myocardial infarction risk, in fact, was not known to the interviewers and probably not to most patients either, and the major attention in this study was on the effects of other risk factors, such as exogenous female hormones or smoking. 11 With regard to confounding, the main findings of this study were not materially influenced by allowance for several identified potential distorting factors, including sociodemographic indicators and the major risk factors for myocardial infarction. Thus this study confirms the indication of a casecontrol study based on 169 incidences of coronary heart disease (angina, myocardial infarction, and sudden unexpected death) in women under age 60 years from Rochester, Minnesota, during 1960 to 1979, which showed a relative risk of 1.9 for women whose age at first pregnancy was under 20 years and 1.8 for those 20 to 24 years compared with never pregnant women and those with later first pregnancy. 9 The results of another large North American case-control study were more controversial and not statistically significant, although the point estimates for women whose first pregnancy was below age 25 years were also above unity in that study." A second interesting finding of this study was the elevated risk among women with lifelong irregular menstrual cycle pattern. Although the rather crude definition used for "menstrual irregularity" does not allow precise definition of the biologic correlates of this find-
1111
Myocardial infarction
Controls
24
28
20-24
76
132
2:25
73
106
Nulligravidas (trend)
29
108
21
23
20-24
71
117
2:25
75
Ill
Nulliparas
35
123
39
43
25-29
47
87
2:30
81
121
Nulliparas (trend)
35
123
Age at first pregnancy (yr) <20
x~
Age at first livebirth (yr) <20
xi (trend)
Age at last livebirth (yr) <25
X~
Relative risk estimates (95% Cl)*
2.31 (1.1 0-4.86) 1.52 (0.89-2.59) 1.55 (0.86-2.82) It 3.30 (p"' 0.07) 2.31 (1.1 0-4.87) 1.47 (0.89-2.44) 1.39 (0.80-2.41) It 3.99 (p"' 0.05) 2.14 ( 1.15-3.97) 1.09 (0.60-1. 98) 1.30 (0.75-2.24) It 4.15 (p"' 0.04)
CI "' Confidence interval. *Mantel-Haenszel estimates adjusted for age m quinquennia. tReference category. ing, it is likely that women with menstrual irregularities have more frequent anovular cycles and several steroid hormone imbalances (i.e., hyperandrogenemia). It is, however, still difficult to reconcile in unifying and widely accepted hormonal correlates the various findings of the present study, including the absence of association with menopausal status (which is in agreement with some but not all previous studies). 6 - 8 Likewise, other pathogenetic hypotheses put forward to explain the lower cardiovascular mortality rates in women based, for instance, on the suggestion that menses may provide a mechanism for the elimination of bloodborne factors that participate in atherogenesis 15 are partly (i.e., positive association with irregular menses) but not totally (i.e., absence of association with age at menopause) consistent with the findings of the present study. The influence of the major risk factors in the present
1112 La Vecchia et al.
study (irregular menstrual pattern and age at first pregnancy or birth) was still evident in middle-aged women, that is, after an interval of several years or decades. This suggests that these factors may influence the subsequent risk of myocardial infarction even after a considerable time, as previously indicated from data on the discontinuation of oral contraceptive use. 16 The negative relationship between age at first pregnancy or birth and the risk of ischemic heart disease, if confirmed, would have important public health implications, particularly if a similar relationship is not restricted to younger and middle-aged women analyzed in the present and previous"· 9 work but also applies to older age groups in whom there is a substantially greater incidence of coronary events. 5 • 10 Therefore it appears that the age at which a woman bears her first child is an important correlate of the subsequent history of several important diseases in terms of either direct (i.e., increased risk of breast cancer with increasing age at first livebirth) 17 or, possibly, inverse association (i.e., decreaseq risk of ischemic heart disease with older age at first livebirth). Data processing and analysis were performed at the computing facilities of the Inter-University Consortium of Lombardy for Automatic Data Processing (CILEA). We thank Ms. Laura Flores fof data management, and Ms. Judy Baggott, Ms. Gigliola Brambilla Pisani, and the G. A. Pfeiffer Memorial Library Staff for editorial assistance.
November 1987 Am J Obstet Gynecol
3.
4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
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