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Duration of lactation and incidence of myocardial infarction in middle to late adulthood

  • Alison M. Stuebe
    Correspondence
    Reprints: Alison M. Stuebe, MD, MSc, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, School of Medicine, University of North Carolina at Chapel Hill, 3010 Old Clinic Building, CB#7516, Chapel Hill, NC 27599-7516
    Affiliations
    Division of Maternal-Fetal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
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  • Karin B. Michels
    Affiliations
    Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

    Department of Obstetrics, Gynecology, and Reproductive Biology, and Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

    Department of Epidemiology, Harvard School of Public Health, Boston, MA
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  • Walter C. Willett
    Affiliations
    Department of Obstetrics, Gynecology, and Reproductive Biology, and Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

    Department of Nutrition, Harvard School of Public Health, Boston, MA

    Department of Epidemiology, Harvard School of Public Health, Boston, MA
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  • JoAnn E. Manson
    Affiliations
    Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

    Department of Epidemiology, Harvard School of Public Health, Boston, MA
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  • Kathryn Rexrode
    Affiliations
    Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
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  • Janet W. Rich-Edwards
    Affiliations
    Connors Center for Women's Health and Gender Biology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

    Department of Epidemiology, Harvard School of Public Health, Boston, MA
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Published:December 29, 2008DOI:https://doi.org/10.1016/j.ajog.2008.10.001

      Objective

      We assessed the relation between duration of lactation and maternal incident myocardial infarction.

      Study Design

      This was a prospective cohort study of 89,326 parous women in the Nurses' Health Study.

      Results

      During 1,350,965 person-years of follow-up, 2540 cases of coronary heart disease were diagnosed. Compared with parous women who had never breastfed, women who had breastfed for a lifetime total of 2 years or longer had 37% lower risk of coronary heart disease (95% confidence interval, 23-49%; P for trend < .001), adjusting for age, parity, and stillbirth history. With additional adjustment for early-adult adiposity, parental history, and lifestyle factors, women who had breastfed for a lifetime total of 2 years or longer had a 23% lower risk of coronary heart disease (95% confidence interval, 6-38%; P for trend = .02) than women who had never breastfed.

      Conclusion

      In a large, prospective cohort, long duration of lactation was associated with a reduced risk of coronary heart disease.

      Key words

      Heart disease remains the leading cause of death for women in the United States.
      • Anderson R.N.
      • Smith B.L.
      Deaths: leading causes for 2002.
      Multiple lifestyle factors contribute to heart disease risk. In addition, hypertension, high cholesterol, and diabetes increase the risk for myocardial infarction.
      See related editorial, page 119
      For Editors' Commentary, see Table of Contents
      Both animal and human studies suggest that lactation may alter maternal glucose and lipid homeostasis and affect blood pressure regulation. Animal studies suggest that lactation has significant effects on lipid homeostasis,
      • Smith J.L.
      • Lear S.R.
      • Forte T.M.
      • Ko W.
      • Massimi M.
      • Erickson S.K.
      Effect of pregnancy and lactation on lipoprotein and cholesterol metabolism in the rat.
      and breast-feeding women have lower triglyceride
      • Darmady J.M.
      • Postle A.D.
      Lipid metabolism in pregnancy.
      and higher high-density lipoprotein (HDL) cholesterol
      • Knopp R.H.
      • Walden C.E.
      • Wahl P.W.
      • et al.
      Effect of postpartum lactation on lipoprotein lipids and apoproteins.
      levels. Moreover, both animal models
      • Katz M.
      • Creasy R.K.
      Cardiovascular and mammary blood flow alterations during pregnancy and nursing in the rabbit.
      • Petersson M.
      • Alster P.
      • Lundeberg T.
      • Uvnas-Moberg K.
      Oxytocin causes a long-term decrease of blood pressure in female and male rats.
      and human studies
      • Light K.C.
      • Smith T.E.
      • Johns J.M.
      • Brownley K.A.
      • Hofheimer J.A.
      • Amico J.A.
      Oxytocin responsivity in mothers of infants: a preliminary study of relationships with blood pressure during laboratory stress and normal ambulatory activity.
      • Mezzacappa E.S.
      • Kelsey R.M.
      • Myers M.M.
      • Katkin E.S.
      Breast-feeding and maternal cardiovascular function.
      • Robson S.C.
      • Dunlop W.
      • Boys R.J.
      • Hunter S.
      Haemodynamic effects of breast-feeding.
      indicate that lactation reduces blood pressure and heart rate.
      Although these studies document metabolic differences during breast-feeding, epidemiologic data suggest these changes may persist after weaning. In a recent large cohort study, each year of cumulative lactation was associated with a 15% reduction in a woman's risk of developing type 2 diabetes in the 15 years after giving birth.
      • Stuebe A.M.
      • Rich-Edwards J.W.
      • Willett W.C.
      • Manson J.E.
      • Michels K.B.
      Duration of lactation and incidence of type 2 Diabetes.
      Other recent studies have found lactation to be positively associated with HDL cholesterol levels
      • Gunderson E.P.
      • Lewis C.E.
      • Wei G.S.
      • Whitmer R.A.
      • Quesenberry C.P.
      • Sidney S.
      Lactation and changes in maternal metabolic risk factors.
      and inversely associated with hypertension
      • Lee S.Y.
      • Kim M.T.
      • Jee S.H.
      • Yang H.P.
      Does long-term lactation protect premenopausal women against hypertension risk? A Korean women's cohort study.
      and the metabolic syndrome.
      • Ram K.T.
      • Bobby P.
      • Hailpern S.M.
      • et al.
      Duration of lactation is associated with lower prevalence of the metabolic syndrome in midlife—SWAN, the study of women's health across the nation.
      Collectively, these data suggest that lactation may have an impact on cardiovascular disease risk.
      Although several authors have examined the effects of lactation on risk factors for cardiovascular disease, to our knowledge no study has examined the association between lactation and cardiovascular events. We therefore studied the association between lactation history and incident fatal and nonfatal myocardial infarction in the Nurses' Health Study (NHS).

      Materials and Methods

      The NHS began in 1976, enrolling 121,700 women from 11 states for a longitudinal, prospective study of women's health. At baseline, participants were between 30 and 55 years of age, and each woman completed a detailed questionnaire regarding medical diagnoses, lifestyle, and reproductive and other variables. Every 2 years, participants completed follow-up questionnaires regarding medical diagnoses and health-related topics.
      • Colditz G.A.
      • Manson J.E.
      • Hankinson S.E.
      The Nurses' Health Study: 20-year contribution to the understanding of health among women.

      Assessment of reproductive and lactation history

      Women in the NHS reported baseline parity in 1976 and incident pregnancies on biennial questionnaires. In 1976, women also reported the number of pregnancies lasting 6 months or more that ended in a stillbirth. Lactation history was assessed once, in 1986, when women reported total duration of lactation for all pregnancies as a categorical variable. At that time, the youngest women in the cohort were 40 years of age, and only 75 births were reported after 1986.

      Ascertainment of myocardial infarction

      In our study, we assessed incident cases of nonfatal myocardial infarction (MI) and mortality caused by coronary heart disease from 1986 to 2002. Women who reported a nonfatal myocardial infarction were asked to release medical records. Physicians blinded to the participants' questionnaires reviewed records to confirm the diagnoses. Confirmed cases met World Health Organization criteria for MI: symptoms associated with diagnostic electrocardiographic changes or elevations in cardiac enzymes.
      Deaths were ascertained from state death records, the national death index, the subject's family, or postal authority reports. Cause of death was determined from hospital records or autopsy, when available. Fatal coronary disease was defined as fatal MI if it was confirmed by hospital records or autopsy, coronary disease was listed as the cause of death on the death certificate and was the underlying and most plausible cause, and evidence of previous coronary disease was available.
      We coded an event as “probable” if the participant reported an infarction that required a hospitalization and was corroborated by a letter or telephone interview but for which hospital records were not obtained. Analyses limited to cases of confirmed coronary heart disease were similar to analyses based on confirmed and probable coronary heart disease; thus, we examined both confirmed and probable cases.

      Ascertainment of covariates

      Women who reported the diagnosis of diabetes on any biennial questionnaire were asked to complete a supplemental form with questions about symptoms, diagnostic tests, and hypoglycemic therapy. Diagnostic criteria and validation for diabetes are reviewed in detail elsewhere.
      • Stuebe A.M.
      • Rich-Edwards J.W.
      • Willett W.C.
      • Manson J.E.
      • Michels K.B.
      Duration of lactation and incidence of type 2 Diabetes.
      Diagnoses of angina, hypertension, or high cholesterol and history of coronary bypass graft surgery were reported on biennial questionnaires. Validation of self-reported hypertension and hypercholesterolemia has been reported elsewhere.
      • Colditz G.A.
      • Martin P.
      • Stampfer M.J.
      • et al.
      Validation of questionnaire information on risk factors and disease outcomes in a prospective cohort study of women.
      Dietary information was collected through detailed food-frequency questionnaires every 4 years. The reproducibility and validity of these questionnaires are described elsewhere.
      • Salvini S.
      • Hunter D.
      • Sampson L.
      • et al.
      Food-based validation of a dietary questionnaire: the effects of week-to-week variation in food consumption.
      • Willett W.C.
      Nutritional epidemiology.
      We calculated a diet score of 1-5 for each woman, based on her quintile of intake of cereal fiber, polyunsaturated fat, trans fat (inverse), and glycemic load (inverse). The higher the score, the better the woman's dietary risk profile.
      • Hu F.B.
      • Manson J.E.
      • Stampfer M.J.
      • et al.
      Diet, lifestyle, and the risk of type 2 diabetes mellitus in women.
      For this analysis, we used data on alcohol consumption reported in 1984, 1986, 1990, 1994, and 1998 and used data on aspirin use reported in 1984 and on each questionnaire from 1988 to 2000. We assessed multivitamin use as reported on each questionnaire from 1986 to 2000.
      We assessed physical activity as reported on questionnaires in 1986, 1988, 1992, 1994, 1996, 1998, and 2000. From these data, we calculated total hours per week engaged in a specified list of moderate to vigorous activities. The reproducibility and validity of self-reported physical activity are described elsewhere.
      • Wolf A.
      • Hunter D.
      • Colditz G.
      • et al.
      Reproducibility and validity of a self-administered physical activity questionnaire.
      Women reported their current height and weight in the baseline enrollment survey in 1976, and they reported weight at age 18 years in 1980. Weight was reassessed with each biennial questionnaire. Self-reported weights are highly correlated with measured weights in our cohort (r = 0.96).
      • Willett W.
      • Stampfer M.J.
      • Bain C.
      • et al.
      Cigarette smoking, relative weight, and menopause.
      Women reported past and current smoking history on each biennial questionnaire. Parental history of diabetes was reported in NHS in 1982 and 1988, and parental history of MI before age 60 was reported in 1976 and 1984. Women also provided information on socioeconomic status. At baseline, each participant reported her parents' employment when she was 16 years of age, providing a measure of childhood socioeconomic status. On the 1992 questionnaire, participants reported educational degrees earned, marital status, and their spouse's highest level of education.

      Statistical analysis

      The relative risk of MI by lactation history was assessed using a Cox proportional hazards model. We evaluated proportionality of hazards by assessing the interaction between lactation duration category and time since last birth. Women contributed person-years from 1986, when lactation duration was ascertained, until diagnosis of myocardial infarction, death, or study end date.
      We examined incident cases of MI from 1986, when cohort members were aged 40-65 years, to 2002, at which point they were aged 56-81 years. Month and year of diagnosis was determined by chart review or participant report. We excluded subjects who were nulliparous (n = 7443) or for whom information on parity (n = 2775) or duration of lactation (n = 17,685) was missing. Parity and baseline body mass index among women missing lactation data were similar to those for whom lactation data were available. We further excluded parous women who had reported only stillbirths (n = 210) or had a history of MI (n = 517), angina (n = 3572), or coronary artery bypass graft (n = 148) before 1986.
      Lifetime lactation history among parous women was stratified into 6 groups: none (referent), longer than 0-3 months, longer than 3-6 months, longer than 6-11 months, longer than 11-23 months, and longer than 23 months. Because our data were reported categorically, we used categorical variables to model our primary analysis. We used midpoints of lactation categories to assess linear trend. A value of 24 months was assigned to participants with greater than 23 months lactation. Two-sided P values are reported for trends, and 95% confidence intervals are reported for hazard ratio estimates.
      All models were age adjusted and included parity and whether the participant had reported any stillbirths. In our adjusted model, we included coronary risk factors and lifestyle factors. To adjust for coronary disease risk, we included participant birthweight, parental history of MI, and body mass index (BMI) at age 18 years. To adjust for lifestyle factors, we also included dietary score quintile, exercise (hours per week), smoking status, multivitamin use, postmenopausal hormone use, aspirin use, and alcohol consumption.
      To assess whether socioeconomic status confounded the association between breastfeeding and MI, we further adjusted for parental occupation, participant degrees earned, marital status, and partner's education. We hypothesized that lactation may have an impact on cardiovascular risk through its effects on hypertension, diabetes, hyperlipidemia, and BMI. To test this hypothesis, we added these intermediates to our covariate-adjusted model to assess whether their inclusion attenuated the observed association.
      We included only covariates in our multivariate models that were a priori suspected risk factors for MI to avoid overfitting. Diet, physical activity, parity, diabetes, hypertension, high cholesterol, current BMI, and smoking status were updated at 2-year intervals.
      BMI was modeled as a continuous variable, whereas BMI at age 18 years (normal, < 25; overweight, ≤ 25-30; or obese, > 30 kg/m2), diet score (quintiles 1-5), hours per week of moderate to vigorous physical activity (< 1, 1 to < 2, 2 to < 4, 4 to < 7, or ≥ 7), birthweight (> 5.5 lb or ≥ 5.5 lb), parity (1, 2, 3, 4, or ≥ 5 births), multivitamin use (yes or no), aspirin use (yes or no), alcohol consumption (0, 0.1-4.9, 5.0-14.9, or ≥ 15.0 g/day), and smoking status (never; past; current, 1-4, 5-14, 15-24, 25-34, 35-44, or ≥ cigarettes/day) were modeled as categorical variables.
      In previous work relating duration of lactation to risk of type 2 diabetes,
      • Stuebe A.M.
      • Rich-Edwards J.W.
      • Willett W.C.
      • Manson J.E.
      • Michels K.B.
      Duration of lactation and incidence of type 2 Diabetes.
      we observed an attenuation of the association with increasing time since last birth. To assess whether the association between lactation and myocardial infarction risk also diminished with time since last birth, we performed a stratified analysis. Women were divided into 2 groups: those with a birth in the previous 30 years and those without a birth in the previous 30 years. We used a cutoff of 30 years to split incident cases of MI evenly. To test for differences in the effects of lactation by parity, we added an interaction term to the covariate-adjusted model.
      For subjects with missing data on covariates, we created a missing indicator variable. We used this approach for subjects lacking data on current BMI, BMI at age 18 years, diet, physical activity, birthweight of subject, smoking status, postmenopausal hormone use, aspirin use, alcohol consumption, and multivitamin use. To assess the impact of missing data on our results, we performed a sensitivity analysis limited to participants with complete covariate data.
      The institutional review board of the Brigham and Women's Hospital approved the study.

      Results

      A total of 89,326 parous women reported lifetime duration of lactation and were eligible for the study. Of these, 63% had ever breastfed. One percent of women reported breastfeeding for 48 months or more, which was the longest duration category assessed. As expected, higher parity was associated with longer duration of lactation. Women who breastfed for longer periods of time were less likely to report a diagnosis of hypertension, high cholesterol, or diabetes; to report a parental history of MI; to have ever smoked; and to be postmenopausal in 1986 (Table 1).
      TABLE 1Age-standardized baseline characteristics of parous women in the Nurses' Health Study in 1986, by duration of lactation (in percent unless indicated otherwise)
      Directly standardized in years to the age distribution of NHS;
      CharacteristicDuration of lactation (mo)
      None> 0-3> 3-6> 6-11> 11-23> 23
      Number of person-years494,667306,669161,586132,492164,74690,805
      BMI, mean25.425.425.125.125.225.5
      BMI age 18 y, mean21.421.421.321.221.221.2
      Hypertension23.322.521.620.319.718.5
      High cholesterol7.37.27.87.06.76.3
      Type 2 diabetes2.11.91.71.61.71.8
      Parental history of MI prior to age 60 y18.418.117.517.416.816.4
      Subject > 5.5 lb at birth7.47.76.67.27.06.7
      Moderate to vigorous exercise (mean hours per wk)1.91.82.12.12.22.2
      Mean diet score
      Intakes of trans fat and cereal fiber, ratio of polyunsaturated fat to saturated fat, and glycemic load were divided into quintiles. Each woman was then assigned a diet score for each nutrient based on her quintile of intake, with a higher score representing a lower risk. The 4 scores were summed, and the mean composite score is presented here;
      2.93.23.03.13.03.0
      Parity
       1 child11.28.37.74.71.50.8
       2 children34.231.032.631.923.88.5
       ≥ 3 children54.660.759.863.474.790.7
      History of stillbirth3.43.23.23.03.13.3
      Smoking history
      Does not total 100% because of missing data. Covariate data were missing for the following proportions: BMI at age 18 years, 13.1%; physical activity, 2.8%; diet score, 6.7%; smoking, 1.1%; participant birthweight, 32.7%; multivitamin use, 5.7%; postmenopausal hormone use, 9.3%; alcohol use, 6.7%; aspirin use, 2.2%;
       Never smoker39.643.043.647.050.055.9
       Past smoker34.535.534.133.632.929.7
       Current smoker25.821.422.019.216.914.2
      Menopausal54.056.752.650.249.347.9
      Hormone replacement therapy
      Percentage of full study cohort.
       Never25.425.722.622.922.924.8
       Past11.812.911.710.910.19.2
       Current12.314.713.913.112.710.0
      Multivitamin use33.841.138.740.439.938.2
      Aspirin use, > 1 tablet/wk63.769.965.165.965.663.2
      No alcohol use24.130.221.824.524.626.5
      Stuebe. Duration of lactation and incidence of MI. Am J Obstet Gynecol 2009.
      a Directly standardized in years to the age distribution of NHS;
      b Intakes of trans fat and cereal fiber, ratio of polyunsaturated fat to saturated fat, and glycemic load were divided into quintiles. Each woman was then assigned a diet score for each nutrient based on her quintile of intake, with a higher score representing a lower risk. The 4 scores were summed, and the mean composite score is presented here;
      c Does not total 100% because of missing data. Covariate data were missing for the following proportions: BMI at age 18 years, 13.1%; physical activity, 2.8%; diet score, 6.7%; smoking, 1.1%; participant birthweight, 32.7%; multivitamin use, 5.7%; postmenopausal hormone use, 9.3%; alcohol use, 6.7%; aspirin use, 2.2%;
      d Percentage of full study cohort.
      During the study period, 2540 incident cases of MI or death because of coronary heart disease were diagnosed during 1,350,965 person-years of follow-up. In the model adjusting for age, parity, and history of stillbirth (Table 2), more than 23 months of lifetime lactation was associated with a hazard ratio (HR) of 0.63 (95% confidence interval [CI], 0.51-0.77) for incident MI, compared with women who had never breastfed (P for trend < .001). When coronary and lifestyle risk factors were added to the model, we found an HR of 0.77 (95% CI, 0.62-0.94) for women with more than 23 months of lifetime lactation (P for trend = .02). When we included measures of childhood and adult socioeconomic status in our analysis, the association between more than 23 months of lifetime lactation and MI remained unchanged (HR, 0.77; 95% CI, 0.62-0.96). Similarly, when we excluded participants with missing covariate data, the point estimate for more than 23 months of lifetime lactation was unchanged (HR, 0.78; 95% CI, 0.62-0.99).
      TABLE 2Incident MI and duration of lactation among parous women in the Nurses' Health Study: prospective analysis using cases from 1986 to 2002
      Cumulative duration of lactation (mo)None> 0-3> 3-6> 6-11> 11-23> 23P for trend
      Cases, n1037627304224241107
      Person-years494,667306,669161,586132,492164,74690,805
      Age, parity, and stillbirth-adjusted HR (95% CI)1.0 (ref)0.90 (0.81-0.99)0.91 (0.8-1.03)0.88 (0.76-1.02)0.77 (0.67-0.89)0.63 (0.51-0.77)< .0001
      Multivariate-adjusted HR (95% CI)
      Hazard ratio and 95% confidence interval (CI) adjusted for age; parity; history of stillbirth; body mass index (BMI) at age 18 years; birthweight of subject; parental history of MI before age 60 years; diet quintile; physical activity; smoking; menopausal status; and use of aspirin, alcohol, multivitamins, and postmenopausal hormones.
      1.0 (ref)1.01 (0.91-1.11)1 (0.88-1.14)1.02 (0.88-1.18)0.93 (0.8-1.07)0.77 (0.62-0.94).02
      All models were adjusted for age, parity, and history of stillbirth.
      Stuebe. Duration of lactation and incidence of MI. Am J Obstet Gynecol 2009.
      a Hazard ratio and 95% confidence interval (CI) adjusted for age; parity; history of stillbirth; body mass index (BMI) at age 18 years; birthweight of subject; parental history of MI before age 60 years; diet quintile; physical activity; smoking; menopausal status; and use of aspirin, alcohol, multivitamins, and postmenopausal hormones.
      We used an interaction term between time since last birth and duration category to test for proportionality of hazards and found no significant effect modification (P = .77) in our multivariate-adjusted model.
      Women who had breastfed for more than 1 year had a coronary and lifestyle-covariate adjusted risk of 0.87 (95% CI, 0.77-0.99) compared with women who had never breastfed. The interaction between lactation duration and parity was not significant (log likelihood test P = .21). The small numbers of cases in analyses stratified by parity did not allow us to distinguish between the effects of long lactation for a single pregnancy vs shorter durations for multiple pregnancies. Adding potential intermediates, including hypertension, diabetes, hypercholesterolemia, and BMI, to the model resulted in an HR of 0.80 (95% CI, 0.65-0.98) for the group with longest duration of lactation (P for trend = .06).
      As we had hypothesized, stratifying the population by time since last birth revealed a stronger association between lactation and MI in the 30 years after a woman's last birth (Table 3). For women without a birth in the previous 30 years, we found no association between lactation and MI, with a multivariate HR of 0.93 (95% CI, 0.79-1.11) for 1 year or more of lactation, compared with women who had never breastfed. Among women with a birth in the previous 30 years, those who breastfed for 1 year or more had a covariate-adjusted HR of 0.80 (95% CI, 0.66-0.97) compared with those who had never breastfed. Among women with a birth in the previous 30 years, those who breastfed for more than 23 months had a covariate-adjusted HR of 0.66 (95% CI, 0.49-0.89) for incident MI or coronary disease death, compared with women who had never breastfed.
      TABLE 3Incident MI and duration of lactation, stratified by time since last birth among parous women in the Nurses' Health Study: prospective analysis using cases from 1986 to 2002
      Cumulative duration of lactation (mo)None> 0-3> 3-6> 6-11> 11-23> 23P for trend
      No birth in last 30 y
       No of cases61642618613013354
       Person-years211,951146,62567,25049,33854,08221,443
       Age, parity, and stillbirth-adjusted HR (95% CI)1.0 (ref)0.96 (0.85-1.09)0.94 (0.79-1.11)0.91 (0.75-1.1)0.82 (0.68-0.99)0.77 (0.58-1.02)0.01
       Multivariate-adjusted HR (95% CI)
      Hazard ratio (HR) and 95% confidence interval (CI) adjusted for age; parity; history of stillbirth; body mass index (BMI) at age 18 years; birthweight of subject; parental history of MI before age 60 years; diet quintile; physical activity; smoking; menopausal status; and use of aspirin, alcohol, multivitamins, and postmenopausal hormones.
      1.0 (ref)1.04 (0.92-1.18)1.02 (0.86-1.21)1.02 (0.84-1.24)0.95 (0.78-1.15)0.90 (0.67-1.19)0.33
      Birth in last 30 y
       No of cases4212011189410853
       Person-years282,716160,04494,33683,155110,66369,362
       Age, parity and stillbirth-adjusted HR (95% CI)1.0 (ref)0.81 (0.69-0.96)0.87 (0.71-1.07)0.81 (0.65-1.02)0.71 (0.57-0.88)0.50 (0.37-0.67)< .0001
       Multivariate-adjusted HR (95% CI)
      Hazard ratio (HR) and 95% confidence interval (CI) adjusted for age; parity; history of stillbirth; body mass index (BMI) at age 18 years; birthweight of subject; parental history of MI before age 60 years; diet quintile; physical activity; smoking; menopausal status; and use of aspirin, alcohol, multivitamins, and postmenopausal hormones.
      1.0 (ref)0.94 (0.79-1.12)0.98 (0.8-1.21)0.96 (0.76-1.21)0.89 (0.71-1.1)0.66 (0.49-0.89).02
      All models were adjusted for age, parity, and history of stillbirth.
      Stuebe. Duration of lactation and incidence of MI. Am J Obstet Gynecol 2009.
      a Hazard ratio (HR) and 95% confidence interval (CI) adjusted for age; parity; history of stillbirth; body mass index (BMI) at age 18 years; birthweight of subject; parental history of MI before age 60 years; diet quintile; physical activity; smoking; menopausal status; and use of aspirin, alcohol, multivitamins, and postmenopausal hormones.

      Comment

      In this analysis of a large, prospective cohort, we found an inverse association between long duration of lactation and MI, independent of known risk factors for cardiovascular disease, including obesity at age 18 years, parental history of MI, smoking, exercise, diet, aspirin use, alcohol consumption, hormone use, and menopausal status.
      Breastfeeding rates in our study population are comparable with contemporary rates in the United States. All of our study participants were registered nurses, and 63% had ever breastfed. More than 10% of the cohort reported a birth in each year from 1954 to 1968, a period during which overall rates of breastfeeding were declining, from about 70% in 1951 to about 30% in 1966.
      • Lawrence R.A.
      • Lawrence R.M.
      Breastfeeding: a guide for the medical profession.
      In 2005, 73% of US women had ever breastfed, 39% were still breastfeeding at 6 months, and 20% were breastfeeding at 1 year.
      Centers for Disease Control and Prevention
      Breastfeeding practices: results from the 2005 National Immunization Survey.
      These data suggest that, at current breastfeeding rates, a substantial number of US women of childbearing age who give birth to 2 or more children will breastfeed for 2 years or longer.
      Our findings must be interpreted in the context of the study design. All observational studies are subject to confounding, and studies of breastfeeding are particularly challenging in this regard. Animal data and human studies have linked obesity and insulin resistance to difficulties with breastfeeding, suggesting that shortened lactation could be a marker for an aberrant metabolic profile.
      • Rasmussen K.M.
      • Hilson J.A.
      • Kjolhede C.L.
      Obesity may impair lactogenesis II.
      • Sebire N.J.
      • Jolly M.
      • Harris J.P.
      • et al.
      Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London.
      Successful, prolonged breast-feeding depends on a wide range of factors, from a woman's choice to begin nursing to the support she receives from her birth attendant, her infant's pediatrician, her family, and her employer. A woman whose circumstances allow prolonged breastfeeding may live in a less stressful environment and thus face a lower risk of cardiovascular disease.
      Secular trends in breastfeeding duration, diet, exercise, and other health behaviors may also affect our results. Of note, all participants in our study are registered nurses, and 97% are white, so confounding by race or socioeconomic status is less likely than in a more diverse cohort. Moreover, when we adjusted for parental occupation, education, partner's education, and marital status, the effect was minimal, making it unlikely that other unmeasured socioeconomic status variables explain the observed association.
      Misclassification is also a potential concern, because lifetime lactation history was self-reported. Promislow et al
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      • Sandler D.P.
      Maternal recall of breastfeeding duration by elderly women.
      examined maternal recall of breastfeeding duration among women aged 69-79 years. The authors compared self-reported duration with prospectively recorded menstrual diaries collected between 1940 and 1966. They observed an overall correlation of 0.55, with a mean difference between recorded and recalled duration of 0 months (SD, 2.7), indicating misclassification but no overall recall bias. Moreover, they found that women with shorter durations tended to overreport, whereas women with longer durations tended to underreport. If such misclassification occurred in our cohort, it would bias our results toward the null. Nevertheless, we observed a substantial, statistically significant association between more than 2 years of lifetime breastfeeding and incident myocardial infarction.
      Notably, we observed a stronger protective association for women who breastfed for longer than 23 months, suggesting either a threshold effect or substantial differences between this group and those with shorter durations of lactation. When we adjusted for multiple coronary risk and lifestyle factors, the inverse association between long duration of breastfeeding and MI was diminished, but the association remained significant, suggesting that other mechanisms also play a role.
      Our findings are consistent with and extend those from earlier reports linking reproductive history to cardiovascular disease risk. Several authors have reported an increased risk of coronary heart disease among women with high parity,
      • Ness R.B.
      • Harris T.
      • Cobb J.
      • et al.
      Number of pregnancies and the subsequent risk of cardiovascular disease.
      • Lawlor D.A.
      • Emberson J.R.
      • Ebrahim S.
      • et al.
      Is the association between parity and coronary heart disease due to biological effects of pregnancy or adverse lifestyle risk factors associated with child-rearing? Findings from the British Women's Heart and Health Study and the British Regional Heart Study.
      although results are mixed
      • de Kleijn M.J.J.
      • van der Schouw Y.T.
      • van der Graaf Y.
      Reproductive history and cardiovascular disease risk in postmenopausal women: a review of the literature.
      • Colditz G.A.
      • Willett W.C.
      • Stampfer M.J.
      • Rosner B.
      • Speizer F.E.
      • Hennekens C.H.
      A prospective study of age at menarche, parity, age at first birth, and coronary heart disease in women.
      • Cooper G.S.
      • Ephross S.A.
      • Weinberg C.R.
      • Baird D.D.
      • Whelan E.A.
      • Sandler D.P.
      Menstrual and reproductive risk factors for ischemic heart disease.
      and may be confounded by socioeconomic status.
      • Steenland K.
      • Lally C.
      • Thun M.
      Parity and coronary heart disease among women in the American Cancer Society CPS II population.
      Preeclampsia and stillbirth
      • Irgens H.U.
      • Reisaeter L.
      • Irgens L.M.
      • Lie R.T.
      Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study.
      • Ray J.G.
      • Vermeulen M.J.
      • Schull M.J.
      • Redelmeier D.A.
      Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
      have also been linked to subsequent cardiovascular risk. Both animal and human studies suggest biologically plausible mechanisms for an association between lactation and coronary heart disease. Lactation influences carbohydrate and lipid metabolism, and oxytocin has been linked to regulation of blood pressure and cardiovascular function.
      Studies in animal models
      • Burnol A.F.
      • Leturque A.
      • Ferre P.
      • Kande J.
      • Girard J.
      Increased insulin sensitivity and responsiveness during lactation in rats.
      • Jones R.G.
      • Ilic V.
      • Williamson D.H.
      Physiological significance of altered insulin metabolism in the conscious rat during lactation.
      and lactating women
      • Butte N.F.
      • Hopkinson J.M.
      • Mehta N.
      • Moon J.K.
      • Smith E.O.
      Adjustments in energy expenditure and substrate utilization during late pregnancy and lactation.
      show that lactation is associated with decreased postpartum insulin resistance, lower insulin-glucose ratios, and increased carbohydrate utilization. Differences in lactation physiology among rodents, ruminants, and humans limit extrapolation of animal data to humans;
      • Bell A.W.
      • Bauman D.E.
      Adaptations of glucose metabolism during pregnancy and lactation.
      however, epidemiologic studies suggest that human lactation is associated with beneficial long-term changes in glucose metabolism. In a previous analysis in the NHS, we found that lifetime lactation was inversely associated with incident type 2 diabetes,
      • Stuebe A.M.
      • Rich-Edwards J.W.
      • Willett W.C.
      • Manson J.E.
      • Michels K.B.
      Duration of lactation and incidence of type 2 Diabetes.
      and a recent study of middle-aged women found an inverse association between lactation and the metabolic syndrome.
      • Ram K.T.
      • Bobby P.
      • Hailpern S.M.
      • et al.
      Duration of lactation is associated with lower prevalence of the metabolic syndrome in midlife—SWAN, the study of women's health across the nation.
      The association of lactation with incident diabetes among women with gestational diabetes is less clear.
      • Kjos S.L.
      • Henry O.
      • Lee R.M.
      • Buchanan T.A.
      • Mishell Jr, D.R.
      The effect of lactation on glucose and lipid metabolism in women with recent gestational diabetes.
      • McManus R.M.
      • Cunningham I.
      • Watson A.
      • Harker L.
      • Finegood D.T.
      Beta-cell function and visceral fat in lactating women with a history of gestational diabetes.
      Both animal and human studies suggest that lactation affects lipid metabolism.
      • Vernon R.G.
      • Pond C.M.
      Adaptations of maternal adipose tissue to lactation.
      In the rat, lipids accumulate in adipose tissue during pregnancy and are mobilized during lactation through local lipoprotein lipase activity.
      • Hamosh M.
      • Clary T.R.
      • Chernick S.S.
      • Scow R.O.
      Lipoprotein lipase activity of adipose and mammary tissue and plasma triglyceride in pregnant and lactating rats.
      • Da Costa T.H.
      • Williamson D.H.
      Regulation of rat mammary-gland uptake of orally administered [1-14C]triolein by insulin and prolactin: evidence for bihormonal control of lipoprotein lipase activity.
      Moreover, lactating rats have reduced visceral fat stores,
      • Moore B.J.
      • Brasel J.A.
      One cycle of reproduction consisting of pregnancy, lactation or no lactation, and recovery: effects on carcass composition in ad libitum-fed and food-restricted rats.
      smaller adipose cells, and reduced peripheral levels of lipoprotein lipase
      • Steingrimsdottir L.
      • Brasel J.A.
      • Greenwood M.R.
      Diet, pregnancy, and lactation: effects on adipose tissue, lipoprotein lipase, and fat cell size.
      compared with nonlactating animals.
      Differences in regional adipose tissue activity during pregnancy and lactation have also been observed in humans.
      • Rebuffe-Scrive M.
      • Enk L.
      • Crona N.
      • et al.
      Fat cell metabolism in different regions in women Effect of menstrual cycle, pregnancy, and lactation.
      These data suggest that women who do not lactate may have greater difficulty mobilizing fat stores after delivery, although data linking lactation with long-term adiposity in human populations are mixed.
      • Butte N.F.
      • Hopkinson J.M.
      Body composition changes during lactation are highly variable among women.
      Pregnancy is also associated with a physiologic increase in serum triglycerides and total cholesterol. These changes resolve more rapidly in women who breastfeed than in those who do not.
      • Darmady J.M.
      • Postle A.D.
      Lipid metabolism in pregnancy.
      Lactating women also have higher levels of HDL cholesterol and apolipoprotein AI than their nonlactating counterparts.
      • Knopp R.H.
      • Walden C.E.
      • Wahl P.W.
      • et al.
      Effect of postpartum lactation on lipoprotein lipids and apoproteins.
      • Kjos S.L.
      • Henry O.
      • Lee R.M.
      • Buchanan T.A.
      • Mishell Jr, D.R.
      The effect of lactation on glucose and lipid metabolism in women with recent gestational diabetes.
      • Erkkola R.
      • Viikari J.
      • Irjala K.
      • Solakivi-Jaakkola T.
      One-year follow-up of lipoprotein metabolism after pregnancy.
      In a recent prospective cohort study, Gunderson et al
      • Gunderson E.P.
      • Lewis C.E.
      • Wei G.S.
      • Whitmer R.A.
      • Quesenberry C.P.
      • Sidney S.
      Lactation and changes in maternal metabolic risk factors.
      reported that these favorable changes in lipid metabolism persist after weaning, suggesting that lactation has a lasting effect on maternal metabolism.
      Lactation may also modify cardiovascular risk through changes in stress response. A recent study found a modest protective association between lactation history and incident hypertension.
      • Lee S.Y.
      • Kim M.T.
      • Jee S.H.
      • Yang H.P.
      Does long-term lactation protect premenopausal women against hypertension risk? A Korean women's cohort study.
      Animal studies suggest that oxytocin, which is released during milk letdown, may affect blood pressure regulation. Petersson et al
      • Petersson M.
      • Lundeberg T.
      • Uvnas-Moberg K.
      Short-term increase and long-term decrease of blood pressure in response to oxytocin-potentiating effect of female steroid hormones.
      found that oxytocin administration produced decreases in blood pressure in rats that persisted for weeks after discontinuation, despite the drug's brief half-life. The authors postulate that oxytocin administration leads to long-term changes in central regulatory pathways. Similarly, observational studies
      • Light K.C.
      • Smith T.E.
      • Johns J.M.
      • Brownley K.A.
      • Hofheimer J.A.
      • Amico J.A.
      Oxytocin responsivity in mothers of infants: a preliminary study of relationships with blood pressure during laboratory stress and normal ambulatory activity.
      • Mezzacappa E.S.
      • Kelsey R.M.
      • Katkin E.S.
      Breast feeding, bottle feeding, and maternal autonomic responses to stress.
      • Johnston J.M.
      • Amico J.A.
      A prospective longitudinal study of the release of oxytocin and prolactin in response to infant suckling in long term lactation.
      • Heinrichs M.
      • Meinlschmidt G.
      • Neumann I.
      • et al.
      Effects of suckling on hypothalamic-pituitary-adrenal axis responses to psychosocial stress in postpartum lactating women.
      • Altemus M.
      • Redwine L.S.
      • Leong Y.-M.
      • Frye C.A.
      • Porges S.W.
      • Carter C.S.
      Responses to laboratory psychosocial stress in postpartum women.
      suggest that nursing mothers have diminished autonomic responses to stressors.
      These observations suggest an important role for lactation in women's health. Fat stores accumulate during pregnancy, assuring that the mother will have adequate resources to compensate for variations in local food supply during the neonatal period.
      • Dall S.R.
      • Boyd I.L.
      Evolution of mammals: lactation helps mothers to cope with unreliable food supplies.
      If these resources are not mobilized during lactation, women may accumulate adipose tissue, and pregnancy-associated metabolic changes may persist for a longer period of time. We speculate that this impaired resetting of postpartum physiology may contribute to long-term disease risk. Further studies will be needed to test this hypothesis.
      In conclusion, we have identified a novel association between more than 2 years of lifetime lactation and MI risk in a large, prospective cohort. This association persists after controlling for multiple lifestyle factors. Studies of metabolic risk profiles among contemporary women are needed to delineate further the relation between lactation and cardiovascular disease risk.

      Acknowledgments

      We thank Bernard Rosner, PhD, for advice on statistical analysis and Karen Corsano and Eileen Hibert for technical support. Members of the Nurses' Health Study were recruited in 1976 from California, Connecticut, Florida, Maryland, Massachusetts, Michigan, New Jersey, New York, Ohio, Pennsylvania and Texas.

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      Linked Article

      • Prospective evidence that lactation protects against cardiovascular disease in women
        American Journal of Obstetrics & GynecologyVol. 200Issue 2
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          In this issue of the Journal, the article by Stuebe et al,1 “Duration of lactation and incidence of myocardial infarction in middle-to-late adulthood,” presents the first evidence that lifetime lactation may influence the onset of cardiovascular events in women beyond the childbearing years. Their findings extend previous work establishing that lactating women exhibit more favorable cardiometabolic profiles (ie, increased high-density lipoprotein cholesterol [HDL-C], lower triglyceride and glucose levels) than nonlactating women.
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