Introduction

High parity has been suggested by several studies to be associated with an increased risk of maternal cardiovascular disease (CVD) independent of middle- or older-age body mass index (BMI), while other studies have found no such independent association. Still, pregnancy is associated with persistent weight gain as well as both short-term and long-term metabolic changes, which all, independent of parity, increase the risk of CVD. Therefore, one question to be raised is if high parity independently increases the risk of CVD or if this association may be confounded, mediated, or modified by other parity-related factors. Two factors of specific interest to investigate are weight gain during reproductive years and lactation. While parity seems to be a risk factor for CVD independent of BMI in middle age, BMI is generally considered a suboptimal measure of body fatness. It could be speculated that weight gained from young adulthood into middle age would more accurately capture fat mass accumulated during reproductive years. Moreover, the regional distribution of fat mass, often measured as waist and hip circumference, has been suggested to be more closely related to CVD risk than BMI, but studies on parity and CVD risk have not previously accounted for this. Lactation has been suggested to restore the metabolic system after pregnancy through both short- and long-term favorable changes in lipid profile and insulin sensitivity as well as through reduced postpartum weight retention. Until recently lactation had not been included in studies of the association between parity and risk of CVD, but a newly published article found the risk of coronary heart disease to only be raised in parous women who did not breast-feed.

Therefore, the objective was to investigate the association between parity and risk of CVD among 16,515 Swedish women with particular focus on the potentially mediating effect of overweight, adult weight gain, body composition, and regional fat distribution. Additionally we wanted to examine the impact of lactation on the association between parity and CVD.

Materials and Methods

The Malmö Diet and Cancer Study (MDCS) is a population-based prospective cohort primarily aiming to investigate the relation between diet and other lifestyle factors and the risk of developing cancer. The source population was defined in 1991 as all persons who were born from 1926 through 1945 living in the city of Malmö in southern Sweden. The cohort was extended in 1995 to include all women born from 1923 through 1950 and all men born from 1923 through 1945. The source population consisted of 74,138 persons and approximately 40% of the source population joined the study. The baseline examination in the MDCS cohort was performed from March 1991 through October 1996. Recruitment procedures and the cohort have been described in detail elsewhere. The Ethics Committee at Lund University approved the design of the MDCS (LU 51-90) and all participants gave written consent. Data were collected through physical examination, self-administered questionnaires, and validated registries.

For the present study, 17,035 women (aged 44.5-73.6 years) of the MDCS cohort were eligible. Women with missing data on parity (n = 290) and women with history of myocardial infarction (MI) or stroke at baseline (n = 230) were excluded. Hence, 16,515 women were included in the analyses.

Subjects, in light clothing without shoes, were weighed on a balance scale (kg) and measured on a fixed stadiometer (cm). BMI was calculated as weight (kg) divided by height (m ² ). Waist circumference (cm) was measured midway between the lowest rib bone and the iliac crest. Hip circumference (cm) was measured horizontally at the level over the buttock corresponding to the largest circumference. Body fat (%) was determined using a bioelectrical impedance analyzer (BIA 109; JRL System, Detroit, MI). Weight at 20 years of age was self-reported. Weight change since age 20 years was calculated by subtracting weight at 20 years of age from weight at baseline.

Information on reproductive factors was provided by subjects in the extensive baseline questionnaire. Number of children was categorized as 0, 1, 2, 3, 4, and ≥5. Information on history of miscarriage was provided by the question “Have you ever had any miscarriage?” and the answer was aggregated into yes or no. Duration of lactation was stated as months of breast-feeding per child (any breast-feeding). Cumulative duration of lactation was defined as the sum of months of breast-feeding for all children. Mean lactation per child was defined as the cumulative duration of lactation divided by number of children. Current hormonal replacement therapy (HRT) was defined as HRT use at baseline.

Dietary habits were assessed by using a modified diet history method, combining a 168-item quantitative diet history questionnaire, a 7-day menu book, and a 1-hour dietary interview. Diet quality was evaluated using a diet quality index. Information on other variables were obtained using a self-administered questionnaire. Total physical activity was acquired by combining work activity (sedentary, moderate, heavy, or very heavy), domestic activity (quartiles of hours of household work), and leisure-time physical activity (quartiles of score). Smoking habits were categorized as current (including irregular), former, or never smoker. Educational level was defined as the number of years of completed education or degree of attained educational level, ie, <9 years, 9 years, high school, or university/college degree. Country of birth was categorized as born in Sweden or born abroad. Through the questionnaire, information was acquired on use of lipid-lowering, antihypertensive, and antidiabetic drugs at baseline. History of diabetes at baseline examination was defined by self-reported diabetes (any diabetes) and/or use of antidiabetic drugs. Information on age and gender was obtained through the Swedish personal identification number.

All subjects were followed up from baseline examination until the first incident CVD event (or first MI or first cerebral infarction), death, loss to follow-up, or end of follow-up by Dec. 31, 2010. Endpoint information was obtained from the Swedish Hospital Discharge Register, the National Cause of Death Register, and the Stroke Register of Malmö. Outcomes were coded in accordance with International Classification of Diseases, Ninth Revision ( ICD-9 ) and International Statistical Classification of Diseases, 10th Revision ( ICD-10 ). A CVD event was defined as fatal or nonfatal MI ( ICD-9 : 410A-410X; ICD-10 : I21), fatal or nonfatal cerebral infarction ( ICD-9 : 434; ICD-10 : I63), or death due to ischemic heart disease ( ICD-9 : 410-414; ICD-10 : I20-I25). MI and cerebral infarction were secondary outcomes. Hemorrhagic strokes were not included as an outcome because of differences in etiology as compared to the above stated outcomes.

Differences in baseline characteristics across parity categories were examined by analysis of variance for continuous variables and by χ ² test for categorical variables. We used Cox proportional hazards model to examine whether parity was associated with risk of CVD, MI, and cerebral infarction. Being the largest group, women with 2 children were chosen as reference group. Person-years of follow-up from the entry of the study (baseline examination) until date of CVD diagnosis or censoring due to death, emigration from Sweden, or end of follow-up (Dec. 31, 2010) was used as the underlying time metric. The proportional hazards assumption of the Cox proportional hazards regression was evaluated by including interaction terms between parity and survival time for the respective outcome and by visual inspection of the respective log-cumulative hazard plot.

Diet quality, smoking, physical activity, HRT, education, country of birth, and miscarriage were included as possible confounders in Cox proportional hazards models. To test for differences in the effects of parity by level of other independent variables, interaction analyses were performed by including the corresponding product in the model. Interaction analyses were performed for anthropometric variables, age, smoking, and length of lactation. To simplify the interpretation of the interaction terms, continuous variables were dichotomized. Age was dichotomized according to the median age of 57 years. According to standard cutoffs, waist circumference was dichotomized into <88 cm and ≥88 cm and BMI into <25 kg/m ² and ≥25 kg/m ² , while body fat mass was dichotomized according to the median of 31%. Cutoff for weight gain since age 20 years was set by the 50th percentile, corresponding to a weight gain of 21.7%. For hip circumference the cutoff was set at 97.0 cm corresponding to the 50th percentile. Cutoff for mean lactation per child was set by the 50th percentile, corresponding to a mean time of lactation per child of 4 months. We performed sensitivity analyses by excluding cases diagnosed within the first year after baseline examination.

Statistical analyses were performed in software (SAS, Version 9.3; SAS Institute, Cary, NC). All tests were 2-sided and P values <.05 were considered statistically significant.

Materials and Methods

The Malmö Diet and Cancer Study (MDCS) is a population-based prospective cohort primarily aiming to investigate the relation between diet and other lifestyle factors and the risk of developing cancer. The source population was defined in 1991 as all persons who were born from 1926 through 1945 living in the city of Malmö in southern Sweden. The cohort was extended in 1995 to include all women born from 1923 through 1950 and all men born from 1923 through 1945. The source population consisted of 74,138 persons and approximately 40% of the source population joined the study. The baseline examination in the MDCS cohort was performed from March 1991 through October 1996. Recruitment procedures and the cohort have been described in detail elsewhere. The Ethics Committee at Lund University approved the design of the MDCS (LU 51-90) and all participants gave written consent. Data were collected through physical examination, self-administered questionnaires, and validated registries.

For the present study, 17,035 women (aged 44.5-73.6 years) of the MDCS cohort were eligible. Women with missing data on parity (n = 290) and women with history of myocardial infarction (MI) or stroke at baseline (n = 230) were excluded. Hence, 16,515 women were included in the analyses.

Subjects, in light clothing without shoes, were weighed on a balance scale (kg) and measured on a fixed stadiometer (cm). BMI was calculated as weight (kg) divided by height (m ² ). Waist circumference (cm) was measured midway between the lowest rib bone and the iliac crest. Hip circumference (cm) was measured horizontally at the level over the buttock corresponding to the largest circumference. Body fat (%) was determined using a bioelectrical impedance analyzer (BIA 109; JRL System, Detroit, MI). Weight at 20 years of age was self-reported. Weight change since age 20 years was calculated by subtracting weight at 20 years of age from weight at baseline.

Information on reproductive factors was provided by subjects in the extensive baseline questionnaire. Number of children was categorized as 0, 1, 2, 3, 4, and ≥5. Information on history of miscarriage was provided by the question “Have you ever had any miscarriage?” and the answer was aggregated into yes or no. Duration of lactation was stated as months of breast-feeding per child (any breast-feeding). Cumulative duration of lactation was defined as the sum of months of breast-feeding for all children. Mean lactation per child was defined as the cumulative duration of lactation divided by number of children. Current hormonal replacement therapy (HRT) was defined as HRT use at baseline.

Dietary habits were assessed by using a modified diet history method, combining a 168-item quantitative diet history questionnaire, a 7-day menu book, and a 1-hour dietary interview. Diet quality was evaluated using a diet quality index. Information on other variables were obtained using a self-administered questionnaire. Total physical activity was acquired by combining work activity (sedentary, moderate, heavy, or very heavy), domestic activity (quartiles of hours of household work), and leisure-time physical activity (quartiles of score). Smoking habits were categorized as current (including irregular), former, or never smoker. Educational level was defined as the number of years of completed education or degree of attained educational level, ie, <9 years, 9 years, high school, or university/college degree. Country of birth was categorized as born in Sweden or born abroad. Through the questionnaire, information was acquired on use of lipid-lowering, antihypertensive, and antidiabetic drugs at baseline. History of diabetes at baseline examination was defined by self-reported diabetes (any diabetes) and/or use of antidiabetic drugs. Information on age and gender was obtained through the Swedish personal identification number.

All subjects were followed up from baseline examination until the first incident CVD event (or first MI or first cerebral infarction), death, loss to follow-up, or end of follow-up by Dec. 31, 2010. Endpoint information was obtained from the Swedish Hospital Discharge Register, the National Cause of Death Register, and the Stroke Register of Malmö. Outcomes were coded in accordance with International Classification of Diseases, Ninth Revision ( ICD-9 ) and International Statistical Classification of Diseases, 10th Revision ( ICD-10 ). A CVD event was defined as fatal or nonfatal MI ( ICD-9 : 410A-410X; ICD-10 : I21), fatal or nonfatal cerebral infarction ( ICD-9 : 434; ICD-10 : I63), or death due to ischemic heart disease ( ICD-9 : 410-414; ICD-10 : I20-I25). MI and cerebral infarction were secondary outcomes. Hemorrhagic strokes were not included as an outcome because of differences in etiology as compared to the above stated outcomes.

Differences in baseline characteristics across parity categories were examined by analysis of variance for continuous variables and by χ ² test for categorical variables. We used Cox proportional hazards model to examine whether parity was associated with risk of CVD, MI, and cerebral infarction. Being the largest group, women with 2 children were chosen as reference group. Person-years of follow-up from the entry of the study (baseline examination) until date of CVD diagnosis or censoring due to death, emigration from Sweden, or end of follow-up (Dec. 31, 2010) was used as the underlying time metric. The proportional hazards assumption of the Cox proportional hazards regression was evaluated by including interaction terms between parity and survival time for the respective outcome and by visual inspection of the respective log-cumulative hazard plot.

Diet quality, smoking, physical activity, HRT, education, country of birth, and miscarriage were included as possible confounders in Cox proportional hazards models. To test for differences in the effects of parity by level of other independent variables, interaction analyses were performed by including the corresponding product in the model. Interaction analyses were performed for anthropometric variables, age, smoking, and length of lactation. To simplify the interpretation of the interaction terms, continuous variables were dichotomized. Age was dichotomized according to the median age of 57 years. According to standard cutoffs, waist circumference was dichotomized into <88 cm and ≥88 cm and BMI into <25 kg/m ² and ≥25 kg/m ² , while body fat mass was dichotomized according to the median of 31%. Cutoff for weight gain since age 20 years was set by the 50th percentile, corresponding to a weight gain of 21.7%. For hip circumference the cutoff was set at 97.0 cm corresponding to the 50th percentile. Cutoff for mean lactation per child was set by the 50th percentile, corresponding to a mean time of lactation per child of 4 months. We performed sensitivity analyses by excluding cases diagnosed within the first year after baseline examination.

Statistical analyses were performed in software (SAS, Version 9.3; SAS Institute, Cary, NC). All tests were 2-sided and P values <.05 were considered statistically significant.

Results

The median follow-up time (10th-90th percentile) for CVD event was 15.8 years (10.5-18.7). During follow-up 1501 events of CVD, 779 events of MI, and 761 events of cerebral infarction occurred. Each woman could contribute with >1 endpoint.

Table 1 shows baseline characteristics of the study participants by parity. Grand multiparous women (≥5 children) were older, more likely to be current smokers, and more likely to have lower physical activity. They also had less education and were more likely to be born outside Sweden. Moreover, grand multiparity was associated with younger age at birth of the first child, longer cumulative duration of lactation, and increased history of having at least 1 miscarriage. Grand multiparity was also associated with higher prevalence of antidiabetic drug use and history of diabetes. Parity associated positively to all anthropometric measures ( Table 1 ), and adjustment for potential confounders hardly changed these results (data not shown). The positive associations between parity and the anthropometric variables remained also in analyses stratified by mean lactation per child (data not shown).

In age-adjusted models, grand multiparity was associated with increased risk of a CVD event as well as events due to MI or cerebral infarction ( Table 2 ). Adding baseline BMI, waist circumference, hip circumference, body fat mass, weight change since age 20 years, and BMI at age 20 years to the models, 1 at a time, all reduced the risk estimates of grand multiparity (data not shown). Adjusting simultaneously for both baseline BMI and weight change since age 20 years did not further attenuate the association, and even after adjustment for diet quality, smoking habits, physical activity, educational level, current HRT, country of birth, and history of miscarriage, the risk remained significantly increased in grand multiparous women for CVD (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.02–1.87, P = .04) and MI (HR, 1.53; 95% CI, 1.04–2.26, P = .03), while the risk of cerebral infarction was attenuated to nonsignificance (HR, 1.45; 95% CI, 0.95–2.22). Further adjusting for mean lactation time per child in parous women only marginally changed the risk estimates (data not shown). Interaction terms between parity and anthropometric measures were nonsignificant for all outcomes, as were interaction terms between parity and age. There was, however, a tendency toward higher estimates for the younger compared to the older grand multiparous women for all outcomes (data not shown). The risk of CVD in the younger grand multiparous women was significantly increased compared to the reference group (HR, 2.56; 95% CI, 1.30–5.08) while the older grand multiparous women did not exhibit any significantly higher risk (HR, 1.23; 95% CI, 0.88–1.72). All other estimates in age-stratified analyses were nonsignificant.

Table 2

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