|Year : 2020 | Volume
| Issue : 2 | Page : 45-50
A study of reproductive factors in Indian women predisposing to coronary artery disease in later life
Lalita Nemani MD, DM, FESC , Indrani Garre Ph.D , Jyotsna Maddury DM, FACC, FICC, FESC , Sudhanshu Garg MD (DM)
Department of Cardiology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
|Date of Submission||08-Jan-2020|
|Date of Decision||13-Feb-2020|
|Date of Acceptance||04-Apr-2020|
|Date of Web Publication||01-Aug-2020|
Dr. Lalita Nemani
Department of Cardiology, Nizam's Institute of Medical Sciences, Hyderabad - 500 082, Telangana
Source of Support: None, Conflict of Interest: None
Background: Reproductive factors in women may predispose to coronary artery disease (CAD) in later life. However, the evidence is meager and varying in response. If the appropriate factors are identified, it would enable much earlier and more aggressive risk factor modification as reproductive factors can be ascertained much earlier than traditional risk factors for CAD. The study aims to evaluate the reproductive factors in women which contribute to CAD in later life. Materials and Method: This is a retrospective study of 500 women. Reproductive factors including pregnancy details and lactation were assessed. The study population was divided into two groups depending on the presence and absence of CAD and reproductive factors compared using MINITAB version 17. Results: The CAD group was a decade older with a significant history of hypertension (P = 0.003) and diabetes (P = 0.02). Age of menarche was earlier in the CAD group (12.74 ± 1.29 years vs. 13.18 ± 1.43 years; P = 0.00) with statistically significant occurrence of early menarche, i.e., ≤12 years (46.8% vs. 33.6%; P = 0.002; risk ratio [RR] = 1.31; odds ratio [OR] = 1.74; 95% confidence interval = 1.1–1.56). Age at first pregnancy was significantly earlier in the CAD group (18.74 ± 2.94 years vs. 19.41 ± 3.36 years; P = 0.018), but early pregnancy (≤18 years) was not statistically significant (34.8% vs. 30.8%; P = 0.34). The CAD group had a higher order of parity (3.12 ± 1.49 vs. 2.67 ± 1.21; P = 0.000), but multiparity (>3 paras) was not significant. History of pregnancy complication (54% vs. 20.8%; P = 0.00; RR = 5.38, OR = 7.67) and pregnancy loss (44.4% vs. 16.4%; P = 0.00; RR = 2.71; OR = 4.07) were significantly higher in the CAD group. The average age of menopause was significantly earlier in CAD (44.25 ± 7.35 years vs. 46.16 ± 6.32 years; P = 0.006), and early menopause (≤45 years) was of borderline significance (P = 0.06; RR = 1.93; OR = 5.08). Breastfeeding did not have any impact. Conclusion: Early menarche, pregnancy complication, and pregnancy loss are associated with CAD in later life. Early menopause irrespective of whether natural or surgical also predisposed to CAD. Age of first pregnancy was earlier and order of parity was higher in the CAD group, but no definite relation between early pregnancy and multiparity with CAD could be established. Intake of hormonal therapy for menstrual irregularity, late menarche and breast feeding did not predispose to CAD.
Keywords: Coronary artery disease, early menarche, early menopause, pregnancy, reproductive factors
|How to cite this article:|
Nemani L, Garre I, Maddury J, Garg S. A study of reproductive factors in Indian women predisposing to coronary artery disease in later life. J Clin Prev Cardiol 2020;9:45-50
|How to cite this URL:|
Nemani L, Garre I, Maddury J, Garg S. A study of reproductive factors in Indian women predisposing to coronary artery disease in later life. J Clin Prev Cardiol [serial online] 2020 [cited 2020 Aug 13];9:45-50. Available from: http://www.jcpconline.org/text.asp?2020/9/2/45/203525
| Introduction|| |
Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in both men and women. Traditional risk factors such as hypertension, diabetes mellitus, hyperlipidemia, smoking, and obesity ATTRIBUTE to significant burden of CVD in either gender. Besides, in women, reproductive factors may contribute to an increased risk of CVD in later life.,, The association between reproductive factors and coronary artery disease (CAD) in women is not clear, evidence is limited, and findings are mixed. The aim of this study was to study the reproductive factors in women's life that contribute to CAD in later life.
| Materials and Methods|| |
Five hundred women from 8672 screened were recruited from the department of cardiology and internal medicine in our institute [Figure 1]. The study was conducted after obtaining the institutional ethical committee approval. Information on reproductive factors was collected through a questionnaire after obtaining informed consent. The reproductive factors assessed for CAD included age of menarche, menstrual irregularities, history of hormonal treatment for menstrual irregularity/contraception or infertility, age of menopause, and type of menopause. Early menarche was defined as menarche ≤12 years and early menopause referred to menopause ≤45 years. Details about the pregnancies such as parity, age of first childbirth, number of live children, number of miscarriages, and the type of delivery were noted. Early pregnancy was defined in our study as first pregnancy <18 years. Multiparity was defined as more than 3 paras. History of complications in pregnancy such as hypertension-preeclampsia, gestational diabetes, premature delivery, low birth weight baby, abortion, and stillbirth were also enquired. Pregnancy loss includes abortion, miscarriages, stillbirth, or neonatal child death in our study. Status of breastfeeding was also noted. Established risk factors for CAD were ascertained. Hypertension, diabetes, and hyperlipidemia were identified by self-reported use of appropriate medications. A self-reported questionnaire assessed smoking, alcohol, and family history of CAD. Body mass index was calculated at baseline, and routine biochemical investigations were performed at baseline. CAD was diagnosed by documented myocardial infarction or acute coronary syndrome, confirmed by conventional or computed tomographic coronary angiogram or previous history of coronary revascularization (either percutaneous coronary intervention or coronary artery bypass grafting). The study group was divided into two groups depending on the presence and absence of CAD.
MINITAB version 17 (MINITAB, LLC) was used for statistical analysis. A comparison between the two groups was done by Student's t-test or Chi-square test. MULTIVARIATE analysis for the significant risk factors was done by binary logistic regression, and P < 0.05 was considered as statistically significant.
| Results|| |
The average age of the entire study population of 500 women was 47.39 ± 12.49 years. History of hypertension was seen in 50.2% (251 patients), diabetes mellitus in 34.4% (174 patients), family history of CAD in 5% (25 patients), and other risk factors in 20.2% (108 patients). The average age of menarche was 13.18 ± 1.43 years, and the average age of menopause was 48.52 ± 4.49 years. The descriptive statistics for reproductive and menstrual factors for the entire population are mentioned in [Table 1] and biochemical parameters in [Table 2].
|Table 1: Descriptive statistics for reproductive and menstrual factors for the entire population|
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There were 250 women in each group (CAD and non-CAD groups). A comparison of traditional and reproductive risk factors between the CAD versus non-CAD groups is presented in [Table 3]. The CAD group, on average, was a decade older with significantly more incidence of coronary risk factors such as hypertension (P = 0.003) and diabetes (P = 0.02).
|Table 3: Comparison of reproductive factors between the coronary artery disease and noncoronary artery disease groups|
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Age of menarche was earlier in CAD than in the non-CAD group, which was statistically significant (12.74 ± 1.29 years vs. 13.18 ± 1.43 years; P = 0.00). Early menarche (≤12 years) was more common in the CAD group (117 out of 250, 46.8%) than in the non-CAD group (84 out of 250, 33.6%), which was statistically significant (P = 0.002; risk ratio [RR] = 1.31; odds ratio [OR] = 1.74; 95% confidence interval [CI] = 1.1–1.56). Box plot and interval plot of menarche age between the CAD and non-CAD groups [Figure 2] show that noncardiac patients had a higher mean age. The CI for noncardiac patients does not overlap with that for the cardiac patient, which indicates that the difference may be significant. Statistical significance of the age difference of menarche in the CAD and non-CAD groups was tested with a two-tail Student's t- test. History of hormonal intake (for menstrual irregularities) was given in 16 females (6.4%) in the CAD group and 39 females (15.6%) in the non-CAD group. The difference in the hormonal intake between CAD and non-CAD was statistically significant (6.4% vs. 15.6%, P = 0.001) for no CAD.
|Figure 2: Box plot and interval plot of menarche age between the two groups|
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Age at first pregnancy was earlier in the CAD group (18.74 ± 2.94 years) than the non-CAD group (19.41 ± 3.36 years), which was statistically significant (P = 0.018). Even though early pregnancy (≤18 years) was more frequent in the CAD group (87 out of 250, 34.8%) than the non-CAD group (77 out of 250, 30.8%), it was not statistically significant (P = 0.34). The CAD group had a higher order of parity (3.12 ± 1.49) than the non-CAD group (2.67 ± 1.21), which was statistically significant (P< 0.001). However, there was no significant difference between the CAD and non-CAD groups when multiparity (>3 paras) was considered.
History of pregnancy complication was present in 136 (54%) women in the CAD group and 52 (20.8%) women in the non-CAD group, which was statistically significant (P < 0.001; RR = 5.38; OR = 7.67; 95% CI = 3.24–8.89). Similarly, pregnancy loss was significantly higher in the CAD group (44.4% vs. 18.8%, P = 0.00; RR = 2.71; OR = 4.07; 95% CI = 1.98–3.70). Interestingly, even though the history of lost pregnancy/child was a statistically significant factor, the number of child or pregnancy loss was not a significant factor for CAD occurrence. A comparison of pregnancy complications between the two groups is shown in [Table 4]. Incidence of breastfeeding was no different in both the groups.
The average age of menopause was earlier in CAD than the non-CAD group (44.25 ± 7.35 years vs. 46.16 ± 6.32 years), which was statistically significant (P = 0.006). Box plot and interval graph of menopause age between the two groups are shown in [Figure 3]. Early menopause (≤45 years) was more frequent in the CAD group (108 out of 250, 43%) than the non-CAD group (88 out of 250, 35%), with borderline P = 0.06. However, the mode of menopause did not matter whether natural or surgical.
|Figure 3: Box plot and interval plot of menopause age between the two groups|
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Both UNIVARIATE and multivariate binary logistic regressions showed that the predictors of CAD were age of menarche, history of lost pregnancy/child, and presence of history of complications during pregnancy [Table 5] and early menopause of borderline significance. Early pregnancy, multiparity, number of live children, and history of breastfeeding were not significant predictive factors for CAD both in univariant and multivariant analyses. As majority had regular menstrual cycles, the relation between menstrual irregularities and CAD could not be determined. In the few patients who reported the use of hormonal therapy either for menstrual irregularities, contraception, or infertility, there was no increased risk of CAD.
|Table 5: Relative risk, odds ratio, and confidence interval for significant risk factors|
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| Discussion|| |
Reproductive factors in women's life provide an early window to assess her risk for CAD in later life.,, These reproductive factors can be ascertained before the onset of traditional risk factors, thus enabling the institution of much earlier and more aggressive risk factor modification. Menarche and menopause are two crucial stages in women's life. Early menarche and early menopause are associated with an increased risk of CAD in most studies. Menstrual irregularities may contribute to CAD, but the evidence is not strong. There is emerging evidence to suggest that adverse pregnancy outcome (APO) is associated with CAD, and such women deserve follow-up in the long run for cardiac assessment. Higher parity (more than 5) may be associated with CAD, but evidence is lacking. Hysterectomy has been linked with increased CAD; however, data are inconclusive. The substantial benefits of breastfeeding in lowering the maternal CAD risk are uncertain.
The present study shows that early menarche (≤12 years),, was a risk factor for CAD with a significant P = 0.002 for menarche ≤12 years and P = 0.018 for menarche ≤10 years. Late menarche (≥16 years) was not a risk factor. The UK Million Women Study reported a U-shaped relationship between age at menarche and later CVD risk. Early (≤10 years) and late (≥17 years) menarche are associated with an increased risk of CVD. The underlying mechanism is uncertain, but insulin resistance and metabolic syndrome have been suggested. Age at menarche was not an independent risk factor for CVD in the Women's Health Initiative Observational Study. Late menarche did not predispose to CAD according to Peters and Woodward prospective study of the UK Biobank cohort. Menstrual irregularity has been associated with incident CVD risk, in the Women's Health Initiative Study but not in the UK Million Women Study. In the present study, the reported incidence of menstrual irregularities among the subjects enrolled was low and statistically negligible. Hence the role of menstrual irregularities in influencing the occurrence of CAD could not be evaluated. However, patients with a history of hormonal intake to regularize their menstrual cycles had less occurrence of CAD in later life. This could suggest that irregular menstrual cycles due to hormonal imbalance have adverse cardiac effects.
In the present study, age at first pregnancy was earlier in the CAD group, but early pregnancy (≤18 years) was not a significant risk factor for CAD. Previous studies have shown an inverse relationship between age at first pregnancy and CVD persisting after adjustment for socioeconomic and lifestyle measures.,, Higher order of parity was seen in the CAD group, but multiparity (>3 paras) as a risk factor for CAD was not evident in the present study. Previous studies have reported a nonlinear J-shaped dose–response between parity and CVD, with every live birth conferring additional risk. Dior et al reported a higher cardiovascular risk for mothers with one child and mothers with >5 children than mothers with 2-4 children. The protective effect of moderate parity may be attributed to enhanced endothelial function (increased NO availability) in pregnancy. The risk associated with nulliparity is contradictory with some indicating lower risk while others indicate high risk. Nulliparous women were excluded from the present study.
Hormonal therapy is commonly prescribed for menstrual abnormalities and infertility. The cardiovascular (CV) risk of infertility therapy is not confirmed and needs further research; however, infertility itself could predispose to CV risk., Oral contraceptive pills (OCPs) are associated with risk of venous thrombosis and myocardial infarction; however, the risk depends on the formulation of the OCP and individual's underlying risk for CVD. In the present study, the use of hormonal therapy for gynecological-obstetrical indications did not predispose to CAD.
Pregnancy complications such as pregnancy-induced hypertension, preeclampsia/eclampsia, gestational diabetes, and APO have been associated with CV risk., The present study also strongly supports the fact that pregnancy-induced hypertension, preeclampsia-eclampsia, and premature delivery but not gestational diabetes or anemia are risk factors for CAD. Pregnancy loss was associated with an increased cardiac risk in our study on a par with previous studies where miscarriage, abortion, stillbirth, or death of child <6 months has been associated with a higher risk of CVD.,,, Endothelial dysfunction contributing to poor placental function during pregnancy resulting in pregnancy loss and the same to CVD later has been postulated.
Menopause is an established risk factor for CAD. Early menopause (<45 years) whether natural or surgical is an important determinant of premature CAD. According to van der Schouw etal., there was a significantly increased risk with decreased age at menopause for each 1 year, and the risk is compounded by a history of smoking, diabetes, and family history of CAD. In the present study, menopause ≤45 years was a risk factor for CAD with borderline significance. Previous studies have shown that lactation is associated with improved maternal cardiometabolic health and longer duration of lactation had a beneficial effect on the cardiometabolic state.,, Parous women who breastfed for ≥5 months seem to be at a decreased risk of CAD later in life, and parous women who never breastfed or discontinued it were at increased risk of CAD. In the present study, breastfeeding incidence and duration were equally common in both the groups and had no effect on CAD.
Major limitation of this study is it being a retrospective study. The study is based on the history of pregnancy-related factors given by the patient with no evidence or documentation. There might be lacunae in their memory of events which have to be considered.
| Conclusion|| |
Early menarche, pregnancy complication, and pregnancy loss irrespective of the number of pregnancy loss are risk factors for CAD in later life. Early menopause irrespective of whether natural or surgical also predisposed to CAD. Age of first pregnancy was earlier and order of parity was higher in the CAD group, but no definite relation between early pregnancy and multiparity with CAD could be established; hence, further studies are required. Hormonal intake for menstrual irregularities, late menarche, and breastfeeding does not predispose to CAD in later life.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
What this study highlights?
This study strongly suggests the women reproductive factors and pregnancy factors which can predispose to CAD in women. These factors can be recognized early, thus enabling early cardiac assessment and follow of such patients to prevent CAD in later life.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]