There is cumulating evidence linking the occurrence of pregnancy complications, including miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes mellitus, preterm birth, and fetal growth restriction, with increased future risk of type 2 diabetes mellitus, and hospitalization and death due to cardiovascular and cerebrovascular diseases. Such association is largely related to genetic predisposition and shared pathophysiological mechanisms and changes, which may precede the index pregnancy. Awareness of this association would allow identification of the at-risk women for implementation of preventive measures to reduce the recurrence risk of these complications and mitigate the future development of metabolic and cardiovascular diseases worldwide.
Introduction
Cardiovascular diseases (CVDs) and type 2 diabetes (T2D) mellitus are major noncommunicable diseases (NCDs) recognized by the World Health Organization (WHO), to which are attributed more than 9 million deaths . There is now evidence that a history of pregnancy complications, such as hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM), increased the future risk of CVD and T2D in women ( Table 1 ). As pregnancy complications occur in 29–36% of pregnancies in the US and UK , obstetric history could help predicting future CVD risk in 20–30% of the estimated 80% parous women worldwide . Therefore, it is possible to identify these high-risk women for preventive measures that impact on future pregnancies and long-term health.
| Obstetric factors | Cardiac Complications a | Vascular complications b | Metabolic Disturbances c | Diabetes mellitus d |
|---|---|---|---|---|
| Parity = 1 | √ | √ | – | – |
| Parity ≥5 | √ | √ | – | – |
| TA | √ | √ | – | √ |
| Pregnancy loss | √ | √ | √ | – |
| Stillbirth | √ | √ | – | – |
| Abruption | √ | √ | – | – |
| GH | √ | √ | √ | – |
| PE/eclampsia | √ | √ | √ | √ |
| GDM | √ | √ | √ | √ |
| PTB | √ | √ | √ | √ |
| LBW/FGR | √ | √ | – | √ |
| LGA | – | – | √ | √ |
a Include coronary artery/ischemic heart disease, myocardial infarction, congestive heart failure, and related deaths.
b Include atherosclerosis, increased intima-media thickness, endothelial dysfunction, increased vascular resistance, hypertension, cerebrovascular diseases and stroke, thromboembolic complications, and related deaths.
c Include dyslipidaemia, metabolic syndrome, and obesity.
d Include abnormal glucose tolerance and frank type 2 diabetes mellitus.
Obstetric conditions and future maternal metabolic complications
There is consensus that GDM is associated with future T2D in the mother . However, other pregnancy conditions can also increase the risk of T2D and the metabolic syndrome (MS).
Hypertensive pregnancy disorders
This category includes gestational hypertension (GH), preeclampsia (PE), and eclampsia. In the limited literature on this association, the hazard ratio (HR) for subsequent T2D was 3.12, 3.53, and 3.68 after GH, mild PE, and severe PE, respectively . Another study found the adjusted HR (aHR) for T2D was significant at 1.52 and 2.22 for GH and superimposed PE, but not for PE/eclampsia (aHR 1.42) . Five years after a pregnancy complicated by the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, there was 4% increase in new-onset diabetes . Thus, the risk of future T2D is influenced by the severity of HPD.
Gestational diabetes mellitus
The risk of future T2D is associated with GDM diagnosed in the first half of pregnancy, obesity, and need for insulin treatment . Nevertheless, even among women tested normal or with impaired glucose tolerance at the postnatal assessment, 10.6% became diabetic 4 years later, which was associated with higher glucose at diagnosis and homocysteine levels at the postnatal assessment . Chinese women with prior GDM converted to T2D at 1.6% per year, resulting in significantly increased T2D (24.4% vs. 5.3%) and impaired glucose regulation (26.6% vs. 14.9%) compared to women with normal glucose tolerance, 15 years after the index pregnancy . Overall, GDM is associated with a sevenfold increased risk of later T2D . Of note, the study on the Northern Finland Birth Cohort of 1986 revealed that while the cumulative incidence of diabetes in the whole study population was 1.3%, concomitant overweight and GDM greatly increased the risk (HR 47.24) . Furthermore, prepregnancy overweight without GDM had a greater effect (HR 12.63) than GDM in normal-weight women (HR 10.61) on future risk of T2D. Similarly, women with previous diet-treated GDM, compared with age-matched controls, had adjusted odds ratio (aOR) of 3.4 for the WHO-defined MS, and body mass index (BMI) >30 kg/m 2 increased prevalence of MS sevenfold compared with BMI <25 kg/m 2 . Therefore, maternal overweight plays an important role here.
Preterm birth
The effect is related to the gestation at preterm birth (PTB), with an aHR of 1.89, 2.57, and 2.14 for T2D following previous PTB at 32–36 weeks, 28–31 weeks, and ≤27 weeks gestation, respectively . There was also an additive effect, for PTB in the first, second, and in both first and second pregnancies, which was associated with an aHR 1.58, 1.88, and 2.30.
First-trimester bleeding
In a study on 782,287 women in Denmark who delivered a singleton infant after 20 weeks gestation in 1978–2007, first-trimester bleeding without miscarriage increased significantly the risk of subsequent maternal T2D (HR 1.51) after adjusting for other adverse pregnancy outcomes .
Combination effects of pregnancy complications
Combination of obesity and GDM , and of PE, PTB, and birth of small-for-gestational-age (SGA) infant increase further the risk of subsequent T2D.
Obstetric conditions and future maternal metabolic complications
There is consensus that GDM is associated with future T2D in the mother . However, other pregnancy conditions can also increase the risk of T2D and the metabolic syndrome (MS).
Hypertensive pregnancy disorders
This category includes gestational hypertension (GH), preeclampsia (PE), and eclampsia. In the limited literature on this association, the hazard ratio (HR) for subsequent T2D was 3.12, 3.53, and 3.68 after GH, mild PE, and severe PE, respectively . Another study found the adjusted HR (aHR) for T2D was significant at 1.52 and 2.22 for GH and superimposed PE, but not for PE/eclampsia (aHR 1.42) . Five years after a pregnancy complicated by the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, there was 4% increase in new-onset diabetes . Thus, the risk of future T2D is influenced by the severity of HPD.
Gestational diabetes mellitus
The risk of future T2D is associated with GDM diagnosed in the first half of pregnancy, obesity, and need for insulin treatment . Nevertheless, even among women tested normal or with impaired glucose tolerance at the postnatal assessment, 10.6% became diabetic 4 years later, which was associated with higher glucose at diagnosis and homocysteine levels at the postnatal assessment . Chinese women with prior GDM converted to T2D at 1.6% per year, resulting in significantly increased T2D (24.4% vs. 5.3%) and impaired glucose regulation (26.6% vs. 14.9%) compared to women with normal glucose tolerance, 15 years after the index pregnancy . Overall, GDM is associated with a sevenfold increased risk of later T2D . Of note, the study on the Northern Finland Birth Cohort of 1986 revealed that while the cumulative incidence of diabetes in the whole study population was 1.3%, concomitant overweight and GDM greatly increased the risk (HR 47.24) . Furthermore, prepregnancy overweight without GDM had a greater effect (HR 12.63) than GDM in normal-weight women (HR 10.61) on future risk of T2D. Similarly, women with previous diet-treated GDM, compared with age-matched controls, had adjusted odds ratio (aOR) of 3.4 for the WHO-defined MS, and body mass index (BMI) >30 kg/m 2 increased prevalence of MS sevenfold compared with BMI <25 kg/m 2 . Therefore, maternal overweight plays an important role here.
Preterm birth
The effect is related to the gestation at preterm birth (PTB), with an aHR of 1.89, 2.57, and 2.14 for T2D following previous PTB at 32–36 weeks, 28–31 weeks, and ≤27 weeks gestation, respectively . There was also an additive effect, for PTB in the first, second, and in both first and second pregnancies, which was associated with an aHR 1.58, 1.88, and 2.30.
First-trimester bleeding
In a study on 782,287 women in Denmark who delivered a singleton infant after 20 weeks gestation in 1978–2007, first-trimester bleeding without miscarriage increased significantly the risk of subsequent maternal T2D (HR 1.51) after adjusting for other adverse pregnancy outcomes .
Combination effects of pregnancy complications
Combination of obesity and GDM , and of PE, PTB, and birth of small-for-gestational-age (SGA) infant increase further the risk of subsequent T2D.
Obstetric conditions and future maternal cardiovascular complications
Apart from HPD, other pregnancy complications are also associated with subsequent cardiovascular morbidity and mortality in the mothers .
Parity
Parous women have a higher CVD prevalence than nulliparous women, the risk increase for having 1–2, 3–4, and ≥5 pregnancies was 2.30, 2.00, and 2.88, respectively, after adjustment for age, race, and smoking, and additional adjustment for statin use, high-density lipoprotein (HDL) cholesterol, and adverse outcome attenuated the risk to 2.02, 1.74 (not significant), and 2.27, respectively . The parity effect interacts with pregnancy complications, for parous women with uncomplicated births had a 1.95-fold higher risk of CVD compared to nulliparous women, while one or more pregnancy complications increased this to 2.67.
Hypertensive pregnancy disorders
A history of HPD impacts on both overall risk of future CVD, as well as on individual categories like hypertension, ischemic heart disease (IHD), and cerebrovascular disease and stroke .
Hypertension
Few studies examined the impact on hypertension alone. On an average of 5 years after a pregnancy complicated by the HELLP syndrome, there was 33% increased new-onset hypertension . In another study, 7 years after a diagnosis of GH or PE, there was increased hypertension (37% and 20%, respectively, vs. 2%) and microalbuminuria (14% and 20%, respectively, vs. 2%), compared with controls, and microalbuminuria was one of the significant factors associated with hypertension . The risk is influenced by the severity of HPD and the order and number of pregnancy affected, as the HR for subsequent hypertension was 5.31, 3.61, and 6.07 for GH, mild PE, and severe PE, respectively , and was 2.70, 4.34, and 6.00 for the first pregnancy, second pregnancy, and both pregnancies, respectively, being complicated by PE .
Ischemic heart disease
When 129,920 women with singleton first-birth deliveries in Scotland between 1981 and 1985 were analyzed 15–19 years later, the aHR for maternal IHD admission or death after prior PE was 2.0 . When parous women aged ≤66 years with angiographically documented coronary artery disease were compared with aged-matched controls, PE during any pregnancy increased the risk almost fivefold (aOR 4.8) . Among 403,550 Swedish women who gave birth to a first child in 1973–1982 and were followed up for 15 years, the adjusted incidence risk ratio (IRR) for dying from or hospitalized for IHD later was 1.7 for HPD overall, but which increased from 1.6 for GH, 1.9 for mild PE, to 2.8 for severe PE . Furthermore, GH in the first but not second pregnancy had an adjusted IRR 1.9, which was increased to 2.8 with HPD in both pregnancies. Thus, the risk is influenced by both severity and recurrence of HPD.
Cardiovascular diseases
The calculated 10-year CVD risk based on the Framingham prediction score for PE is increased (OR 1.31) . In a review and meta-analysis on a dataset of 3,488,160 women with 198,252 affected by PE, the relative risk (RR) was 3.70 for hypertension, 2.16 for IHD, 1.81 for stroke, 1.79 for venous thromboembolism, and overall mortality after PE increased (RR 1.49) after 14.5 years . McDonald et al. analyzed five case–control and ten cohort studies that included 116,175 women with and 2,259,576 without PE or eclampsia, and confirmed that PE or eclampsia increased subsequent cardiac disease in case–control (OR 2.47) and cohort (RR 2.33) studies, and cerebrovascular disease (RR 2.03)and cardiovascular mortality (RR 2.29). Furthermore, the RR of cardiac disease increased from 2.00 and 2.99 to 5.36 for mild, moderate, and severe PE, respectively. Similarly, in the latest meta-analysis, a history of PE/eclampsia increased subsequent fatal or diagnosed CVD (OR 2.28), cerebral vascular disease (OR 1.76), and hypertension (RR 3.13) . In addition, PE increased ischemic stroke in women aged 15–44 years (aOR 1.63) .
The severity of HPD influenced the risk of different cardiovascular events . Compared with GH, severe PE increased the aHR for first-time cardiovascular events (3.3 vs. 2.8) , cardiovascular death (2.89 vs. 2.47) , and thromboembolism (1.91 vs. 1.03 and aHR 2.3 ). Concomitant PTB probably reflected increased severity of PE, thus PTB further increased the aHR for stroke from 2.04 with PE alone to 3.22 . Indeed, women with PE in the first delivery in Norway had a 1.2-fold higher long-term risk of death, while the risk was 1.56-fold higher for those with additional PTB, and PE requiring PTB increased greatly the risk of death from cardiovascular causes (HR 8.12) and stroke (HR 5.08), compared to PE with delivery at term (HR 1.65) for death from cardiovascular causes . Similarly, from the perspective of PTB, PE was an independent obstetric risk factor (HR 2.2) for CVD and total cardiovascular hospitalizations in women followed up for ≥10 years after PTB . In one of the longest follow-up studies in which the median age of enrollment was 26 years and median follow-up time was 37 years, having a PE was independently associated with CVD death (mutually aHR = 2.14), with the effect greater for PE ≤34 weeks (HR 9.54) than PE >34 weeks (HR 2.08), and at 30-years follow-up, the cumulative CVD-death survival for early PE was 85.9%, late PE was 98.3%, and 99.3% for women without PE . Similarly, a Norwegian study showed increased aHR for cardiovascular death (3.4), IHD (4.7), and cerebrovascular death (2.1) for one lifetime pregnancy with term PE, and for preterm PE the aHR increased to 9.4, 9.3, and 10.4, respectively, while one or more subsequent normal pregnancy following term PE in the first pregnancy attenuated the risk to 1.5, 1.7, and 1.4 (not significant), respectively, and for preterm PE it was attenuated to 2.4, 3.7, and 1.12 (not significant), respectively . On the other hand, while the aHR for cardiovascular death for all PE was 1.9, this increased progressively with recurrence of PE once, one or more, or two or more pregnancies after the first one to 2.0, 2.3, and 5.0, respectively, while the corresponding risk for women without PE in the first pregnancy was 2.0, 2.1, and 3.8, respectively. Therefore, the ultimate risk is influenced by the gestation at, and the order and number of, pregnancies affected by PE. PE after the first pregnancy has a greater impact than PE in the first pregnancy on cardiovascular death, which was also correlated with the number of subsequent pregnancies with PE irrespective of the first pregnancy outcome.
The Northern Finnish Birth Cohort of 1966 ( n = 10 314), followed-up for an average 39.4 years, was examined for the impact of GH, PE/eclampsia, and superimposed PE . The aHR for CVD was 1.45, 1.40, and 2.06, respectively; for IHD, it was 1.44, 1.36, and 1.86, respectively; for myocardial infarction (MI), only GH (aHR 1.75) and superimposed PE (aHR 2.18) were significant; for death from MI, only GH (aHR 3.00) and superimposed PE (aHR 5.12) were significant; for heart failure, it was 1.79, 1.69, and 3.32, respectively; for ischemic cerebrovascular disease, only GH was significant (aHR 1.59). Superimposed PE therefore posed a greater risk than PE, probably consequent to preexisting vascular damage from the chronic hypertension.
Gestational diabetes mellitus
Underlying insulin resistance is one of the links between GDM with future T2D and hypertension . Indeed, Chinese women with GDM had a significantly increased rate of hypertension (35.6% vs.16.0%) compared with women with normal glucose tolerance 15 years after the index pregnancy , and an OR of 1.26 was found in the calculated 10-year CVD risk for GDM . Women with history of GDM had more noninvasive cardiac diagnostic procedures (OR 1.8), simple cardiovascular events (OR 2.7), and total cardiac hospitalization (OR 2.3), when followed up for ≥10 years, and GDM was independently associated with cardiovascular hospitalizations (aHR 2.6) compared with obesity (aHR 2.5), and preeclampsia (aHR 2.4) . Women with history of GDM had higher risk of CVD (aHR 1.85), which occurred on average 7 years earlier . In women with previous PTB, any form of diabetes mellitus (HR 2.0) was an independent risk factor for the increased cardiovascular events and total cardiovascular hospitalizations more than 10 years later . Therefore, severity of GDM similarly impacts on the subsequent risk of CVD.
Preterm birth
PTB was associated with subsequent higher blood pressure (BP) and IHD (HR 2.09) independent of major cardiovascular risk factors . Prior PTB also impacts on risk of death, with adjusted IRR of 1.3 for dying from or hospitalized for IHD later in life , HR of 1.98 for subsequent cardiovascular death , and HR 1.8 for the risk of IHD admission or death . In addition, PTB increased significantly the risk of deaths from cardiovascular causes (HR 2.95) and stroke (HR 1.91) . The combination of PTB with PE in the first delivery increased significantly the risk of death, with relative HR 8.12 and 5.08 for death from cardiovascular causes and stroke, respectively, while it was only 1.65 for death from cardiovascular causes for PE with delivery at term .
In a study utilizing three Scottish data sources on 750,350 women who delivered a live singleton infant following their first pregnancy, and between 35 and 65 years of age at their first IHD event, PTB overall was associated with aHR 2.26 for IHD deaths, but the aHR was lower (2.14) for spontaneous than for elective (2.49) PTB . Similarly, aHR for total IHD events was 1.58 overall, 1.46 for spontaneous, and 1.81 for elective PTB. This probably reflected the need for intervention, and the trend of association between PTB and IHD increased with decreasing age at first event suggested an underlying genetic predisposition to both placental dysfunction and IHD.
The effect of gestation at and number of PTBs on subsequent CVD risk remains unclear. In one study, PTB at ≤27 weeks posed higher risk for hypertension (aHR 1.49) and IHD (aHR 1.61), but not for thromboembolism, compared with PTB at later gestation, while PTB in both first and second pregnancies posed higher risk for hypertension (aHR 1.39), IHD (aHR 1.36), and thromboembolism (aHR 1.80), compared with PTB in either the first or the second pregnancy . On the other hand, another study found no difference between PTB at <34 and ≥34 weeks gestation, and between those with induced versus spontaneous PTB, although simple cardiac events increased from 3.6% to 4.1%, and total cardiovascular hospitalizations from 5.0% to 5.5%, for women with one versus with two or more PTBs . Another study showed that the aHR of 1.36 for CVD with prior PTB was attenuated after exclusion of PE or SGA, and although recurrent PTB increased the risk for ischemic events from 1.22 to 1.78 compared to one PTB, the risk was similar for early, moderate, and late PTB . In the latest review, for a given history of PTB, the aHR was 1.2–2.9 for CVD morbidity, 1.3–2.1 for IHD, 1.7 for stroke, and 4.1 for atherosclerosis, and that the effect of two previous PTB was greater than that for two or more pregnancies with only one PTB .
Birth of SGA and growth-restricted infants
Delivery of an SGA infant was associated with subsequent higher BP and dying from or hospitalized for later IHD (adjusted IRR 1.8) . While delivering a singleton SGA infant in the first pregnancy increased subsequent death from cardiovascular causes (HR of 2.56) , lower birth weight short of being SGA still impacts on the risk of IHD. Smith et al. demonstrated that the maternal risk of IHD admission or death (aHR) for having a baby in the lowest birth weight quintile for gestational age was 1.9. When birth weight ≥3500 g was used as the reference group, the aHR for death due to IHD and admission/death due to IHD were 11.3 and 4.3, respectively, for birth weight <2500 g, 5.4 and 2.7, respectively, for birth weight at 2500–2999 g, and 2.5 (not significant) and 1.5, respectively, for birth weight at 3000–3499 g. Offspring birth weight is actually inversely correlated with maternal cardiovascular mortality, the aHR for a 1-standard deviation increase in offspring birth weight was 0.87, an effect that was greater for CVD than other outcomes . Subsequently, another study confirmed the associated risk between LBW offspring with maternal future CVD mortality (aHR 1.85), and a 1-standard deviation higher offspring birth weight reduced CVD mortality (aHR 0.89) .
Pregnancy loss, including miscarriage, recurrent miscarriage, and stillbirth
Pregnancy loss (miscarriage and stillbirth), in the absence of the aforementioned complications, can still be associated with increased maternal risk of future CVD.
In the Danish study on 782,287 women who delivered a singleton after 20 weeks, those with prepregnancy CVD had 2.2-fold increased risk of first-trimester bleeding without miscarriage, while miscarriage increased significantly the risk of subsequent maternal hypertension (HR 1.20), IHD (HR 1.58), stroke (HR 1.41), and thrombotic event (HR 1.61), after adjusting for other adverse pregnancy outcomes . Furthermore, the number of miscarriages influenced the risk of MI, with an age-adjusted OR of 1.4 per miscarriage on top of the overall age-adjusted OR of 2.1 . In the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, among the 11,518 women ever pregnant and assessed at age 35–66 years with a mean follow-up of 10.8 years, previous miscarriage increased the risk of MI (age-aHR 1.42), and more than two miscarriages increased this risk further (4.34) . Recurrent miscarriage (>3) remained a significant predictor (aHR 5.06) after full adjustment for confounding factors, while no effect was found with therapeutic abortion. Furthermore, MI, cerebral infarction, and renovascular hypertension, were increased at 13%, 16%, and 20%, respectively, for women with miscarriage, and each additional miscarriage increased the rate of these outcomes by 9%, 13%, and 19%, respectively, the association being strongest in women aged <35 years . A meta-analysis of ten studies with 517,504 subjects in the coronary heart disease and 134,461 subjects in the cerebrovascular disease analyses confirmed increased risk for coronary heart disease by a history of miscarriage (OR 1.45) and recurrent miscarriage (OR 1.99), but not for cerebrovascular disease (OR 1.11) . Familial and genetic factors may be involved, as the incidence of IHD was increased in parents of women with two miscarriages (HR 1.25) and three or more miscarriages (HR 1.56) before their first birth, but there was no relationship with the number of therapeutic terminations .
In the EPIC cohort, the fully aHR for MI was 3.43 among women with prior stillbirth , which increased by 2.69, 1.74, 2.42 times the rate of MI, cerebral infarction, and renovascular hypertension, respectively, compared with women who had no stillbirth . Similarly, the history of stillbirth increased subsequent death from cardiovascular causes (HR 1.80) after a median follow-up of 14.8 years in women with a first singleton delivery . Thus, recurrent miscarriage and stillbirth probably share common pathophysiological pathways and genetic predispositions with subsequent CVD.
Combination of pregnancy complications and the placental syndrome
The additive effects of PTB and FGR on the impact of PE on future CVD risk are illustrated by the observation that HPD, PTB, and SGA together increased the adjusted IRR to 2.6, higher than that for any individual complication . Different combinations can come up with different effect magnitudes. For instance, HR for future IHD is 3.9 for PTB plus birth weight in the lowest quintile, 4.5 for PTB plus PE, 3.3 for PE plus birth weight in the lowest quintile, and 7.0 for all three complications together . Likewise, the aHR for stroke increased from 2.04 with PE alone to 3.22 with PTB in addition, which was further aggravated by the effects of age to become highest among the 15–18-year-olds in the HPD group (HR 13.4) followed by women ≥35 years (HR 5.56) . Indeed, PE, PTB, and SGA together increased further the HR for hypertension, IHD, stroke, congestive heart failure, T2D, and thromboembolism ; and for cardiovascular mortality, the HR for SGA plus PTB increased from 1.90 for PTB alone to 3.30, while the combination of PTB, SGA, and PE increased this to 3.85 .
The additive effect of PE, PTB, and FGR/LBW could be attributed to maternal placental syndrome, which include HPD and abruption or infarction of placenta, and which arise most often in women with metabolic risk factors for CVD. In 1.03 million women free from CVD before their first documented pregnancy, with the mean age at index pregnancy of 28.2 years, 7% were found with placental syndrome, which was significantly associated with future CVD (aHR 2.0), coronary heart disease (aHR 2.0), cerebrovascular disease (aHR 1.9), peripheral vascular disease (aHR 3.0), and composite CVD (aHR 2.0) . For individual manifestations, the aHR was 1.7 for abruption or placental infarction, 1.8 for GH, and 2.1 for PE. Placental syndrome resulting in poor fetal growth increased the HR to 3.1 and to 4.4 when intrauterine fetal death occurred.
As alluded to before, maternal age and obesity could influence the ultimate risk of CVD. The Northern Finland Birth Cohort of 1986 showed that HPD concomitant with overweight and GDM increased the HR to 9.16, while in normal-weight women GDM increased only the risk for T2D (HR 10.61) but not hypertension. On the other hand, even if the antenatal OGTT was normal, prepregnancy overweight increased the risk for hypertension (HR 2.86), indicating that overweight exerts an effect as important, if not greater, than some of the pregnancy complications on future CVD risk .
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