REVIEW
Heart, Lung and Circulation (2014) 23, 203–212 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2013.10.087
Cardiovascular Risk, Lipids and Pregnancy: Preeclampsia and the Risk of Later Life Cardiovascular Disease Francesca Charlton, BA, BMed Sci, Jane Tooher, MSc, Kerry-Anne Rye, PhD, Annemarie Hennessy, PhD, FRACP, MBA* Lipid Research Group and Vascular Immunology Research Group, Heart Research Institute, and the School of Medicine, University of Western Sydney, Australia Received 20 September 2013; accepted 20 October 2013; online published-ahead-of-print 29 October 2013
It has been widely thought that the effects of hypertension in pregnancy reversed after delivery and hypertension values returned to their pre-pregnancy level as it was seen as a disease of short duration in otherwise healthy young women. However, recent studies have demonstrated that the principal underlying abnormality, endothelial dysfunction, remains in women who had preeclampsia and that it is this damage that increases the risk of developing cardiovascular disease (CVD) in later life. The contributions of hypertension and dyslipidaemia before and during the pregnancy are also important and contribute to future risk. Serum lipids are complex and change dramatically in pregnancy. In general there is an increase in most plasma lipid components, notably triglycerides, total cholesterol and the major particles of HDL and LDL. Aberrations or exaggerations in this shift (i.e. decrease HDL and a greater increase in LDL) are associated with poor outcomes of pregnancy such as preeclampsia. Long term cardiovascular disease is influenced by preeclampsia and in part potentially by the lipid changes which escalate late in disease. Whether we can influence the risk of preeclampsia by controlling cardiovascular risk factors preceding or during preeclampsia, or cardiovascular disease after preeclampsia is yet to be determined. Ultimately, strategies to control lipid concentrations will only be viable when we understand the safety to the mother at the time of the pregnancy, and to the foetus both immediately and in the very long term. Strategies to control blood pressure are well established in the non-pregnant population, and previous preeclampsia and gestational hypertension should be considered in any cardiovascular risk profile. Whether control of blood pressure in the pregnancy per se is of any longer term benefit is also yet to be determined. Keywords
Preeclampsia Hypertension Pregnancy Cardiovascular disease Lipids
Background It has been widely thought that the effects of hypertension in pregnancy reversed once the baby was delivered and hypertension values returned to their pre-pregnancy level as it was seen as a disease of short duration in otherwise healthy young women. However, recent studies have demonstrated that the principal underlying abnormality, endothelial dysfunction, remains in women who had hypertensive disorder
of pregnancy (HDP) and that it is this damage that increases the risk of developing cardiovascular disease (CVD) in later life [1,2]. Adams and Macgillivray (1961) [3] first noticed an association between preeclampsia and future hypertension in 1961 with Chesley et al. (1968) [4] obtaining similar results. Recent linkage studies have demonstrated the size of the association between HDP and particular components of future CVD. The increased risk of developing CVD varies between the studies but the greater risk in earlier studies may
*Corresponding author at: Building 30, Narellan Road, Campbelltown, NSW, Australia. Tel.: +61 418273658/2462020901; fax: +61 246344011., Emails: [email protected], [email protected] © 2013 Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).
204
F. Charlton et al.
be associated with small numbers and the change in the diagnostic criteria for HDP over time. The range of risk for future hypertension due to HDP is from 1.50 to 20.00 (Table 1). Recent studies with a large number of participants demonstrate a relative risk of between 2.35 and 3.70 which may provide a more accurate link. The risk of future ischaemic heart disease has also been examined in recent studies and shows a risk of between 1.65 and 3.61. Of the studies that
examined the risk of future cerebrovascular disease the risk varies from 1.39 to 3.59 (Table 1). There is an increased risk of death from CVD following hypertension in pregnancy from 1.65 to 3.07 (Table 2). More recently a large meta-analysis by Bellamy et al. (2007) [2] included 25 studies and showed that women who had preeclampsia in their pregnancy had a relative risk of 3.70 (2.70–5.05) for hypertension 14 years post the index
Table 1 HDP and Risk of Cardiovascular Disease, Hypertension, Cerebrovascular Disease and Ischaemic Heart Disease. Author
No. Participants
Years to Follow-up
Outcome
RR/OR/HR
Adams and Macgillivray (1961) [3]
334
17
Hypertension
5.91 (3.89–8.98)
Epstein (1964) [5]
162
15
Hypertension
5.34 (2.50–11.44)
Carleton et al. (1988) [6]
46
10
Hypertension
1.50 (0.28–8.16)
Nisell et al. (1995) [7]
89
7
Hypertension
8.80 (1.16–66.59)
North et al. (1996) [8]
100
5
Hypertension
20.0 (2.79–143.38)
33
Hypertension
2.35 (2.08–2.65)
Ischaemic Heart Disease
1.65 (1.26–2.16)
Cerebrovascular disease
1.39 (0.89–2.17)
Hannaford et al. (1997) [9]
23 000
Hubel et al. (2000) [10]
93
32
Hypertension
5.00 (1.19–20.92)
Marin et al. (2000) [11]
93
10
Hypertension
3.70 (1.72–8.97)
Irgens et al. (2001) [12]
626 272
13
Ischaemic heart disease
3.61 (0.76–17.18)
Smith et al. (2001) [13]
129 920
15–19
Ischaemic heart disease
1.70 (0.90–3.35)
Sattar et al. (2003) [14]
80
19
Hypertension
3.50 (0.77–15.83)
33–52
Hypertension
2.62 (1.77–3.86)
Cerebrovascular disease
2.10 (1.02–4.32)
Wilson et al. (2003) [15]
Ray et al. (2005) [16]
3593
10 310
15
Ischaemic heart disease
2.10 (1.82–2.42)
Cardiovascular disease
2.10 (1.82–2.42)
Wikstrom et al. (2005) [17]
403 550
23–32
Ischaemic heart disease
2.80(2.20–3.70)
Bellamy et al. (2007) [2]
198 252
10–14
Ischaemic heart disease
2.16 (1.86–2.52)
Cerebrovascular disease
1.81 (1.45–2.27)
NA
Cerebrovascular disease
2.03 (1.54–2.67)
15
Hypertension
3.60 (3.43–3.80)
Cerebrovascular disease
6.0 (5.45–6.77)
McDonald et al. (2008) [18] Lykke et al. (2009) [19]
2 375 751 782 287
(mild preeclampsia) (severe preeclampsia) 1.66 (1.29–2.14) Magnussen et al. (2009) [20]
15 065
Garovic et al. (2010) [21]
4782
16
Hypertension
3.10 (2.20–4.30)
4782
Cerebrovascular disease
2.10 (1.19–3.71)
Table 2 HDP and Death from CVD. Author Chesley et al. (1968) [4]
No. Participants
Outcome
RR/OR/HR
22–43
Death
7543
50
Death
1.90 (1.02–3.52)
Irgens et al. (2001) [12]
626 272
13
Death
1.65 (1.01–2.70)
Funai et al. (2005) [23]
37 061
24–36
CVD Death
3.07 (2.18–4.34)
Bellamy et al. (2007) [2]
198 252
10–14
Overall Death
1.49 (1.05–2.14)
Na 37
CVD Death CVD Death
2.29 (1.73–3.04) 2.14 (1.29–3.57)
Jonsdottir et al. (1996) [24]
McDonald et al. (2008) [18] Mongraw-Chaffin et al. (2010) [22]
270
Years to Follow-up
2 375 751 14 403
3.0
205
Cardiovascular Risk, Lipids and Pregnancy
pregnancy. The relative risk for stroke was 1.81 (1.45–2.27) after 10 years while the relative risk for ischaemic heart disease was 2.16 (1.86–2.52) after 12 years. The risk of cardiovascular death following preeclampsia demonstrated a hazard ratio of 2.14 (1.29–3.57) 37 years from the index pregnancy, and an even greater risk if preeclampsia developed before 34 weeks gestation with a hazard ratio of 9.54 (4.50–20.26) [22]. Lykke et al. (2009) [19] showed a difference between women who had a mild form of the disease compared to those with a severe form of the disease with a relative risk of 3.60 (3.43–3.80) compared to 6.0 (5.45–6.77) respectively for future hypertension at 14 years follow-up. This result is consistent with other studies which demonstrate that the earlier the development of preeclampsia the greater the risk of future CVD [13,16,22]. Other studies have demonstrated that gestational hypertension also increases the risk of CVD [15,17,25]. Women who experience HDP are also at greater risk of cardiovascular mortality [23,26]. Bellamy et al. (2007) [2] demonstrated that the risk of death from CVD following pre-term preeclampsia was RR 7.71 (4.40–13.52). A study by Skjærven et al. (2012) [27] demonstrated that women who had only one pregnancy affected by preeclampsia were at greater risk of death from CVD than those who remained normotensive. They also found that the risk of death from CVD was greater if the pregnancy ended prematurely.
Lipids and Pregnancy Risk Having identified the association with hypertension, other potentially contributing factors can also be examined. There has been considerable recent interest in serum lipids in pregnancy and preeclampsia. As early as 1934, studies had described increased serum cholesterol and phospholipid which increase towards term and decrease after delivery [28,29]. More recent work has identified a trend towards abnormal lipid profile being a risk associated with increased blood pressure or preeclampsia in pregnancy.
Cholesterol Fractions in the Circulation Low density lipoproteins (LDL) are the second smallest lipoprotein particle and their principal role is in the transport of cholesterol to cells where delivery is facilitated via the LDL receptor. The smaller, more dense LDL being associated with greater cardiovascular risk compared to larger, more buoyant, LDL particles. The main components of LDL include apoB and esterified cholesterol molecules. The outer surface consists of unesterified cholesterol, phospholipid and a single apoB-100 molecule. Oxidised LDL has a particularly damaging effect on endothelial function [30]. High density lipoproteins (HDL) are the smallest and most dense of all plasma lipoproteins. They consist of a hydrophobic core of cholesteryl esters and triglycerides surrounded by
a surface monolayer of phospholipids, unesterified cholesterol and apolipoproteins [31]. The three most abundant HDL apolipoproteins are apoA-I, apoA-II and apoA-IV [32]. ApoA-I and apoA-II comprise about 70% and 20% of the total HDL protein, respectively. Most HDL particles also contain other minor apolipoproteins, including apoA-IV, apoA-V, apo C-I, apo-CII, apo-CIII, apoD, apoE, apoJ and apoL [33].
LDL, HDL and CV Risk Large prospective studies, as again such as in the Framingham Heart Study, have clearly shown that LDL-Cholesterol (LDL-C) is positively and HDL-Cholesterol (HDL-C) levels are inversely associated with cardiovascular risk [34]. For every 0.025 mmol/L (1 mg/dL) increase in HDL-C, the risk of having a cardiovascular event reduces by 2–3%. Importantly, a low HDL-C level (generally regarded by current treatment guidelines as
Heart, Lung and Circulation (2014) 23, 203–212 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2013.10.087
Cardiovascular Risk, Lipids and Pregnancy: Preeclampsia and the Risk of Later Life Cardiovascular Disease Francesca Charlton, BA, BMed Sci, Jane Tooher, MSc, Kerry-Anne Rye, PhD, Annemarie Hennessy, PhD, FRACP, MBA* Lipid Research Group and Vascular Immunology Research Group, Heart Research Institute, and the School of Medicine, University of Western Sydney, Australia Received 20 September 2013; accepted 20 October 2013; online published-ahead-of-print 29 October 2013
It has been widely thought that the effects of hypertension in pregnancy reversed after delivery and hypertension values returned to their pre-pregnancy level as it was seen as a disease of short duration in otherwise healthy young women. However, recent studies have demonstrated that the principal underlying abnormality, endothelial dysfunction, remains in women who had preeclampsia and that it is this damage that increases the risk of developing cardiovascular disease (CVD) in later life. The contributions of hypertension and dyslipidaemia before and during the pregnancy are also important and contribute to future risk. Serum lipids are complex and change dramatically in pregnancy. In general there is an increase in most plasma lipid components, notably triglycerides, total cholesterol and the major particles of HDL and LDL. Aberrations or exaggerations in this shift (i.e. decrease HDL and a greater increase in LDL) are associated with poor outcomes of pregnancy such as preeclampsia. Long term cardiovascular disease is influenced by preeclampsia and in part potentially by the lipid changes which escalate late in disease. Whether we can influence the risk of preeclampsia by controlling cardiovascular risk factors preceding or during preeclampsia, or cardiovascular disease after preeclampsia is yet to be determined. Ultimately, strategies to control lipid concentrations will only be viable when we understand the safety to the mother at the time of the pregnancy, and to the foetus both immediately and in the very long term. Strategies to control blood pressure are well established in the non-pregnant population, and previous preeclampsia and gestational hypertension should be considered in any cardiovascular risk profile. Whether control of blood pressure in the pregnancy per se is of any longer term benefit is also yet to be determined. Keywords
Preeclampsia Hypertension Pregnancy Cardiovascular disease Lipids
Background It has been widely thought that the effects of hypertension in pregnancy reversed once the baby was delivered and hypertension values returned to their pre-pregnancy level as it was seen as a disease of short duration in otherwise healthy young women. However, recent studies have demonstrated that the principal underlying abnormality, endothelial dysfunction, remains in women who had hypertensive disorder
of pregnancy (HDP) and that it is this damage that increases the risk of developing cardiovascular disease (CVD) in later life [1,2]. Adams and Macgillivray (1961) [3] first noticed an association between preeclampsia and future hypertension in 1961 with Chesley et al. (1968) [4] obtaining similar results. Recent linkage studies have demonstrated the size of the association between HDP and particular components of future CVD. The increased risk of developing CVD varies between the studies but the greater risk in earlier studies may
*Corresponding author at: Building 30, Narellan Road, Campbelltown, NSW, Australia. Tel.: +61 418273658/2462020901; fax: +61 246344011., Emails: [email protected], [email protected] © 2013 Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).
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F. Charlton et al.
be associated with small numbers and the change in the diagnostic criteria for HDP over time. The range of risk for future hypertension due to HDP is from 1.50 to 20.00 (Table 1). Recent studies with a large number of participants demonstrate a relative risk of between 2.35 and 3.70 which may provide a more accurate link. The risk of future ischaemic heart disease has also been examined in recent studies and shows a risk of between 1.65 and 3.61. Of the studies that
examined the risk of future cerebrovascular disease the risk varies from 1.39 to 3.59 (Table 1). There is an increased risk of death from CVD following hypertension in pregnancy from 1.65 to 3.07 (Table 2). More recently a large meta-analysis by Bellamy et al. (2007) [2] included 25 studies and showed that women who had preeclampsia in their pregnancy had a relative risk of 3.70 (2.70–5.05) for hypertension 14 years post the index
Table 1 HDP and Risk of Cardiovascular Disease, Hypertension, Cerebrovascular Disease and Ischaemic Heart Disease. Author
No. Participants
Years to Follow-up
Outcome
RR/OR/HR
Adams and Macgillivray (1961) [3]
334
17
Hypertension
5.91 (3.89–8.98)
Epstein (1964) [5]
162
15
Hypertension
5.34 (2.50–11.44)
Carleton et al. (1988) [6]
46
10
Hypertension
1.50 (0.28–8.16)
Nisell et al. (1995) [7]
89
7
Hypertension
8.80 (1.16–66.59)
North et al. (1996) [8]
100
5
Hypertension
20.0 (2.79–143.38)
33
Hypertension
2.35 (2.08–2.65)
Ischaemic Heart Disease
1.65 (1.26–2.16)
Cerebrovascular disease
1.39 (0.89–2.17)
Hannaford et al. (1997) [9]
23 000
Hubel et al. (2000) [10]
93
32
Hypertension
5.00 (1.19–20.92)
Marin et al. (2000) [11]
93
10
Hypertension
3.70 (1.72–8.97)
Irgens et al. (2001) [12]
626 272
13
Ischaemic heart disease
3.61 (0.76–17.18)
Smith et al. (2001) [13]
129 920
15–19
Ischaemic heart disease
1.70 (0.90–3.35)
Sattar et al. (2003) [14]
80
19
Hypertension
3.50 (0.77–15.83)
33–52
Hypertension
2.62 (1.77–3.86)
Cerebrovascular disease
2.10 (1.02–4.32)
Wilson et al. (2003) [15]
Ray et al. (2005) [16]
3593
10 310
15
Ischaemic heart disease
2.10 (1.82–2.42)
Cardiovascular disease
2.10 (1.82–2.42)
Wikstrom et al. (2005) [17]
403 550
23–32
Ischaemic heart disease
2.80(2.20–3.70)
Bellamy et al. (2007) [2]
198 252
10–14
Ischaemic heart disease
2.16 (1.86–2.52)
Cerebrovascular disease
1.81 (1.45–2.27)
NA
Cerebrovascular disease
2.03 (1.54–2.67)
15
Hypertension
3.60 (3.43–3.80)
Cerebrovascular disease
6.0 (5.45–6.77)
McDonald et al. (2008) [18] Lykke et al. (2009) [19]
2 375 751 782 287
(mild preeclampsia) (severe preeclampsia) 1.66 (1.29–2.14) Magnussen et al. (2009) [20]
15 065
Garovic et al. (2010) [21]
4782
16
Hypertension
3.10 (2.20–4.30)
4782
Cerebrovascular disease
2.10 (1.19–3.71)
Table 2 HDP and Death from CVD. Author Chesley et al. (1968) [4]
No. Participants
Outcome
RR/OR/HR
22–43
Death
7543
50
Death
1.90 (1.02–3.52)
Irgens et al. (2001) [12]
626 272
13
Death
1.65 (1.01–2.70)
Funai et al. (2005) [23]
37 061
24–36
CVD Death
3.07 (2.18–4.34)
Bellamy et al. (2007) [2]
198 252
10–14
Overall Death
1.49 (1.05–2.14)
Na 37
CVD Death CVD Death
2.29 (1.73–3.04) 2.14 (1.29–3.57)
Jonsdottir et al. (1996) [24]
McDonald et al. (2008) [18] Mongraw-Chaffin et al. (2010) [22]
270
Years to Follow-up
2 375 751 14 403
3.0
205
Cardiovascular Risk, Lipids and Pregnancy
pregnancy. The relative risk for stroke was 1.81 (1.45–2.27) after 10 years while the relative risk for ischaemic heart disease was 2.16 (1.86–2.52) after 12 years. The risk of cardiovascular death following preeclampsia demonstrated a hazard ratio of 2.14 (1.29–3.57) 37 years from the index pregnancy, and an even greater risk if preeclampsia developed before 34 weeks gestation with a hazard ratio of 9.54 (4.50–20.26) [22]. Lykke et al. (2009) [19] showed a difference between women who had a mild form of the disease compared to those with a severe form of the disease with a relative risk of 3.60 (3.43–3.80) compared to 6.0 (5.45–6.77) respectively for future hypertension at 14 years follow-up. This result is consistent with other studies which demonstrate that the earlier the development of preeclampsia the greater the risk of future CVD [13,16,22]. Other studies have demonstrated that gestational hypertension also increases the risk of CVD [15,17,25]. Women who experience HDP are also at greater risk of cardiovascular mortality [23,26]. Bellamy et al. (2007) [2] demonstrated that the risk of death from CVD following pre-term preeclampsia was RR 7.71 (4.40–13.52). A study by Skjærven et al. (2012) [27] demonstrated that women who had only one pregnancy affected by preeclampsia were at greater risk of death from CVD than those who remained normotensive. They also found that the risk of death from CVD was greater if the pregnancy ended prematurely.
Lipids and Pregnancy Risk Having identified the association with hypertension, other potentially contributing factors can also be examined. There has been considerable recent interest in serum lipids in pregnancy and preeclampsia. As early as 1934, studies had described increased serum cholesterol and phospholipid which increase towards term and decrease after delivery [28,29]. More recent work has identified a trend towards abnormal lipid profile being a risk associated with increased blood pressure or preeclampsia in pregnancy.
Cholesterol Fractions in the Circulation Low density lipoproteins (LDL) are the second smallest lipoprotein particle and their principal role is in the transport of cholesterol to cells where delivery is facilitated via the LDL receptor. The smaller, more dense LDL being associated with greater cardiovascular risk compared to larger, more buoyant, LDL particles. The main components of LDL include apoB and esterified cholesterol molecules. The outer surface consists of unesterified cholesterol, phospholipid and a single apoB-100 molecule. Oxidised LDL has a particularly damaging effect on endothelial function [30]. High density lipoproteins (HDL) are the smallest and most dense of all plasma lipoproteins. They consist of a hydrophobic core of cholesteryl esters and triglycerides surrounded by
a surface monolayer of phospholipids, unesterified cholesterol and apolipoproteins [31]. The three most abundant HDL apolipoproteins are apoA-I, apoA-II and apoA-IV [32]. ApoA-I and apoA-II comprise about 70% and 20% of the total HDL protein, respectively. Most HDL particles also contain other minor apolipoproteins, including apoA-IV, apoA-V, apo C-I, apo-CII, apo-CIII, apoD, apoE, apoJ and apoL [33].
LDL, HDL and CV Risk Large prospective studies, as again such as in the Framingham Heart Study, have clearly shown that LDL-Cholesterol (LDL-C) is positively and HDL-Cholesterol (HDL-C) levels are inversely associated with cardiovascular risk [34]. For every 0.025 mmol/L (1 mg/dL) increase in HDL-C, the risk of having a cardiovascular event reduces by 2–3%. Importantly, a low HDL-C level (generally regarded by current treatment guidelines as
