Preeclampsia complicates 2–7% of all pregnancies and is associated with considerable maternal and fetal morbidity.1 Studies in the past decade show that women with a history of preeclampsia have an increased risk of development of thrombotic and cardiovascular disease later in life.2–6 Preeclampsia and cardiovascular diseases are thought to have disease mechanisms in common.7–9 Traditional cardiovascular risk factors are present in nulliparous women who subsequently have development of preeclampsia.8,9 Therefore, the cardiovascular risk profiles in formerly preeclamptic women are likely to reflect the pre-existing constitution rather than a consequence of hypertensive pregnancy itself.8,9
Early onset of preeclampsia is clinically considered as the most important indicator of severity of preeclampsia.1 The remote risk for cardiovascular disease is higher the earlier the onset of preeclampsia, and it is sevenfold increased if preeclampsia occurs at less than 32 weeks of gestation compared with term onset preeclampsia.5
Preeclampsia has been linked with a circulatory risk profile (hypertension or latent hypertension),7,10,11 metabolic syndrome,12–14 thrombophilia,15-18 and hyperhomocysteinemia.15-18 Most studies involved a single risk profile in relation to preeclampsia in the preceding pregnancy. Therefore, any possible interrelation between these profiles within women with a history of preeclampsia is currently unclear.
The extent to which the prevalence of underlying cardiovascular and prothrombotic risk factors increases after earlier onset of preeclampsia is unknown. In the present study, we have attempted to elucidate this question. A secondary aim of this study was to estimate the possible overlap between separate risk profiles within women with a history of preeclampsia. Therefore, we evaluated the prevalence of four risk profiles (circulatory risk profile, metabolic syndrome, thrombophilia, and hyperhomocysteinemia) in a cohort of women 6–12 months after a pregnancy complicated by preeclampsia.
MATERIALS AND METHODS
We conducted a retrospective analysis of 1,297 women with a history of preeclampsia who were consecutively screened for possible cardiovascular and prothrombotic risk factors (January 2004 and December 2010). All women were screened at our preconception clinic, a tertiary referral center of the Radboud University Nijmegen Medical Center. All measurements were performed in the nonpregnant state, 6–12 months after pregnancy complicated by preeclampsia. Preeclampsia was diagnosed if women had blood pressure of 140/90 mm Hg or higher, measured twice, 6 or more hours apart, and consistent proteinuria of 300 mg or more for 24 hours after gestational week 20 in previously normotensive women.19 Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome was defined according to the criteria of the International Society on the Study of Hypertension in Pregnancy.20 Intrauterine growth restriction (IUGR) was defined as birth weight less than the 10th percentile of the national birth weight chart.21 Gestational age at delivery was taken as a proxy for onset of preeclampsia. At the time of measurements, none of the women used hormonal contraceptives, nor were they breastfeeding. All women were native Dutch. The study was approved by the Medical Ethics Committee of the Radboud University Nijmegen Medical Center (2007/252).
At enrollment, all participants collected urine in the 24 hours preceding the measurements. The 24-hour urine sample was assayed for albumin, protein, and creatinine to calculate the (micro)albuminuria corrected for creatinine output (g/mol creatinine) and total protein level (g/24 h) (Aeroset ).
All measurements were performed in the morning, in the fasting state (overnight). Height and body mass (Seca 888 scale) were measured. Body surface area was calculated using the Du Bois and Du Bois formula22 for the normalization of plasma volume.
Blood pressure and heart rate were measured oscillometrically (Vital Signs Monitor 1846) at 3-minute intervals for 30 minutes in the right upper arm in the upright position. We used the median of nine consecutive measurements. Measurements were performed with the cuff size recommended for the arm circumference. We recorded systolic and diastolic blood pressures (mm Hg), mean arterial blood pressure (mm Hg), and heart rate (beats per minute).
Venous blood samples were taken from an antecubital vein and analyzed for metabolic parameters: glucose, insulin, total cholesterol, high-density and low-density lipoproteins, and triglycerides (Aeroset). To estimate insulin resistance, homeostasis model assessment index was calculated (insulin [milliunits/L] × glucose [mmol/L]/22.5) as the product of fasting glucose and insulin.23 Factor V Leiden (F5 R506Q) and prothrombin (G20210A) mutation analyses were performed by routine polymerase chain reaction techniques. Citrated blood was centrifuged and plasma was assayed for total protein S, free protein S, and the protein C activity. Total homocysteine levels were measured using high-performance liquid chromatographic assay.
Plasma volume (mL) was measured using the 125I-Human Serum Albumin indicator dilution technique (125I-HSA). Plasma volume was calculated by dividing the total injected radioactivity by the virtual volume-specific radioactivity at time zero, as described elsewhere.24 Plasma volume was normalized by dividing total plasma volume by body surface area (mL/m2).
Echocardiographic measurements were obtained by an experienced cardiology technician. Measurements were performed in left lateral position using a cross-sectional phased array echocardiographic Doppler system (Vivid 7). Left ventricular outflow tract velocity was measured using pulse wave Doppler, and mid systolic left ventricular outflow diameter also was measured. Stroke volume was calculated by multiplying the left ventricular outflow tract velocity integral and the left ventricular outflow tract area (as calculated from the left ventricular outflow tract diameter (
). Heart rate was determined as the reciprocal of the time interval between the R waves of the electrocardiogram measured during the Doppler measurements. This heart rate was used only for the calculation of cardiac output. Cardiac output was calculated as stroke volume multiplied by heart rate. Total vascular resistance was calculated as 80 times the mean arterial pressure, divided by the cardiac output (80×mean arterial pressure÷cardiac output).
Circulatory risk profile was defined as hypertension or the use of antihypertensive medication or signs of latent hypertension in the absence of metabolic syndrome. Hypertension was defined as systolic blood pressure 140 mm Hg or higher or diastolic blood pressure 85 mm Hg or higher, or latent hypertension as reduced plasma volume (plasma volume less than 1,405 mL/m2) or increased total peripheral vascular resistance (more than 1,600 dynes × sec/cm5), or both. Hypertensive women who additionally met the criteria for metabolic syndrome were allocated to the metabolic syndrome profile to prevent women from being counted twice on the basis of their blood pressure. Women who used antihypertensive medication were excluded from analysis of plasma volume and vascular resistance to prevent any confounding effect of medication.
Metabolic syndrome was defined using World Health Organization criteria,25 ie, by the concomitant presence of insulin resistance (fasting insulin 9.2 milliunits/L or higher or fasting glucose 6.1 mmol/L or higher or homeostasis model assessment index 2.2 or more) and two or more of the following factors: hypertension (systolic blood pressure 140 mm Hg or higher or diastolic blood pressure 85 mm Hg or higher or the use of antihypertensive medication); obesity (body mass index [calculated as weight (kg)/[height (m)]2] 30 or higher); dyslipidemia (triglycerides 1.69 mmol/L or higher or high-density lipoprotein 0.9 mmol/L or less); or microalbuminuria (urine albumin 0.30 g/mol creatinine or more or urine protein 0.30 g/24 h or more).
Hereditary thrombophilia was defined as the presence of factor V Leiden or prothrombin 20210A mutation or protein S levels or protein C activity below the normal range (free protein S less than 55%, protein C activity less than 70%). Hyperhomocysteinemia was defined as a fasting homocysteine more than 12.1 micromol/L.26
To illustrate the relationship between gestational age at delivery in previous pregnancy and the prevalence of cardiovascular and prothrombotic risk factors, the study group was divided into four subgroups based on the gestational age at previous delivery (more than 22 to 28 weeks or less, more than 28 to 32 weeks or less, more than 32 weeks to 37 weeks or less, and more than 37 weeks of gestation). Outcome variables are presented as frequencies and percentage including 95% confidence interval (CI) for estimated proportions. For all risk factors, the relative risks with corresponding 95% CIs for each gestational age group were calculated, with the more than 37 weeks of gestation group used as reference. Trends in risk factors by onset of preeclampsia in the previous pregnancy were studied by linear regression analysis; gestational age at delivery was used as a continuous variable.
The change in cardiovascular and prothrombotic risks with each additional week of gestation in the preceding pregnancy was expressed by hazard ratios. Hazard ratios were estimated using multivariable regression analysis, with adjustments made for the following predefined factors: age, parity, smoking, or HELLP or IUGR in the preceding pregnancy. Statistical significance (two-sided P value) was set at P≤.05. The statistical analyses were performed using the standard statistical software package SPSS 16.0.
The inter-relation between the four risk profiles within formerly preeclamptic women was studied with the use of a scaled rectangle diagram similar to Venn diagrams in which each rectangle area is scaled according to the prevalence of the attribute.27 Overlapping areas are proportional to the prevalence of joint occurrence of attributes.
From the 1,297 formerly preeclamptic women included in our study, 63 women had to be excluded because of one or more missing values in any of the studied risk profiles. The remaining 1,234 women with a complete set of study variables were available for analysis. The characteristics of these women are shown in Table 1. Women delivered at a median of 33 weeks of gestation (interquartile range 29–36, range 19) in their previous pregnancy. The screening for possible risk factors was performed at a median of 7 months postpartum (interquartile range 6–10, range 6).
Any of the four risk profiles (circulatory profile, metabolic syndrome, thrombophilia, or hyperhomocysteinemia) was present in 958 of 1,234 (77.6%, 95% CI 75.3–80.0%) formerly preeclamptic women (Table 2). The prevalence of having any risk profile decreased with gestational age at delivery in the preceding pregnancy (P for linear trend <.01). Absence of any of the four risk profiles occurred in 276 of 1,234 (22.4%, 95% CI 20.0–24.7%) of the formerly preeclamptic women.
Hypertension was present in 318 of 1,234 formerly preeclamptic women (25.8%, 95% confidence interval 23.3–28.2%). From these, 152 of 1,234 women (12.4%, 95% CI 10.5–14.2%) had hypertension in the absence of metabolic syndrome; 166 of 1,234 (13.4%, 95% CI 11.5–15.4%) additionally fulfilled the World Health Organization criteria for metabolic syndrome and were analyzed as such.
Circulatory risk profile was present in 816 of 1,234 women (66.1%, 95% CI 63.5–68.8%) (Table 3). The prevalence decreased with gestational age at delivery in the preceding pregnancy (P for linear trend <0.01). In addition to the 12.4% women with overt hypertension, 664 of 1,234 women (53.8%, 95% CI 51.0–56.6%) of formerly preeclamptic women had latent hypertension. In formerly preeclamptic women not using antihypertensive medication, 512 of 1,054 (48.6%, 95% CI 45.6–51.6%) had low plasma volume and 247 of 1,054 (23.4%, 95% CI 20.9–26.0%) had increased vascular resistance.
Metabolic syndrome was present in 191 of 1,234 women (15.4%, 95% CI 13.5–17.5%) (Table 4). The prevalence decreased with gestational age at delivery in the preceding pregnancy (P for linear trend <.01). The prevalence of all components of the metabolic syndrome also decreased with gestational age at previous delivery (P for linear trend <.01), except for obesity. Hyperinsulinemia was present in 742 of 1,234 (60.1%, 95% CI 57.4–62.9%) formerly preeclamptic women. From these, 206 of 742 (27.7%, 95% CI 24.5–31.0) met the criteria of metabolic syndrome and 536 of 742 (72.3%, 95% CI 69.0–75.5%) did not.
Thrombophilia was present in 133 of 1,234 (10.8%, 95% CI 9.1–12.5) formerly preeclamptic women (Table 5); 130 of 133 (98%, 95% CI 95.2–99.2%) of the women with thrombophilia had only one thrombophilic factor. Women with either factor V Leiden or prothrombine 20210A mutation all were heterozygous. The prevalence of thrombophilia did not change with gestational week at previous delivery (P for trend .22). Factor V Leiden was the most prevalent thrombophilic factor in 60 of 1,234 (4.9%, 95% CI 3.7–6.1%).
Hyperhomocysteinemia was present in 231 of 1,234 (18.7%, 95% CI 16.5–20.9%) formerly preeclamptic women (Table 6). The prevalence decreased with gestational age at delivery in the preceding pregnancy (P for linear trend <.01).
Table 7 summarizes the hazard ratios for all four studied profiles associated with each additional week at delivery in the preceding pregnancy. Except for thrombophilia, all profiles show a decreasing prevalence with each additional week at delivery in the preceding pregnancy (ie, the later onset of preeclampsia). These trends were preserved after adjustment for age, parity, smoking, and the additional diagnoses of HELLP syndrome or IUGR as indicated by the adjusted hazard ratios.
Figure 1 demonstrates the prevalence of the four studied risk profiles and their interrelation. In total, 958 of 1,234 (77.6%, 95% CI 75.3–80.0%) formerly preeclamptic women had one or more risk profiles. Three hundred seventeen of 1,234 (25.7%, 95% CI 23.3–28.1%) women with a history of preeclampsia had more than one risk profile, more specifically 278 of 1,234 (22.5%, 95% CI 20.2–24.9%) women had two concurrent risk profiles, 37 of 1,234 (3%, 95% CI 2.1–4.0%) women had three concurrent risk profiles, and only 2 of 1,234 (0.2%, 95% CI 0.0–0.4%) women had all four risk profiles after a pregnancy complicated by preeclampsia. Metabolic syndrome, thrombophilia, and hyperhomocysteinemia each co-occurred considerably with the highly prevalent circulatory risk profile. Co-occurrence of risk profiles other than the circulatory risk profile was uncommon (less than 2%).
We have tested in each patient the four most common risk factors associated with preeclampsia. This allowed us to study the interrelationship between the risk profiles. Two thirds of formerly preeclamptic women demonstrated a (latent) hypertensive hemodynamic profile 6–12 months postpartum. One fourth of formerly preeclamptic women had hypertension, and 50% of these hypertensive women additionally met the criteria for metabolic syndrome. The high prevalence of the circulatory risk profile (66%) was mainly attributable to reduced plasma volume status. Low plasma volume after preeclampsia predisposes to recurrent preeclampsia, IUGR, and preterm birth in subsequent pregnancy.24 Low plasma volume reflects reduced cardiovascular reserve capacity, a condition that, together with increased vascular resistance, relates to the development of chronic hypertension within the next decade. Timely blood pressure--lowering leads to reductions in vascular disease risk and premature death.28,29 Therefore, formerly preeclamptic women may well benefit from circulatory follow-up, most accessibly by blood pressure measurements, even in women who are normotensive in the first year after pregnancy. Circulatory follow-up does not necessitate the measurement of plasma volume status and total peripheral vascular resistance per se.
The prevalence of the metabolic syndrome in formerly preeclamptic women (15%) was approximately three times higher than that of the general Dutch female population of comparable age (5%).30 The prevalence of metabolic syndrome and all its components—except obesity—decreased with gestational age at delivery. This observation suggests that the other components relate to severity of preeclampsia, whereas obesity does not. Metabolic syndrome not only increases the risk of (recurrent) preeclampsia13,14,31,32 but also increases the risk of later cardiovascular disease33,34 and diabetes mellitus.33,35,36 These risks can be reduced by weight management and physical activity, or by medical treatment when lifestyle adjustments are ineffective.37-39 Recognizing the metabolic syndrome in formerly preeclamptic women is likely efficient and cost-effective.40,41
The prevalence of factor V Leiden (4.9%) and prothrombin 20210A (2.7%) mutation in our study were comparable to those in the Dutch general population,42,43 whereas those of protein C (1.7%) and protein S (1.8%) deficiency were slightly increased.44,45 The added value of routine screening for these factors in formerly preeclamptic women seems limited. However, a recent randomized trial in women with hereditable thrombophilia and previous early-onset hypertensive disease in pregnancy has demonstrated a reduction of recurrent preeclampsia by combined treatment with low-molecular-weight heparin and aspirin.46 Our study was not designed to answer definitively the question of to what extent the association between thrombophilia and preeclampsia is causal or if women should be routinely screened and treated for possible thrombophilia after preeclampsia. If the decision to screen and treat is made, it would seem more reasonable to test all formerly preeclamptic women rather than only those with early-onset disease.
Almost one out of five formerly preeclamptic women had hyperhomocysteinemia (19%), which is four times higher than in the general population. Hyperhomocysteinemia co-occurred with the circulatory risk profile in 69% of the cases. This evident overlap might be explained by increased vascular tone, given that hyperhomocysteinemia induces vascular damage by the formation of free oxygen radicals, ultimately resulting in proliferation of smooth muscle cells and alterations in endothelial function and structure.47 Screening and treatment for hyperhomocysteinemia could be considered for four reasons. First, hyperhomocysteinemia increases the risk of future cardiovascular disease; however, supplementation has not been proven effective in reducing that risk.48 Second, multivitamin supplementation containing folic acid in women with hyperhomocysteinemia reduces the risk of preeclampsia.49,50 Third, hyperhomocysteinemia increases the risk of venous and arterial thrombosis that can be reduced by vitamin supplementation.15,16,51 Fourth, hyperhomocysteinemia is associated with fetal closure defects that can be reduced by vitamin B supplementation.52 For these reasons, it seems warranted to screen formerly preeclamptic women for hyperhomocysteinemia. Formerly preeclamptic women are likely to benefit from screening and tailored treatment for their risk profiles.53
Our study may have some methodologic limitations. First, our study population represents that of a tertiary clinic. This may limit generalization of the results to the general population of formerly preeclamptic women because of possible overrepresentation of women with a history of more severe preeclampsia. It is conceivable that this may have resulted in overestimation of the prevalence of risk profiles. This effect is probably small, because adjustments for co-occurrence of HELLP and the delivery of IUGR, as indicators of severity of preeclampsia, did not affect the results, Second, the formerly preeclamptic women in our study were evaluated 6–12 months postpartum. We cannot rule out possible overestimation of the prevalence of cardiovascular risk factors because improvement still may continue thereafter. Although further recovery has been reported up to 2 years postpartum,54 abnormal hemodynamic variables in formerly preeclamptic women largely (more than 80%) resolve within 6 months after giving birth. Third, our study includes only Caucasian women. This may limit generalization, because other ethnic groups may display different profiles.
In conclusion, 77.6% of women with a history of preeclampsia have one or more cardiovascular or prothrombotic risk factors. The circulatory risk profile was most prevalent. The prevalence of the circulatory risk profile and also components of the metabolic syndrome other than obesity and hyperhomocysteinemia relate inversely with the gestational age at delivery in preceding pregnancy. Although these trends were statistically significant, the differences were small. The prevalence of thrombophilia is unaffected by the gestational age at delivery. Apart from the highly prevalent circulatory risk profile, we found minimal overlap between the metabolic syndrome, hyperhomocysteinemia, and thrombophilia. Early identification and tailored management of cardiovascular risk factors have the potential to favorably influence the incidence of recurrent hypertensive disease in future pregnancies and also the long-term cardiovascular morbidity and mortality in this population of women at high risk.
1. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365:785–99.
2. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 2007;335:974.
3. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ 2001;323:1213–7.
4. Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 2005;366:1797–803.
5. Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet 2001;357:2002–6.
6. Wilson BJ, Watson MS, Prescott GJ, Sunderland S, Campbell DM, Hannaford P, et al.. Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. BMJ 2003;326:845.
7. Magnussen EB, Vatten LJ, Smith GD, Romundstad PR. Hypertensive disorders in pregnancy and subsequently measured cardiovascular risk factors. Obstet Gynecol 2009;114:961–70.
8. Romundstad PR, Magnussen EB, Smith GD, Vatten LJ. Hypertension in pregnancy and later cardiovascular risk: common antecedents? Circulation 2010;122:579–84.
9. Ray JG, Vermeulen MJ, Schull MJ, McDonald S, Redelmeier DA. Metabolic syndrome and the risk of placental dysfunction. J Obstet Gynaecol Can 2005;27:1095–101.
10. Spaanderman M, Ekhart T, van EJ, de LP, Peeters L. Preeclampsia and maladaptation to pregnancy: a role for atrial natriuretic peptide? Kidney Int 2001;60:1397–406.
11. Zandstra M, Stekkinger E, van der Vlugt MJ, van Dijk AP, Lotgering FK, Spaanderman ME. Cardiac diastolic dysfunction and metabolic syndrome in young women after placental syndrome. Obstet Gynecol 2010;115:101–8.
12. Forest JC, Girouard J, Masse J, Moutquin JM, Kharfi A, Ness RB, et al.. Early occurrence of metabolic syndrome after hypertension in pregnancy. Obstet Gynecol 2005;105:1373–80.
13. Pouta A, Hartikainen AL, Sovio U, Gissler M, Laitinen J, McCarthy MI, et al.. Manifestations of metabolic syndrome after hypertensive pregnancy. Hypertension 2004;43:825–31.
14. Stekkinger E, Zandstra M, Peeters LL, Spaanderman ME. Early-onset preeclampsia and the prevalence of postpartum metabolic syndrome. Obstet Gynecol 2009;114:1076–84.
15. Dekker GA, de Vries JI, Doelitzsch PM, Huijgens PC, von Blomberg BM, Jakobs C, et al.. Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol 1995;173:1042–8.
16. Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, et al.. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;340:9–13.
17. Mello G, Parretti E, Marozio L, Pizzi C, Lojacono A, Frusca T, et al.. Thrombophilia is significantly associated with severe preeclampsia: results of a large-scale, case-controlled study. Hypertension 2005;46:1270–4.
18. van Pampus MG, Dekker GA, Wolf H, Huijgens PC, Koopman MM, von Blomberg BM, et al.. High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia. Am J Obstet Gynecol 1999;180:1146–50.
19. Diagnosis and management of preeclampsia and eclampsia. ACOG practice bulletin No. 33. Obstet Gynecol 2002;99:159–67.
20. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 2000;183:S1–22.
21. Kloosterman GJ. Intrauterine growth and intrauterine growth curves [in Dutch]. Ned Tijdschr Verloskd Gynaecol 1969;69:349–65.
22. Du BD, Du Bois EF. A formula to estimate the approximate surface area if height and weight be known. 1916. Nutrition 1989;5:303–11.
23. Bonora E, Targher G, Alberiche M, Bonadonna RC, Saggiani F, Zenere MB, et al.. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 2000;23:57–63.
24. Scholten RR, Sep S, Peeters L, Hopman MT, Lotgering FK, Spaanderman ME. Prepregnancy low-plasma volume and predisposition to preeclampsia and fetal growth restriction. Obstet Gynecol 2011;117:1085–93.
25. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539–53.
26. Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, et al.. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997;277:1775–1781.
27. Marshall RJ. Displaying clinical data relationships using scaled rectangle diagrams. Stat Med 2001;20:1077–88.
28. Gueyffier F, Boutitie F, Boissel JP, Pocock S, Coope J, Cutler J, et al.. Effect of antihypertensive drug treatment on cardiovascular outcomes in women and men. A meta-analysis of individual patient data from randomized, controlled trials. The INDANA Investigators. Ann Intern Med 1997;126:761–7.
29. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–13.
30. Bos MB, de Vries JH, Wolffenbuttel BH, Verhagen H, Hillege JL, Feskens EJ. The prevalence of the metabolic syndrome in the Netherlands: increased risk of cardiovascular diseases and diabetes mellitus type 2 in one quarter of persons under 60 [in Dutch]. Ned Tijdschr Geneeskd 2007;151:2382–8.
31. Rodie VA, Freeman DJ, Sattar N, Greer IA. Pre-eclampsia and cardiovascular disease: metabolic syndrome of pregnancy? Atherosclerosis 2004;175:189–202.
32. Sep SJ, Smits LJ, Prins MH, Spaanderman ME, Peeters LL. Simple prepregnant prediction rule for recurrent early-onset hypertensive disease in pregnancy. Reprod Sci 2009;16:80–7.
33. Ford ES. Risks for all-cause mortality, cardiovascular disease, and diabetes associated with the metabolic syndrome: a summary of the evidence. Diabetes Care 2005;28:1769–78.
34. Franco OH, Massaro JM, Civil J, Cobain MR, O'Malley B, D'Agostino RB Sr. Trajectories of entering the metabolic syndrome: the framingham heart study. Circulation 2009;120:1943–50.
35. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005;365:1415–28.
36. Hanson RL, Imperatore G, Bennett PH, Knowler WC. Components of the “metabolic syndrome” and incidence of type 2 diabetes. Diabetes 2002;51:3120–7.
37. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2–97.
38. Dunkley AJ, Charles K, Gray LJ, Camosso-Stefinovic J, Davies MJ, Khunti K. Effectiveness of interventions for reducing diabetes and cardiovascular disease risk in people with metabolic syndrome: systematic review and mixed treatment comparison meta-analysis. Diabetes Obes Metab 2012;34:616–25.
39. Orozco LJ, Buchleitner AM, Gimenez-Perez G, Roque IF, Richter B, Mauricio D. Exercise or exercise and diet for preventing type 2 diabetes mellitus. The Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.:CD003054. DOI: 10.1002/14651858.CD003054.pub3.
40. Korczak D, Dietl M, Steinhauser G. Effectiveness of programmes as part of primary prevention demonstrated on the example of cardiovascular diseases and the metabolic syndrome. GMS Health Technol Assess 2011;7:Doc02.
41. Waugh N, Scotland G, McNamee P, Gillett M, Brennan A, Goyder E, et al.. Screening for type 2 diabetes: literature review and economic modelling. Health Technol Assess 2007;11:iii-xi, 1.
42. Rees DC. The population genetics of factor V Leiden (Arg506Gln). Br J Haematol 1996;95:579–86.
43. Rosendaal FR, Vos HL, Poort SL, Bertina RM. Prothrombin 20210A variant and age at thrombosis. Thromb Haemost 1998;79:444.
44. Dykes AC, Walker ID, McMahon AD, Islam SI, Tait RC. A study of Protein S antigen levels in 3788 healthy volunteers: influence of age, sex and hormone use, and estimate for prevalence of deficiency state. Br J Haematol 2001;113:636–41.
45. Koster T, Rosendaal FR, Briet E, van der Meer FJ, Colly LP, Trienekens PH, et al.. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood 1995;85:2756–61.
46. de Vries JI, van Pampus MG, Hague WM, Bezemer PD, Joosten JH. Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset preeclampsia in women with inheritable thrombophilia: the FRUIT-RCT. J Thromb Haemost 2011;10:64–72.
47. Weiss N, Keller C, Hoffmann U, Loscalzo J. Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia. Vasc Med 2002;7:227–39.
48. Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, et al.. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med 2010;170:1622–31.
49. Bodnar LM, Tang G, Ness RB, Harger G, Roberts JM. Periconceptional multivitamin use reduces the risk of preeclampsia. Am J Epidemiol 2006;164:470–7.
50. Wen SW, Chen XK, Rodger M, et al.. Folic acid supplementation in early second trimester and the risk of preeclampsia. Am J Obstet Gynecol 2008;198:45–7.
51. Mills JL, McPartlin JM, Kirke PN, Lee YJ, Conley MR, Weir DG, et al.. Homocysteine metabolism in pregnancies complicated by neural-tube defects. Lancet 1995;345:149–51.
52. Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects. Implications for prevention. JAMA 1995;274:1698–702.
53. Sattar N, Greer IA. Pregnancy complications and maternal cardiovascular risk: opportunities for intervention and screening? BMJ 2002;325:157–60.
54. Berks D, Steegers EA, Molas M, Visser W. Resolution of hypertension and proteinuria after preeclampsia. Obstet Gynecol 2009;114:1307–14.