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RESEARCH: Elisabeth Balstad Magnussen, Lars Johan Vatten, Tom Ivar Lund-Nilsen, Kjell Åsmund Salvesen, George Davey Smith, and Pål Richard Romundstad Prepregnancy cardiovascular risk factors as predictors of pre-eclampsia: population based cohort study BMJ 2007; 335: 978 [Abstract] [Full text]

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Previous oral contraceptive use is likely to increase the risk of pre-eclampsia

Ellen CG Grant   (8 November 2007)

Cardiovascular risk factors and pre-eclampsia.

Giuseppe Lippi, Martina Montagnana, Massimo Franchi   (10 November 2007)

Pre-eclampsia is an inflammatory disorder

Jecko V Thachil   (11 November 2007)

A misleading 'week in numbers'

Kate S Robertson   (12 November 2007)

Previous oral contraceptive use is likely to increase the risk of pre-eclampsia 8 November 2007
Ellen CG Grant, physician and medical gynaecologist Kingston-upon-Thames, KT2 7JU Send response to journal: Re: Previous oral contraceptive use is likely to increase the risk of pre-eclampsia	Leanne Bellamy and colleagues found that women who have had pre- eclampsia have an increased risk of cardiovascular disease, including an almost fourfold increased risk of hypertension and an approximately twofold increased risk of fatal and non-fatal ischaemic heart disease, stroke, and venous thromboembolism in later life and a small increase in risk of death.1 These are all well established vascular complications of oral contraceptive use. Elizabeth Magnussen and colleagues were puzzled that in their study, women who were using OCs at baseline (average age 26) had a reduced risk of pre-eclampsia in pregnancy 4 years later (average age 30).2 At baseline only 11.5% of all women studied had never used OCs. More than half (56%) of the ever users had stopped using OCs an average of 4 years before becoming pregnant. Vascular side effects, such as headaches, migraine, hypertension or thrombosis, are the commonest reasons women stop using OCs while still needing contraception. Early discontinuations prevent more serious complications developing. Although longer use of oral contraceptives increases the risk of vascular diseases, individual sensitivity is also important. Even with oral contraceptives causing most endometrial arteriolar development, only 60% and not all of women developed headaches or migraine in the first 12 months of use. In the 1968 I reported that, for a large range of oral contraceptives, the first year headache incidence and number of endometrial biopsies with well-developed arteriolar corresponded with the first year discontinuation rate.3 There is also a synergistic effect with smoking and some women with frequent migraine due to both prefer to stop using oral contraceptives rather than to stop smoking. Oral contraceptive use also increases the risk of pyelonephritis and renal hypertension. Pre-eclampsia is prbably an adverse vascular reaction to the high levels of progesterone and oestogen in pregnancy. Many women most developing pre-eclampsia may have been already been warned of their increase vascular over-reactivity by previous adverse reactions to taking contraceptive progesterones and oestrogens. Women who have developed the anti-phospholipid syndrome due to taking oral contraceptives may have a residual life time’s increased risk of thrombosis and pregnancy complications such as pre-eclampsia and an increased risk of a rapidly developing form of arteriosclerosis.4 An previous study of 3973 nulliparous women who had recently used oral contraceptives for 8 years or more before becoming pregnant had double the risk of developing pre-eclampsia and four times more risk if they had never smoked.5 1 Bellamy L, Casas J-P, Hingorani AD, and Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis.BMJ, Nov 2007; doi:10.1136/bmj.39335.385301.BE 2 Magnussen EB, Vatten LJ, Lund-Nilsen TI, Salvesen KA, Smith GD, Romundstad PR. Prepregnancy cardiovascular risk factors as predictors of pre-eclampsia: population based cohort study. BMJ,Nov 2007 doi:10.1136/bmj.39366.416817.BE 3 Grant ECG. Grant ECG. Relation between headaches from oral contraceptives and development of endometrial arterioles. BMJ 1968;3:402-5. 4 Grant ECG Systemic lupus erythematosus. Lancet 2001 358:586. 5 Thadhani R, Stampfer MJ, Chasan-Taber L, Willett WC, Curhan GC. A prospective study of pregravid oral contraceptive use and risk of hypertensive disorders of pregnancy. Contraception 1999;60:145-50. Competing interests: None declared
Cardiovascular risk factors and pre-eclampsia. 10 November 2007
Giuseppe Lippi, Associate Professor of Clinical Biochemistry Sez. Chimica Clinica, Università di Verona, Osp. Policlinico, 37134 - Verona, Italy, Martina Montagnana, Massimo Franchi Send response to journal: Re: Cardiovascular risk factors and pre-eclampsia.	Giuseppe Lippi, Martina Montagnana, Massimo Franchi. We have read with interest the recent article of Balstad Magnussen et al., who concluded that women with cardiovascular risk factors may be predisposed to pre-eclampsia (1). Basically, positive associations were found between serum levels of triglycerides, cholesterol, low density lipoprotein cholesterol, non-high density lipoprotein cholesterol, and risk of pre-eclampsia. We performed a similar analysis on a cluster of 37 women with physiological pregnancy (2) and 28 women with pre-eclampsia, matched for the major demographic factors, including maternal age and trimester of pregnancy. Among the cardiovascular risk factors investigated, we observed that women with pre-eclampsia had significantly median higher triglycerides (273 versus 204 mg/dL; p=0.018), higher atherogenic index of plasma (calculated as log[triglycerides/ high density lipoprotein cholesterol]) (0.229 versus 0.030, p=0.011) and lower high density lipoprotein cholesterol (62 versus 78 mg/dL; p=0.025). On the contrary, the median concentration of cholesterol (271 versus 261 mg/dl, p=0.300), low density lipoprotein cholesterol (128 versus 134 mg/dL, p=0.304) and lipoprotein(a) (251 versus 183 mg/L, p=0.374) did not differ significantly between women with pre-eclampsia and those with physiological pregnancy. Although we confirm that women with pre-eclampsia may display an adverse lipid profile, in our investigation this was limited to triglycerides, high density lipoprotein cholesterol and atherogenic index of plasma. References 1. Magnussen EB, Vatten LJ, Lund-Nilsen TI, Salvesen KA, Smith GD, Romundstad PR. Prepregnancy cardiovascular risk factors as predictors of pre-eclampsia: population based cohort study. BMJ. 2007 Nov 1; [Epub ahead of print]. 2. Lipid and lipoprotein profile in physiological pregnancy. Lippi G, Albero A, Montagnana M, Salvagno GL, Scevarolli S, Franchi M, Guidi GC. Clin Lab 2007;53:173-7. Competing interests: None declared
Pre-eclampsia is an inflammatory disorder 11 November 2007
Jecko V Thachil, Haematologist Royal Liverpool University Hospital Send response to journal: Re: Pre-eclampsia is an inflammatory disorder	The two research articles in the BMJ this week highlights the link between pre-eclampsia and cardiovascular diseases including ischaemic heart disease, hypertension and stroke 1, 2. The common factor described is endothelial dysfunction observed in all these conditions. What triggers this endothelial damage is not yet conclusively proven. In this context, it is interesting to note that atherosclerosis; an initiating factor for most of these vascular diseases has been increasingly recognised as an inflammatory disorder 3. Inflammatory markers like C-reactive protein (CRP), serum fibrinogen levels, VonWillebrand factor levels and plasma thrombomodulin have been demonstrated to increase in atherosclerosis and are also considered as laboratory risk factors for ischaemic heart disease, diabetes mellitus and cerebrovascular disease 4,5, 6. The concept that obesity represents an “inflammatory state” has also gained credence over the past decade7. If these different conditions are described as risk factors for pre-eclampsia it is only rational to think that inflammation may play an important role in the pathophysiology of this pathologic state of pregnancy. Some interesting work has been performed in this area which may prove that pre-eclampsia is indeed another inflammatory disorder. Firstly, Paternoster et al looked at the CRP levels in hypertensive disorders of pregnancy 8. A total of 322 pregnant women at 24 to 32 weeks' gestation were enrolled with a control group of 190 women. The hypertensive group was divided into those with pre-eclampsia (63 patients), women with transient hypertension (31 patients), those who had Haemolysis, Elevated Liver enzymes and Low Platelet (HELLP) syndrome (19 patients) and a final group who had chronic hypertension (19 patients). Serum CRP concentrations were significantly higher in all the three groups in whom hypertension developed during pregnancy compared to the controls and interestingly also when compared to those with chronic hypertension. The study also showed CRP levels in patients with pre-eclampsia had an inverse correlation with birth weight and gestational week at delivery. He et al undertook studies on perturbations of haemostatic function after a history of pre-eclampsia to determine the future risk of coronary heart disease 9. This follow-up study included 25 women with a history of pre-eclampsia. Compared to control women, who had undergone a normal pregnancy, the pre-eclampsia patients had increased plasma levels of VonWillebrand factor and fibrinogen. The VonWillebrand factor and fibrinogen levels also correlated with the degree of blood pressure elevation but not to the degree of proteinuria during the index pregnancy. The trial group concluded that persistent endothelial dysfunction with continuing haemostatic alterations along with dyslipoproteinemia after pre -eclampsia may indicate a proneness to future CHD. Finally, Boffa et al measured plasma thrombomodulin levels in primigravidae at risk for pre-eclampsia at weeks 12, 24 and 32 of gestation and after delivery 10. Plasma thrombomodulin elevations were not observed until week 32 in uneventful pregnancies, but were present by week 24 in patients who later developed hypertensive complications. They identified a net individual plasma thrombomodulin increase [greater than or equal to 4.2 ng/ml between weeks 12 and 24] and/or plasma thrombomodulin level greater than or equal to 47.5 ng/ml at week 32 as predictive of the development of hypertensive complications with 80% accuracy. Thus, in addition to considering pre-eclampsia as a risk factor for future vascular events in women, it is also important to consider it as an inflammatory disease to help in identifying parameters predictive of its severity and novel therapeutic strategies. References 1. Magnussen EB, Vatten LJ, Lund-Nilsen TI, Salvesen KA, Smith GD, Romundstad PR. Prepregnancy cardiovascular risk factors as predictors of pre-eclampsia: population based cohort study. BMJ. 2007; 335: 978. 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. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999; 340:115-26. 4. Shah SH, Newby LK. C-reactive protein: a novel marker of cardiovascular risk. Cardiol Rev. 2003;11: 169-79 5. Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med. 2007; 262:157-72. 6.Zhang X, Hu Y, Hong M, Guo T, Wei W, Song S. Plasma thrombomodulin, fibrinogen, and activity of tissue factor as risk factors for acute cerebral infarction. Am J Clin Pathol. 2007 ;128: 287-92 7. Mehta S. Farmer JA. Obesity and inflammation: a new look at an old problem. Curr Atheroscler Rep.2007; 9: 134-8. 8. Paternoster DM, Fantinato S, Stella A, Nanhorngue KN, Milani M, Plebani M, Nicolini U, Girolami A. C-reactive protein in hypertensive disorders in pregnancy. Clin Appl Thromb Hemost. 2006; 12: 330-7 9. He S, Silveira A, Hamsten A, Blomback M, Bremme K. Haemostatic, endothelial and lipoprotein parameters and blood pressure levels in women with a history of preeclampsia. Thromb Haemost.1999; 81: 538-42. 10. Boffa MC, Valsecchi L, Fausto A, Gozin D, Vigano' D'Angelo S, Safa O, Castiglioni MT, Amiral J, D'Angelo A. Predictive value of plasma thrombomodulin in preeclampsia and gestational hypertension. Thromb Haemost.1998; 79: 1092-5. Competing interests: None declared
A misleading 'week in numbers' 12 November 2007
Kate S Robertson, staff grade psychiatrist Huntercombe Hospital- Stafford ST19 9QT Send response to journal: Re: A misleading 'week in numbers'	With reference to the risk of pre-eclampsia in women who take the contraceptive pill, in 'the week in numbers' at the beginning of the journal, either the oral contraceptive pill is a lot less effective than has previously been claimed, or the words 'at baseline' were left out. Competing interests: None declared