Extra material

Appendix 1: Search methods

Figures

Appendix 4: Pre-eclampsia in developing countries

Appendix 1: Search methods

We searched The Cochrane Database of Systematic Reviews, the trials register of the Cochrane Pregnancy and Childbirth Group, CENTRAL and EMBASE for systematic reviews and randomised trials. Searches were updated in November 2005. The search strategy and methods for the Cochrane reviews are described in the generic protocol (Meher S, Duley L, on behalf of the Prevention of Pre-eclampsia Cochrane Review authors. Interventions for preventing pre-eclampsia and its consequences: generic protocol. Cochrane Database Syst Rev 2005;(2):CD005301). In brief, studies were included if:

Randomised trials

Participants were pregnant women. For prevention of pre-eclampsia, women were (a) normotensive, grouped by whether risk status at trial entry high, moderate, low or undefined; (b) hypertensive, all high risk, grouped by whether gestational or chronic hypertension; or (c) undefined. Women randomised after delivery were excluded.

Comparisons of intervention/s with placebo or no intervention. Treatment reviews also included comparisons of one intervention with another

Outcomes for mother and baby included mortality, substantive morbidity, side effects, adverse events, and use of health service resources. For prevention, main outcomes were pre-eclampsia, severe hypertension, death of the baby, preterm birth, and small for gestational age

Appendix 2: Extra references

References to trials and systematic reviews discussed in the text

Meher S, Duley L. Rest for preventing pre-eclampsia and its complications in women with normal blood pressure. Cochrane Database Syst Rev (in press).
Meher S, Abalos E, Carroli G. Bed rest with or without hospitalisation for hypertension during pregnancy. Cochrane Database Syst Rev 2005;(4):CD003514.
Meher S, Duley L. Exercise or other physical activity for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev (in press).
Kramer M, Kakuma R. Energy and protein intake in pregnancy. Cochrane Database Syst Rev 2003;(4):CD000032.
Duley L, Henderson-Smart D, Meher S. Altered dietary salt for preventing pre-eclampsia, and its complications. Cochrane Database Syst Rev 2005;(4):CD005548.
Meher S, Duley L. Garlic for preventing pre-eclampsia. Cochrane Database Syst Rev (in press).
Atallah A, Hofmeyr G, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 2002;(1):CD001059.
Rumbold A, Duley L, Crowther C, Hasslam R. Antioxidants for preventing pre-eclampsia. Cochrane Database Syst Rev 2005;(4):CD004227.
Duley L, Henderson-Smart D, King J, Knight M. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2003;(4):CD004659.
Abalos E, Duley L, Steyn D, Henderson-Smart D. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 2001;(2):CD002252.
Meher S, Duley L. Progesterone for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev (in press).
Mello G, Parretti E, Fatini C, Riviello C, Gensini F, Marchionni M, et al. Low-molecular-weight heparin lowers the recurrence rate of preeclampsia and restores the physiological vascular changes in angiotensin-converting enzyme DD women. Hypertension 2005;45:86-91.
Ferrier C, Koeferl U, Duerig P, Schneider H. Effects of LMW-heparin and low-dose aspirin on renal uric acid handling in high-risk pregnancies. Hyper Preg 2000;19(suppl 1):O68.
Collins R, Yusuf S, Peto R. Overview of randomised trials of diuretics in pregnancy. BMJ 1984;291:1129.
Kr�ner C, Turnbull D, Wilkinson C. Antenatal day care units versus hospital admission for women with complicated pregnancy. Cochrane Database Syst Rev 2001;(4):CD001803.
Turnbull DA, Wilkinson C, Gerard K, et al. Clinical, psychosocial, and economic effects of antenatal day care for three medical complications of pregnancy: a randomised controlled trial of 393 women. Lancet 2004;353:1104-09.
Duley L, Henderson-Smart D. Drugs for rapid treatment of very high blood pressure during pregnancy. Cochrane Database Syst Rev 2002;(4):CD001449.
Churchill D, Duley L. Interventionist versus expectant care for severe pre-eclampsia before term. Cochrane Database Syst Rev 2002;(3):CD003106.
Duley L, Williams J, Henderson-Smart D. Plasma volume expansion for treatment of women with pre-eclampsia. Cochrane Database Syst Rev 1999;(4):CD001805.
Ganzevoort W, Rep A, Bonsel GJ et al. A randomised controlled trial comparing two temporising management strategies, one with and one without plasma volume expansion, for severe and early onset pre-eclampsia. BJOG 2005;112:1358-68.
Barrilleaux PS, Martin JN Jr, Klauser CK, Bufkin L, May WL. Postpartum intravenous dexamethasone for severely preeclamptic patients without hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome: a randomized trial. Obstet Gynecol 2005;105:843-8.
Gulmezoglu AM, Hofmeyr GJ , Oosthuisen MM. Antioxidants in the treatment of severe pre-eclampsia: an explanatory randomised controlled trial. Brit J Obstet Gynaecol 1997;104:689-96.
Matchaba P, Moodley J. Corticosteroids for HELLP syndrome in pregnancy. Cochrane Database Syst Rev 2004;(1):CD002076.
Duley L, Gulmezoglu A, Henderson-Smart D. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia. Cochrane Database Syst Rev 2003;(2):CD000025.
Duley L, Henderson-Smart D. Magnesium sulphate versus diazepam for eclampsia. Cochrane Database Syst Rev 2003;(4):CD000127
Duley L, Henderson-Smart D. Magnesium sulphate versus phenytoin for eclampsia. Cochrane Database Syst Rev 2003;(4):CD000128.
Duley L, Gulmezoglu A. Magnesium sulphate versus lytic cocktail for eclampsia. Cochrane Database Syst Rev 2000;(3):CD002960.
Magee L, Sadeghi S. Prevention and treatment of postpartum hypertension. Cochrane Database Syst Rev 2005;(1):CD004351.

Other references

World Health Organization International Collaborative Study of Hypertensive Disorders of Pregnancy. Geographic variation in the incidence of hypertension in pregnancy. Am J Obstet Gynecol 1988;158:80-3.
National Institute of Clinical Excellence, Scottish Executive Health Department , Department of Health Social Services and Public Safety Northern Ireland. Why Mothers Die 2000-2002. The sixth report on confidential enquiries into maternal deaths in the United Kingdom. London: RCOG Press, 2004.
Duley L. Maternal mortality associated with hypertensive disorders of pregnancy in Africa, Asia, Latin America and the Caribbean. Br J Obstet Gynaecol 1992; 99:547-53.
Wilson BJ, Watson MS, Prescott GJ, et al. Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. BMJ 2003; 326:845-9.
Roberts J, Cooper D. Pathogenesis and genetics of pre-eclampsia. Lancet 2001; 357:53-6.
Roberts J, Lain K. Recent Insights into the pathogenesis of pre-eclampsia. Placenta 2002; 23:359-72.
National Institute for Clinical Excellance. Antenatal care. Routine care for the healthy pregnant woman. National Institute for Clinical Excellance Clinical Guideline 6, London 2003.
Conde-Agudelo A , Villar J, Lindheimer M. World Health Organisation systematic review of screening tests for preeclampsia. Am J Obstet Gynecol 2004; 104:1367-91.
Higgins JR, de Swiet M. Blood pressure measurement and classification in pregnancy. Lancet 2001; 357:131-5.
Kincaid Smith P, North RA, Fairley KF, Kloss M , Ihle BU. Prevention of pre-eclampsia in high risk women with renal disease: a prospective randomized trial of heparin and dipyridamole. Nephrology 1995;1:297-300.
Hauth JC, Ewell MG , Levine RJ, Esterlitz JR, Sibai B, Curet LB et al. Pregnancy outcomes in healthy nulliparas who developed hypertension. Obstet Gynecol 2000; 95:24-8.
Villar J, Carroli G, Wojdyla D et al. Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions? Am J Obstet Gynecol (in press) 2006.
Douglas K, Redman C. Eclampsia in the United Kingdom. BMJ 1994; 309:1395-400.
Sheth S, Chalmers I. Magnesium for preventing and treating eclampsia: time for international action. Lancet 2002; 359:1872-3.
Sevene E, Lewin S, Mariano A, Woelk G, Oxman AD, Matinhure S et al. System and market failures: the unavailability of magnesium sulphate for the treatment of eclampsia and pre-eclampsia in Mozambique and Zimbabwe. BMJ 2005; 331:765-9.
Thompson S, Neal S, Clark V. Clinical risk management in obstetrics: eclampsia drills. BMJ 2004; 328:269-71.
Magpie Trial Collaborative Group. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet 2002; 359:1877-90.
Chien PFW, Arnott N, Gordon A, Owen P, Khan KS. How useful is uterine artery Doppler flow velocimetry in prediction of pre-eclampsia, intrauterine growth retardation and perinatal death? An overview. BJOG 2000; 107:196-208.
Knight M, Duley L, Henderson-Smart D, King J. Antiplatelet agents for prevention and treatment of pre-eclampsia and its complications. Cochrane Database Syst Rev 2000, Issue 2. Art. No.: CD000492. DOI: 10.1002/14651858.CD000492 .
Hofmeyr GJ, Kulier R. Abdominal decompression in normal pregnancy. Cochrane Database Syst Rev 1998;(1):CD001062.
Zhang J, Wu TX, Liu GJ. Chinese herbal medicine for the treatment of pre-eclampsia. Cochrane Database Syst Rev (in press).
Redman C, Roberts J. Management of pre-eclampsia. Lancet 1993; 341(8858):1451-

Figure A:� Summary of results from trials comparing an antihypertensive drug with placebo/no intervention

Figure B:� Summary of results from trials comparing alternative antihypertensive drugs for very high blood pressure ...

Figure C:� Summary of results from trials comparing a policy of stabilisation and delivery with expectant care ...

Figure D:� Summary of results from trials evaluating magnesium sulphate for prevention of eclampsia

Figure E:� Summary of results from trials comparing alternative anticonvulsant drugs for eclampsia

Figure A:� Summary of results from trials comparing an antihypertensive drug with placebo/no intervention for women with mild-moderate hypertension

Figure B:� Summary of results from trials comparing alternative antihypertensive drugs for very high blood pressure: effect on persistent hypertension

Figure C:� Summary of results from trials comparing a policy of stabilisation and delivery with expectant care for women with severe early onset pre-eclampsia

Figure D:� Summary of results from trials evaluating magnesium sulphate for prevention of eclampsia

Figure E:� Summary of results from trials comparing alternative anticonvulsant drugs for eclampsia

(a) Magnesium sulphate versus diazepam

Appendix 3: Ongoing research

Prevention of pre-eclampsia

Antioxidant vitamins C and E

Australian Collaborative Trial of Supplements with vitamin C and E (ACTS ISRCTN00416244). Recruitment closed 2005. Comparison of 1000 mg vitamin C and 400 IU vitamin E daily with placebo. Planned sample size 1,870 women.

Vitamins in Pre-eclampsia (VIP ISRCTN62368611). 2404 women in the UK randomised to 1000 mg vitamin C and 400 IU vitamin E daily or placebo. Results expected in 2006.

Diabetes and Pre-eclampsia Intervention Trial (DAPIT ISRCTN27214045). Women with type 1 diabetes in preceding pregnancy randomised to 1000 mg vitamin C and 400 IU vitamin E daily or placebo. Planned sample size 945 women, recruitment started in April 2003, Northern Ireland.

Combined Antioxidants and Pre-eclampsia Prediction Studies (CAPPS NCT00135707). Comparison of 1000 mg vitamin C and 400 IU vitamin E with placebo. Recruitment 2003-7, in 14 US hospitals. Planned sample size 10,000 women.

International Trial of Antioxidant for The Prevention of Preeclampsia (INTAPP ISRCTN85024310). Nulliparous women randomised to 1000 mg vitamin C and 400 IU Vitamin E or placebo. Recruitment 2004-8. Co-ordinated from Quebec, Canada.

Brazilian trial of antioxidant therapy to prevent pre-eclampsia (NCT00097110). Comparison of 1000 mg vitamin C and 400 IU vitamin E with placebo. Recruitment 2003-7. Planned sample size 734 women.

Antiplatelet drugs

Perinatal Antiplatelet Review of International Studies (PARIS) collaboration is using data from individual women in each study for a meta-analysis, to provide better information about which women are most likely to benefit from antiplatelet therapy. Analyses due to be completed in 2006.

Mild-moderate hypertension

Control of Hypertension in Pregnancy Study (CHIPS ISRCTN57277508). Women with mild-moderate pre-existing or gestational hypertension at 20-33 weeks randomised to �less tight� or �tight� control of hypertension. Pilot study of 132 women completed 2004.

Appendix 4: Pre-eclampsia in developing countries

Nearly 529,000 women die every year as a result of complications arising from pregnancy and childbirth, 99% in low and middle income countries. Although differences between regions are huge, these deaths are heavily concentrated amongst the poor

Hypertensive disorders of pregnancy account for 10-15% of maternal deaths, most associated with eclampsia. For every woman who dies, many more suffer debilitating sequelae

Pre-eclampsia and eclampsia can rapidly become a life-threatening emergency, yet in many low and middle income countries few women have access to hospitals or specialist obstetric care. During pregnancy and childbirth many women are cared for only by relatives or traditional birth attendants

Even when antenatal care is available women often come for the first time late in pregnancy, thereby missing the opportunity for screening, detection, and referral of those with, or at risk of, pre-eclampsia

Mortality associated with preterm birth is much higher than in developed countries, as access to neonatal intensive care is limited

For women who do manage to access the health care services, barriers to appropriate care remain. Clear guidelines and coherent strategies for implementation of care will help optimise the use of limited resources. For example, despite robust evidence supporting magnesium sulphate as an inexpensive and effective intervention for prevention and treatment of eclampsia, it is still not widely available in some low and middle income countries