Postgraduate Training Course in Reproductive Health/Chronic Disease

Incidence, morbidity and mortality of pre-eclampsia and eclampsia

Review prepared for the 12th Postgraduate Course in Reproductive Medicine and Biology, Geneva, Switzerland

Dr Güler Şahin
Tutor: Dr A. Metin Gülmezoglu
Department of Obstetrics and Gynaecology
Yuzuncu Yil University Hospital
Van-Turkey
2003

See also presentation

Abstract

Objective

To evaluate the incidence, adverse outcomes, prevention and treatment strategies in pre-eclampsia and eclampsia.

Method

The literature search included Medline and articles from the WHO systematic review of incidence, prevalence of maternal mortality and morbidity 1997-2002. The search was restricted to studies published in English language between 1990-2002, that included a definition of the disease.

Results

Twelve relevant articles out of 187 were included in the review. Most (93%) were excluded because they were either irrelevant or did not define the disease. The incidence of pre-eclampsia and eclampsia was higher in developing countries with the highest rate reported for pre-eclampsia as 7.1% (deliveries) in Zimbabwe and for eclampsia as 0.81% (deliveries) in Colombia. The pattern of complications was similar in all countries but the rates could not be compared as the definition of the adverse outcomes differed. The maternal and fetal mortality rates were higher in developing countries. The highest maternal mortality rate was 0.4% for pre-eclampsia reported in the Magpie trial and as 6.1% for eclampsia reported from Colombia.So far no effective intervention has been reported for prevention of pre-eclampsia. MgSO4 was proven to be superior compared to phenytoin and diazepam in reducing the risk of eclampsia and perhaps maternal mortality but with no significant reduction on adverse fetal outcomes.

Conclusions

Pre-eclampsia and eclampsia are important health issues that have to be dealt with especially in developing countries where the incidence and rates of adverse outcomes are higher. So far no effective intervention for prevention of pre-eclampsia is available. Making MgSO4 available in the prevention and treatment regimens of eclampsia has been shown to decrease eclampsia rates and probably maternal mortality, with no significant beneficial effect on neonatal outcomes.

Introduction

Pre-eclampsia / eclampsia is associated with raised blood pressure and proteinuria and eclampsia is defined as the occurrence of one or more convulsions usually superimposed on pre-eclampsia. Pre-eclampsia is a frequent disorder with a reported incidence of 2-8% among pregnancies. However geographic, social, economic and racial differences are thought to be responsible for incidence rates up to 3 times higher in some populations (1,2). In some countries such as Colombia it is the main cause of maternal mortality. Up to 42% of maternal deaths are attributed to this disorder in Colombia (2). Pre-eclampsia / eclampsia probably accounts for more than 50 000 maternal deaths worldwide each year (2,3). Besides it is associated with fivefold increase in perinatal mortality. The socio-economic impact in developing countries is huge even more so if we consider that in countries such as Colombia maternal mortality is ten times higher than United States (2). Although the rate of pre-eclampsia and the number of maternal deaths from hypertension in pregnancy has fallen steadily over recent years in some developing countries, in places where maternal mortality is high most of these deaths are associated with pre-eclampsia. Even in countries with low maternal mortality a substantial proportion will be due to pre-eclampsia / eclampsia. For example in the United Kingdom pre-eclampsia and eclampsia together account for 15% of direct maternal deaths and two-thirds are related to pre-eclampsia (4,5). Pre-eclampsia / eclampsia remains one of the most common reasons for women to die during pregnancy worldwide as 12% of all maternal deaths is caused by eclampsia (6).
In spite of its importance for public health the aetiology of this disorder is unknown. It is a multisystem disorder with various forms which are believed to result from a failure of the normal invasion of trophoblast cells, leading to maladaptation of maternal spiral arterioles (7). It can also be associated with hyperplacentation disorders such as diabetes, hydatiform mole and multiple pregnancies. Nutritional, environmental and genetic factors play a role in the maternal systemic reaction that produces the clinical signs and symptoms of the disorder (2).
The epidemiology of this multisystem disorder, varying between little systemic involvements to multiorgan failure, is complicated by differences in definition, inaccuracy of diagnosis and the outcomes. Unfortunately, there has been little progress in predicting the disorder compared to advances made in eliminating other serious medical conditions. The magnitude of the problem and the impact on the mother and the neonate needs to be highlighted and updated especially in developing countries where the incidences are high. In addition to the immediate burden there are long-term consequences of the disease. Unless effective prevention strategies are developed and implemented, the huge cost of critical care for the mother, the newborn and the long-term problems in the premature or intrauterine growth retarded baby will continue to impact on health systems.

Objectives

• To provide recent data on incidence/prevalence of pre-eclampsia and eclampsia in developed and developing countries.
• To provide up-to- date information on maternal and fetal morbidity and mortality estimates due to pre-eclampsia and eclampsia.
• To provide up-to-date information on effective interventions for the prevention and treatment of pre-eclampsia and eclampsia

Methods

Medline and the WHO systematic review of incidence/prevalence of maternal mortality and morbidity datasets were searched. Pre-eclampsia, eclampsia, maternal mortality, morbidity were the words used for the electronic database search. To assess the current view of the problem the search was restricted to the study period from 1990 to 2002. Abstracts of the studies identified were evaluated to exclude the obviously irrelevant publications. The full text of the remaining studies that provided information on the current state, prevention and treatment policies were assessed. Articles that were not published in English and that did not have a definition for pre-eclampsia were excluded. Results are expressed in tables without formal pooling.

Results

The search strategy yielded 187 articles between 1990 and 2002. After assesssing the titles and abstracts 34 were judged to be relevant and assessed further. Twelve out of 34 were finally included in this review. The rest either did not have a definition for pre-eclampsia or were found to be irrelevant because they were studying the certain risk factors in the aetiology of pre-eclampsia. Five out of 12 of the studies were hospital based descriptive (8,9,10,11,12), 1 out of 12 was population based cross-sectional (13), 6 out of 12 were randomised controlled trials (4,14,15,15,16,17).
The objective of individual studies differed. In the Saudi Arabian study (8) medical records of 10407 pregnant women were scrutinized to investigate the association of fetal gender with pre-eclampsia. The study from Zimbabwe (9) included 50806 pregnant women from 3 hospitals to asses the effect of seasonal changes on the incidence of pre-eclampsia. Eight hundred and forty five women with new hypertension in the second half of pregnancy were included in the Australian study to investigate whether gestational hypertension progresses to pre-eclampsia (12). To highlight the epidemiology of eclampsia 164 cases of eclampsia among 20277 deliveries in Colombia (10) and 383 eclampsia cases from 279 hospitals in UK (11) were investigated. The cross sectional population based study using the Norwegian Medical Birth Registry analysed the effect of seasonal variations in the occurrence of pre-eclampsia (13). Three out of 6 of the randomised trials investigated the effect of low dose aspirin on the prevention of pre-eclampsia and the adverse outcomes (15,16,17). In the remaining three randomised articles benefit of MgSO4 in pre-eclamptic and eclamptic patients were investigated (4,14,15).
The design and the definitions used in the studies are summarized in table 1. Ten out of 12 studies did not describe how blood pressure measurements were made. The definitions also varied among different studies.
Reported incidence of pre-eclampsia and eclampsia are summarized in table 2.
Major maternal complications seen in pre-eclampsia and eclampsia are shown in table 3. The mortality rate due to pre-eclampsia ranged from none to 0.4 %. Not surprisingly maternal deaths due to eclampsia are higher compared to pre-eclampsia. It ranges from 1.8%-6.1% with the lowest in UK and highest in Colombia.  The rates of the complications reported by the studies are presented in table 3 and 4. It is not possible to compare the rates because the definitions of the complications are not consistent.
Adverse perinatal outcomes are summarized in table 4. We cannot comment on low Apgar scores because cut-off point is reported as <7, < 6 and < 5 in different studies. The rate of birth weight below 10th percentile ranges from 8.9% to 17%, admission to neonatal intensive care unit (NICU) from 2% to 50.2% stillbirth rate from 1.6% to 21.9% and perinatal mortality rate from 3% to 30.7%. Higher rates are seen in eclampsia and are reported from developing countries.
As can be seen from tables 3 and 4 randomised placebo controlled trials of low dose aspirin with large number of data have not shown reduction in the adverse outcomes and the incidence of the disease (15,16,17). Randomised controlled MgSO4-placebo studies in severe pre-eclampsia have shown that MgSO4 reduces the risk of eclampsia and probably maternal death but does not significantly reduce the adverse perinatal outcomes (4,14). Treatment with MgSO4 compared to Phenytoin and diazepam supported the evidence in favour of MgSO4 rather than diazepam or phenytoin because it reduced the risk of recurrent convulsions, non-significantly reduces maternal mortality but not morbidity or perinatal mortality and morbidity (15).

Discussion

Pre-eclampsia, a disorder of unknown aetiology, has several different definitions such as that made by the American College of Obstetricians and Gynecologists (ACOG) (18), The National Institute of Health, National High Blood Pressure Education Programme (NHBPEP) Working group (19), International Society For The Study Of Hypertension In Pregnancy (ISSHP) Australasian Society (20), Canadian Hypertension Society (21) and authors of various studies (22). The review confirms the widespread variation in definitions for the disorder. A definition for the diagnostic procedure was the second important problem. Eighty three percent of the studies did not have a definition for diagnostic procedure. In the 2 studies that had a definition for blood pressure measurements one used Vth Korotkoff sound, the other used IVth Korotkoff sound in the diagnosis of the condition. For proteinuria mainly dipstick analysis of a random urine sample is used as the diagnostic procedure. Unfortunately, such measurements correlate poorly with 24-hour urine samples in the diagnosis of abnormal proteinuria, as concentration of the urine when tested can affect the results (23). Heterogeneity of definitions of the disorder and the consistency and validity of the diagnostic procedures are problems that have to be considered when making comparisons. A global consensus should be introduced for the definition and the diagnostic procedure as it is not only important for diagnosis but for the follow up of this important public health issue.
The data regarding incidence of maternal mortality, stillbirth, neonatal, perinatal mortality and morbidity are presented using different denominators such as pregnancy, delivery and mothers. As a result the incidences among countries are not easy to compare to each other. Taking these special problems into consideration from the studies that have been evaluated the rate of pre-eclampsia is higher in developing countries with the highest rate reported from Zimbabwe as 7.1% when reports with similar definition for incidences are compared. Similarly the rate of eclampsia is higher in developing countries with the highest rate reported from Colombia as 8.1/1000 deliveries and the lowest in UK as 4.9/10000 deliveries. These results imply that pre-eclampsia and eclampsia constitute a worldwide public health problem to be dealt with especially in developing countries.
From the studies being evaluated it can be seen that so far primary prevention of pre-eclampsia is not possible. Low dose aspirin has not proven to be effective in reducing the rate and the adverse maternal and fetal outcomes in primiparous women (15,16,17). Calcium supplementation is promising in low intake population, although further research is needed (24).
Despite considerable regional variation in incidence of pre-eclampsia and eclampsia no matter where you live surprisingly similar morbidity and mortality patterns are observed. However the rates of morbidity are not comparable, as the data are not defined clearly and consistently. For example, liver involvement can include a spectrum of disorders from slight transaminase level elevation to liver failure.
The maternal mortality rates in women with pre-eclampsia were reported higher in developing countries with the highest reported as 0.4% in the Magpie trial. The highest mortality rate reported for eclampsia was from Colombia reported as 6.1%. Adverse perinatal outcomes were also higher in developing countries compared to developed countries.
Three studies with large data in this review have focused on reducing these adverse maternal and fetal outcomes. Treatment strategies that are considered effective in managing pre-eclampsia and eclampsia are: Antihypertensives are recommended for severe hypertension, but their usefulness in treating mild to moderate hypertension is not yet clear (25,26). Introduction of MgSO4 in severe pre-eclampsia has proven to be effective in reducing the rate and risk of eclampsia and is reported that it probably reduces the risk of maternal deaths without a significant effect on perinatal outcomes. Also it has been reported that there is now compelling evidence in favour of magnesium sulphate for routine anticonvulsant management of women with eclampsia, rather than diazepam or phenytoin (4,14,15). 

Conclusion

1. Pre-eclampsia and eclampsia remain as continuing problems worldwide with a higher incidence in developing countries.
2. A universal definition for the disease and diagnostic procedure should be introduced.
3. Implementation of medical interventions that have been demonstrated to be effective in the treatment and prevention of the disease is necessary: MgSO4 should be available in the treatment regimen of eclampsia and severe pre-eclampsia worldwide.
4. Further multicentre large-scale studies on the prevention, treatment and aetiology of the disease are needed to understand and reduce the incidence and adverse outcomes of the disease.

References

1. Geographic variation in the incidence of hypertension in pregnancy. World Health Organization International Collaborative Study of Hypertensive Disorders of Pregnancy. Am J Obstet Gynecol. 1988 Jan;158(1):80-3. [PubMed]
2. Lopez-Jaramillo P, Casas JP, Serrano N. Preeclampsia: from epidemiological observations to molecular mechanisms. Braz J Med Biol Res. 2001 Oct;34(10):1227-35. [PubMed]
3. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet. 1995 Jun 10;345(8963):1455-63. [PubMed]
4. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet. 2002 Jun 1;359(9321):1877-90. [PubMed]
5. Walker JJ. Pre-eclampsia. Lancet. 2000 Oct 7;356(9237):1260-5. [PubMed]
6. Murray CJL, Lopez AD. Health dimensions of sex and reproduction. Murray CJL, Lopez AD.(III) 1998.Cambridge MA, Harvard School of Public Health. Global Burden of Disease and Injury Series. Murray CJL and Lopez AD.
7. Meekins JW, Pijnenborg R, Hanssens M, McFadyen IR, van Asshe A. A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies. Br J Obstet Gynaecol. 1994 Aug;101(8):669-74. [PubMed]
8. Makhseed M, Musini VM, Ahmed MA. Association of fetal gender with pregnancy-induced hypertension and pre-eclampsia. Int J Gynaecol Obstet. 1998 Oct;63(1):55-6. [PubMed]
9. Wacker J, Schulz M, Fruhauf J, Chiwora FM, Solomayer E, Bastert G. Seasonal change in the incidence of preeclampsia in Zimbabwe. Acta Obstet Gynecol Scand. 1998 Aug;77(7):712-6. [PubMed]
10. Conde-Agudelo A, Kafury-Goeta AC. Epidemiology of eclampsia in Colombia. Int J Gynaecol Obstet. 1998 Apr;61(1):1-8. [PubMed]
11. Douglas KA, Redman CW. Eclampsia in the United Kingdom. BMJ. 1994 Nov 26;309(6966):1395-400. [PubMed]
12. Saudan P, Brown MA, Buddle ML, Jones M. Does gestational hypertension become pre-eclampsia? Br J Obstet Gynaecol. 1998 Nov;105(11):1177-84. [PubMed]
13. Magnu P, Eskild A. Seasonal variation in the occurrence of pre-eclampsia. BJOG. 2001 Nov;108(11):1116-9. [PubMed]
14. Coetzee EJ, Dommisse J, Anthony J. A randomised controlled trial of intravenous magnesium sulphate versus placebo in the management of women with severe pre-eclampsia. Br J Obstet Gynaecol. 1998 Mar;105(3):300-3. [PubMed]
15. Golding J. A randomised trial of low dose aspirin for primiparae in pregnancy. The Jamaica Low Dose Aspirin Study Group. Br J Obstet Gynaecol. 1998 Mar;105(3):293-9. [PubMed]
16. Rotchell YE, Cruickshank JK, Gay MP, Griffiths J, Stewart A, Farrell B, Ayers S, Hennis A, Grant A, Duley L, Collins R. Barbados Low Dose Aspirin Study in Pregnancy (BLASP): a randomised trial for the prevention of pre-eclampsia and its complications. Br J Obstet Gynaecol. 1998 Mar;105(3):286-92. [PubMed]
17. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet. 1994 Mar 12;343(8898):619-29. [PubMed]
18. The hypertensive disorders of pregnancy. Report of a WHO study group. World Health Organ Tech Rep Ser. 1987;758:1-114. [PubMed]
19. National Institutes of Health. Working group report on high blood pressure in pregnancy. NIH Publication 2000;No.00-3029. [Free Full Text]
20. Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM. The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy. 2001;20(1):IX-XIV. [PubMed]
21. Helewa ME, Burrows RF, Smith J, Williams K, Brain P, Rabkin SW. Report of the Canadian Hypertension Society Consensus Conference: 1. Definitions, evaluation and classification of hypertensive disorders in pregnancy. CMAJ. 1997 Sep 15;157(6):715-25. [Free Full Text]
22. Redman CW, Jefferies M. Revised definition of pre-eclampsia. Lancet. 1988 Apr 9;1(8589):809-12. [PubMed]
23. Meyer NL, Mercer BM, Friedman SA, Sibai BM. Urinary dipstick protein: a poor predictor of absent or severe proteinuria. Am J Obstet Gynecol. 1994 Jan;170(1 Pt 1):137-41. [PubMed]
24. Hofmeyr GJ, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems.(Cochrane review). Issue 2, 2003. [Abstract]
25. Duley L, Henderson-Smart DJ. Magnesium sulphate versus phenytoin for eclampsia (Cochrane Review). Issue 2, 2003. [Abstract]
26. Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy ( Cochrane Review). Issue 2, 2003. [Abstract]

Table 1. Study characteristics and definition of  pre-eclampsia/eclampsia and the diagnostic procedure in developing and developed countries.(NR: Not reported)

Table 2.Study characteristics and incidence of pre-eclampsia/eclampsia in developing and developed countries.( * Placebo group only, NR:not reported)

Table 3. Maternal complications of pre-eclampsia/eclampsia in developed and developing countries.(NR: Not reported)

Table 4. Perinatal complications of pre-eclampsia/eclampsia in developed and developing countries.(NR: Not reported)

Print this page

Edited by Aldo Campana,