Pre-eclampsia - study group consensus statement

Categories of recommendation

Recommendations fall into three categories:

  1. Recommendations for clinical practice (principally aimed at Fellows and Members of the Royal College of Obstetricians and Gynaecologists) based upon research evidence (where available) and the consensus view of the Group. The clinical practice recommendations have been graded from ‘A’ to ‘C’ according to the strength of evidence on which each is based (Table 26.1). The scheme for the grading of recommendations is based on the system adopted by both the NHS Executive and the Scottish Intercollegiate Guidelines Network.
  2. Recommendations for future research in those clinical areas where the Group identified a need for further evidence on which to base practice.
  3. Recommendations relating to health education and health policy.

Table 26.1. Grading of recommendations

Grade Recommendation
A Requires at least one randomised controlled trial as part of the body of literature of overall good quality and consistency addressing the specific recommendation.
B Requires availability of well-conducted clinical studies but no randomised clinical trials on the topic of recommendation.
C Requires evidence from expert committee reports or opinions and/or clinical experience of respected authorities. Indicates absence of directly applicable studies of good quality.

General conclusions

Worldwide, each year, more than four million women will develop pre-eclampsia and approximately 100 000 women will have eclamptic convulsions, with over 90% occurring in developing countries. Pre-eclampsia complicates 2–3% of all pregnancies (5–7% in nulliparous women) and 2% of women with pre-eclampsia will develop eclampsia.

Pre-eclampsia is a multisystemic syndrome usually recognised by new onset hypertension and proteinuria appearing in the second half of pregnancy. Clinicians should be aware that pre-eclampsia may occasionally occur with hypertension in the absence of proteinuria (and proteinuria without hypertension) but with other features such as eclampsia, renal impairment, thrombocytopenia, liver dysfunction or fetal compromise.

Our understanding of the pre-eclampsia syndrome would be facilitated by recognition of discrete subsets of women with pre-eclampsia including early onset disease and those associated with fetal growth restriction.

Recommendations for clinical practice

  1. Women with previous pre-eclampsia should be offered counselling, if possible preconceptually, and given realistic estimates of the likelihood of recurrence. Facilities for local expert counselling should be available as widely as possible. (Grade A)
  2. Women with underlying medical conditions associated with an increased risk of pre-eclampsia should be offered prepregnancy counselling to explain this risk and to encourage early attendance for specialist antenatal care. (Grade A)
  3. Many women with subfertility are at increased risk of pre-eclampsia. This is due to a combination of the underlying medical condition such as polycystic ovary syndrome and the risk of multiple pregnancy. This risk should be explained to the women and specialist antenatal care provided. (Grade B)
  4. It should be considered that women at increased risk of pre-eclampsia requiring assisted reproduction should have only one embryo transferred. (Grade C)
  5. Care pathways should be in place to provide appropriate specialist obstetric care for those identified to be at risk of pre-eclampsia. (Grade A)
  6. Women with underlying medical conditions associated with an increased risk of pre-eclampsia require increased antenatal surveillance and should be managed by clinicians with expertise in the diagnosis and management of pre-eclampsia. (Grade A)
  7. Women with multiple pregnancies are at increased risk of pre-eclampsia and should receive specialist antenatal care. (Grade A)
  8. All women with blood pressure greater than 140/90 mmHg with or without proteinuria should be referred to a day assessment or obstetric unit. (Grade A)
  9. All women with persistent proteinuria, even in the absence of hypertension, should be referred for further investigation. (Grade A)
  10. All women should have access to a day assessment unit. (Grade A)
  11. Although pregnancies associated with an abnormal uterine artery Doppler waveform are at significant risk of adverse outcome (particularly severe pre-eclampsia requiring early delivery) its introduction as a screening test for all women cannot currently be recommended other than in clinical trials. (Grade B)
  12. Antiplatelet therapy, in particular, low dose (< 75 mg) aspirin, reduces the risk of pre-eclampsia by around 15% for women at both low and high risk. There appears to be a similar reduction in the risk of perinatal death. Aspirin should be considered, particularly for women at high risk. In countries with a high prevalence of pre-eclampsia, more widespread use may be worthwhile. (Grade B)
  13. All new interventions to prevent pre-eclampsia should be properly evaluated in large randomised trials before being introduced into clinical practice. (Grade A)
  14. Data from small trials are promising that supplementation with vitamins C and E may reduce the risk of pre-eclampsia. Large trials are now underway. In the meantime, supplementation with vitamins C and E cannot be recommended for clinical care. (Grade B)
  15. Automated instruments for blood pressure measurement are generally not validated for use during pregnancy and pre-eclampsia. Therefore, the use of mercury sphygmomanometers remains preferable. If used, automated instruments require the calibration to be checked regularly. (Grade B)
  16. If automated devices are used for monitoring in an intensive care area, the accuracy of the devices should be confirmed with mercury sphygmomanometers on a regular basis or an intra-arterial line should be considered. (Grade A)
  17. Measurement of blood pressure in pregnancy and pre-eclampsia should include the following:
    • instrument: mercury/aneroid sphygmomanometer or validated automated device
    • cuff size: it is imperative that the appropriate cuff size is used; it is better to use one that is too big than one that is too small
    • setting: relaxed, quiet environment, preferably after rest
    • position: lying at a 45-degree angle or sitting (cuff at heart level)
    • arm: left or right (higher value if difference is greater than 10 mmHg)
    • dependent arm, if in a lateral position
    • Korotkoff sounds: first (systolic) and fifth (diastolic); if diastolic is persistently less than 40 mmHg use muffling or fourth sound and make a note.

    (Grade A)

  18. There is considerable observer error involved in dipstick urinalysis for proteinuria. This can be overcome by the use of automated dipstick readers, which significantly improve false positive and false negative rates. (Grade C)
  19. The definition of gestational proteinuria is derived from studies calculating the 95th centile for an uncomplicated population. A protein loss of over 300 mg in 24 hours is associated with an increased morbidity to the mother and her baby. (Grade B)
  20. There is considerable variation between laboratory assays for the quantification of proteinuria. This, combined with the unknown errors associated with 24-hour urine collection, means that new tests at point of care have potential advantages over the current gold standards. An elevated protein creatinine ratio of greater than 30 mg/mmol correlates with a 24-hour protein excretion greater than 300 mg and should be used to check for significant proteinuria. (Grade C)
  21. Due to the variation in urine concentration, largely determined by hydration, all urine screening in obstetric day units should be by protein creatinine ratio. This can be by laboratory test or at point of care. (Grade C)
  22. New urinalysis devices and dipsticks should be tested for accuracy and predictive values before being introduced into clinical practice. (Grade C)
  23. Women with severe pre-eclampsia should have early referral to a specialist centre. A woman should not be transferred unless it is considered safe to do so and she has been stabilised. (Grade C).
  24. There should be regional consensus guidelines agreed by all relevant parties. (Grade A)
  25. Women with elevated blood pressure should be given antihypertensive therapy consistent with local protocols. (Grade A)
  26. Magnesium sulphate is the anticonvulsant of choice for both prevention and treatment of eclampsia (including treatment of acute seizure). Magnesium sulphate is recommended for women with pre-eclampsia deemed at risk of seizure and for whom there is a plan for delivery. Magnesium sulphate is relatively low cost and therefore of particular relevance in developing countries. (Grade A)
  27. Women with a history of severe early onset pre-eclampsia, especially if associated with growth restriction or late fetal loss, should be screened for antiphospholipid syndrome and the implications for future pregnancies should be discussed. (Grade B)
  28. Women who had early severe pre-eclampsia or pre-eclampsia associated with fetal growth restriction, stillbirth or abruption, may be tested for hyperhomocysteinuria, factor V Leiden, protein S, protein C and antithrombin (AT) deficiency but the implications for future pregnancies have yet to be determined. (Grade C)

Recommendations for research

  1. The Study Group strongly supports the development of international collaborative research programmes in pre-eclampsia research.
  2. The establishment of a maternal and fetal medicine network of centres committed to high quality research should be strongly encouraged, as adequate patient numbers will not be achievable through independent centre-based research or even nationwide approaches.
  3. There is a need for large, well-designed screening studies to develop reliable and valid screening tools for pre-eclampsia. An international research framework would be invaluable in implementing improved methods of universal clinical screening for pre-eclampsia, including evaluation of the impact on maternal and fetal outcome.
  4. Communication and international collaboration are also considered essential in the undertaking of trials of prophylactic treatments for pre-eclampsia. This Group strongly recommended the sharing of protocols and data to facilitate such efforts.
  5. Women involved in research to study the aetiology of pre-eclampsia should be more carefully defined in relation to clinical symptoms and disease progression than women undergoing routine clinical care. Depending upon the nature of the particular study, the following must be precisely specified:
    • normality in the first half of pregnancy and in the interval after delivery
    • degree of hypertension and proteinuria
    • gestational age at delivery
    • parity
    • absence of other conditions, such as pre-existing hypertension and intrauterine growth restriction.
  6. Studies of pre-eclampsia should always be supported by carefully collected clinical details of the index pregnancy. Researchers should use strict phenotypic criteria and recruit women at the time of the pre-eclamptic episode, if possible, rather than relying on hospital records for phenotyping. This is particularly apposite in relation to gestational age at sampling of tissue from women with disorder, e.g. expression of many genes and proteins is gestationally related. The methods of determination of gestational age should be clearly stated in all research studies. Whenever possible, a group of nonpregnant healthy control women should be included as well as normal pregnancy control women.
  7. The understanding of pre-eclampsia would be facilitated by a comparison of similarities and differences between pre-eclamptic pregnancies and pregnancies complicated by intrauterine fetal growth restriction (secondary to placental insufficiency).
  8. The pathogenesis of pre-eclampsia may incorporate two stages: deficient trophoblast invasion of spiral arteries and widespread oxidative stress and inflammatory response – particularly targeting the endothelial cell resulting in a multisystem disorder.
  9. Poor placentation and the syndrome of pre-eclampsia should be considered as closely related but fundamentally separate disorders which are not inevitably linked.
  10. Impaired trophoblast invasion of the spiral arteries is an important antecedent to pre-eclampsia and mechanisms determining incomplete trophoblast invasion require further study.
  11. There is a need for the re-evaluation of patterns of trophoblast invasion in different subcategories of pre-eclampsia and in gestational hypertension, normotensive fetal growth restriction and preterm birth.
  12. In studies of the extent of trophoblast invasion, real placental bed biopsies (not basal plate), including myometrium as well as decidua, should be studied. For evaluation of the depth of trophoblast invasion, interstitial and endovascular invasion should be distinguished, since there is no current evidence for shallow invasion of both interstitial and endovascular trophoblast.
  13. Since studies from the placenta of women with pre-eclampsia show evidence of both apoptosis and necrosis (aponecrosis), there is a further need to look for markers of aponecrosis in villous tissue of placenta and in maternal blood samples.
  14. Studies in vitro of tissue obtained from women with pre-eclampsia frequently use an immunohistochemical approach to determine whether expression of proteins is altered in comparison to normal pregnancies. However, many confounding data have arisen, particularly in studies of placenta, from the use of antibodies which have been poorly characterized. All immunohistochemical studies should include data on antibody specificity/and validation.
  15. Care is required in extrapolation of in vitro data to the in vivo situation. The testing of hypotheses by description of gene and protein expression in tissue from women with pre-eclampsia should ideally be accompanied by functional studies before conclusions are drawn.
  16. Oxidative stress is considered to play an important role in pre-eclampsia but evaluation of oxidative stress is problematical, with many pitfalls in the variety of methods employed. There is a need for development of a new and reliable method for assay of oxidative stress (e.g. lipid peroxides); this may help to identify women at risk.
  17. In light of the recognised importance of oxidative stress in pre-eclampsia, investigations of the genetic contribution to pre-eclampsia should include investigation of polymorphisms of genes for enzymes involved in antioxidant defence.
  18. Further evaluation is required into the use of uterine artery Doppler screening for pre-eclampsia. Future research should also consider the clinical effect of interventions in women who are screen-positive. This would probably require multicentre randomised controlled trials.
  19. Large, multicentre prospective studies are required to investigate the gestational relationship between pre-eclampsia and circulating and cellular markers of inflammation, lipids and adiposity. Attention should be paid to potential differences in women with early and late onset disease.
  20. Further studies are required in adipocytes of women with pre-eclampsia to determine the origin of increased leptin concentrations and fatty acids and to identify lipolytic agents.
  21. In view of the markedly increased risk of pre-eclampsia in obese women, public health research should concentrate upon obesity prevention and on studies to determine whether increased physical activity may reduce the incidence of pre-eclampsia in overweight women.
  22. Studies of the genetic origins of pre-eclampsia should always include investigation of both maternal and fetal genes and researchers should ensure that studies are sufficiently large for adequate statistical power for testing of multiple genes. This may require an international collaborative approach.
  23. Further studies are needed to assess the role of inherited thrombophilias in adverse pregnancy outcome, including severe pre-eclampsia. Given the high rate of placental thrombosis and infarcts associated with pre-eclampsia and other adverse outcome, randomised trials should assess the role of heparin and low molecular weight heparin in the prevention of recurrence of adverse pregnancy outcome, including severe pre-eclampsia.
  24. Oxidative stress, endothelial dysfunction and activation of the clotting system can all cause or be caused by an inflammatory response. A marked systemic inflammatory response is a feature of normal pregnancy. Pre-eclampsia is the extreme and decompensated end of a continuum of such changes common to all pregnancies. Future research should recognise the fundamental unity of the different pathological processes (oxidative stress, endothelial dysfunction, inflammatory activation) known to contribute to pre-eclampsia and the fact that normal pregnancy and pre-eclampsia are not different conditions but different parts of the same spectrum of changes.

Recommendations for health policy and education

  1. There is a need for emphasis of the national and global importance of pre-eclampsia. There is a requirement to increase community awareness with a view to reducing the current serious morbidity.
  2. Development of effective methods of screening would enable tailoring of antenatal care to lower the incidence of pre-eclampsia.
  3. To date, no biochemical, genetic or ultrasound test to screen for pre-eclampsia is currently recommended for routine obstetric care.
  4. Women with recognised risk factors such as obesity, multiple pregnancy, maternal disease, family history and past history should have antenatal care to reflect that risk.
  5. There has been a marked increase in knowledge and understanding relating to the pathogenesis of pre-eclampsia. However, further studies are required as there is still much to be established. Developing accurate methods of predicting pre-eclampsia is a priority, as this would lead to targeted intervention. Studies to date have begun to lead to the development of rational prophylactic treatment strategies, such as aspirin and maybe antioxidants. This would appear to be a fruitful area for further research funding.
Date published: 01/09/2003

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