Of all serious medical complications of pregnancy, pre-eclampsia dominates as relatively common, dangerous, unpredictable in its course and difficult to manage. In all formal reports of maternal and perinatal mortality, it features prominently.
This article deals with certain aspects of the disorder that have not been as well covered in the literature as other elements. The clinical manifestations are manifold, variable and sometimes, if unrecognised, can have unfortunate results. The first truism to accept is that there is no such entity as ‘mild’ pre-eclampsia. All cases have the potential to undergo a transition to a life-threatening illness for mother and baby and, therefore, close monitoring as an inpatient is essential.
Pre-eclampsia is a disease of the placenta and its vasculature. The placenta cannot be directly examined and its function is poorly assessed by current techniques. The derangements that come to clinical attention are protean, variable and, in the early stages of pre-eclampsia, may not include hypertension, the usual diagnostic entry point.
For these reasons, every woman, particularly those in the first pregnancy, should be regarded as being at risk. It is largely to detect pre-eclampsia that repeated visits to the obstetrician are necessary, since it may be absent at an antenatal visit yet present in a severe form within days.
A perplexing feature of pre-eclampsia is the fact that it may present with symptoms before any clinical signs appear. In other cases, there may be some clinical signs, but minimal or absent hypertension, and even these cases may progress undetected and lead to fetal death, eclampsia, abruption or other severe maternal complications. Many women who ultimately develop severe pre-eclampsia experience suggestive symptoms in the days or weeks before diagnosis, including headaches, visual disturbance, swelling, dyspnoea, nausea or vomiting, reduced fetal activity and, particularly in the worst cases, a severe pain in the upper abdomen or lower chest that has distinctive diagnostic characteristics that are defined in a paper detailing many cases.1
The term chosen for this pain is ‘pre-eclamptic angina’, angina being used in its original sense as signifying a severe cramp-like pain. The presence of pre-eclamptic angina signifies a grave prognosis for mother and baby, as it is a feature of only the worst type of pre-eclampsia. It is a sign of imminent calamity and terrible complications may be seen in those women who manifest pre-eclamptic angina. Its genesis lies in hepatic infarcts and haemorrhages, which were well documented by Sheehan in his landmark text2 describing the pathology at postmortem of many cases of severe pre-eclampsia and eclampsia. This severe, and often recurring, symptom (sometimes first experienced a week or more before presentation) is a marker of a dangerous and unstable state. Those with pre-eclamptic angina are in need of urgent delivery. Women with any of the above symptoms require careful evaluation, with attention to pre-eclampsia as the possible underlying cause.
Signs and laboratory features
The classical sign of pre-eclampsia is hypertension, but it is usually episodic and may be entirely absent when the woman is seen in the morning, but severe and dangerous by the late afternoon or at night. This reversal of the diurnal rhythm of blood pressure in pre-eclampsia was described decades ago.3 The presence of hyperactivity of the deep tendon reflexes or clonus is of great concern and suggests nervous system involvement and risk of progression to complications, even eclampsia.
Tenderness of the liver accompanies the pain mentioned above and should be taken as a worrying feature. Oedema is often seen, but is not invariable and many women develop substantial oedema in normal pregnancy so careful evaluation is necessary. Proteinuria is a sign of severity and is not required to diagnose pre-eclampsia as in many pre-eclamptic women it is not present until the disease reaches a late stage. Thus many with the disease do not have proteinuria at presentation and its absence cannot be taken as reassuring, while its presence indicates a more advanced stage and those with it are at greater risk. In years past, heavy proteinuria was taken as an absolute indication for delivery. Now, with better fetal assessment and monitoring, pregnancy may be allowed to proceed in the presence of proteinuria, but only at very early gestations where it is felt that prolongation is essential for fetal reasons, as continuation of pregnancy in this situation is always at the cost of risk to the baby and mother. Proteinuria is a reliable indicator of severity signifying the need for intensive repeated monitoring of the baby as old studies confirmed that proteinuria correlates with higher risk of fetal demise.4
The laboratory features of pre-eclampsia are well known, but the presence of normal tests does not exclude the disorder and should not provide reassurance. The most reliable test, although even it may mislead in some cases, is plasma uric acid5 that rises in most cases, but not until the disease is entering a more severe state. It should not exceed 0.33 in any pregnant woman (unless there is renal disease or dehydration and it is not reliable with twins) and should not exceed the same numerical value as the gestational age before 34 weeks – thus at 28 weeks, it should be no higher than 0.28.
Thrombocytopenia, any evidence of haemolysis or a high haemoglobin (indicating plasma volume contraction), elevation of alanine aminotransferase and any elevation in creatinine are all worrying features. In 1954, the combination of some of these abnormalities was described6 in very advanced cases, but this classic description went largely ignored until the acronym ‘HELLP’ was applied to this clinical subgroup many years later7 and this has benefited women and babies as it is a memorable term and has increased the recognition of a severe variant of pre-eclampsia that sometimes does not manifest hypertension, but is nevertheless very dangerous.
Complications and their prevention
Pre-eclampsia is a progressive disorder that worsens always, sometimes gradually and sometimes with fulminating rapidity. Therefore, repeated assessment of mother and baby is necessary. Ideally, this should be in hospital – so volatile and unpredictable is pre-eclampsia that it demands in-patient observation and care. It cannot safely be dealt with as an outpatient and neither can it be assessed reliably in a period of a few hours as its worst signs may not be present until later.
I believe that there is no place for the recently developed ‘maternal fetal assessment unit’ in the evaluation of cases of suspected pre-eclampsia, as a reliable predictive assessment cannot be made in a short period of time. Ongoing inpatient care is essential for these women.
The aim of continuing care in hospital is to assess maternal and fetal fitness to continue the pregnancy, and to control hypertension. Pre-eclampsia worsens until delivery, and even for some time afterwards. For this reason it is always in the mother’s best interests to deliver the baby, but in very early cases it is usually necessary to attempt prolongation for fetal benefit, even though this exposes the mother to the hazards of eclampsia, abruption, hypertensive cerebral haemorrhage, pulmonary oedema, retinal detachment, hepatic haemorrhage and renal impairment or failure. Such attempts at prolongation require the most assiduous and diligent of monitoring, and should only be undertaken at a tertiary centre with the best available modalities of fetal and maternal surveillance and, ideally, assistance from a physician trained in Obstetric Medicine.
When the baby is mature, there is no benefit that justifies the risk in deferring delivery. A recent study8 randomised women with pre-eclampsia between 34 and 37 weeks to either immediate delivery or attempted prolongation. This valuable work showed no difference in fetal outcome, but more maternal complications in those where delivery was not undertaken promptly. For this reason, after 34 weeks it is difficult to justify continuing the pregnancy in women with definite pre-eclampsia. Moreover, when the decision is taken to deliver the baby, it should be accomplished without delay. Where betamethasone administration is required for fetal lung maturation it is reasonable to wait, provided the fetus is constantly monitored. Otherwise, even overnight delay may expose the baby and mother to unnecessary risk such that if delivery is determined to be necessary it should not wait until the next morning. Many cases have deteriorated in that interim period.
However, delivery alone is insufficient management of pre-eclampsia. It must always be combined with control of abnormalities and preparation of the patient including any or all of the following: control of severe hypertension by use of oral or intravenous agents, correction of disordered fluid status, correction of coagulopathy, and prophylaxis against eclampsia by means of magnesium sulphate. Not all those with pre-eclampsia require magnesium. The indications are uncontrolled hypertension, persistent headache or vomiting, altered conscious state, tremor or agitation, hyperreflexia with or without clonus and, of course, eclampsia itself. Any woman requiring magnesium must be delivered as soon as possible and the magnesium continued for 24 hours.
When is delivery necessary?
As mentioned above, after 34 weeks there is little benefit and considerable hazard in continuing the pregnancy with definite pre-eclampsia. The decision to terminate the pregnancy earlier than 34 weeks is always difficult, and involves consideration of a number of factors. Prediction of progression in pre-eclampsia is imprecise and unreliable, although the recently available test ‘Placental Growth Factor’ has been shown of reasonable predictive value in studies elsewhere.9 This test may well provide a useful enhancement to the current care of women with pre-eclampsia.
The following factors represent maternal endpoints. Once reached, any one of these indicates that delivery is necessary or that if continuation (to achieve fetal viability) is to be attempted it carries high risk:
- failure of blood pressure control despite use of any two drugs in standard doses;
- worsening thrombocytopenia;
- pre-eclamptic angina or liver test abnormalities;
- rising creatinine, oliguria despite adequate hydration, or heavy proteinuria;
- pulmonary oedema;
- persistent neurological symptoms, any alteration of conscious state, confusion or persistent headache;
- antepartum haemorrhage; or
- other persistent symptoms such as vomiting or accumulating oedema.
Fetal indications often constitute the reason for delivery. These include the following:
- abnormal fetal CTG monitoring or flow aberrations on ultrasound;
- subnormal growth between ultrasound examinations;
- reduction in amniotic fluid volume; and
- achievement of sufficient maturity, namely 34 weeks, but earlier in severe cases.
In many cases, a combination of subcritical factors may decide the need for delivery, even though no single factor, by itself, would constitute an endpoint. When pre-eclampsia complicates diabetes, renal disease, lupus or any other medical or obstetric (for example, intrauterine growth restriction) disorder, the prognosis is worse and the decision for delivery should be made at the slightest sign of deterioration, usually earlier than in cases not complicated by a second disorder.
It should also be recognised that the whole situation of being under surveillance for a life-threatening condition is so stressful for the patient that she may decide she cannot tolerate further uncertainty and, in these cases, it is entirely correct to agree to her request for delivery, even if things may seem medically stable. It is the patient and her family who suffer most and her opinion must be taken seriously.
After delivery, the disease remains active for at least a week and sometimes longer. The woman’s blood pressure commonly reaches severe levels three to seven days postpartum10 and eclampsia has been seen several days after delivery. This postnatal hypertension may need ongoing drug therapy. Thus, continued surveillance of the mother is well justified and she should not be sent home less than a week after delivery. The blood test abnormalities slowly return to normal, but it may take many days for the platelet count to rise, liver enzymes to fall and renal function to recover.
It is a great pity, but nevertheless the truth, that medicine has not yet mastered the prediction or management of this enigmatic disorder and has no cure other than delivery. This situation may change with future advances, but in the meantime the best that can be offered is diligent and insightful care and meticulous monitoring, bearing in mind that, if the pregnancy is continued too long and warning features not heeded, a serious complication is very likely to occur in every case of pre-eclampsia, and this may include fetal or maternal death.
- Preeclamptic angina–a pathognomonic symptom of preeclampsia.Walters BN. Hypertens Pregnancy. 2011;30(2):117-24.
- Pathology of toxemia of pregnancy.Sheehan HL and Lynch JB. 1973. Edinburgh: Churchill Livingstone.
- Reversed diurnal blood pressure rhythm in hypertensive pregnancies.Redman CW, Beilin LJ, Bonnar J.Clin Sci Mol Med Suppl. 1976;3:687s-689s.
- Proteinuria and outcome of 444 pregnancies complicated by hypertension. Ferrazzani S, Caruso A et al. Am J Obstet Gynecol. 1990;162:366-71.
- Plasma-urate measurements in predicting fetal death in hypertensive pregnancy. Redman CW, Beilin LJ, Bonnar J, Wilkinson RH. Lancet. 1976 Jun 26;1(7974):1370-3.
- Intravascular hemolysis, thrombocytopenia and other hematologic abnormalities associated with severe toxemia of pregnancy. Pritchard JA, Weisman R, Ratnoff OD, Vosburgh GJ: N Engl J Med. 1954;250(3):89-98.
- Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Weinstein L.Am J Obstet Gynecol. 1982;142(2):159-67.
- Management of late preterm pregnancy complicated by mild preeclampsia: A prospective randomized trial. Martin JN, Owens MY, Thigpen B et al. Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 2012;2:180.
- Angiogenic growth factors in the diagnosis and prediction of pre-eclampsia. Verlohren S, Stepan H, Dechend R; Clin Sci (Lond). 2012;122(2):43-52.
- Hypertension in the puerperium after preeclampsia. Walters BN, Walters T. Lancet. 1987;2(8554):330.