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Objective To evaluate the safety and outcome of women undergoing expectant management of early onset, severe pre-eclampsia.
Design Prospective case series extending over a five-year period.
Setting Tygerberg Hospital, a tertiary referral centre.
Population All women (n= 340) presenting with early onset, severe pre-eclampsia, where both the mother and the fetus were otherwise stable.
Methods Frequent clinical and biochemical monitoring of maternal status, together with careful blood pressure control, in a high care obstetric ward.
Main outcome measures Major maternal complications and prolongation of gestation.
Results Multigravid women constituted 67% of the group. Antenatal biochemistry was reassuring with some expected, but not severe, deteriorations. Twenty-seven percent of women experienced a major complication, but few had poor outcomes. No maternal deaths occurred. Most major complications resolved quickly, necessitating only three admissions (0.8%) to the intensive care unit. One woman required dialysis. Pregnancies were prolonged by a mean (median) number of 11 days (9) before delivery, with more time being gained at earlier gestations. The postpartum inpatient stay (89%≤ 7 days, bearing in mind that 82% of women were delivered by caesarean section) was not extended.
Conclusion Careful noninvasive management of early onset, severe pre-eclampsia in a tertiary centre can diminish and limit the impact of serious maternal complications. Valuable time to prolong the pregnancy and improve neonatal outcome is thereby gained.
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The clinical course of women with early onset, severe pre-eclampsia may be associated with progressive deterioration of the maternal condition. Thus, because delivery is the only way of arresting the disease, there is broad agreement on delivery in the presence of multi-organ dysfunction, fetal distress or once a gestation of 34 weeks has been reached. Delivery at early gestations, however, is associated with high perinatal mortality and morbidity resulting from prematurity1–3. In addition, recent research suggests that fetal lung maturity is not accelerated in pre-eclamptic pregnancies4. On the other hand, prolonging pregnancy by expectant management may result in increased maternal morbidity and even mortality5,6. This has led to certain particularly aggressive management policies1. Ultimately the potential benefits for the fetus must be balanced against the potential dangers to the mother, such as death or cerebral haemorrhage. Two randomised controlled trials7,8 have shown encouraging results regarding perinatal outcome with an expectant management approach. The safety of this approach for the mother, however, needs to be evaluated over longer periods, as the serious maternal complications are less frequent. Even if the occurrence or impact of serious maternal complications can be diminished, a point will be reached where the maturity of the fetus is judged to be sufficient to deliver electively. This study was undertaken to assess expectant management of early onset, severe pre-eclampsia on the maternal outcome and prolongation of gestation.
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Over a five-year period (April 1992–March 1997), all women with singleton pregnancies presenting with early onset (≥ 24 and < 34 weeks of gestation), severe pre-eclampsia, where both the mother and the fetus were otherwise stable, were studied. Exclusion criteria from this study were major maternal complications (defined below) or fetal distress after viability. The definitions of hypertension and proteinuria used were those put forward by Davey and MacGillivray9 and accepted by the International Society for the Study of Hypertension in Pregnancy. Severe hypertension was accepted as a diastolic blood pressure measurement of ≥ 120 mmHg on one occasion or a diastolic blood pressure measurement of ≥ 110 mmHg on two occasions, four hours or more apart.
Recruited women were admitted to a high care ward for intensive, noninvasive monitoring of the maternal and fetal status. Gestation was determined by means of last menstrual period, obstetric ultrasound or both. Maternal monitoring included four-hourly blood pressure measurement, clinical evaluation twice daily and daily urine testing for protein and glucose. Blood pressure was carefully controlled to levels below 160/110 mmHg, using a stepwise approach with up to three oral anti-hypertensive agents (i.e. methyldopa, prazosin and nifedipine). Oral nifedipine or intravenous dihydralazine was used to control hypertensive peaks. Magnesium sulphate was given to women who developed eclampsia while prophylaxis with this agent was only considered during intrapartum management, according to the discretion of the managing clinician. A full blood count, renal function tests, liver function tests and 24-hour urine collection for creatinine clearance and protein quantification were all performed twice weekly. Failure to control blood pressure or the development of major maternal or fetal complications were indications for delivery. Women reaching a minimum gestation of 34 weeks without complications were delivered electively.
Major maternal complications included: pulmonary oedema (clinical and radiographic diagnosis); haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome (platelet count < 100 × 109/L, aspartate aminotransferase > 40 μ/L, alanine aminotransferase > 53 μ/L, haemolysis as demonstrated by lactate dehydrogenase > 350 μ/L, peripheral blood smear or haptoglobin level); admission to the adult intensive care unit; placental abruption (retroplacental clot covering > 15% of placental surface); maternal death; eclampsia; and severe renal impairment (defined as serum urea value > 10 mmol/L before delivery and rising further after delivery or with a lower value before delivery, rising to > 10 mmol/L after delivery). Complications were identified from detailed casenote contents and individually reviewed by the first author. Confirmed complications were noted regardless of their severity or clinical impact. Thus confirmed pulmonary oedema was included whether responding quickly to clinical management in the high care ward or necessitating admission to an intensive care unit. The following fetal complications were regarded as indications for delivery: fetal distress on nonstress test (baseline variability < 5 over 60 minutes, repeated late decelerations or both); reversed end diastolic flow velocity (Doppler ultrasound); and other problems, such as intrauterine death.
Birth centiles based on the local population10 were used in the analysis. Data are expressed as mean with standard deviation and median with range. Differences in means were analysed using the two-tailed Student's t test. For data not normally distributed the Mann-Whitney U test was used. The χ2 test was applied to qualitative variables, with Yate's correction when the expected number was from 5 to 10, or with Fisher's method when it was below five. A P value of < 0.05 was regarded as significant. The study protocol was approved by the local ethics committee.
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During the five year trial period 33,832 women were delivered in the study hospital, while 2390 women (7.1%) with any form of pre-eclampsia (mild or severe, early or late onset) were managed. Three hundred and forty women with singleton pregnancies were entered into the trial. Primigravid women accounted for 33% and multigravid women for 67% of this total. Eighty-four multigravid women (36%) had experienced previous preeclampsia or hypertension. No women were excluded from analysis after entry into the trial. The characteristics of women on admission are shown in Table 1.
Table 1. Characteristics of women on admission. PE = pre–eclampsia; CHT = chronic hypertension; SIPE= superimposed pre–eclampsia.
|Age (years)||340||26.6||5.6||26||14–42|| |
| Multigravid||228||28.8||4.9||28||18–42||< 0.001|
| PE||292||25.7||5.2||25||14–42|| |
| CHTSIPE||48||32||4.9||32.5||19–42||< 0.001|
| Gravidity||340||2.3||1.3||2||1–8|| |
| PE||292||2.1||1.1||2||1–7|| |
| CHT SIPE||48||3.5||1.6||3||1–8||< 0.001|
| PE||292||0.8||0.9||1||0–4||< 0.001|
|Gestation admission||340||29.9||2.0||30||24–34|| |
Forty-eight percent of women were admitted with a diastolic blood pressure of ≥ 110 mmHg, even though 213 women (62.6%) had received anti-hypertensive agents before admission. In most cases this was in the form of parenteral dihydralazine or a single oral dose of nifedipine for acute blood pressure control. Thirty-one percent of women were transferred on one or even two oral maintenance anti-hypertensive agents, and 30% of women on magnesium sulphate. Only 7% of women were on low dose aspirin therapy at the time of transfer.
The mean (SD) and median [range] numbers of days gained antepartum by expectant management were 11 days (7) and 9 days [1–47], respectively. The spectrum is shown in Table 2. Table 3 shows the days gained according to the anti-hypertensive agent(s) received prior to admission.
Table 2. Days gained at each entry gestation in the study.
|Gestational entry (week)||No. (n= 340)||Mean||Median||SD||Range|
Table 3. Days gained according to the anti-hypertensive agent(s) received prior to admission (on transfer). Acute = acute phase agents: dihydralazine or single dose of nifedipine only; Oral = maintenance therapy: methyldopa, apresoline, prazosin, diuretics, nifedipine in divided doses, p-blockers and ACE inhibitors ± acute phase agents.
| ||Without agent||Acute||Oral|
|No. of women||127||107||106|
|Mean days gained||10.8||10.3||11.8|
|Median days gained||9||9||10|
Fetal distress was the most common indication for delivery (n= 151, 44.4%), with maternal reasons accounting for 88 deliveries (25.9%). Thirty-five women (10.3%) were delivered for combined (maternal/fetal) reasons while 12 (3.5%) went into spontaneous labour. Fifty-four women (15.9%) did not develop complications requiring delivery, from admission until 34 weeks of gestation, and thus reached our defined point for elective delivery. Induction of labour was attempted in 103 women with a viable pregnancy (30.7%), with 46 (44.6%) achieving a vaginal delivery. Overall, 63 women were delivered vaginally (18.5%) and 277 by caesarean section (81.5%). Placental abruption, as diagnosed by inspection of the placenta, was the most common major maternal complication (n= 69) with fetal distress most often the first, or only warning sign. Other major maternal complications are shown in Table 4. The blood pressure values and special investigation results on admission and delivery are shown in Tables 5 and 6.
Table 4. Maternal complications. Values are given as n (%). HELLP= haemolysis, elevated liver enzymes and low platelets.
|Placental abruption||69 (20.2)|
|HELLP syndrome||18 (5.2)|
|Loss of blood pressure control||18 (5.3)|
|Pulmonary oedema||7 (2.1)|
|Severe renal impairment||6 (1.7)|
|Intensive care unit admission||3 (0.8)|
|Patients with a major complication||92 (27)|
Table 5. Blood pressure (mmHg) values. Values are given as mean (SD).
|Systolic||158 (18)||150 (16)||2.5×108|
|Diastolic||105 (11)||96 (11)||7.2×1014|
Table 6. Special investigation results. Values are given as median (range). Hct = haematocrit; AST = aspartate amino transferase; ALT = alanine amino transferase; LDH = lactate dehydrogenase; Alb = serum albumin; CCC = corrected creatinine clearance; Prottot= total protein in a 24-hour urine collection.
|Hct (%)||36 (23–45)||34 (22–46)||<0.01|
|Platelet count(109/L)||195 (60–410)||177 (27–344)||<0.01|
|Urea (mmol/L)||3.7 (1.7–9.2)||5.1 (1.9–12.1)||<0.01|
|Uric acid (mmol/L)||0.35 (0.19–0.55)||0.39 (0.14–0.67)||<0.01|
|AST (ug/L)||23 (8–251)||21 (6–555)||0.11|
|ALT(ug/L)||16 (5–281)||18 (4–331)||0.05|
|LDH(ug/L)||227 (132–605)||224 (107–1531)||0.53|
|Alb (g/L)||28 (13–42)||25 (12–36)||<0.01|
|CCC (mL/min)||92 (36–240)||97 (39–175)||0.94|
|Prottot (g)||1 (0.16–6)||2.8 (0.1–24)||<0.01|
The mean (SD) period of postpartum hospitalisation was 5 days (3). While 25% of women did not require anti-hypertensive medication at discharge, 53% were discharged on a single agent, 18.2% on two agents and 3.8% on three or four agents.
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Most of the women in the study were multigravid. Pregnancies were prolonged by a mean number of 11 days before delivery, with greater periods of time being gained at earlier gestations. Maternal biochemistry was reassuring during the antenatal period with a few expected, but not severe, deteriorations. Although 27% of women experienced a major complication, few had serious clinical impact. There were no maternal deaths and only three women (0.8%) were admitted to the adult intensive care unit. A single woman required dialysis. On the whole, major complications resolved quickly without the need for adult intensive care unit admission. The relatively short postpartum inpatient stay (89%≤ 7 days, bearing in mind that 82% of women were delivered by caesarean section) supports this assertion.
Nulliparity is widely considered to be a hallmark of pre-eclampsia11,12, however, multigravid women (67%) dominated the index study. This figure is in keeping with the findings of other studies from this region (i.e. 69%13, 64%14 and 76%6). A number of reasons can be advanced to explain this situation. Women with this form of pre-eclampsia have been reported to be at increased risk for undiagnosed renal disease and chronic hypertension15. In this study multigravid women and women with superimposed pre-eclampsia were significantly older than primigravid women and those with primary disease (Table 1), and thus they may have had more underlying pathology. Reports have also shown that nulliparous women who develop pre-eclampsia in pregnancy and those developing early, severe pre-eclampsia are at increased risk for having the condition repeat in subsequent pregnancies16,17.
Recently, subclinical abnormalities in haemostasis, metabolism and volume homeostasis have been described and linked to pre-eclampsia18. Dekker et al.19 found that more than 50 percent of women with a history of severe, early onset pre-eclampsia showed such covert abnormalities. Another explanation for multiparous women presenting with pre-eclampsia for the first time is the change of sexual partner. It has been stated that while genuine pre-eclampsia is a disease of first pregnancies, the protective effect of multiparity is lost with a change of partner20. This is not an uncommon feature among the study population. The problem may therefore be one of primipaternity rather than primigravidity21. This aspect was not specifically addressed in the index study.
Table 2 shows that more days were gained among women admitted at earlier gestations. However, the numbers of women from 24–26 weeks were small. From 27–32 weeks the number of days gained remained fairly constant, and from 33 weeks the figure decreased as the elective cut off gestation of 34 weeks was reached.
Control of the blood pressure was carefully applied as reflected in Table 5, with only 18 women (5.3%) having loss of blood pressure control as an indication for delivery (Table 4). It should be noted that although hypertensive disorders in pregnancy, specifically intracerebral haemorrhage, are important causes of maternal mortality in South Africa22, no cases of intracerebral haemorrhage occurred in the index study. The rate of placental abruption was high (20.2%), despite careful control of the blood pressure but the occurrence of HELLP syndrome (5.2%) was much lower than the figure of 20% reported in a recent overview of HELLP syndrome in severe pre-eclampsia23. Table 3 was constructed in order to ascertain whether women, transferred on anti-hypertensive medication, were more or perhaps less stable, thus influencing the antenatal period gained. There were no significant differences between the groups in terms of days gained before delivery. Thus earlier stabilisation with anti-hypertensives (before or during transfer) to the tertiary unit did not extend into a greater gain of days before delivery or signify a faster progression of disease with fewer days being gained.
The dangerous maternal complications of severe pre-eclampsia are well known. Irrespective of the management strategy chosen, the ultimate goal must first be the safety of the mother and second the delivery of a live infant who will not require intensive and prolonged neonatal care. Sibai et al.5 reported the results of expectant management of 60 consecutive women with severe pre-eclampsia in the second trimester. Although there was no maternal mortality, they were concerned at the ‘very high’ rate of maternal morbidity. In a later publication the same group24, again addressing severe pre-eclampsia in the second trimester, reported a much-improved outcome. In 1990 Odendaal et al.7 reported a randomised controlled trial comparing aggressive to expectant management for women with severe pre-eclampsia with gestational ages of 28–34 weeks. They showed no increase in maternal complications and a significant prolongation of pregnancy in women managed expectantly. Oláh et al.25, in a case control study, found more maternal complications in the expectant management group but still advocated this approach for pregnancies < 32 weeks of gestation. In the same year Moodley et al.6 reported a maternal complication rate in early, severe pre-eclampsia of 30.8%. Their study included pregnancies with gestations ranging from 11–32 weeks. The findings of Sibai et al.8 in their randomised controlled trial, comparing aggressive to expectant management for women with severe pre-eclampsia at 28–32 weeks of gestation, concurred with those of Odendaal et al.7, but severe maternal complications are less frequent than severe perinatal ones. Consideration of the relatively small numbers in these two trials7,8 leads to the conclusion that the perinatal outcome was better assessed than the maternal outcome.
In the index study the major complications were accepted as pulmonary oedema, intensive care unit admission, HELLP, placental abruption, death, eclampsia and severe renal impairment. Ninety-two women (27%) experienced at least one major complication, but in terms of death (n= 0), intensive care admission (n= 3), and renal dialysis (n= 1), the numbers were small for such a high risk group. In addition, the impact of such complications was seldom dramatic, as they were intensively, though rarely invasively, sought and managed, enabling a recovery swift enough not to influence the discharge date indicated by the most common obstetric intervention (i.e. caesarean section).
Expectant management of early onset, severe pre-eclampsia should only be undertaken by an experienced team offering continuous monitoring and care. Early referral of such women to tertiary care centres is important26. Here the women need to be carefully re-evaluated and cases with major maternal or fetal compromise need to be excluded from expectant management. Thereafter, intensive (preferably not invasive) maternal and fetal monitoring must be applied, with pragmatic cut off points for initiation and termination of such management24,27. The expectant approach needs to be used with discretion and in the knowledge that for some women it will achieve little gain in time. All such women are hospitalised because complications cannot be accurately predicted and dangerous elevations in blood pressure may occur with alarming rapidity.