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Non-proteinuric pre-eclampsia - a novel risk indicator in women with gestational

hypertension

Short title: Non-proteinuric pre-eclampsia – a novel risk indicator

Caroline SE HOMERa PhD

Mark A BROWNb,c,d MD

George MANGOSb,c,d MD

Gregory K DAVISb MD

aCentre for Midwifery, Child and Family Health, Faculty of Nursing, Midwifery and

Health, University of Technology Sydney, Australia

bDepartment of Women’s Health and cRenal Medicine and dMedicine, St George

Hospital and University of New South Wales, Kogarah. Sydney NSW 2217. Australia

Sources of financial support: Nil

Presentation information: 27th Triennial Congress of the International Confederation

of Midwives, Brisbane, Australia. July 2005.

Correspondence: Professor Mark A Brown

Dept. Renal Medicine.

St George Hospital & University of NSW.

Kogarah. Sydney. NSW. 2217. Australia.

Email: mbrown@unsw.edu.au

Reprints will not be available

Word count: Paper: 3497 words. Abstract: 150 words

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ABSTRACT

Objective: To determine whether outcomes differed for pre-eclamptic (PE) women

according to the presence of proteinuria and whether non-proteinuric PE is similar to

gestational hypertension (GH).

Design: From 1987-2005, at three hospitals in Sydney, Australia, women referred to

the obstetric medicine team were recruited. Outcomes for three groups were compared

- proteinuric PE, non-proteinuric PE and GH.

Results: Women with proteinuric PE were more likely to have severe hypertension

(39% vs 30%, p=0.003), deliver preterm infants (39% vs 30%, p=0.007) and had a

higher perinatal mortality rate (25.2 vs 5.7 per 1000, p=0.02) than those with non-

proteinuric PE, who were more likely to have thrombocytopenia and liver disease.

Women with non-proteinuric PE were more likely to have multiple pregnancies

(3.9%vs 9.9%, p<0.001), experience severe hypertension (8.9% vs 29.7%, p<0.001),

and deliver preterm infants (11.3% vs 30.2%, p<0.001) who were small for gestation

age (12.7% vs 20.9%, p<0.001) than those with GH.

Conclusion: This study highlights differences between non-proteinuric PE and GH.

The sub-classification of ‘non-proteinuric PE’ should be added to existing

classification systems to alert clinicians to potential risks.

Key Words

Hypertension in pregnancy, pre-eclampsia, gestational hypertension, proteinuria

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CONDENSED ABSTRACT

This study highlights the differences between pre-eclampsia and gestational

hypertension and suggests the sub-classification of ‘non-proteinuric pre-eclampsia’ be

added to existing classification systems.

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INTRODUCTION

Hypertensive disorders in pregnancy are common, affecting around 10-12% of

pregnant women. About 3-4% have pre-eclampsia (PE), a similar proportion has

gestational hypertension (GH) and 1-2% has pre-existing chronic hypertension. [1]

There is a lack of data available on the outcomes of hypertensive pregnancies,

particularly for women with a consistent diagnosis of gestational hypertension

compared with pre-eclampsia. Population-based research in Australia [2-4] has relied

on data sets that are known to suffer from under-reporting and misclassification of

gestational hypertension and pre-eclampsia [5,6].

Since 1987, we have maintained a prospective database of all women who were

referred to two obstetric medicine physicians, either during pregnancy or in the

immediate postpartum period. To date, women having 3,345 pregnancies have

received this care. This study builds on a previous analysis of this database that was

published in 1996 [1].

In this study, we used a consistent diagnostic approach with each woman classified by

one of two physicians. The hospitals involved used a single uniform management

policy. The aim of the study was to determine 1) whether outcomes differed within

pre-eclamptic women according to the presence or absence of proteinuria, using the

International Society for the Study of Hypertension in Pregnancy (ISSHP)

classification system [7] and 2) whether non-proteinuric pre-eclampsia was similar to

gestational hypertension.

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MATERIALS AND METHODS

Classification of hypertension in pregnancy

Several groups have developed classification schemes in an attempt to produce

consistency in clinical practice and research [8-14].

Unfortunately, the classifications systems differ making comparisons across studies

difficult [15].

The definitions used in this study are:

Gestational Hypertension (GH): average SBP ≥ 140mmHg and/or DBP ≥

90mmHg (phase 5) (after overnight rest in hospital, or after completion of a

day assessment visit), developing after 20 weeks gestation, without any

evidence of multi-system dysfunction (eg. kidneys, brain, liver, clotting).

Preeclampsia (PE): development of SBP ≥ 140mmHg and/or DBP ≥

90mmHg after 20 weeks gestation in women with no previous history of

hypertension, cardiac or renal disease plus evidence of other organ

involvement (eg proteinuria, renal insufficiency, liver disease, neurological

problems, haematological disturbances, fetal growth restriction).

Chronic Hypertension (CH): hypertension that is present in the

preconception period, or the first half of pregnancy. It may be essential, or

secondary.

Chronic Hypertension and PE: superimposed PE in women with underlying

CH.

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White Coat Hypertension (WCH): raised BP in the presence of a clinical

attendant but normal BP in their usual environment as assessed by ambulatory

or home BP monitoring. This caries a fairly good prognosis in pregnancy.16

Subjects

From 1987, a prospective database of all women who were referred to one of two

renal physicians (MAB, GM) has been maintained. This study was approved by the

Ethics Committee of the South Eastern Sydney Area Health Service (Southern

Section: 05/41).

Women who were booked to attend one of three hospitals for the birth of their baby

and referred to the obstetric medicine renal team by an obstetrician or obstetric

registrar were included in the study. Women were referred at any stage during

pregnancy, labour or the early postpartum period. The babies were born from January

1987 to January 2005.

Indications for referral were:

• Hypertension failing to settle after overnight rest in hospital or repeated high

measures in a day-only unit;

• The presence of proteinuria, neurological factors, abnormal biochemistry

(elevated serum transaminase or creatinine levels) or thrombocytopenia;

• Recurrent admissions for hypertension; or

• A suspected secondary cause for hypertension.

There were no specific exclusion criteria but it is possible that women with very

mild or transient gestational hypertension may not have been referred to this

service.

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Setting

The study took place in three hospitals in southern Sydney. One was a public referral

centre, the others were private hospitals. The public hospital is a teaching hospital

without a neonatal intensive care unit or a dedicated specialist maternal-fetal medicine

unit, delivering approximately 2400 babies per year. Women whose babies are likely

to be born prior to 32 weeks gestation are usually transferred to a tertiary centre with

these additional services. Outcomes were still recorded for these mothers and babies.

The same obstetricians and physicians practice at the two private hospitals as the

public hospital using the same management protocol. The private hospitals together

deliver approximately 2700 women per year, making around 5000 births per year

[17].

Once women were referred, the renal physicians, an obstetrician and a midwife

managed them as a team. Since 1998, referred women at the public referral hospital

were enrolled into the Risk Associated Pregnancy (RAP) Team which incorporated

the two physicians, an obstetrician and a group of midwives who were particularly

trained and committed to caring for pregnant women with hypertension.

The management of these pregnant women was overseen by two physicians and two

obstetricians. The units were guided by consistent and strictly adhered to protocols

that guided the measurement of blood pressure, the management of hypertension and

episodes of severe hypertension, the use of antihypertensive agents and the optimum

time for delivery. The protocols have standardised the management of women across

the three sites (available at http://web.med.unsw.edu.au/stgrenal/HT_Pregnancy.htm).

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Classification

The definitions, classifications and complications of hypertension in pregnancy used

in the study were those of the ISSHP [7] as described above. Pre-eclampsia differs

from eclampsia in that the latter has convulsions as part of its definition. This is an

uncommon event in developed countries with good antenatal care and for this reason

eclampsia is included within the classification “pre-eclampsia”. The definition of

proteinuria was a spot urine protein/creatinine ratio (≥ 30mg protein per mmol

creatinine) [18] used for the past eight years, and ≥ 300mg per day in the years before

this. Dipstick urine was rarely relied upon to make the diagnosis of proteinuria, if so a

definition of consistently ≥ ‘2+’ (1g/L) dipstick proteinuria was used [19]. Severe

hypertension was defined as ≥ 170 mmHg systolic and/or ≥ 110 mmHg diastolic. The

classification was made after delivery hence accounting for women who progressed

from GH to PE. Non-proteinuric PE was defined as meeting the clinical criteria for

PE without proteinuria.

Women who had thrombocytopenia (<150 x 109L) were retained in the GH group

only if they had thrombocytopenia prior to the onset of hypertension as this was

thought to be due to Thrombocytopenia of Pregnancy. Small for gestational age was

defined as <10th percentile and was not a criteria for PE.

Data collection

Data were collected on each woman in the study at the time of referral and after the

birth by the staff involved in the care and management. This data sheet was collected

by the attending physicians at the time of discharge from hospital. The final

hypertensive diagnosis was made by one of the two attending physicians and recorded

on this data sheet. The data sheet was forwarded to a research midwife who collected

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additional data from the woman’s medical records at the three hospitals. Data for

women or babies who were transferred to other hospitals were collected from these

centres. Data were entered into a MS Access© database by a research midwife.

The maternal biochemical and hematological data used in the analysis were those

closest to delivery and always recorded in the seven days prior to the birth of the

baby. Complications were those which occurred any time between presentation and

discharge from hospital.

Analysis

Data were converted from the MS Access© database into SPSS for statistical analysis.

The primary diagnoses for the whole database were: gestational hypertension; pre-

eclampsia; chronic hypertension and superimposed pre-eclampsia; essential

hypertension; renal or other conditions; and, white-coat hypertension. It is

acknowledged that white-coat hypertension was under-reported because this diagnosis

was not included in this database until 2005 [20].The analysis in this report is

confined to women with a diagnosis of pre-eclampsia or gestational hypertension.

A univariate analysis was initially performed followed by a multivariate analysis for

the non-proteinuric versus GH analysis. A P < 0.05 was taken as an alpha level of

statistical significance.

In light of recent evidence that uric acid may have a role in vascular dysfunction [21],

the effect of hyperuricemia (UAC > 0.35mmol/L) was examined in more detail in the

three groups (proteinuric PE, non-proteinuric PE and GH) on two primary neonatal

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outcomes: prematurity and small for gestational age. Recent research has suggested

that women with GH and hyperuricemia had fetal outcomes similar to that of PE and

that within PE there were different outcomes according to hyperuricemia [21]. Odds

ratios and 95% confidence intervals were calculated for these final comparisons.

RESULTS

During the period January 1987 to January 2005, 3345 women were referred. Fifteen

women (0.4%) did not have a diagnosis identified and have been removed from the

subsequent analyses. Of the remainder, 1192 (36%) had gestational hypertension and

1348 (40%) had pre-eclampsia (by a clinical definition, that is, with or without

proteinuria). The remainder of the cohort (24%) had chronic hypertension with

superimposed pre-eclampsia, essential hypertension or secondary hypertension (renal

or other conditions).

The outcomes of women with PE (n=1348) were examined, comparing proteinuric

versus non-proteinuric PE. Of this group, 958 (71%) women had proteinuria and 357

(26%) had no proteinuria. In 33 (3%) of cases there was uncertainty so they were

excluded from the analysis.

There were no significant differences between these subsets of pre-eclamptic women

in terms of age (30 years in both groups), primiparity (71% vs 67%, p=0.2),

proportion of multiple pregnancies (8% vs 10%, p=0.2), gestation at booking visit (13

vs 14wks, p=0.4), first trimester systolic (116 vs 117mmHg, p=0.6) or diastolic (71 vs

70mmHg, p=0.5) blood pressures, gestation at initial physician consultation (35.1 vs

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35.3wks, p=0.5) or number of days from diagnosis to delivery (7.8 vs 14.1 days,

p=0.08). There were also no significant differences between the sub-groups in relation

to neurological complications (11% vs 15%, p=0.1), rates of induction of labour (56%

vs 48%, p=0.1) or caesarean section (53% vs 51%, p=0.8), proportion of female

babies (51% vs 46%, p=0.1) or admission to a neonatal intensive care unit (2.1% vs

1.4%, p=0.4). Twenty percent of babies from both groups were small for gestational

age.

In the univariate analysis, women with proteinuric PE were significantly more likely

to have severe hypertension (39% vs 30%, p=0.003), deliver preterm infants (39% vs

30%, p=0.007) and their babies had a higher perinatal mortality rate (25.2 vs 5.7 per

1000, p=0.02) than women with non-proteinuric PE. In contrast, women with non-

proteinuric PE were significantly more likely to have hyperuricemia (67% vs 61%,

p=0.03), renal insufficiency (15% vs 11%, p=0.04), thrombocytopenia, and liver

disease (Table 1).

In a multivariate analysis that controlled for parity, women with proteinuric PE were

still significantly more likely to have severe hypertension, deliver preterm infants and

have a higher perinatal mortality rate while those with non-proteinuric PE were

significantly more likely to have thrombocytopenia and liver disease (Table 2).

The outcomes of women with non-proteinuric PE (n=356) were compared with those

with gestational hypertension (n=1192). There were no significant differences in:

gestation at booking visit (13 vs 14wks, p=0.5), first trimester systolic blood pressure

(119 vs 117mmHg, p=0.2), gestation at initial physician consultation (35.7 vs

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35.3wks, p=0.3) or number of days from diagnosis to delivery (16 vs 14). There were

also no significant differences in induction of labour (45% vs 48%, p=0.7), caesarean

section (43% vs 52%, p=0.07), female babies (48% vs 46%, p=0.6), admission to a

neonatal intensive care unit (0.5% vs 1.4%, p=0.09) or perinatal mortality rate (6.7 vs

5.7 per 1000, p=0.8).

There were significant differences in the complications of renal insufficiency,

thrombocytopaenia, liver disease and neurological involvement as these are inherent

in the definition associated with a diagnosis of non-proteinuric PE (Table 3).

In a multivariate analysis that controlled for parity, women with non-proteinuric PE

were significantly more likely to have a multiple pregnancy, experience severe

hypertension and deliver preterm infants who were small for gestation age than those

with GH, although the perinatal mortality rate was no different (Table 4).

Hyperuricemia was associated with a statistically significant higher rate of preterm

birth in women with proteinuric PE (Table 5). Hyperuricemia in women with

proteinuric PE was associated with increased odds of having a preterm birth (45% vs

28%, p<0.001; OR 2.1, 95% CI 1.6-2.8) but not increased odds of having a small for

gestational age baby (22% vs 17%, p=0.9; OR 1.3, 95% CI 0.9-1.9). In women with

GH, hyperuricemia was associated with increased odds of being born small for

gestational age (15% vs 10%, p=0.01; OR 1.62, 95% CI 1.11-2.36). No other

statistically significant differences were seen between the groups in relation to these

selected outcomes (preterm birth, SGA, perinatal mortality) and hyperuricemia.

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DISCUSSION

The key findings of this study are that: 1) women with clinical features of pre-

eclampsia that includes proteinuria have a worse pregnancy outcome, in particular

greater perinatal mortality, than those without proteinuria, and 2) women with clinical

features of pre-eclampsia without proteinuria have worse pregnancy outcomes,

including more prematurity and small for gestational age babies, than women whose

only maternal problem is de novo hypertension (gestational hypertension). Whilst the

first observation is not new the latter is one which should provoke new thinking about

the way we currently classify women with hypertension in pregnancy.

Any classification system is useful only if it helps discriminate groups of hypertensive

pregnant women with practical, clinical and/or research utility. Previous researchers

have recommended that efforts should be made to recognise different subsets of

women with pre-eclampsia and to examine them separately for both outcome and

pathophysiologic features [22-24]. While there is debate about whether proteinuria

should remain a ‘sine qua non’ for the clinical diagnosis of pre-eclampsia [25]

proteinuria remains a hallmark of the disorder, an easily measurable clinical tool and a

requirement for a research diagnosis of PE [7]. This study examined the outcomes of

women with PE depending on whether they had proteinuria or not according to the

ISSHP classifications and has highlighted the clinically different implications

between making a diagnosis of pre-eclampsia or gestational hypertension.

Women with proteinuric PE experienced more adverse outcomes than those with non-

proteinuric PE, particularly preterm birth and perinatal deaths. This supports a

classification system that divides pre eclamptic women into those with or without

proteinuria [26].

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In contrast, and probably by definition, women with non-proteinuric PE have more

organ dysfunction, such as hepatic and platelet complications, than those with

proteinuric PE. While this finding is, in part, due to the classification system per se, it

is also evident that it defines a group of women with potentially serious problems. It is

worth emphasizing that in this analysis any one or more features of such organ

dysfunction defined a group of women at greater risk of developing severe

hypertension or other adverse outcomes than those without any of these features. The

occurrence of liver dysfunction and renal impairment was not coincident enough to

draw any analogies between pre-eclampsia and other vasoconstrictive disorders such

as the hepato- renal syndrome.

Proteinuria in combination with hypertension has long been considered predictive of

increased adverse outcomes for mothers and babies [27,28]. Women with proteinuric

pre-eclampsia have poorer outcomes than those with gestational hypertension (non-

proteinuric) alone [29]. However, it appears that the presence or absence of

proteinuria is more important than the amount excreted. Research examining the

effect of differing levels of proteinuria (5-9.9g/24hr) has suggested that women with

pre-eclampsia and high levels of proteinuria did not have higher rates of maternal

morbidity than those with lower levels of proteinuria. Neonates whose mothers had

very high levels of proteinuria were delivered at an earlier gestational age than

women with lower but still significant levels of proteinuria (<5g/24hr) and had more

neonatal complications related to prematurity [30]. These authors suggested that the

increased adverse perinatal outcomes for babies were associated with the degree of

prematurity rather than the proteinuria level.

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Research on some of the same cohort as presented in this study examined whether a

discriminant value of proteinuria in 321 women with proteinuric pre-eclampsia

predicted adverse maternal and fetal outcomes [25]. We demonstrated that there was

an increased risk of adverse maternal and fetal outcomes with increasing proteinuria,

however, it was not possible to define a level of proteinuria (using the spot

protein/creatinine ratio) that could be used as a definitive discriminant value for

adverse outcomes. Of interest, these increased maternal and fetal risks became

significant in women over 35 years at a protein excretion of roughly 5g per day,

similar to the study by Newman et al [30].

There is general clinical acceptance that proteinuric pre-eclampsia is a real and

significant entity. What diagnosis then, do we give to hypertensive pregnant women

with organ dysfunction e.g. liver disease, renal insufficiency, who do not have

proteinuria? To address this question we examined outcomes between this group i.e.

‘non-proteinuric PE’ and those with gestational hypertension. By definition the

former group had to have higher maternal morbidity but we questioned whether any

fetal, perinatal or severe hypertension differences might exist.

Our findings were significant in that women with non-proteinuric pre-eclampsia were

more likely to have babies who are preterm and small for gestational age and were 4-5

times more likely to have episodes of severe hypertension. The failure to demonstrate

a difference in perinatal death rate between these groups may reflect a type II error.

There were only 353 women in the non-proteinuric pre-eclampsia group and 1200 in

the gestational hypertension group. Given the perinatal mortality rate (PNM) rate in

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both these groups was low, it is likely that a larger sample would be required to

demonstrate a difference.

Our data show that even though ‘non-proteinuric pre-eclampsia’ has significant

implications for mother and baby we can reassure these women and those with

gestational hypertension that perinatal survival rates are as good as for the overall

pregnant population. The perinatal mortality rate for women with GH was 7.5 per

1000 births, lower than the overall perinatal mortality rate in the state of New South

Wales, Australia, from 1998-2003 which has varied from 8.6 to 9.6 per 1,000 births

[17]. This overall rate includes high and low risk women so it might be expected to be

higher than the rate just in women with GH. The perinatal mortality rate in

normotensive women in a South Australian cohort was 6.9-8.0 per 1000 which

suggests that the PNM rate in women with GH (7.5) is similar to that of normotensive

women. Nevertheless, the fact that fetal growth restriction was greater in women with

‘non-proteinuric PE’ highlights that this is not really the same disorder as the very

benign condition of gestational hypertension and it is inappropriate to consider these

conditions as one. In addition, this cohort of women with GH was managed by an

experienced team using a standard protocol and frequent follow up. It is possible that

their favourable outcome was either due to a benign natural history or related to the

standard protocol and system of care.

A fundamental question becomes whether proteinuric pre-eclampsia, ‘non-proteinuric

pre-eclampsia’ and gestational hypertension are part of a pathophysiological spectrum

or separate disorders. The first two share the same clinical features except a measured

protein excretion of greater than 300mg/day. It is possible that intact immunoreactive

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albumin excretion rates are abnormal in women with ‘non-proteinuric’ pre-eclampsia

or that protein fragment or non-immune albumin excretion is abnormal. To the best of

our knowledge such studies have not been done so far. In light of the long standing

measurement of uric acid in pre-eclampsia and the recent recognition that this may be

involved in vascular reactivity we examined whether outcomes might have differed

within groups according to uric acid levels, perhaps to give clues to a pathologic role

for uric acid rather than it being a ‘bystander’ marker of disease due to renal urate

retention. We found that women with non-proteinuric PE were slightly but

significantly more likely to have hyperuricemia compared with those with proteinuric

PE (67% vs 61%,) or GH (42%). Within the proteinuric PE group, hyperuricemia was

associated with increased odds of having a preterm birth. This cannot be explained by

an increased propensity to induce labour in this group once an increased uric acid was

detected as this has never been an indication for delivery in these hospitals; further,

the incidence of hyperuricaemia was slightly greater in women with ‘non-proteinuric

pre-eclampsia’ yet no difference in any fetal or other outcome was apparent according

to the presence or absence of hyperuricemia. Within the GH group, hyperuricemia

was associated with increased odds of having a small for gestational age baby.

Therefore, both women with GH and those with PE had slightly different fetal

outcomes according to hyperuricemia consistent with one recent study [21]. We can

interpret this as pre-eclampsia being a useful clinical marker of fetal outcome in these

groups but this finding gives us little further insight into potential pathophysiologic

differences between the various hypertensive disorders of pregnancy.

There are some potential limitations of our study, including the potential for selection

bias, quality of the classifications, consistency of management and potential for

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under-estimation of adverse outcomes. The potential for selection bias arises, as some

women who had hypertension in pregnancy may have not been included into the

database if they did not require significant management and therefore were not

referred. This likelihood is low as referral to the physicians is an accepted part of

clinical management in these hospitals.

The risk of poor consistency of clinical management or inaccurate classification is

also very small. During this 18-year period, classification and management of

hypertension has changed, as have facilities available for neonatal resuscitation and

care. The classifications and management used throughout the study period have

accounted for these changes and have consistently remained in line with Australian

and international systems and evidence [7,8]. The management of hypertension has

been directed by the same two physicians throughout this time period and has been

uniform and driven by standard protocols.

Finally, as our three hospitals have no neonatal intensive care unit we do not receive

referrals for very preterm babies; 90% of our women were ≥ 34 weeks at delivery and

adverse events in babies born earlier may be underestimated giving rise to type II

errors even though outcome data from all these women were included in the analysis.

Birth at less than 34 weeks gestation is known to be associated with a higher perinatal

mortality and morbidity rate (30-31).

CONCLUSION

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The study has examined whether pre-eclampsia should be routinely diagnosed and

classified as ‘proteinuric’ or ‘non-proteinuric’, and whether the latter diagnosis is in

any way different for mother and baby than a diagnosis of ‘gestational hypertension’.

We have shown clearly that ‘non-proteinuric PE’ has poorer outcomes for women and

their babies than does ‘gestational hypertension’ but is a more benign condition than

proteinuric PE. It is clear that non-proteinuric PE is not the same condition as GH. On

the basis of this evidence, we suggest that ‘non-proteinuric PE’ is a useful sub-

classification of pre-eclampsia that should be added to existing classification systems

to alert clinicians to potential maternal and fetal risks. It is evident that GH has a good

prognosis provided these women are carefully observed to exclude those who change

from GH to PE [33]. Accordingly, we propose a classification of hypertensive

disorders in pregnancy that stratifies maternal and fetal risks more than present

classification systems (Figure 1).

We propose that this potential classification system be tested in a new cohort of

patients as a system that significantly discriminates maternal and fetal risks in routine

clinical practice.

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ACKNOWLEDGEMENTS

We would like to acknowledge Kim Ikin and Jennifer Mathews for their assistance in

maintaining the database and collecting the data.

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24

Table 1: Significantly different maternal and neonatal outcomes by Pre-eclampsia diagnosis and

presence of proteinuria

Proteinuric

PE

N=958

Non-

proteinuric PE

N=357

p

Plasma albumin (g/L) [SD] 30 [11] 32 [8] <0.001

Hyperuricaemia (>0.35mmol/L) 61 67 0.03

Gestation at birth (wks) [SD] 36.7 [2.8] 37.3 [2.2] <0.001

Severe hypertension 38.7 29.7 0.003

Renal insufficiency 10.6 15.1 0.04

Thrombocytopaenia (<100 x 109L) 4.5 9.9 <0.001

Thrombocytopaenia (<150 x 109L) 17.9 43.5 <0.001

Liver disease 15.9 28.8 <0.001

Preterm (<37 weeks) 39 30 0.007

PNM (per 1000) 25.2 5.67 0.02

Note: Data are presented as a mean [standard deviation] or percentage (%). PNM = perinatal mortality

25

Table 2: Multivariate analysis of outcomes according to absence (odds ratio 1.0) or presence of

proteinuria, with and without adjustments for parity. Women with proteinuria were more likely

to have severe hypertension, higher perinatal mortality and prematurity.

P

Unadjusted ed

OR (95% CI)

Unadjusted

OR (95% CI)

Adjusted#

Gestation at delivery

>37 weeks 0.006 1.0* 1.0*

<37 weeks 1.44 (1.11-1.88) 1.46 (1.11-1.92)

Severe hypertension

No 0.003 1.0* 1.0*

Yes 1.50 (1.15-1.95) 1.28 (0.98-1.68)

Thrombocytopenia (<100)

No <0.001 1.0* 1.0*

Yes 0.43 (0.26-0.69) 0.5 (0.30-0.83)

Thrombocytopenia (<150)

No <0.001 1.0* 1.0*

Yes 0.28 (0.22-0.37) 0.32 (0.24-0.42)

Liver disease

No <0.001 1.0* 1.0*

Yes 0.46 (0.34-0.63) 0.41 (0.30-0.57)

Perinatal mortality

No 0.026 1.0* 1.0*

Yes 4.70 (1.11-

19.96)

4.28 (1.01-

18.16)

#adjusted for parity

26

Table 3: Significantly different maternal and neonatal outcomes according to a diagnosis of non-

proteinuric Pre-eclampsia or Gestational Hypertension (GH).

GH

N=1192

Non-proteinuric PE

N=357

p

Mean age (yrs) 29.2 [5.3] 30.0 [4.7] 0.01

Primigravida 59.9 66.7 0.03

Multiple pregnancy 3.9 9.9 <0.001

Mean 1st trimester DBP (mmHg) 73 [8] 70 [10] 0.003

Hyperuricemia (>0.35mmol/L) 42 67 <0.001

Gestation at birth (wks) 38.4 [1.7] 37.3 [2.2] <0.001

Severe hypertension 8.9 29.7 <0.001

Renal insufficiency 0.0 14.9 <0.001

Thrombocytopenia (<100 x 109L)* 0.4 9.5 <0.001

Thrombocytopenia (<150 x 109L)* 3.1 42.5 <0.001

Liver disease 0.0 28.8 <0.001

Neurological complications 0.0 15.1 <0.001

Preterm (<37 weeks) 11.3 30.2 <0.001

SGA <10th percentile 12.7 20.9 <0.001

Note: Data are presented as a mean [standard deviation] or percentage (%). *Cases of

thrombocytopenia in the GH group often antedated the hypertension and were thought to be due to

Thrombocytopenia of Pregnancy.

27

Table 4: Multivariate analysis of outcomes according to gestational hypertension (odds ratio 1.0)

or non-proteinuric pre-eclampsia, with and without adjustments for parity. Women with non-

proteinuric pre-eclampsia were more likely to have severe hypertension, small for gestational age

babies and prematurity.

P

Unadjusted

OR (95% CI)

Unadjusted

OR (95% CI)

Adjusted#

Gestation

>37 weeks <0.001 1.0* 1.0*

<37 weeks 3.32 (2.48-4.45) 3.52 (2.57-4.81)

Severe hypertension

No <0.001 1.0* 1.0*

Yes 4.54 (3.33-6.18) 4.97 (3.62-6.84)

SGA

No <0.001 1.0* 1.0*

Yes 1.96 (1.41-2.63) 2.03 (1.47-2.80)

Multiple pregnancy

No <0.001 1.0* 1.0*

Yes 2.71 (1.72-4.28) 2.68 (1.61-4.46)

Perinatal mortality

No 0.8 1.0* 1.0*

Yes 1.17 (0.25-5.55) 1.05 (0.22-5.10)

#adjusted for parity. SGA = small for gestational age.

28

Table 5: Pregnancy outcomes according to presence or absence of hyperuricemia (Plasma Uric

acid > 0.35mmol/L) in women with pre-eclampsia (PE) (both proteinuric and non-proteinuric)

and gestational hypertension (GH). Hyperuricemia was associated with more prematurity in

women with proteinuric pre-eclampsia and with more small for gestational age babies in women

with gestational hypertension but not with any other pregnancy outcome.

Hyperuricaemia Outcome %

Proteinuric PE No Preterm birth 27.9

Yes 44.9 (p<0.001)

No SGA 17.3

Yes 21.8

No Perinatal mortality 2.4

Yes 2.6

Non-proteinuric PE No Preterm birth 25.5

Yes 32.0

No SGA 18.5

Yes 21.6

No Perinatal mortality 0.9

Yes 0.4

GH No Preterm birth 10.0

Yes 13.4

No SGA 9.8

Yes 15.0 (p=0.01)

No Perinatal mortality 0.8

Yes 0.7

SGA = small for gestational age ( <10th percentile).

29

Figure 1: A classification of hypertensive disorders in pregnancy that stratifies maternal and fetal risks more than present classification systems. SBP = systolic blood pressure; DBP = diastolic blood pressure.

1. Gestational hypertension: average SBP ≥ 140mmHg and/or DBP ≥ 90mmHg

(phase 5) (after overnight rest in hospital, or after completion of a day assessment

visit), developing after 20 weeks gestation, without any evidence of organ system

dysfunction (eg. kidneys, brain, liver, clotting).

2. Pre-eclampsia

a. Proteinuric: development of SBP ≥ 140mmHg and/or DBP ≥ 90mmHg

after 20 weeks gestation in women with no previous history of

hypertension or renal disease plus proteinuria, defined as a spot

protein/creatinine ratio above 30mg/mmol or else as 24hr urinary protein

excretion above 300mg/day.

b. Non-proteinuric: as above but without proteinuria. This group carries

increased fetal and maternal risks compared with gestational

hypertension alone.

3. Chronic hypertension in pregnancy

a. Hypertension that is present in the preconception period, or the first half

of pregnancy. It may be essential, or secondary

b. With superimposed proteinuric pre-eclampsia: new onset proteinuria

in women with underlying chronic hypertension.

4. ‘White coat hypertension’ in pregnancy: raised BP in the presence of a clinical

attendant but normal BP in their usual environment as assessed by ambulatory or

home BP monitoring. This disorder carries an increased risk of developing true

gestational hypertension or pre-eclampsia but overall has a good prognosis without

the need for antihypertensive therapy.