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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: [email protected]
Reprints will not be available
Word count: Paper: 3497 words. Abstract: 150 words
2
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
3
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.
4
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.
5
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.
6
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.
7
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).
8
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
9
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
10
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
11
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
12
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.
13
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].
14
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.
15
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
16
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
17
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
18
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
19
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.
20
ACKNOWLEDGEMENTS
We would like to acknowledge Kim Ikin and Jennifer Mathews for their assistance in
maintaining the database and collecting the data.
21
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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.