ARTICLES

THE LANCET Vol 355 January 8, 2000 87

Summary
Background We investigated the relation between
fetoplacental growth and the use of oral antihypertensive
medication to treat mild-to-moderate pregnancy hypertension.
Methods The study design was a metaregression analysis of
published data from randomised controlled trials. Data from
a paper that was regarded as an extreme statistical outliner
were excluded from primary analyses. The change in (group)
mean arterial pressure (MAP) from enrolment to delivery was
compared with indicators of fetoplacental growth.
Findings Greater mean difference in MAP with
antihypertensive therapy was associated with the birth of a
higher proportion of small-for-gestational-age (SGA) infants
(slope: 009 [SD 003], r
2
=048, p=0006, 14 trials) and
lower mean birthweight significant after exclusion of data
from another paper regarded as an extreme statistical
outliner (slope: 1449 [698] r
2
=016, p=0049, 27). No
relation with mean placental weight was seen (slope 201
[162], r
2
=015, p=025, 11 trials).
Interpretation Treatment-induced falls in maternal blood
pressure may adversely affect fetal growth. Given the small
maternal benefits that are likely to be derived from therapy,
new data are urgently needed to elucidate the relative
maternal and fetal benefits and risks of oral antihypertensive
drug treatment of mild-to-moderate pregnancy hypertension.
Lancet 2000; 355: 8792
See Commentary page xxx
Departments of Obstetrics and Gynaecology
(P von Dadelszen MRCOG, M P Ornstein MD, L A Magee FRCPC),
Medicine (Prof S B Bull PhD, Prof A G Logan FRCPC, L A Magee), and
Paediatrics (Prof G Koren MD), University of Toronto, Toronto,
Canada
Correspondence to: Dr L A Magee, 600 University Avenue, Suite
428, Toronto, Ontario, Canada M5G 1X5
(e-mail: laura.magee@utoronto.ca)
Introduction
Hypertension complicates 10% of pregnancies,
1
and is
associated with an increase in maternal morbidity and
mortality, as well as in perinatal mortality, intrauterine
growth restriction, prematurity, and complications of
prematurity (such as respiratory distress syndrome). The
excess perinatal morbidity and mortality reflect both the
fetal syndrome of pre-eclampsia (ie, fetal distress,
intrauterine growth restriction) and the consequences of
delivery due to deteriorating maternal disease.
The goal of antihypertensive treatment is to improve
maternal and perinatal outcomes. Historically, there has
been concern that lower blood pressure will reduce the
perfusion of the intervillous space of the placenta, which
does not autoregulate its blood flow. This is an especial
concern in disorders that are associated with placental
abnormalities, either a primary defect in placentation
2
(ie,
pre-eclampsia) or accelerated placental ageing
3
(eg,
chronic hypertension), or both.
As part of a larger meta-analysis of randomised
controlled trials of antihypertensive therapy for mild-to-
moderate pregnancy hypertension,
4
we found that
there was a statistical trend towards an increase in
small-for-gestational-age (SGA) infants among women
taking antihypertensive therapy, compared with those
who took placebo or no therapy (odds ratio 131
[95% CI 098175], n=15 trials, 1782 women),
irrespective of both underlying type of hypertension
and drug class. This treatment effect was,
however, inconsistent in both its magnitude and
direction. A previous Cochrane review
5
attributed the
heterogeneity to the results of the trial by Butters and
colleagues
6
that compared long-term atenolol with
placebo for chronic hypertension in pregnancy, and found
a large increase in SGA infants among atenolol-treated
patients. In that small trial, there were two
postrandomisation withdrawals from the control group for
severe hypertension, leading some,
5
but not all
7
researchers to discount the studys findings and its
therapeutic implications. Other explanations for the
heterogeneity among treatment trials have not been
considered, including the magnitude of treatment-
induced falls in maternal blood pressure.
Any effect of antihypertensive therapy on fetal growth
is important to clarify, because the likely maternal benefits
(ie, a decrease in episodes of blood pressure
>160/100110 mm Hg) are small. A reduction in
intrauterine growth velocity could certainly lead to
premature iatrogenic intervention during pregnancy
(resulting in prematurity-related neonatal mortality and
morbidity), neurodevelopmental abnormalities (particularly
in low-birthweight babies
8
), and, possibly, cardiovascular
health problems in later life.
9
Fall in mean arterial pressure and fetal growth restriction in
pregnancy hypertension: a meta-analysis
P von Dadelszen, M P Ornstein, S B Bull, A G Logan, G Koren, L A Magee
Articles
We assessed the relation between the magnitude of
antihypertensive-induced falls in maternal blood pressure
and fetoplacental growth by metaregression analysis. The
controversial data from Butters and colleagues
6
were
excluded from the primary analyses. Our study was done
within the context of a systematic review of randomised
controlled trials of oral antihypertensive drugs to treat
mild-to-moderate pregnancy hypertension.
Methods
As part of a larger meta-analysis,
4
MEDLINE was searched for
published randomised controlled trials (196697; key words:
antihypertensive agents, bedrest, hospitalisation, plasma volume
expansion, plasma substitutes, maternal mortality, pregnancy,
pregnancy complications, perinatology, neonatology, infant
newborn diseases, infant, infant mortality), Excerpta Medica
(1989-92) was consulted to identify Clinical and Experimental
Hypertension in Pregnancy (now Hypertension in Pregnancy), which
was hand-searched for 199297. In addition, we went through
the references of retrieved papers, and a standard toxicology
text.
10
Titles, abstracts, or photocopies of the methods of
retrieved papers were screened and data abstracted
independently by two retrievers who corroborated their findings
(ie, double-checked their data and resolved disagreement through
discussion). The most up-to-date data were abstracted from
duplicate publications.
Inclusion criteria were: English/French language, human
pregnancy, randomised controlled trial, orally administered drug
or non-drug therapy for mild-to-moderate pregnancy
hypertension, and assessment of the effectiveness of maternal
antihypertensive therapy or perinatal risk, or both. Seemingly
inadequate methods of randomisation (eg, randomisation by
alternate allocation) were included because most reports failed to
describe the method of randomisation adequately. Trials that
administered either placebo/no therapy or antihypertensive
therapy to controls were included, because our interest was in the
treatment-induced change in mean arterial pressure (MAP).
Abstracts were excluded. Abstracted data were entered into the
Review Manager Software, version 3.1 (UK Cochrane
Collaboration, Oxford, UK).
Trials were divided into three types as follows: chronic
hypertension treated throughout pregnancy; mild-to-moderate late-
onset hypertension (ie, pregnancy-induced hypertension, gestational
hypertension, or chronic hypertension treated only later in
pregnancy) randomised to either treatment or placebo/no therapy;
and late-onset hypertension randomised to one of two active agents.
MAP, defined as diastolic blood pressure + (pulse pressure/3),
was chosen as an integrated measure of perfusion pressure. When
not reported directly, MAP was calculated from reported systolic
and diastolic blood pressure, the validity of this value was
checked by use of data from studies that reported all three
measurements (ie, MAP, systolic and diastolic blood pressure).
For each trial, the change in MAP from trial entry to the last
record in pregnancy was calculated from treatment values; this
defined mean differences in MAP for each trial. Therefore, a
positive difference in MAP reflected a greater fall in MAP in the
treatment group than in the control group. Most trials did not
report how blood pressure was measured, or specify the
Korotkoff phase used to define diastolic blood pressure.
The severity of hypertension was defined by mean at
enrolment: mild (MAP 107113 mm Hg), moderate (MAP
114129 mm Hg) or severe (MAP 130 mm Hg). Both the dose
and duration of therapy were found for the groups of treated
women and controls. Fetal outcomes of interest were: gestational
age at delivery, SGA infants (definition recorded), mean crude
birthweight, and mean placental weight.
For quantitative meta-analysis, the summary statistic was the
Peto odds ratio (defined as [O-E]/V, where O is the observed
number of events, E is the expected number of events, and V is
the exact hypergeometric variance of O).
11
Calculations were
based on the fixed-effects model, which assumed that between-
trial variation in outcome was due to chance alone.
The primary objective of the metaregression was to estimate
the association of treatment-induced difference in MAP with
measures of fetoplacental growth (ie, SGA infants, birthweight,
and placental weight [by mean difference between groups]), by
use of summary data from each trial. Other risk factors for poor
fetoplacental growth (type of hypertension, type of
antihypertensive therapy, and difference between groups in
treatment duration) were of secondary interest but could not be
included in the regression because of the limited number of trials
that reported these endpoints. Nonetheless, before the meta-
regression, colinearity between difference in MAP and each of
these factors was assessed by non-parametric methods
12
(ie,
Spearmans, Mann-Whitney U test, or Kruskal-Wallis test, as
appropriate). Lack of evidence for colinearity was taken as
support that the coefficient for difference in MAP in the
regression model would remain the same (or change only slightly)
irrespective of what else was included in the model.
12
The metaregression was done by weighted least-squares
regression. The relation between difference in MAP and each of
the measures of fetoplacental growth was estimated by Pearsons
r
2
. A p value <005 was considered to be significant. For the SGA
outcome, the natural logarithm of the odds ratio for a given trial
was used as the dependent variable in the regression.
11
For the
continuous outcomes (ie, birthweight and placental weight), the
mean difference between treatment groups was used. Each study
was weighted in the metaregression to account for the fact that
the trials were of different size, and therefore, study-specific effect
measures (ie, natural logarithm of the odds ratio or mean
differences) were not all measured with equal precision.
12
The
weights were determined as inverse of the variance of the study-
specific outcome variable.
12
We weighted each data point by
multiplying both the independent (ie, difference in MAP) and the
dependent variable (eg, natural logarithm of the odds ratio for a
given trial for SGA infants) by the square root of the weight.
To be conservative,
13
we omitted the data of Butters and
colleagues
6
from the primary analysis. This trial was identified to
be a statistical outlier (by our work and by others). However, we
also did a sensitivity analysis in which data from the paper by
Butters and colleagues were included, and both non-parametric
(Spearmans)
12
and parametric (Pearsons r) methods were used.
Secondary analyses included the relation between other risk
factors for poor fetoplacental growth and measures of that growth.
Results
45 randomised controlled trials (41 publications)
1453
were
identified that randomly allocated 3773 women with
mild-to-moderate pregnancy hypertension to oral anti-
hypertensive treatment. Seven trials (six publications)
6, 1418
randomised women with chronic hypertension to therapy
or placebo/no therapy. A further 38 trials randomly
allocated women with late-onset hypertension to
antihypertensive therapy or either placebo/no therapy (15
trials),
1933
or other antihypertensive therapy (23 trials, 20
publications).
3453
The drugs used in these trials were: methyldopa (dose
range 5004000 mg/day); -blockersacebutolol
(4001200 mg/day), atenolol (50200 mg/day), labetalol
(2002400 mg/day), metoprolol (50300 mg/day),
oxprenolol (80640 mg/day), pindolol (1025 mg/day),
propranolol (30160 mg/day); thiazide diuretics
bendrofluazide (510 mg/day), chlorothiazide (10 g/day),
hydrochlorthiazide (50 mg/day); ketanserin (2080
mg/day); hydralazine (25200 mg/day); calcium-channel
blockersisradipine (5 mg/day), nicardipine (600
mg/day), nifedipine (40120 mg/day), verapamil
(360480 mg/day); and clonidine (1501200 g/day).
Only the dosing rage was reported for each trial. For drug
versus drug trials, -blockers were always the
experimental intervention, and methyldopa was always
the control or standard treatment.
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88 THE LANCET Vol 355 January 8, 2000
In terms of quality, 12 (27%) of 45 randomised
controlled trials described adequate allocation conceal-
ment, 40 (89%) described successful randomisation by
balanced baseline maternal characteristics between
groups, and 13 (29%) described adequate outcome-
assessment masking. There was no apparent impact of
these factors on trial outcomes (data not presented).
No collinearity was detected between mean difference
in MAP and either mean difference in treatment duration
of antihypertensive therapy (Spearmans =010, p=068,
19 trials) or mean total duration of therapy in the
experimental group of antihypertensive versus placebo/no
therapy trials (=010, p=084, eight trials). The median
(range) duration of therapy for all trials was 80
(187275) weeks, and all women were treated during the
third trimester.
Mean difference in MAP did not differ between trials
that enrolled women with chronic hypertension
(534 [200 to 1900] mm Hg, six trials) or late-onset
hypertension (070 [1300 to 1576], p=027, 23 trials).
There was a trend towards greater treatment-induced
mean difference in MAP among trials that administered
placebo/no therapy to controls: -blockers versus
placebo/no therapy (593 [133799] mm Hg, seven
trials), other antihypertensives versus placebo/no therapy
(502 [200 to 1900] mm Hg, six trials), -blocker
versus other antihypertensive therapy (135 [1300 to
1576] mm Hg, 12 trials), or other antihypertensive versus
other antihypertensive (030 [200 to 173], p=005,
four trials).
15 trials (13 publications)
6,15,16,24,25,27,29,31,35,37,45,46,53
that
randomly allocated treatment to 1587 women, described
both mean blood pressure control and the proportion of
SGA infants. All but five trials defined SGA as
birthweight below 10th centile for gestational age, with
appropriate tables: three trials (two publications
16,27
) did
not define SGA (but the author of one publication
16
with
two trials has routinely used below 10th centile for
gestational age in other publications), one used below 5th
centile for gestational age,
35
and another used below 250
in Ushers curve.
45
Greater treatment-induced mean
difference in MAP was associated with a higher
proportion of SGA infants (figure 1); results are presented
by type of hypertension and treatment of control group for
clarity. With the paper by Butters and colleagues
6
excluded, the slope was 009 (SE 003; r
2
=048, p=0006).
With the inclusion of the paper by Butters and
colleagues,
6
the slope of the linear-regression line was the
same by non-parametric analyses (009 [004], p=001) or
parametric analyses (009 [004], p=0065). The latter
was not significant, due to expansion of the SE of the
regression coefficient.
Analysis according to the type of hypertension was
possible only for the late-onset hypertension groups, since
there were only three chronic hypertension trials (apart
from that of Butters and colleagues). The subgroup
results were similar to those overall, whether controls were
treated with placebo/no therapy (slope 012 [005],
p=012, five trials) or antihypertensive drug therapy (slope
021 [007], p=004, six trials). There was no association
between mean difference in duration of therapy and the
log odds of SGA infants (p=092, ten trials). Mean total
treatment duration for treatment group of
antihypertensive treatment versus placebo/no therapy
trials was also not significantly related to the log odds of
an SGA infant (p=030, seven trials).
27 trials (25 publications)
1416,24,25,27,2932,3537,39,4143,4648,5053
randomly allocating treatment to 2305 women, described
both mean blood pressure control and mean birthweight.
Treatment-induced mean difference in MAP was not
significantly associated with lower mean birthweight
(figure 2). However, the data point from the trial by
Jannet and colleagues
48
(which did not report the
incidence of SGA infants) was an extreme statistical
outlier, and was excluded from the sensitivity analysis. By
the use of weighted non-parametric Spearmans
regression,
12
a significant relation was demonstrated
(slope:1449 [698], r
2
=016, p=0049), such that over
the range of reported mean difference in MAP, a
10 mm Hg fall in MAP was associated with a 145 g
decrease in birthweight. Just 16% of the variation in mean
birthweight between groups could be explained by the
differential fall in MAP between treatment and control
groups, and three trials (two
18,22
in this analysis) reported
ARTICLES
THE LANCET Vol 355 January 8, 2000 89
3
N
a
t
u
r
a
l

l
o
g
a
r
i
t
h
m

o
d
d
s
r
a
t
i
o

(
S
G
A
)
2
1
0
1
2
50 25 0 25 50 75 100
Difference in MAP (mm Hg)
Chronic hypertension (drug vs placebo)
Late-onset hypertension (drug vs placebo)
Late-onset hypertension (drug vs drug)
Butters and
colleagues
500
250
0
Difference in MAP (mm Hg)

1
5

1
2

1
0

5 0
2

5
5

0
7

5
1
0

0
1
2

5
1
5

0
1
7

5
250
500
750
1000
Chronic hypertension (drug vs placebo)
Late-onset hypertension (drug vs placebo)
Late-onset hypertension (drug vs drug)
Jannet and
colleagues
Butters and
colleagues
M
e
a
n

d
i
f
f
e
r
e
n
c
e

i
n
b
i
r
t
h
w
e
i
g
h
t

(
g
)
Figure 1: Relation between fall in MAP and proportion of SGA
infants
Spearmans =069 (p=0007) without Butters and colleagues trial,
6
=064 (p=001) with that trial.
Figure 2: Relation between fall in MAP and low birthweight
Spearmans =046 (p=0021) without both outlier trials;
6,48
=031
(p=0122) with both outlier trials; =044 (p=0025) without trial of
Jannet and colleagues;
48
=030 (p=014) without trial of Butters and
colleagues.
6
significant differences in gestational age at delivery. With
inclusion of Butters and colleagues trial
6
(and exclusion
of that of Jannet and colleagues
48
), the slope of the linear-
regression line did not change by either non-parametric
analyses (1406 [918], p=002) or parametric analyses
(1406 [918], p=014); however, inclusion of Jannet
and colleagues (and exclusion of that of Butters and
colleagues) shows that the relation was dependent on
omitting this trial (slope: 384 [654], p=014 [non-
parametric], p=056 [parametric]). There are no
methodological problems in the trial of Jannet and
colleagues (women randomly assigned metoprolol or
nicardipine) that could explain the marked disparity in its
results.
Analysis by type of hypertension and antihypertensive
treatment showed non-significant inverse relations
between difference in MAP and mean birthweight:
chronic hypertension (slope 1860 [2091], p=044, five
trials), late-onset hypertension with placebo/no therapy of
controls (1669 [1166], p=023, six trials), and late-
onset hypertension with antihypertensive therapy of
controls (1747 [1527], p=027, 14 trials). There was
no association between either mean difference in duration
of therapy (p=060, 19 trials) or mean total duration of
therapy among the treatment group of drugs versus
placebo/no therapy trials (p=034, nine trials).
11 trials (ten publications)
14,16,25,31,32,36,41,47,48,50
randomly
allocating treatment to 1119 women, reported both mean
blood pressure control and mean placental weight. No
significant relation was seen between mean difference in
MAP and mean placental weight (p=025, 11 trials).
Subgroup analysis was possible only for the late-onset
hypertension trials that compared two antihypertensive
drugs; no significant relation was found (p=047, six
trials). There was no significant association between mean
difference in duration of therapy and mean placental
weight (p=088, nine trials).
Discussion
By meta-analysis, we investigated the apparent
heterogeneity of the influence of oral antihypertensive
treatment on the odds ratio for delivering an SGA infant.
Despite exclusion of the trial
6
by Butters and colleagues,
we found a relation between mean treatment-induced falls
in MAP and impaired fetal growth, as assessed by
birthweight corrected for gestational age (usually defined
as <10th centile). This relation could not be explained by
type of hypertension, type of antihypertensive agent, or
mean duration of therapy, since none of these were related
to mean difference in MAP.
A puzzling finding is that antihypertensive therapy was
associated with poor fetal growth, whereas the duration of
that therapy was not. The mean difference in treatment
duration between groups was very small, and could not
explain the difference in fetal growth between groups,
overall. However, even among placebo/no therapy
controlled trials, the mean total duration of therapy did
not relate to fetal growth; in this analysis, all women were
treated for a median of 103 weeks, and a minimum of 33
weeks in the third trimester. Possibly antihypertensive
treatment during this period of greatest fetal growth
velocity is most important.
That antihypertensive therapy may adversely affect
intrauterine fetal growth is a clinically important finding.
The exclusion of the trial by Butters and colleagues from
the analysis increases the clinical impact, given the
concerns expressed about this small trial with
methodological problems.
No relation between mean difference in MAP and
crude mean birthweight was seen, when we excluded only
the trial by Butters and colleagues. However, two of the
trials in the analysis found a significant difference in
gestational age at delivery, which is the most important
determinant of birthweight. In addition, the trial by Jannet
and colleagues
48
was a statistical outlier in finding a much
greater difference in both fall in MAP and birthweight
between groups, for reasons that were unexplained by trial
design or type of antihypertensive (ie, nicardipine vs
metoprolol); with exclusion of this trial, we still showed a
significant relation between mean difference in MAP and
mean birthweight, Over the reported range of fall in MAP,
a 10 mm Hg fall was associated with a 145 g decrease in
mean birthweight. However, this post-hoc analysis must
be viewed with caution. No relation was seen between
mean difference in MAP and mean placental weight.
Previously, -blockers have been singled out as being
the class of antihypertensive associated with an increased
risk of poor fetal growth.
54
However, the influence of MAP
on the odds ratio for SGA infants appeared to be
unrelated to the type of antihypertensive treatment. It is
unlikely that different classes of antihypertensive
medication, with differing modes of pharmacological
action, would have consistent fetoplacental toxic effects
and, consequently, cause reduced fetal growth. More
likely is that the observed effect on fetal growth was
related to uteroplacental perfusion abnormalities, but this
conjecture remains unproven.
Certainly, vasoactive medication could influence fetal
growth. This could be a directly toxic pharmacological
effect, affecting metabolism within the fetoplacental unit
or the transfer of nutrients across the placenta. Reduced
perfusion pressure within the intervillous space could
similarly affect both the placenta and the fetus
symmetrically, or, in the face of abnormal placentation,
differentially; we could neither exclude nor confirm an
associated abnormality of placental growth, given that fall
in MAP and placental weight were not related. A
reduction in intervillous perfusion may also cause
sufficient stress to accelerate fetal pulmonary maturation.
This mechanism would be consistent with the previously
observed treatment-induced decrease in respiratory
distress syndrome in a previously published meta-
analysis,
5
as well as our previous meta-analysis.
4
Fetuses
subjected to in-utero stress are less likely than those
without such stress to develop respiratory distress
syndrome,
55,56
when delivered in good condition. Although
the observed reduction in intrauterine growth velocity
may be associated with improved neonatal outcome (ie,
respiratory distress syndrome), there are concerns that
such an adverse intrauterine environment could both
increase the risk of iatrogenic antenatal and intrapartum
interventions and lead to an excess of health problems in
adulthood.
9
This metaregression is limited in several ways. This
analysis was restricted to published randomised controlled
trials, augmented by results published only in the
Cochrane reviews after personal communication with the
trialists; this leaves analysis open to both publication bias
and the file drawer effect. Not all trials reported the
covariates of interest (principally blood pressure) or all
fetal outcomes of interest (principally, the proportion of
SGA infants). Use of averages of covariates measured in
ARTICLES
90 THE LANCET Vol 355 January 8, 2000
the individual patient (eg, difference in MAP) must be
done with caution because they may not adequately
reflect important between-patient, within-trial
differences.
57
The practice of omitting data from trials that
are statistical outliers has been recommended by some
13
but not all authorities.
12
Finally, meta-analyses and
metaregressions are, by their nature, observational and
retrospective. Therefore, they should only be considered
hypothesis-generating, and a prelude to a randomised
controlled trial.
58
In summary, the implications of the observed impact of
the treatment-induced fall in blood pressure on fetal
growth must be considered seriously. Women are unlikely
to suffer from either acute or chronic deleterious effects,
over the 9 months of pregnancy, from blood pressures
that are below 170/110 mm Hg.
59,60
At present, we cannot
be sure of the impact that antihypertensive treatment for
mild-to-moderate pregnancy hypertension may have on
perinatal outcomes. New data from clinical trials are
needed.
Contributors
P von Dadelszen, M P Ornstein, and L A Magee were responsible for the
data abstraction and statistical analyses (meta-analysis and meta-
regression). A G Logan and G Koren aided in the design of the stidy and
acted as content experts in the fields of hypertension and perinatal
morbidity, respectively. S B Bull aided in the statistical analysis.
P von Dadelszen and L A Magee wrote the manuscript.
Acknowledgments
This work was supported by the Physicians Services Incorporated and an
educational grant from the Department of Medicine, Mount Sinai
Hospital, Toronto, Canada. S B Bull and A G Logan are senior scientists
of the Samuel Lunenfeld Research Institute of Mount Sinai Hospital,
Toronto. G Koren is the CIBC World Market Childrens Miracle
Foundation Chair in child health research, Hospital for Sick Children,
Toronto, Canada.
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