1. family and parenting
2. motherhood
3. pregnancy

(Control
CHIPS Trial
of Hypertension In Pregnancy Study)
Research Protocol
16 November 2011
CLINICAL Co-ordinating Centre:
DATA Co-ordinating Centre:
University of British Columbia
Maternal Fetal Medicine Division
Department of Obstetrics & Gynaecology
2H30-4500 Oak Street
Vancouver BC CANADA V6H 3N1
Tel: 604-875-2959 Fax: 604-875-3212
Email: [email protected]
Website: http://www.utoronto.ca/cmicr/chips/
University of Toronto
The Centre for Mother, Infant, and Child Research
(CMICR)
C8-2075 Bayview Avenue
Toronto, Ontario, CANADA M4N 3M5
Tel: 416-480-5629 Fax: 416-480-5633
Email: [email protected]
Website: http://www.utoronto.ca/cmicr/chips/
CHIPS Trial Protocol (Version 16 November 2011)
TABLE OF CONTENTS
1. INTRODUCTION............................................................................................................................... 3
1.1 BACKGROUND .......................................................................................................................................................................................................... 3
1.2 RISKS TO THE BABY .................................................................................................................................................................................................. 3
1.3 RISKS TO THE MOTHER ........................................................................................................................................................................................... 3
1.4 POTENTIAL RISKS OF ANTIHYPERTENSIVE TREATMENT .................................................................................................................................. 4
1.5 PRINCIPAL RESEARCH QUESTION(S) ..................................................................................................................................................................... 4
1.6 THE NEED FOR A TRIAL .......................................................................................................................................................................................... 4
1.7 RELEVANT SYSTEMATIC REVIEW(S) ...................................................................................................................................................................... 5
1.8 HOW THE RESULTS OF THE TRIAL WILL BE USED ............................................................................................................................................... 6
1.9 RISKS TO THE SAFETY OF PARTICIPANTS INVOLVED IN THE TRIAL................................................................................................................ 6
2. THE TRIAL ......................................................................................................................................... 6
2.1 TRIAL DESIGN ........................................................................................................................................................................................................... 6
2.2 TRIAL INTERVENTIONS ........................................................................................................................................................................................... 6
2.2.1 RECRUITMENT AND RANDOMISATION ........................................................................................................................................................ 6
2.2.2 ‘LESS TIGHT’ CONTROL GROUP .................................................................................................................................................................... 7
2.2.3 ‘TIGHT’ CONTROL GROUP .............................................................................................................................................................................. 7
2.2.4 BOTH GROUPS .................................................................................................................................................................................................. 7
2.3 ARRANGEMENTS FOR ALLOCATING PARTICIPANTS TO TRIAL GROUPS.......................................................................................................... 8
2.4 METHODS FOR PROTECTING AGAINST SOURCES OF BIAS ................................................................................................................................ 8
2.4.1 CONTAMINATION............................................................................................................................................................................................ 8
2.4.2 CO-INTERVENTIONS ....................................................................................................................................................................................... 8
2.5 INCLUSION/EXCLUSION CRITERIA........................................................................................................................................................................ 9
2.5.1 INCLUSION CRITERIA ...................................................................................................................................................................................... 9
2.5.2 EXCLUSION CRITERIA ..................................................................................................................................................................................... 9
2.6 DURATION OF TREATMENT PERIOD .................................................................................................................................................................... 9
2.7 FREQUENCY AND DURATION OF FOLLOW-UP .................................................................................................................................................... 9
2.8 PRIMARY AND SECONDARY OUTCOME MEASURES........................................................................................................................................... 10
2.8.1 PRIMARY: PREGNANCY LOSS OR ‘HIGH LEVEL’ NEONATAL CARE FOR > 48HR ................................................................................. 10
2.8.2 SECONDARY: ONE/MORE SERIOUS MATERNAL COMPLICATION(S) ..................................................................................................... 10
2.8.3 OTHER OUTCOMES........................................................................................................................................................................................ 11
2.9 HOW OUTCOMES WILL BE MEASURED AT FOLLOW-UP ................................................................................................................................... 12
2.10 HEALTH SERVICES ISSUES................................................................................................................................................................................... 12
2.10.1 ECONOMIC EVALUATION........................................................................................................................................................................... 12
2.10.2 OTHER HEALTH SERVICES RESEARCH ISSUES......................................................................................................................................... 13
2.11 SAMPLE SIZE ......................................................................................................................................................................................................... 13
2.12 RECRUITMENT ...................................................................................................................................................................................................... 13
2.13 COMPLIANCE ........................................................................................................................................................................................................ 14
2.14 LIKELY RATE OF LOSS TO FOLLOW-UP ............................................................................................................................................................. 14
CHIPS Trial Protocol (Version 16 November 2011)
Page 1 of 30
2.15 CENTRES INVOLVED ........................................................................................................................................................................................... 14
2.16 ANALYSES .............................................................................................................................................................................................................. 14
2.17 FREQUENCY OF ANALYSES................................................................................................................................................................................. 15
2.18 PLANNED SUBGROUP ANALYSES ....................................................................................................................................................................... 15
2.19 TIMELINE FOR THE STUDY................................................................................................................................................................................. 16
3. DETAILS OF THE TRIAL TEAM ................................................................................................... 16
3.1 ARRANGEMENTS FOR DAY-TO-DAY MANAGEMENT OF THE TRIAL.............................................................................................................. 16
3.2 THE STEERING, ADJUDICATION, AND DATA SAFETY & MONITORING COMMITTEES ............................................................................ 16
CHIPS Trial Protocol (Version 16 November 2011)
Page 2 of 30
1. INTRODUCTION
1.1 BACKGROUND
According to population-based data, 7-9% of pregnancies are complicated by hypertension [i.e., diastolic blood
pressure (dBP) ≥ 90mmHg](1;2). Approximately 1% of pregnancies are complicated by pre-existing
hypertension, 5-6% by gestational hypertension without proteinuria (half present preterm), and 2% by preeclampsia (usually defined as gestational hypertension with proteinuria)(3). Pre-existing hypertension presents
before pregnancy or before 20 weeks gestation, and may be primary or secondary (e.g., to renal disease)(4).
Gestational hypertension presents at ≥ 20 weeks (with/without proteinuria)(5). Pre-existing or gestational
hypertension may be non-severe or severe, usually defined as a BP of ≥160-170/110mmHg.
For the planned CHIPS Trial, our focus is women with hypertension that presents at <34 weeks, and is
non-severe, non-proteinuric, and either pre-existing (1% of all pregnancies) or gestational (2-3% of all
pregnancies). At present, it is unclear how best to manage their non-severe, non-proteinuric hypertension.
Current practice approaches include both ‘less tight’ control (allowing BP to be higher than normal) and ‘tight’
control (normalising BP). The effects of each approach on perinatal and maternal outcomes needs to be
determined. As emphasized by the apparent perinatal advantages of ‘less tight’ control in the CHIPS Pilot
Trial, a definitive RCT, such as the proposed CHIPS Trial, now needs to be conducted.
1.2 RISKS TO THE BABY
Babies born to hypertensive pregnant women have an excess of perinatal complications. It is difficult to
ascertain the exact risks by hypertension type due to methodological problems with published studies: most
data come from tertiary care centres; definitions of outcomes vary; factors (including antihypertensive therapy)
that may confound the BP/fetal growth relationship are not accounted for; studies were undertaken during
periods when perinatal care was less advanced; and clinicians have made little progress since 1996 when this
was so coherently summarised(6). These concerns notwithstanding, the reported perinatal mortality rate for
pregnancies complicated by pre-existing hypertension has been as high as 4% (40/1000)(7-10). For women
with either pre-existing or gestational hypertension, the risk of perinatal death or serious morbidity is 16% and
‘high level’ neonatal care as high as 36%(11;12). In 2006, babies of hypertensive mothers represented 14% of
neonatal intensive care unit (NICU) admissions in Canada, and 50% had lengths of stay of 11-59 weeks(13).
There are two primary pathways through which babies of hypertensive mothers become sick enough to
require ‘high level’ neonatal care: poorer fetal growth and/or perinatal asphyxia. Among women with preexisting or non-proteinuric gestational hypertension, the risk of a small for gestational age (SGA) infant (<10th
centile) is approximately 15%(14-22). Approximately 20% of women with pre-existing hypertension and 40%
of women with non-proteinuric gestational hypertension who present before 34 weeks will develop
superimposed pre-eclampsia(15;17;23-30), with SGA risk up to 40%(31-37). Perinatal asphyxia may be acute
(as a result of placental abruption(38)) or chronic (as a result of chronic uteroplacental insufficiency(39)), at
preterm and term gestations(40). These SGA or asphyxiated infants are often admitted to ‘high level’ neonatal
care because of short-term complications, such as hypothermia, respiratory failure, and feeding problems(4146). These infants are at higher risk of adverse neurological outcomes and cognitive function in childhood(4753). The SGA infants are also at increased risk of cardiovascular and endocrine complications in adulthood(5462), possibly through fetal programming and/or developmental epigenetic programming in utero (Fetal
Programming Hypothesis)(63).
1.3 RISKS TO THE MOTHER
Among non-pregnant women, only if hypertension is very severe and uncontrolled are hypertensive end-organ
complications a concern in the short term (i.e., over days to weeks); immediate antihypertensive therapy is then
warranted. Among non-pregnant women with non-severe hypertension, hypertensive end-organ complications
are a concern only over the long term (i.e., decades); a diagnosis of hypertension is made carefully over months
and even when that diagnosis is made, a dBP <100mmHg does not necessarily warrant antihypertensive
therapy when women are otherwise well (for example, without renal disease)(64). Thus, any treatment of nonsevere hypertension in pregnancy would be based on the potential benefits and risks for the baby.
In addition to the hypertension per se, clinicians have additional concerns about pregnant women with nonsevere hypertension because these women are at risk of superimposed pre-eclampsia and its associated endorgan complications. Pre-eclampsia occurs in approximately 20% of women with pre-existing hypertension
and 40% of women with non-proteinuric gestational hypertension who present before 34 weeks(15;17;26;6571). Pre-eclampisa is a disorder of placental development, and the most popular theory describes a mismatch
between uteroplacental supply and fetal demands(72). As a result, there is placental release of biological factors
that cause systemic maternal endothelial cell dysfunction and the end-organ complications of pre-eclampsia,
CHIPS Trial Protocol (Version 16 November 2011)
Page 3 of 30
which include severe hypertension, eclampsia, pulmonary edema, and HELLP syndrome (haemolysis, elevated
liver enzyme, and low platelet syndrome). Although there is consensus that sustained severe hypertension (dBP
≥110mmHg) should be treated with antihypertensive therapy, severe maternal hypertension is a poor surrogate
for maternal risk. For example, in published RCTs of pregnant women who received ‘tight’ BP control with
antihypertensive therapy, brief episodes of severe hypertension occurred in approximately 11%, but serious
maternal complications were rare: no stroke, a single maternal death , and an incidence of eclampsia of
<1%(73-78). Therefore, alone, severe hypertension is not considered to be an outcome that would guide
clinical practice. Excluding severe hypertension, serious maternal complications occurred in 2-4% of women in
our CHIPS feasibility study(79) and CHIPS Pilot Trial(26;80;81).
1.4 POTENTIAL RISKS OF ANTIHYPERTENSIVE TREATMENT
At present, control of maternal BP with antihypertensive therapy is widely available to hypertensive pregnant
women. However, as the placenta does not autoregulate blood flow, there is a historical concern that lowering
BP may decrease placental perfusion, and because of poorer fetal growth and/or metabolic derangements,
babies may do more poorly. This is true regardless of the underlying pathophysiology of the maternal hypertension (Section 2.5). At present, the literature is not robust enough to guide decision-making about optimal
use of antihypertensives for non-severe hypertension in pregnancy. CHIPS is designed to address this issue.
1.5 PRINCIPAL RESEARCH QUESTION(S)
Primary: For pregnant women with non-severe, non-proteinuric maternal hypertension at 14-33 weeks, will
‘less tight’ control (target dBP of 100mmHg) vs. ‘tight’ control (target dBP of 85mmHg) increase (or decrease)
the likelihood of pregnancy loss or ‘high level’ neonatal care for more than 48hr?
Secondary: Will ‘less tight’ vs. ‘tight’ control increase (or decrease) the likelihood of serious maternal
complications?
Other: Will ‘less tight’ vs. ‘tight’ control: i) increase (or decrease) the likelihood of serious perinatal
complications?; ii) increase (or decrease) the likelihood of severe hypertension and pre-eclampsia?; iii) increase
(or decrease) the likelihood of maternal satisfaction with care?; and iv) result in significant changes in dBP or
health care costs?
1.6 THE NEED FOR A TRIAL
The overarching hypothesis underlying CHIPS is that ‘less tight’ control may improve uteroplacental perfusion,
fetal growth, and through these, fetal/neonatal well-being. We seek to determine whether ‘less tight’
control (target dBP of 100mmHg) vs. ‘tight’ control (target dBP of 85mmHg) of non-severe maternal
hypertension will decrease fetal/neonatal risk without increasing maternal risk.
Over the past 8 years, our research agenda has focussed on setting the groundwork for the CHIPS Trial.
We are interested in women with non-severe non-proteinuric hypertension at <34 weeks (3-4% of
pregnancies) who are at significant risk of maternal and perinatal complications. Based on meta-analyses of
RCTs, arguments can be made for and against ‘less tight’ BP control (Section 1.4) (82-85). ‘Less tight’ control
(allowing for higher BP levels) may decrease the risk of SGA infants, but may also increase the risk of
transient, severe maternal hypertension, antenatal hospitalisation, and proteinuria at delivery. Our metaanalyses of existing trials do not provide sufficient evidence on which to base clinical decisions because of
reporting bias and between-trial heterogeneity in outcome. Currently, guidelines are founded mainly on expert
opinion(86-88). In our national survey (1999), Canadian obstetricians were divided on the dBP goal for
treatment of non-severe hypertension (89).
In April ‘03, we started the CHIPS Pilot Trial to determine whether a full CHIPS trial would be possible.
In the CHIPS Pilot, we sought to determine whether: clinicians could comply with the interventions, their
compliance would result in ‘less tight’ and ‘tight’ control of dBP, there would be a dBP difference between
groups, and women were satisfied with their care(26;80;81). From Apr ’03 to Dec ’04, the CHIPS Pilot
recruited in 17 centres in Canada, Australia, New Zealand and the UK. Subject inclusion criteria were: dBP 90109 mmHg, pre-existing/ gestational hypertension, live fetus(es), and 20-33+6 weeks; women with systolic BP
(sBP) 160mmHg, proteinuria, a contraindication, or major fetal anomaly were excluded. A total of 132
women were randomised to ‘less tight’ (N=66) or ‘tight’ control (N=66). Most clinicians (79% in each group)
complied with the intervention. Mean dBP was significantly lower for the ‘tight’ control group: -3.5 mmHg,
95% credible interval [-6.4, -0.6]. Women were satisfied with their care in terms of willingness to have the same
treatment again in another pregnancy [60 (92.3%) ‘less tight’ vs. 53 (89.8%) ‘tight’ control] or recommend that
treatment to a friend [61 (93.9%) ‘less tight’ vs. 58 (95.1%) ‘tight’ control]. Table 1 shows rates of
antihypertensive treatment and other outcomes.
CHIPS Trial Protocol (Version 16 November 2011)
Page 4 of 30
Table 1: CHIPS Pilot Trial maternal and perinatal outcomes [mean±SD or N (%) women]
Antihypertensive use after randomisation
Severe hypertension
Proteinuria
Serious maternal complications
Preterm birth
Birthweight (g)
Neonatal intensive care unit (NICU) admission
Serious perinatal complications
‘Less tight’ control (N=66)
49 (69.7%)
38 (57.6%)
16 (24.2%)
3 (4.6%)
24 (36.4%)
2675 ± 858
15 (22.7%)
9 (13.6%)
‘Tight’ control (N=65*)
58 (89.2%)
26 (40.0%)
20 (30.8%)
2 (3.1%)
26 (40.0%)
2501 ± 855
23† (35.9%)
14 (21.5%)
* One woman opted not to continue with the Trial.
† One baby was admitted to NICU and subsequently died; in the CHIPS Pilot publication, NICU admission was reported for survivors.
These promising results have now confirmed the feasibility and importance of a trial to determine the
effects of ‘less tight’ vs. ‘tight’ control of non-proteinuric non-severe pregnancy hypertension on fetal/neonatal
illness and serious maternal complications. As such, the proposed CHIPS Trial needs to be conducted now
so that clinical management is based on solid evidence. Two international trials of anti-oxidants for preeclampsia prevention demonstrated harm(90;91), reminding us that clinical management should not be based
solely on promising pilot data or expert opinion, but rather, on definitive RCTs(92).
1.7 RELEVANT SYSTEMATIC REVIEW(S)
We conducted three relevant systematic reviews of RCTs prior to designing CHIPS(83;84;93;94), and a
relevant Cochrane review has recently been updated(95;96). In these reviews, we have included a total of 31
RCTs (3,462 women) that examined the impact of differential BP control (of non-severe pre-existing(97-102)
or gestational(75;76;103-125) hypertension) on maternal and perinatal outcomes. All of these cited trials
compared antihypertensive treatment with placebo/no therapy. In the ‘treatment’ groups of cited trials,
women were randomised to receive antihypertensive treatment to achieve a dBP of <90mmHg; in the CHIPS
Trial, this group is referred to as the ‘tight’ control group. In the placebo or ‘no therapy’ arms of the cited
trials, women received placebo or ‘no treatment’, with antihypertensive therapy added if their BP rose to 160170/100-110mmHg; in the CHIPS Trial, this group is the ‘less tight’ control group. That is, the ‘no treatment’
or placebo arms of the cited trials did in fact receive antihypertensive treatment, if necessary, to control BP.
We believe that our terms better reflect the fact that all women in the Trial have dBP observed and have clear
plans for management of their BP based on the two policies: either ‘tight’ or ‘less tight’ control of dBP.
There was a tendency for ‘less tight’ control (compared with ‘tight’ control) to be associated with fewer
SGA infants (<10th centile) (RR 0.89, 95% CI [0.73, 1.08]). The between-trial heterogeneity in outcome was not
fully explained by antihypertensive type and was explored by meta-regression analysis. There was a significant
and linear correlation between the decrease in mean arterial pressure, and both an increase in incidence of SGA
infants (slope 0.13±0.03, r2=0.54, p=0.002, N=15 trials) and decrease in birthweight (slope -17.55±6.67,
r2=0.19, p=0.01, N=34 trials)(84;126). (Spontaneously, when BP is lower in pregnancy, outcomes are worse. A
dBP <70mmHg in pregnancy is associated with both lower birthweight and higher perinatal mortality(127).
Perinatal and neurodevelopmental outcomes are worse, for preterm and term growth-restricted babies, who are
born to normotensive mothers, compared with those born to hypertensive mothers(128;129).) ‘Less tight’
control increased the risk of severe hypertension (RR 2.12 [1.77, 2.53]) and proteinuria at delivery (RR 1.20
[1.02, 1.41]), but there was significant between-trial heterogeneity in outcomes. In 31 trials (3,462 women),
there was one maternal death [in the ‘tight’ control group(130)] and no reported stroke.
To synthesise the results of the reviews: How best to manage non-severe non-proteinuric hypertension in
pregnancy is still unclear. 'Tight' control reduces the risk of severe maternal hypertension and proteinuria at
delivery, but ‘less tight’ control may decrease the risk of SGA infants. However, the reviews do not provide
sufficient evidence to determine the relative benefits and risks of antihypertensive therapy for non-severe
pregnancy hypertension. In addition, reporting bias and between-trial heterogeneity in outcome lead to further
confusion. Canadian obstetricians are divided on this issue but have indicated a willingness to enrol women
into CHIPS(89). Our Pilot Trial demonstrated that ‘less tight’ (vs. ‘tight’) control results in higher dBP, that
clinicians can comply with the interventions, and that women are satisfied with their care; there was also a
tendency for improved perinatal outcomes associated with ‘less tight’ control. Thus, we believe that the
CHIPS Trial is feasible and critically needed.
CHIPS Trial Protocol (Version 16 November 2011)
Page 5 of 30
Choice of antihypertensive agent: There is little to guide the choice of agent. A total of 31 other trials
compared one oral antihypertensive with another (most commonly beta-blockers vs. methyldopa), but the
same dBP goal was applied to women in both treatment groups(131-161). Beta-blockers (and labetalol in
particular) may be more effective antihypertensives than is methyldopa (RR 0.75, 95% 0.58, 0.94) (10 trials, 539
women), but no other differences in maternal or perinatal outcomes were demonstrated (19 trials, 1,282
women)(95). No adverse effects of nifedipine(162), atenolol(163) or methyldopa(164) have been demonstrated
on paediatric health or neurodevelopment, but data are too limited to guide the choice of antihypertensive
agent. Labetalol and methyldopa are the oral agents used most frequently in Canada(89).
1.8 HOW THE RESULTS OF THE TRIAL WILL BE USED
The results of the CHIPS Trial will inform both women and clinicians about treatment of non-severe
hypertension, nationally and internationally. Pregnant women will have better information on the impact of
treatment on perinatal and maternal outcomes, enabling them to make informed choices, particularly about any
‘trade-offs’ in maternal and fetal risk. National (Society of Obstetricians & Gynaecologists of Canada, Canadian
Hypertension Society) and international (International Society for the Study of Hypertension in Pregnancy)
specialty societies are in need of high quality evidence in order to inform clinical practice guidelines. This
research question has been long-debated without a final conclusion; it will remain highly relevant in 6 years’
time when the final results of the CHIPS Trial will be available.
1.9 RISKS TO THE SAFETY OF PARTICIPANTS INVOLVED IN THE TRIAL
The interventions of ‘less tight’ and ‘tight’ BP control are both used in current clinical practice and endorsed by
international guidelines(88;165;166). There will be no additional risks to women participating in CHIPS, over
and above those associated with contemporary recommended therapy for non-severe hypertension. It is
possible that there may be some risks associated with either ‘less tight’ or ‘tight’ control, but that is what
CHIPS is designed to address. Given uncertainty about maternal and fetal risks associated with policies of ‘less
tight’ or ‘tight’ BP control in pregnancy, we plan interim analyses to examine safety (Section 2.17).
2. THE TRIAL
Our hypothesis is that ‘less tight’ (vs. ‘tight’) control will be both more effective (result in fewer fetal/neonatal
losses or sick babies) and less costly (result in use of fewer health care resources).
2.1 TRIAL DESIGN
CHIPS will be an open, multicentre, international, randomised controlled trial with an intention-to-treat
analysis. The study is pragmatic: that is, it will be undertaken to reflect real clinical practice rather than the very
tightly controlled circumstances of explanatory trials(167-169). The pragmatic approach is important in this
trial, where the interventions are policies of ‘less tight’ and ‘tight’ control, and it is not possible to blind
clinicians or patients to the dBP goals of each treatment group. In addition, the policies are complex,
consisting of a series of components including the possible treatment, changing dosage, and differential
monitoring, all of which reflect the way the treatments would be applied in normal clinical practice(170-172).
The primary outcome is outcome for the babies, irrespective of the way the policies are administered.
Eligible women will be randomised centrally to either ‘less tight’ control (aiming for dBP of 100 mmHg) or
‘tight’ control (aiming for dBP of 85mmHg) of their hypertension. Randomisation will be stratified, by both
centre and type of hypertension, and blocked.
2.2 TRIAL INTERVENTIONS
2.2.1 RECRUITMENT AND RANDOMISATION
Each study site co-ordinator will:
i) identify women who are <34 weeks with non-severe nonproteinuric pre-existing or gestational hypertension;
ii) confirm their eligibility (Section 2.5);
iii) liaise with the maternity care provider to obtain his/her
support for the trial;
iv) obtain informed consent;
v) collect baseline data; and
vi) randomise women to one of the two trial groups (Figure 1).
Figure 1: CHIPS Trial design [dBP (diastolic BP)]
CHIPS Trial Protocol (Version 16 November 2011)
Page 6 of 30
2.2.2 ‘LESS TIGHT’
CONTROL GROUP
(FIGURE 2)
The dBP treatment goal is
100mmHg
For safety, if dBP is ≥
105mmHg, then
antihypertensive medication
must be started or increased in
dose.
For dBP <100mmHg,
antihypertensive therapy
should be decreased in dose or
stopped, as appropriate.
† If sBP ≥ 160 mmHg, increase dose of existing medication, or start antihypertensive
medication, to get sBP < 160 mmHg.
2.2.3 ‘TIGHT’ CONTROL
GROUP
(FIGURE 3)
The dBP treatment goal is
85mmHg.
For safety, if dBP is ≤
80mmHg, then
antihypertensive medication
must be decreased in dose or
discontinued.
If dBP is > 85mmHg, then
antihypertensive therapy
should be started or increased
in dose.
† If sBP ≥ 160 mmHg, increase dose of existing medication, or start antihypertensive
medication, to get sBP < 160 mmHg.
2.2.4 BOTH GROUPS
All BP targets are based on measurements made by a health professional, as CHIPS must be large and
international, and will be primarily an outpatient trial run through many obstetric and medical offices.
Korotkoff phase V (disappearance of sounds) should be used for diastolic BP. Korotkoff phase IV
(muffling) should be used for diastolic BP only if the Korotkoff sounds are audible as the level approaches
0mmHg.
Self-assessment of BP (at home or elsewhere) may be used. Many home BP monitors have not been
validated for use in pregnancy or for women with pre-eclampsia, which will develop in one third of
participants in CHIPS(26;173). Thus, changes in antihypertensive medication should not be made based on
home BP measurements alone. 24hr ambulatory BP monitoring will not be performed as it is impractical and
not widely available.
Most clinicians treat non-severe pregnancy hypertension with either labetalol or methyldopa; both are listed
among the drugs of first choice in national and international guidelines(88;174;175). When antihypertensive
therapy is required to reach the target dBP, clinicians will be asked to use labetalol in women who are not
already on antihypertensives. If there are reasons why labetalol would not be a good choice for a particular
woman (e.g., severe asthma), then methyldopa(89) should be prescribed, followed in preference by nifedipine
XL(88). The recommended starting doses (and daily maximums) of these antihypertensive agents are as
follows: labetalol 100-200 mg BID (max 1200mg/d), methyldopa 250-500mg BID (max 2g/d), nifedipine XL
20-30mg OD (max 120mg/d), and as additional therapy, hydralazine 10mg QID (max 200mg/d). Women
currently on an antihypertensive at enrolment may switch to labetalol, or if they prefer, continue on their usual
medication, but the following must not be used: ACE inhibitors and angiotensin receptor antagonists (which
are fetotoxic), direct renin inhibitors, and atenolol (which may impair intrauterine fetal growth)(88;176).
CHIPS Trial Protocol (Version 16 November 2011)
Page 7 of 30
A small patient-held (paper) diary, modelled on that used in the CHIPS Pilot, will be provided to centres
for local use. The diary will remind each woman and her caregivers about standardised method of BP
measurement and minimise contamination (Section 2.4.1).
There is no standard of care for many obstetric interventions and tests of fetal well-being. CHIPS is a
pragmatic trial, and the protocol will allow centres to provide their usual form of care. This may involve
differential monitoring which will reflect the way the treatments would be applied in normal clinical
practice(177). However, data will be collected on potential co-interventions (e.g., bedrest or hospitalisation)
and their impact on outcome examined by secondary analyses (Section 2.16).
2.3 ARRANGEMENTS FOR ALLOCATING PARTICIPANTS TO TRIAL GROUPS
Randomisation will be centrally controlled using the telephone computerised randomisation service at the Data
Co-ordinating Centre (DCC) [at the Centre for Mother, Infant, and Child Research (CMICR), University of
Toronto] that centres can access 24hr/day using a toll-free line. A back up pager system is maintained at all
times to ensure availability of trial staff to handle technical difficulties or questions regarding trial entry. If the
automated system fails, hand randomisation will be undertaken. Randomisation will be stratified by centre (to
prevent any imbalance between groups in aspects of maternal or neonatal care that may differ between centres)
and type of hypertension (in the event that treatment effects differ by type of hypertension). It would not be
feasible to conduct the Trial solely among women with either pre-existing or gestational hypertension because
of the sample sizes required.
2.4 METHODS FOR PROTECTING AGAINST SOURCES OF BIAS
Masking to the next allocated treatment will be achieved by central randomisation and random block sizes.
Outcomes have been defined to be as objective as possible. It is not possible to mask physicians or patients
to the interventions allocated or undertaken. However, for our primary outcome of pregnancy loss or ‘high
level’ neonatal care for >48hr, ascertainment will not be biased. There will be central adjudication of the
secondary maternal outcome by a committee of relevant experts, who are not involved in the care of women
or babies in the trial and who are masked to group allocation (Section 3.2).
Measurement of BP will be as accurate as possible in a large and pragmatic trial such as CHIPS. Clinical BP
measurements, at pre-specified intervals in pregnancy, will be an ‘other’ outcome and will be abstracted from
the diary or clinical records. These clinical measurements will be taken as part of usual care, and are the BP
values that clinicians are responding to in order to achieve the target dBP. 24hr ambulatory BP monitoring will
not be performed given its unavailability in all centres and the potential to be a barrier to recruitment given the
extra effort and minor discomfort involved. As noted above, self-assessment of BP may be used to monitor
dBP, but these measurements should be confirmed before changing antihypertensive therapy to achieve the
target dBP (Section 2.2.4).
2.4.1 CONTAMINATION
Women in the ‘less tight’ control group may have their BP normalised; valid reasons include the development
of indications for antihypertensive therapy among non-pregnant patients (e.g., renal failure). Women in the
‘tight’ control group may receive ‘less tight’ control, although most reasons for this (e.g., fetal compromise)
constitute indications for imminent delivery. Contamination will be minimised by: i) having each woman carry
a small diary that will have the target dBP clearly marked on it, and she will present the diary to her caregiver at
all outpatient (and if applicable, inpatient) visits; ii) having special study stickers, with the target dBP clearly
marked on them for the antenatal notes; and iii) providing women with routine contact with the study coordinator (at 14-20, 21-28, 29-33, 34-40 weeks, and at delivery) by telephone or at clinical visits, according to
local site logistics; these contacts will allow the co-ordinator to review ongoing compliance with the
intervention, and permit reminders (to women and clinicians) at the local level throughout the trial. If after
randomisation, women or clinicians change their minds about the allocated treatment, the reason(s) for this
will be documented.
2.4.2 CO-INTERVENTIONS
Clinicians and women will not be masked to allocated group. Women in the ‘less tight’ control group may have
more antenatal maternal surveillance. Women in the ‘tight’ control group may have more fetal surveillance if
fetal growth or monitoring are abnormal. Given that there is no standard of care for many obstetric
interventions and tests of fetal well-being, the protocol will allow centres to provide their usual ‘real-world’
care(178). However, a balance between groups in centre-related practices should be achieved by stratification
of randomisation by centre. Data will be collected on potential co-interventions such as: numbers/type of
outpatient antenatal visits, use of antepartum home care programmes, hospitalisation and/or bedrest, home BP
monitoring, and tests of fetal well-being (e.g., non-stress test).
CHIPS Trial Protocol (Version 16 November 2011)
Page 8 of 30
2.5 INCLUSION/EXCLUSION CRITERIA
The target population consists of women with non-severe, non-proteinuric pre-existing or gestational
hypertension who are at 14-33+6 weeks gestation. It is a historical view that pre-existing and gestational
hypertension are completely different entities. Increasingly, there is recognition of a shared underlying
pathophysiology (e.g., genetics, metabolic syndrome), and, despite differences in maternal age and
environment, there is a convergence of clinical hypertension and cardiovascular events over time(179-181).
Women who are (or have been) on antihypertensive medication may be included in the study as long as they
meet eligibility criteria, although their antihypertensive medication may be decreased in dose or stopped if they
are randomised to ‘less tight’ control of dBP.
2.5.1 INCLUSION CRITERIA
o Pre-existing or gestational hypertension: Pre-existing hypertension is dBP ≥ 90mmHg before pregnancy
or 20 weeks’ gestation. Gestational hypertension is dBP ≥ 90mmHg that develops after 20 weeks(182).
o dBP of 90-105mmHg if NOT TAKING antihypertensive therapy, or dBP of 85-105mmHg if
TAKING antihypertensive therapy: Eligibility will be based on BP measurements taken by a health care
professional (see Section 2.2.4). dBP must be in the eligible range twice, at least four hours apart, or on
two consecutive outpatient visits, with the second measurement being within one week of
randomisation. The conventional definition of hypertension (dBP of ≥ 90mmHg) will be used for
women not taking an antihypertensive. For women taking an antihypertensive(s), a dBP ≥ 85mmHg will
be accepted as indicating hypertension. These women are likely to be hypertensive in the conventional
sense when off medication. If women on antihypertensive therapy are randomised to ‘less tight’ control,
medication will be decreased/stopped if dBP is < 100mmHg.
o Live fetus: Confirmed within one week before randomisation.
o Gestational age 14-33+6 weeks: As measured by last menstrual period or dating ultrasound(183).
Enrolment from 14 weeks (and not earlier) will: minimise enrolment of women who will ultimately
miscarry and eliminate theoretical concerns about drug-induced birth defects, and facilitate recruitment
of women with pre-existing hypertension early in pregnancy when plans are made for BP management
throughout pregnancy. Most importantly, from a neonatal perspective, if one dBP goal is better for the
fetus than the other, then this is most likely to be seen with a longer duration of treatment in pregnancy.
2.5.2 EXCLUSION CRITERIA
o Severe systolic hypertension: defined as a sBP ≥160mmHg at randomisation(64;184).
o Proteinuria: defined as ≥ 0.3g/d by 24hr urine collection, or if a 24hr urine collection is not available, by
a urinary protein:creatinine ratio of ≥ 30 mg/mmol or urinary dipstick of ≥ 2+(185).
o Use of an ACE inhibitor at >14+0 weeks’ gestation.
o Contraindication to either arm of the trial or to pregnancy prolongation: Contraindications to ‘less tight’
control include renal disease. Contraindications to ‘tight’ control include acute stroke. Contraindications
do NOT include fetal compromise (e.g., intrauterine growth restriction, or oligohydramnios), as these
fetuses may benefit, in particular, from ‘less tight’ BP control. Women for whom delivery is anticipated
within one week should not be enrolled.
o Known multiple gestation
o Known lethal or major fetal anomaly
o Plan to terminate pregnancy
o Prior participation in the main CHIPS Trial
2.6 DURATION OF TREATMENT PERIOD
The treatment goal (i.e., ‘less tight’ vs. ‘tight’ control) will be applied from the time of randomisation until
delivery (maximum, 28 weeks). Postpartum, clinicians will choose their own BP goals.
2.7 FREQUENCY AND DURATION OF FOLLOW-UP
Babies will be followed until 28 days of life (or primary hospital discharge or 36 weeks corrected gestational
age), whichever is later. Women will be followed until 6 weeks after birth or pregnancy loss (or until primary
hospital discharge if later).
o Clinic or study visit within 4 weeks after randomisation: Women will have their dBP measured by their
clinician, and their antihypertensive medication (and any changes at that visit) will be recorded. This
information will be used to evaluate compliance in CHIPS.
CHIPS Trial Protocol (Version 16 November 2011)
Page 9 of 30
o Other antenatal contact with the site co-ordinator: This will occur at pre-specified times (i.e., 14-20, 21-28,
29-33, 34-40 weeks, and at delivery). Contact will be by clinic visits and/or telephone calls, depending on
local site logistics. In so doing, the site co-ordinator will maintain contact with women, encourage ongoing
compliance, and assess co-interventions (including treatments and monitoring), and disruption of home
and work life. Outcome data will be collected from the maternal and baby’s charts, during the woman’s
hospital stay for the birth, and the baby’s hospital stay.
o Follow-up at 6-12 weeks post-delivery (or loss) and for preterm babies, when the baby is at 36 weeks
corrected gestational age: Contact will be by telephone, clinic or home visit. A standardised questionnaire
will be used to inquire about satisfaction with care and any major maternal or neonatal morbidity after
hospital discharge until 6 weeks postpartum (for the mother) or 28 days of life or 36 weeks corrected
gestational age (for the baby).
2.8 PRIMARY AND SECONDARY OUTCOME MEASURES
2.8.1 PRIMARY: PREGNANCY LOSS OR ‘HIGH LEVEL’ NEONATAL CARE FOR > 48HR
Our primary outcome is a measure of ‘sick’ babies: pregnancy loss or ‘high level’ neonatal care for > 48hr.
The outcome is clear-cut and adjudication will not be necessary. For the few women enrolled with unknown
multiple gestations, the primary outcome will have occurred if one fetus/neonate achieves the outcome, as the
unit of analysis will be women (Section 2.16).
Pregnancy loss is defined as miscarriage, ectopic pregnancy, pregnancy termination, stillbirth, or neonatal
death (Table 2). Pregnancy loss is included because all fetuses and neonates must be eligible for the primary
outcome. We have included miscarriage
Table 2: Definitions to pregnancy loss
and pregnancy termination given
proposed enrolment from 14 weeks.
Pregnancy loss
Definition
Pregnancy termination may occur for
Miscarriage
Death of a fetus <500g or <20 weeks
Ectopic pregnancy
Pregnancy outside the uterine cavity
static fetal growth, but will most likely be
Pregnancy
termination
With reason specified, including statis fetal growth
for fetal anomalies, which we expect to be
Stillbirth
Death of a fetus ≥500g or ≥20 weeks
equally distributed between groups. Our
Neonatal death
Death of a newborn within the first 28 days of life
sample size calculation has accounted for
this (Section 2.11).
‘High level’ neonatal care for > 48hr will be recorded up to 28 days of life or until primary hospital
discharge (home) (whichever is later). Among our study population, ‘high level’ neonatal care is common,
biologically credible, practical, and measurable, with significant cost implications to the health care system(186).
In 2006, babies of hypertensive mothers comprised 14% of NICU admissions in Canada(187). ‘High level’
neonatal care captures neonates who are ‘sick’ through either prematurity, growth restriction or asphyxia, and the
outcome is potentially responsive to the intervention of ‘less tight’ control if it improves uteroplacental
perfusion, as hypothesized. ‘High level’ neonatal care is meaningful to mothers(188;189). ‘High level’ neonatal
care is relevant to preterm and term infants, with the majority of admissions among term infants(190). Parental
separation whilst babies are in ‘high level’ neonatal care is a major stressor to parents, even when the baby is not
seriously ill(191). As such, this would be an outcome that parents would wish to avoid. Avoidance of parental
separation is a long-standing concern of neonatologists(192;193). Finally, ‘high level’ neonatal care is costly
($1,180 to $1,702 per day(194)), even in the absence of morbidities without long-term consequences(195).
A duration of admission of > 48hr has been set to avoid including those babies who are admitted to ‘high
level’ neonatal care only briefly for observation or septic work-up. Excluding babies admitted for less than one
day is the practice of the Canadian Neonatal Network Database(196;197) and in 2006, only 1.4% of babies of
hypertensive mothers stayed in NICU for 24-48hr; 46.5% stayed for 2-10 days (with an equal distribution of
length of stay during this time period), 50% stayed for 11-59 days, and 5.4% stayed for ≥ 60 days(198).
Although criteria for admission to, and discharge from, ‘high level’ neonatal care will vary between
centres(199;200), randomisation will be stratified by centre to achieve a balance of these practices between
groups. Indications for ‘high level’ neonatal care will be documented as ‘other outcomes’ (Section 2.8.3). Criteria
for centre participation are based on the ability to immediately resuscitate babies and access ongoing, ‘high level’
neonatal care.
2.8.2 SECONDARY: ONE/MORE SERIOUS MATERNAL COMPLICATION(S)
Serious maternal complications, measured up to 6 weeks postpartum (or until primary maternal hospital
discharge, if later), are defined as death or one or more life-threatening maternal complications (as defined in
Table 3). Central adjudication by uninvolved individuals will be undertaken (Section 3.2).
CHIPS Trial Protocol (Version 16 November 2011)
Page 10 of 30
Table 3: Definitions of components of the secondary maternal outcome
Outcome
Stroke
Eclampsia
Blindness
Uncontrolled hypertension
Inotropic support
Pulmonary oedema
Respiratory failure
Myocardial ischemia or MI
Hepatic dysfunction
Hepatic haematoma or
rupture
Renal failure
Transfusion
Other
Definition
Acute neurological event with deficits lasting > 24hr, not due to a post-ictal state
Generalised convulsion in the absence of a history of epilepsy
Either retinal or cortical, defined as loss of visual acuity in the presence of intact pupillary
response to light
Need for a third parenteral antihypertensive agent
Use of vasopressors to keep sBP > 90mmHg or a MAP > 70 mmHg
Diagnosed clinically with one/more of oxygen saturation < 95%, diuretic treatment or x-ray
confirmation
Intubation, ventilation (either by ETT or non-invasively), or need for > 50% oxygen for > 1hr
which is not due to Caesarean section
By characteristic ECG changes and markers of myocardial necrosis
INR>1.2 in the absence of DIC or treatment with warfarin, OR, in the presence of DIC or
treatment with warfarin: either mixed hyperbilirubinaemia >17μM or hypoglycaemia
[<2.5mM] in the absence of insulin
Presence of a blood collection under the hepatic capsule as confirmed by imaging or at
laparotomy
Serum creatinine >200µM
Of any blood product
As detailed, with appropriate information from hospital records
DIC (disseminated intravascular coagulation), ETT (endotracheal tube), INR (international normalised ratio), MAP (mean arterial pressure),
MI (myocardial infarction), sBP (systolic BP)
2.8.3 OTHER OUTCOMES
OTHER PERINATAL (TABLE 4)
‘High level’ neonatal care
unit length of stay
Sex
Gestational age at delivery
(wk)
Birthweight (g)
Apgar score
Oxygen
Ventilatory support
Surfactant use
Severe respiratory distress
Respiratory distress
syndrome (RDS)
Bronchopulmonary
dysplasia
Central nervous system
morbidity
Intraventricular
haemorrhage
Cystic periventricular
leukomalacia
Retinopathy of prematurity
Hypoxic-ischemic
encephalopathy
Parenchymal
haemorrhage
Necrotising enterocolitis
‘Early-onset’ sepsis
Length of stay (hr)
Post-discharge morbidity
Definition
Hr and >7 days, including indication for admission
Male/female/uncertain
Wk, <37 and <34 weeks
<2500, <1250, <3rd and <10th centile for gestational age and sex(201;202)
5-min <7, 10-min <5 or <7
After initial resuscitation defined as first 10 minutes of life; duration of oxygen
After initial resuscitation, with/without intubation; duration of ventilation
Yes/no, # doses
Requiring assisted ventilation for ≥24hr beginning within the first 72hr of life
Assisted ventilation and supplemental oxygen within the 1 st 24hr of life, for ≥24hr AND either
X-ray compatible with RDS or surfactant given within the 1 st 24hr of life
For infants born at <32 wk, supplemental oxygen for a chronic pulmonary disorder at a
corrected gestational age of 36 wk
Either ventricular enlargement with/without a germinal matrix or intraventricular
haemorrhage, by cranial imaging/autopsy in the first 2 wk of life OR parenchymal
echodensities/lucencies in the white or gray matter on one/more brain imaging
studies/autopsy done after 21d of life(203)
Periventricular cystic changes in white matter, excluding sub-ependymal and choroid
plexus cysts, by cranial ultrasound, CT, MRI or at autopsy
Stage 4 or 5 in one/both eyes (intraretinal ridge with extraretinal fibrovascular proliferation,
or retinal detachment, respectively) by worst stage in the most severely affected eye at 4
wk
For infants born at ≥35 wk who have moderate-severe encephalopathy (clinical seizures or
≥3 of: lethargy, decreased spontaneous activity, distal flexion/full extension, focal/general
hypotonia, weak/absent suck or incomplete Moro primitive reflexes, and autonomic
system abnormalities {constricted/dilated/deviated/unresponsive pupils, bradycardia or
variable heart rate, or periodic breathing/apnea}) AND ≥2 of 10min Apgar <5, cord or
postnatal ABG pH <7.0 within 1hr of birth, cord or postnatal ABG base deficit >16mEq/L, or
need for any ventilation from birth for ≥10min(204)
Yes/no
Perforation of the intestine, pneumatosis intestinalis or air in the portal vein, diagnosed by
x-ray, surgery, or autopsy(205)
Within first 48hr of life, confirmed by positive blood or cerebrospinal fluid cultures
Hr
If discharged before 28d of life.
CHIPS Trial Protocol (Version 16 November 2011)
Page 11 of 30
OTHER MATERNAL (TABLE 5)
Each component of
secondary outcome
Pre-labour dBP at specified
time points
Definition
For list and definitions, see Table 3. Includes post-discharge morbidity up to 6wk
postpartum
Within 4wk post-randomisation and as applicable, at 14-20, 21-28, 29-33, 34-40 wk, and at
delivery
Methods for dBP
measurement at
compliance visit
Mercury, aneroid, automated
Oral antihypertensive
therapy before delivery
Yes/no and type
Severe hypertension
sBP ≥ 160mmHg or dBP≥110mmHg
Yes/no according to ≥ 2+ by urinary dipstick, ≥ 30mg/mmol urinary creatinine by spot
testing, elevated urinary albumin:creatinine ratio according to local criteria, or ≥ 0.3 g/d
by 24hr urine collection
Symptoms of pre-eclampsia Headache, visual disturbances, persistent right upper quadrant or epigastric pain, severe
nausea or vomiting, chest pain, dyspnoea
Signs of pre-eclampsia
In addition to severe hypertension: eclampsia, placental abruption, or pulmonary
edema(64)
Elevated aspartate or alanine aminotransferase or lactate dehydrogenase with
Abnormal maternal
symptoms, or platelet <100,000x109/L
laboratory testing
Caesarean section, sponatenous vaginal, operative vaginal
Mode of delivery
Proteinuria
Days in hospital after
delivery
Corticosteroids
Yes/no, antenatal/postnatal
WOMEN’S VIEWS
Using a structured postpartum questionnaire modelled on that used in the CHIPS Pilot, satisfaction (i.e.,
willingness to have the same treatment again in a subsequent pregnancy or recommend the same treatment to a
friend).
HEALTH-CARE COSTS
The planned analysis will take a ministry of health perspective to determine if ‘less tight’ vs. ‘tight’ control of dBP
increases or decreases health-care costs, as discussed in Section 2.10.1
2.9 HOW OUTCOMES WILL BE MEASURED AT FOLLOW-UP
Data for the primary (fetal/neonatal) and secondary (maternal) outcomes will be obtained by reviewing the
maternal and infant medical records immediately following the birth (or pregnancy loss), and then again after the
mother’s and infant’s(s’) discharge home. Supplemental information, about potential post-discharge maternal or
neonatal morbidities in the 6 weeks following birth for the mother, or 28 days of life for the baby (or 36 weeks
corrected gestational age), will be obtained by contacting women at 6-12 weeks postpartum and/or from medical
records. Contact will be by telephone, home or clinic visit, as appropriate for the centres; a structured
questionnaire will be used to collect the necessary information.
At the time of the study contacts, the local site co-ordinator will abstract the post-randomisation clinical
dBP measurements from the patient-held diary that will contain dBP measurements from all obstetric care
providers. If the diary is lost, dBP measurements will be abstracted from the structured antenatal sheets that
are relatively standardised, based on our experience with international RCTs.
2.10 HEALTH SERVICES ISSUES
2.10.1 ECONOMIC EVALUATION
The economic hypothesis for the study is that a policy of ‘less tight’ control of maternal BP will result in a
lower incidence of pregnancy loss or ‘high level’ neonatal care for > 48hr (without an increase in maternal
risk), and therefore, lower health care costs (i.e., a win-win situation). A Ministry of Health perspective will be
taken(206). Resources used and their unit prices will be determined. Data will be collected on resources
consumed following randomisation and up to 28d of age (or primary hospital discharge if later) for the baby,
and 6 weeks following delivery (or primary hospital discharge if later) for the mother. Information will come
CHIPS Trial Protocol (Version 16 November 2011)
Page 12 of 30
from the clinical case report forms. Estimates of unit costs for the mother will be obtained directly from 6
participating hospitals in Canada (three teaching and three community hospitals). Costs considered will include:
antihypertensive/other medication; professional fees for outpatient visits; admissions to hospital; obstetric
care; tests of maternal or fetal well-being; and neonatal care. Local experts will be interviewed to assist with
identification of appropriate fees for each service or treatment.
2.10.2 OTHER HEALTH SERVICES RESEARCH ISSUES
Women’s satisfaction with the intervention and Trial participation will be evaluated (see Section 2.8.3).
2.11 SAMPLE SIZE:
514 women/group (1,028 women total)
We estimate that the rate of pregnancy loss or ‘high level’ neonatal care for > 48hr will be 33%.
o We anticipate that 3% of Trial participants will have a miscarriage, ectopic pregnancy, or elective
termination. Based on the CHIPS Pilot Trial, 50% of Trial participants will have pre-existing hypertension,
and two-thirds of them may be recruited at 14-20 weeks. Among these women, we anticipate rates of 1%
for elective termination and 4% for miscarriage and ectopic pregnancy, giving a figure of 2/3 x5%=3%
overall for miscarriage or elective termination(26).
o We anticipate that 0.4% of Trial participants will have a perinatal loss (stillbirth or neonatal death), based on
data from trials published since 1992(105;207;208) (including the CHIPS Pilot(209)) when there was
widespread use of antenatal corticosteroids.
o We anticipate that 30% of babies will be admitted to ‘high level’ neonatal care for > 48hr. This is based on:
i) a rate of 31.8% [95% CI 26.5, 37.7] for ‘high level’ neonatal care among trials published since
1992(105;210-212); ii) in the CHIPS Pilot Trial (the only trial for which this information is available), 23
infants were admitted to ‘high level’ neonatal care, and of these babies, 95.8% stayed for more than one day;
and iii) in the Canadian Neonatal Network database for 2006, 98.6% of babies of hypertensive mothers
stayed for > 48hr(213).
We have based our sample size on a clinically important reduction in pregnancy loss or ‘high level’
neonatal care for > 48hr from 33% to 25%. When surveyed (Aug ’07), 100% (95% CI of 90% to 100%) of
potential site investigator respondents endorsed this decrease as one that would change their clinical practice.
The final sample size of 514/group was based on a two-tailed alpha of 0.05, power of 80%, rates of the
primary outcome of 33% in the ‘tight’ control group and 25% in the ‘less tight’ control group (after a crossover
of 10% of patients to the alternate treatment), and two interim analyses (after 1/3 and 2/3 of patients have
been evaluated for the primary outcome). The sample size was inflated by 1% to account for loss to follow-up.
The sample size was calculated by chi-square using the EAST software and the Lan DeMets spending function
with O'Brien-Fleming type boundaries. Note that the use of logistic regression for the primary outcome
(Section 2.16) increases the statistical power of the analysis(214).
This sample size will give us 78% power (alpha of 0.05, two-sided) to find an increase of 5% in adverse
maternal outcome in the ‘less tight’ control group. This is based on a risk of serious maternal complications of
7% in the ‘tight’ control group, based on inclusion of additional maternal outcomes from the PIERS (Preeclampsia Integrated Estimate of Risk Study) project.
2.12 RECRUITMENT
The CHIPS Pilot Trial confirmed the feasibility of the CHIPS Trial. In our survey of Canadian obstetricians,
almost all respondents indicated willingness to enrol eligible women in a RCT such as CHIPS(89).
We are interested in women with pre-existing (1%) or gestational hypertension with onset at <34 weeks (23%) at 14-33 weeks’ gestation, with prevalence figures cited from population-based literature. Guidelines do
not mandate that BP must be repeatedly elevated, despite the fact that transient elevations of BP in pregnancy
are well-described. However, to be eligible for CHIPS (as in the CHIPS Pilot Trial), a woman must have
persistent hypertension (i.e., dBP ≥90mmHg, twice, at least four hours apart, or on two consecutive outpatient
visits, with the second measurement being within one week of randomisation; see Section 2.5.1). Of course,
persistent hypertension will be less common than transient hypertension. We believe that such selection of
truly hypertensive pregnant women is appropriate, given inaccuracies of BP measurement, and uncertainty
about the relative benefits and harms of antihypertensive therapy in pregnancy.
There is a tendency to overestimate recruitment rates(215). We have based our estimated recruitment rate
on figures from the CHIPS Pilot, although we expect that recruitment rates will be higher in CHIPS given the
measures we have taken to decrease observed barriers to recruitment. In the Pilot, eligible and consenting
women made up 0.16% of all deliveries. In a centre with 4,000 deliveries per year, 6 women will be enrolled
per year. Based on the EECV2 Trial, we anticipate that 25 centres will join annually. Thus, to complete
CHIPS Trial Protocol (Version 16 November 2011)
Page 13 of 30
enrolment in 4 years, 50 centres will be required. Presently, the CMICR has co-ordinated and is co-ordinating
similar large, international RCTs. Recruitment strategies will vary depending on site logistics. In general,
women will be informed about the study at prenatal visits (with obstetricians, obstetric internists, family
physicians or midwives) or at admission to hospital (if delivery is not imminent; women in labour are not
eligible).
2.13 COMPLIANCE
In the CHIPS Pilot, clinician compliance was assessed by a masked adjudication committee that reviewed
clinician response to dBP measurements, as recorded in the patient-held diary. Clinician compliance with the
interventions was good throughout the trial (79% in both groups). Cross-over was 10% for each arm. It was
unclear which type of BP control the others received, although most would have been appropriate for either
arm of the Trial. The CHIPS Pilot showed that such a compliance assessment is not feasible for a large trial
because it was slow, onerous for those involved, and did not permit contemporaneous feedback at a local level.
For CHIPS, compliance will be determined by assessing dBP and antihypertensive dosage within 4 weeks
after randomisation. At this early time point, dBP should not reflect disease progression (primarily
development of superimposed pre-eclampsia), and so clinician actions and patient compliance should be
reflected in measured dBP. Later in the Trial, dBP will also reflect disease progression. BP will be taken by the
woman’s clinician in an unmasked fashion, in the standardised fashion, three times, with the average of the
second and third measurements taken as the dBP for that visit(216).
Protocol compliance will be promoted by each site co-ordinator, who will review the patient diary (as done
centrally for all women in the CHIPS Pilot) at the planned contacts at 14-20, 21-28, 29-33, 34-40 weeks, and at
delivery. Compliance will be checked quarterly for the trial overall, and by centre. If poor protocol compliance
is noted generally within a centre, we will work with the centre to identify and resolve the reasons for poor
compliance.
2.14 LIKELY RATE OF LOSS TO FOLLOW-UP: 1 %
In the CHIPS Pilot, in which women were enrolled from 20-33+6 weeks, our loss to follow-up was 0.8%
(1/132 women). CMICR has a history of very low rates of loss to follow-up. In the Term Breech Trial, 2,088
women were recruited from 121 centres world-wide, and only five women (0.2%) were lost to follow-up for
the primary outcomes. The possibility of drop-out is higher in CHIPS compared with the Term Breech Trial,
in that women may be recruited earlier in pregnancy. However, we shall minimise loss to follow-up by having
the site study co-ordinator establish a close relationship with the study participants. The co-ordinator will keep
in regular contact with the women and their maternity care providers (Section 2.7), and be available to answer
any questions about the Trial. This will facilitate ascertainment of neonatal outcomes (up to 28 days of life,
primary hospital discharge, or 36 weeks corrected gestational age) and maternal outcomes (up to 6 weeks
postpartum or until primary hospital discharge). Therefore, in the main CHIPS Trial, we will recruit from 1433+6 weeks, and estimate a loss to follow-up rate of 1% for the primary outcome (i.e., 20 women).
2.15 CENTRES INVOLVED: 50 centres for 4 years
Potential sites participated in the CHIPS Pilot Trial, previously expressed interest in CHIPS, and/or are active
participants in ongoing international, clinical trials co-ordinated through CMICR. To date, 60 centres have
provided letters of support. These centres are located in Canada, Argentina, Australia, Brazil, Chile, France,
Israel, Jordan, Malayasia, New Zealand, South Africa, The Netherlands, UK, and USA.
International collaboration (developed, academic developing world) is required for timely completion of
the Trial. For approval by the Working Group (Section 3.1), all interested centres must complete a survey
about aspects of their maternal and neonatal care necessary to operationalise the protocol and measure the
primary (fetal/neonatal) and secondary (maternal) outcomes for all eligible patients. The Trial Team has
extensive experience in conduct of multicentre RCTs, including international research ethics board
applications, regulations, and indemnification, through co-ordination of trials such as MACS, MACS5, Early
ECV2, and Twin Birth Study.
2.16 ANALYSES
An intention-to-treat approach will be taken: that is, for the purpose of analysis, all women will be included in
the group to which they have been randomised. If women are lost to follow-up, they will be included in their
randomised group for all outcomes for which we have information. Descriptive statistics will be calculated to
check for major dissimilarities between study groups with respect to baseline information.
The unit of analysis will be women. For the few enrolled women who are found to have multiple
pregnancies that were unidentified at enrolment, an outcome for the pregnancy will have occurred if any fetus
CHIPS Trial Protocol (Version 16 November 2011)
Page 14 of 30
suffers the outcome. Outcomes among infants in a multiple pregnancy are correlated, and from the patient
perspective, taking home a child with a significant physical or developmental impairment is an outcome that
affects the family unit, and not just the child involved. The denominator for ‘high level’ neonatal care
admission and length of stay, and neonatal morbidities will be live births. The analysis will be adjusted for any
imbalance in multiples between groups.
The primary outcome (of pregnancy loss or ‘high level’ neonatal care for > 48hr) will be analysed by
logistic regression, adjusted for stratification factors (centre, type of hypertension), multiple pregnancies (that
were not known at randomisation), use of antihypertensive therapy at randomisation, previous severe
hypertension in this pregnancy, and gestational diabetes. Alpha will be set at 0.046, based on Lan DeMets
spending function with O'BrienTable 4: Analyses
Fleming type boundaries. Table 4
Analysis Number
% of patients
N women Z value P value
displays the proportion of the overall
1 (Interim, first)
33.3%
338
3.71
0.00021
target number of patients included in
2 (Interim, second)
66.7%
677
2.51
0.01203
the analyses at each point, test statistic,
3 (Final)
100%
1,015
1.99
0.046
and p-value used to assess significance
at each analysis.
For all dichotomous outcomes, logistic regression will be used to compare odds between groups,
controlling for any difference between groups on a pre-randomisation factor known or suspected to be a risk
factor for the primary or one of the secondary outcomes [e.g., type of underlying hypertension, type and
duration of pre-randomisation antihypertensive therapy, recruiting centre]. For dichotomous outcomes, the
adjusted OR [95% CI], and number needed to treat (NNT) to avoid one adverse outcome, will be calculated to
determine the magnitude of the treatment effect. Significant p-values will be <0.01 (two-tailed) for the
secondary and <0.001 (two-tailed) for 'other' outcomes (given the number of comparisons and to avoid overinterpretation of statistically significant findings). The NNTs will be based on the adjusted risk differences
using methods proposed by Thompson, Warn & Turner(217). As secondary analyses for primary and
secondary outcomes, for the purposes of hypothesis generation, we will perform a compliance-adjusted
analysis, and an analysis adjusted for any between-group differences in co-interventions (Section 2.13).
Clinical mean dBP will be compared between groups by a repeated measures analysis. It is anticipated that
women will be enrolled in the Trial and deliver at different time points, such that BP values will not be
available for all of the pre-specified intervals (i.e., 14-20, 21-28, 29-33, 34-40 weeks, and at delivery). As for the
CHIPS Pilot(218), the analysis will account for any such imbalance in the repeated measurements of BP. A
general linear model will be used with a random effect for patient, and fixed effects for treatment group and
time point, fitted using Markov chain Monte Carlo methods facilitated by the software WinBUGS using vague
prior distributions(219). P <0.01 will indicate statistical significance to avoid over-interpretation of findings.
2.17 FREQUENCY OF ANALYSES
Two interim analyses are planned after enrolment of (and complete data collection for) 1/3 (~338) and 2/3
(~677) of the women. P values of <0.0002 and <0.0120, two-tailed, will be used as guidelines by the Data
Safety Monitoring Board (DSMB) at CMICR for considering the early termination of the Trial at the first and
second interim analyses, respectively (Section 2.16). If a superior strategy is identified at the second interim
analysis, the study may be terminated, and women may be switched to the superior strategy.
2.18 PLANNED SUBGROUP ANALYSES
Interaction(s) between treatment effects (e.g., SGA infants) and prognostic factors (e.g., previous preeclampsia) or antihypertensive drug will be examined. Rates of the primary and secondary outcomes will be
examined by type of hypertension, and for high vs. low perinatal mortality settings. These analyses will be lowpowered and considered exploratory.
CHIPS Trial Protocol (Version 16 November 2011)
Page 15 of 30
2.19 TIMELINE FOR THE STUDY: Each year starts in April (Apr/2008 until Mar/2014 = 6 years)
Activity
Develop a manual of
operations
for DCC & participating centres
Develop & pre-test data forms
and distribute to centres
Organise Trial in participating
centres (including REB
approval)
Program randomisation service
Develop database
Recruitment in all centres
Data collection & management
for primary outcome
Data collection & management
for follow-up
Analyses
2008-9
2009-10
2010-11
2011-12
2012-13
Interim
Interim
2013-14
Final & Economic
DCC (Data Co-ordinating Centre), REB (research ethics board)
3. DETAILS OF THE TRIAL TEAM
3.1 ARRANGEMENTS FOR DAY-TO-DAY MANAGEMENT OF THE TRIAL
Randomisation will be centrally controlled using the telephone computerised randomisation service (at the
DCC at the CMICR, Toronto) that centres can access 24hr/day using a toll-free line. A back up pager system
is maintained at all times to ensure availability of trial staff to handle technical difficulties or questions
regarding trial entry. If the automated system fails, hand randomisation will be undertaken.
Clinical trial co-ordination (Vancouver) will be managed on a day to day basis at the Maternal-Fetal
Medicine Division, Department of Obstetrics & Gynaecology, UBC by a small Working Group that will
include Magee, the CMICR Research Manager, and the CHIPS research staff (trial co-ordinator and research
assistant). This group will meet weekly by telephone link.
Data management (Toronto) will be co-ordinated by the CMICR in close collaboration with Magee (by
telephone link). Baseline data will be transmitted to the DCC during the randomisation telephone call.
Outcome and other descriptive data will be collected on paper forms and originals mailed to the DCC with
copies kept locally. Data will be scanned into a ‘TELEForm’ data management system. This approach has
proven to be reliable in previous multicentre RCTs, and will enable CHIPS to be conducted in a variety of
settings in which pregnancy hypertension is a major problem, but ready internet access is not available. Logic
and range checks will verify the accuracy of the data. Data forms with errors or missing data will be returned to
the clinical centres for correction and/or completion.
Dr. Laura Magee is the Principal Investigator and will be responsible for distribution of funds, progress and
timely completion of the trial, liaison with participating centres, administration of the study, and answering
questions about management of pregnancy hypertension. Dr. Elizabeth Asztalos (Director, CMICR) will be
responsible for the work of the Data Co-ordinating Centre.
3.2 THE STEERING, ADJUDICATION, AND DATA SAFETY & MONITORING COMMITTEES
The Steering Committee includes all co-investigators, the CMICR Research Manager, a CIHR representative,
and the CHIPS research staff. The Committee will be responsible for the conduct of the study and will meet
every two to three months.
A Maternal Adjudication Committee of hypertension experts, who are masked to group allocation and
uninvolved in the care of women in the trial, will review the recorded serious maternal complications, to
confirm inclusion in the secondary maternal outcome.
The CMICR has a Data Safety Monitoring Board (DSMB) that will be called upon to monitor compliance
and cross-over, and review any unexpected adverse events. The DSMB will meet as required, by
teleconference, to review the results of the interim analyses and any unexpected adverse events. The DSMB
has the right to review any variables that may have an impact on the trial. The trial has an ISRCTN (71416914)
and will be conducted according to Good Clinical Practice Guidelines, and be reported in accordance with the
CONSORT statement.
CHIPS Trial Protocol (Version 16 November 2011)
Page 16 of 30
Reference List
(1) Allen VM. The effect of hypertensive disorders in pregnancy on perinatal outcomes: a populationbased cohort study. Ottawa: National Library of Canada, 2002.
(2) Lindberg BS. Epidemiology of hypertension during pregnancy. Int J Technol Assess Health Care
1992; 8 Suppl 1:57-62.
(3) Saftlas AF, Olson DR, Franks AL, Atrash HK, Pokras R. Epidemiology of preeclampsia and
eclampsia in the United States, 1979- 1986. Am J Obstet Gynecol 1990; 163(2):460-465.
(4) Helewa ME, Burrows RF, Smith J, Williams K, Brain P, Rabkin SW. Report of the Canadian
Hypertension Society Consensus Conference: 1. Definitions, evaluation and classification of
hypertensive disorders in pregnancy. CMAJ 1997; 157(6):715-725.
(5) Helewa ME, Burrows RF, Smith J, Williams K, Brain P, Rabkin SW. Report of the Canadian
Hypertension Society Consensus Conference: 1. Definitions, evaluation and classification of
hypertensive disorders in pregnancy. CMAJ 1997; 157(6):715-725.
(6) Misra DP. The effect of the pregnancy-induced hypertension on fetal growth: a review of the
literature. Paediatr Perinat Epidemiol 1996; 10(3):244-263.
(7) Ferrazzani S, Caruso A, De Carolis S, Martino IV, Mancuso S. Proteinuria and outcome of 444
pregnancies complicated by hypertension. Am J Obstet Gynecol 1990; 162(2):366-371.
(8) Mabie WC, Pernoll ML, Biswas MK. Chronic hypertension in pregnancy. Obstet Gynecol 1986;
67(2):197-205.
(9) Rey E, Couturier A. The prognosis of pregnancy in women with chronic hypertension. Am J Obstet
Gynecol 1994; 171(2):410-416.
(10) Sibai BM, Abdella TN, Anderson GD. Pregnancy outcome in 211 patients with mild chronic
hypertension. Obstet Gynecol 1983; 61(5):571-576.
(11) Magee LA, von Dadelszen P, Chan S, Gafni A, Gruslin A, Helewa M et al. The Control of
Hypertension In Pregnancy Study pilot trial. BJOG 2007; 114(6):770, e13-770, e20.
(12) Magee LA, von Dadelszen P, Bohun CM, Rey E, El Zibdeh M, Stalker S et al. Serious perinatal
complications of non-proteinuric hypertension: an international, multicentre, retrospective cohort
study. J Obstet Gynaecol Can 2003; 25(5):372-382.
(13) Wingert A. Canadian Neonatal Network admissions for babies of hypertensive mothers. Personal
communication July 31, 2007.
(14) Barton JR, O'Brien JM, Bergauer NK, Jacques DL, Sibai BM. Mild gestational hypertension remote
from term: progression and outcome. Am J Obstet Gynecol 2001; 184(5):979-983.
(15) Brown MA, Buddle ML. The importance of nonproteinuric hypertension in pregnancy. Hypertens
Pregn 2002; 14:57-65.
(16) Ferrazzani S, Caruso A, De Carolis S, Martino IV, Mancuso S. Proteinuria and outcome of 444
pregnancies complicated by hypertension. Am J Obstet Gynecol 1990; 162(2):366-371.
CHIPS Trial Protocol (Version 16 November 2011)
Page 17 of 30
(17) Horsager R, Adams M, Richey S, Leveno KJ, Cunningham FG. Outpatient management of mild
pregnancy induced hypertension. 15th Annual Meeting of The Society of Perinatal Obstetricians,
Atlanta, Georgia 1995.
(18) Mabie WC, Pernoll ML, Biswas MK. Chronic hypertension in pregnancy. Obstet Gynecol 1986;
67(2):197-205.
(19) Rey E, Couturier A. The prognosis of pregnancy in women with chronic hypertension. Am J Obstet
Gynecol 1994; 171(2):410-416.
(20) Saudan P, Brown MA, Buddle ML, Jones M. Does gestational hypertension become pre-eclampsia?
Br J Obstet Gynaecol 1998; 105(11):1177-1184.
(21) Scott A, Moar V, Ounsted M. The relative contributions of different maternal factors in small-forgestational-age pregnancies. Eur J Obstet Gynecol Reprod Biol 1981; 12(3):157-165.
(22) Sibai BM, Abdella TN, Anderson GD. Pregnancy outcome in 211 patients with mild chronic
hypertension. Obstet Gynecol 1983; 61(5):571-576.
(23) Barton JR, O'Brien JM, Bergauer NK, Jacques DL, Sibai BM. Mild gestational hypertension remote
from term: progression and outcome. Am J Obstet Gynecol 2001; 184(5):979-983.
(24) Ferrazzani S, Caruso A, De Carolis S, Martino IV, Mancuso S. Proteinuria and outcome of 444
pregnancies complicated by hypertension. Am J Obstet Gynecol 1990; 162(2):366-371.
(25) Mabie WC, Pernoll ML, Biswas MK. Chronic hypertension in pregnancy. Obstet Gynecol 1986;
67(2):197-205.
(26) Magee LA, von Dadelszen P, Chan S, Gafni A, Gruslin A, Helewa ME et al. The CHIPS Pilot Trial
(Control of Hypertension In Pregnancy Study). JOGC 2006; 28(5):416.
(27) Magee LA, von Dadelszen P, Bohun CM, Rey E, El Zibdeh M, Stalker S et al. Serious perinatal
complications of non-proteinuric hypertension: an international, multicentre, retrospective cohort
study. J Obstet Gynaecol Can 2003; 25(5):372-382.
(28) Rey E, Couturier A. The prognosis of pregnancy in women with chronic hypertension. Am J Obstet
Gynecol 1994; 171(2):410-416.
(29) Saudan P, Brown MA, Buddle ML, Jones M. Does gestational hypertension become pre-eclampsia?
Br J Obstet Gynaecol 1998; 105(11):1177-1184.
(30) Sibai BM, Abdella TN, Anderson GD. Pregnancy outcome in 211 patients with mild chronic
hypertension. Obstet Gynecol 1983; 61(5):571-576.
(31) Report of the National High Blood Pressure Education Program Working Group on High Blood
Pressure in Pregnancy. Am J Obstet Gynecol 2000; 183(1):S1-S22.
(32) Ferrazzani S, De Carolis S, Pomini F, Testa AC, Mastromarino C, Caruso A. The duration of
hypertension in the puerperium of preeclamptic women: relationship with renal impairment and
week of delivery. Am J Obstet Gynecol 1994; 171(2):506-512.
(33) Mabie WC, Pernoll ML, Biswas MK. Chronic hypertension in pregnancy. Obstet Gynecol 1986;
67(2):197-205.
CHIPS Trial Protocol (Version 16 November 2011)
Page 18 of 30
(34) Rey E, Couturier A. The prognosis of pregnancy in women with chronic hypertension. Am J Obstet
Gynecol 1994; 171(2):410-416.
(35) Sibai BM, Abdella TN, Anderson GD. Pregnancy outcome in 211 patients with mild chronic
hypertension. Obstet Gynecol 1983; 61(5):571-576.
(36) Sibai BM, Anderson GD. Pregnancy outcome of intensive therapy in severe hypertension in first
trimester. Obstet Gynecol 1986; 67(4):517-522.
(37) Sibai BM, Lindheimer MD, Hauth J, et al for the National Institute of Child Health and Human
Development Network of Maternal-Fetal Medicine Units. Risk factors for preeclampsia, abruptio
placentae, and adverse neonatal outcomes. N Engl J Med 1998; 339:667-671.
(38) Zetterstrom K, Lindeberg SN, Haglund B, Hanson U. Maternal complications in women with
chronic hypertension: a population-based cohort study. Acta Obstet Gynecol Scand 2005; 84(5):419424.
(39) Ghosh B, Mittal S, Kumar S, Dadhwal V. Prediction of perinatal asphyxia with nucleated red blood
cells in cord blood of newborns. Int J Gynaecol Obstet 2003; 81(3):267-271.
(40) Ananth CV, Getahun D, Peltier MR, Smulian JC. Placental abruption in term and preterm gestations:
evidence for heterogeneity in clinical pathways. Obstet Gynecol 2006; 107(4):785-792.
(41) Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O'Sullivan F, Burton PR et al. Antepartum risk
factors for newborn encephalopathy: the Western Australian case-control study. BMJ 1998;
317(7172):1549-1553.
(42) Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A. Morbidity and mortality among verylow-birth-weight neonates with intrauterine growth restriction. The Vermont Oxford Network. Am J
Obstet Gynecol 2000; 182(1 Pt 1):198-206.
(43) Kramer MS, Olivier M, McLean FH, Willis DM, Usher RH. Impact of intrauterine growth
retardation and body proportionality on fetal and neonatal outcome. Pediatrics 1990; 86(5):707-713.
(44) McIntire DD, Bloom SL, Casey BM, Leveno KJ. Birth weight in relation to morbidity and mortality
among newborn infants. N Engl J Med 1999; 340(16):1234-1238.
(45) Stanley CA, Baker L. The causes of neonatal hypoglycemia. N Engl J Med 1999; 340(15):1200-1201.
(46) Tyson JE, Kennedy K, Broyles S, Rosenfeld CR. The small for gestational age infant: accelerated or
delayed pulmonary maturation? Increased or decreased survival? Pediatrics 1995; 95(4):534-538.
(47) Hack M, Klein NK, Taylor HG. Long-term developmental outcomes of low birth weight infants.
Future Child 1995; 5(1):176-196.
(48) Kok JH, den Ouden AL, Verloove-Vanhorick SP, Brand R. Outcome of very preterm small for
gestational age infants: the first nine years of life. Br J Obstet Gynaecol 1998; 105(2):162-168.
(49) Naeye RL, Peters EC. Antenatal hypoxia and low IQ values. Am J Dis Child 1987; 141(1):50-54.
(50) Nelson KB, Ellenberg JH. Antecedents of cerebral palsy. Multivariate analysis of risk. N Engl J Med
1986; 315(2):81-86.
CHIPS Trial Protocol (Version 16 November 2011)
Page 19 of 30
(51) Richards M, Hardy R, Kuh D, Wadsworth ME. Birth weight and cognitive function in the British
1946 birth cohort: longitudinal population based study. BMJ 2001; 322(7280):199-203.
(52) Spinillo A, Capuzzo E, Egbe TO, Fazzi E, Colonna L, Nicola S. Pregnancies complicated by
idiopathic intrauterine growth retardation. Severity of growth failure, neonatal morbidity and twoyear infant neurodevelopmental outcome. J Reprod Med 1995; 40(3):209-215.
(53) Strauss RS. Adult functional outcome of those born small for gestational age: twenty-six-year followup of the 1970 British Birth Cohort. JAMA 2000; 283(5):625-632.
(54) Barker DJ. The long-term outcome of retarded fetal growth. Clin Obstet Gynecol 1997; 40(4):853863.
(55) Eriksson JG, Forsen T, Tuomilehto J, Winter PD, Osmond C, Barker DJ. Catch-up growth in
childhood and death from coronary heart disease: longitudinal study. BMJ 1999; 318(7181):427-431.
(56) Forsen T, Eriksson JG, Tuomilehto J, Osmond C, Barker DJ. Growth in utero and during childhood
among women who develop coronary heart disease: longitudinal study. BMJ 1999; 319(7222):14031407.
(57) Hales CN. Non-insulin-dependent diabetes mellitus. Br Med Bull 1997; 53(1):109-122.
(58) Law CM, de Swiet M, Osmond C, Fayers PM, Barker DJ, Cruddas AM et al. Initiation of
hypertension in utero and its amplification throughout life. BMJ 1993; 306(6869):24-27.
(59) Leon DA, Lithell HO, Vagero D, Koupilova I, Mohsen R, Berglund L et al. Reduced fetal growth
rate and increased risk of death from ischaemic heart disease: cohort study of 15 000 Swedish men
and women born 1915- 29. BMJ 1998; 317(7153):241-245.
(60) Nimrod CA, Gruslin A. Biology of normal and deviant fetal growth. In: Reece EA H, editor.
Philadelphia: Lippincott-Raven Publishers, 1999: 267-278.
(61) Osmond C, Barker DJ, Winter PD, Fall CH, Simmonds SJ. Early growth and death from
cardiovascular disease in women. BMJ 1993; 307(6918):1519-1524.
(62) Rich-Edwards JW, Stampfer MJ, Manson JE, Rosner B, Hankinson SE, Colditz GA et al. Birth
weight and risk of cardiovascular disease in a cohort of women followed up since 1976. BMJ 1997;
315(7105):396-400.
(63) Ingelfinger JR. Prematurity and the legacy of intrauterine stress. N Engl J Med 2007; 356(20):20932095.
(64) Magee LA, Helewa M, Rey E, Cote AM, Douglas J, Gibson P et al. Clinical Practice Guideline:
Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. JOGC 2007; In
press.
(65) Barton JR, O'Brien JM, Bergauer NK, Jacques DL, Sibai BM. Mild gestational hypertension remote
from term: progression and outcome. Am J Obstet Gynecol 2001; 184(5):979-983.
(66) Ferrazzani S, Caruso A, De Carolis S, Martino IV, Mancuso S. Proteinuria and outcome of 444
pregnancies complicated by hypertension. Am J Obstet Gynecol 1990; 162(2):366-371.
CHIPS Trial Protocol (Version 16 November 2011)
Page 20 of 30
(67) Mabie WC, Pernoll ML, Biswas MK. Chronic hypertension in pregnancy. Obstet Gynecol 1986;
67(2):197-205.
(68) Magee LA, von Dadelszen P, Bohun CM, Rey E, El Zibdeh M, Stalker S et al. Serious perinatal
complications of non-proteinuric hypertension: an international, multicentre, retrospective cohort
study. J Obstet Gynaecol Can 2003; 25(5):372-382.
(69) Rey E, Couturier A. The prognosis of pregnancy in women with chronic hypertension. Am J Obstet
Gynecol 1994; 171(2):410-416.
(70) Saudan P, Brown MA, Buddle ML, Jones M. Does gestational hypertension become pre-eclampsia?
Br J Obstet Gynaecol 1998; 105(11):1177-1184.
(71) Sibai BM, Abdella TN, Anderson GD. Pregnancy outcome in 211 patients with mild chronic
hypertension. Obstet Gynecol 1983; 61(5):571-576.
(72) von Dadelszen P, Magee LA, Lee SK, Stewart SD, Simone C, Koren G et al. Activated protein C in
normal human pregnancy and pregnancies complicated by severe preeclampsia: a therapeutic
opportunity? Crit Care Med 2002; 30(8):1883-1892.
(73) Blake S, MacDonald D. The prevention of the maternal manifestations of pre-eclampsia by intensive
antihypertensive treatment. Br J Obstet Gynaecol 1991; 98(3):244-248.
(74) Bortolus R, Ricci E, Chatenoud L, Parazzini F. Nifedipine administered in pregnancy: effect on the
development of children at 18 months. Br J Obstet Gynaecol 2000; 107(6):792-794.
(75) Catalano D, Ercolano S, Pollio F, Ascione L, Russo C, DeSanti B et al. Valuazione della monoterapia
con nifedipina nel management della gestosi EPH [Evaluation of nifedipine monotherapy in the
management of pregnancy hypertension]. Giornale Italiono Di Ostebricia e Ginecologia 1997; 6:373375.
(76) Gruppo di Studio Ipertensione in Gravidanza. Nifedipine versus Expectant Management in Mild to
Moderate Hypertension in Pregnancy. Br J Obstet Gynaecol 1998; 105:718-722.
(77) Magee LA, Ornstein MP, von Dadelszen P. Fortnightly review: management of hypertension in
pregnancy. BMJ 1999; 318(7194):1332-1336.
(78) Odendaal HJ, Schabort I, Pattinson RC. Prazosin for the treatment of hypertension in pregnancy: a
randomized control trial. Oxford Database of Perinatal Trials 1991.
(79) Magee LA, von Dadelszen P, Bohun CM, Rey E, El Zibdeh M, Stalker S et al. Serious perinatal
complications of non-proteinuric hypertension: an international, multicentre, retrospective cohort
study. J Obstet Gynaecol Can 2003; 25(5):372-382.
(80) Magee LA, von Dadelszen P, Chan S, Gafni A, Gruslin A, Helewa ME et al. The CHIPS Pilot Trial
(Control of Hypertension In Pregnancy Study). BJOG 2007; (in press).
(81) Magee LA, von Dadelszen P, Chan S, Gafni A, Gruslin A, Helewa ME et al. The CHIPS Pilot Trial
(Control of Hypertension In Pregnancy Study). Hypertens Pregn 2006; 25(Supplement 1):21.
(82) Magee LA, Ornstein MP, von Dadelszen P. Fortnightly review: management of hypertension in
pregnancy. BMJ 1999; 318(7194):1332-1336.
CHIPS Trial Protocol (Version 16 November 2011)
Page 21 of 30
(83) Magee LA, Duley L. Oral beta-blockers for mild to moderate hypertension during pregnancy.
Cochrane Database Syst Rev 2000;(4):CD002863.
(84) von Dadelszen P, Magee LA. Fall in mean arterial pressure and fetal growth restriction in pregnancy
hypertension: an updated metaregression analysis. JOGC 2002; 24:941-945.
(85) von Dadelszen P, Ornstein MP, Bull SB, Logan AG, Koren G, Magee LA. Fall in mean arterial
pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis. Lancet 2000;
355(9198):87-92.
(86) Report of the National High Blood Pressure Education Program Working Group on High Blood
Pressure in Pregnancy. Am J Obstet Gynecol 2000; 183(1):S1-S22.
(87) Brown MA, Hague WM, Higgins J, Lowe S, McCowan L, Oats J et al. The detection, investigation
and management of hypertension in pregnancy: executive summary. Aust N Z J Obstet Gynaecol
2000; 40(2):133-138.
(88) Rey E, LeLorier J, Burgess E, Lange IR, Leduc L. Report of the Canadian Hypertension Society
Consensus Conference: 3. Pharmacologic treatment of hypertensive disorders in pregnancy. CMAJ
1997; 157(9):1245-1254.
(89) Caetano M, Ornstein M, von Dadelszen P, Hannah ME, Logan AG, Gruslin A et al. A survey of
Canadian practitioners regarding the management of the hypertensive disorders of pregnancy.
Hypertens Pregn 2003; 23(1):61-74.
(90) Rumbold AR, Crowther CA, Haslam RR, Dekker GA, Robinson JS. Vitamins C and E and the risks
of preeclampsia and perinatal complications. N Engl J Med 2006; 354(17):1796-1806.
(91) Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH. Vitamin C and vitamin E in pregnant women
at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006;
367(9517):1145-1154.
(92) Chappell LC, Seed PT, Briley AL, Kelly FJ, Lee R, Hunt BJ et al. Effect of antioxidants on the
occurrence of pre-eclampsia in women at increased risk: a randomised trial. Lancet 1999; 354:810816.
(93) Magee LA, Ornstein MP, von Dadelszen P. Fortnightly review: management of hypertension in
pregnancy. BMJ 1999; 318(7194):1332-1336.
(94) von Dadelszen P, Ornstein MP, Bull SB, Logan AG, Koren G, Magee LA. Fall in mean arterial
pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis. Lancet 2000;
355(9198):87-92.
(95) Abalos E, Duley L, Steyn D, Henderson-Smart D. Antihypertensive drug therapy for mild to
moderate hypertension during pregnancy. Cochrane Database Syst Rev 2007;(1):CD002252.
(96) Magee LA. Review: drugs for mild-to-moderate hypertension in pregnancy reduce risk for severe
hypertension but not preeclampsia. ACP J Club 2007; 147(1):9.
(97) Arias F, Zamora J. Antihypertensive treatment and pregnancy outcome in patients with mild chronic
hypertension. Obstet Gynecol 1979; 53(4):489-494.
(98) Butters L. Essential hypertension in pregnancy. Nurs Times 1990; 86(44):53.
CHIPS Trial Protocol (Version 16 November 2011)
Page 22 of 30
(99) Sibai BM, Grossman RA, Grossman HG. Effects of diuretics on plasma volume in pregnancies with
long-term hypertension. Am J Obstet Gynecol 1984; 150(7):831-835.
(100) Sibai BM, Mabie WC, Shamsa F, Villar MA, Anderson GD. A comparison of no medication versus
methyldopa or labetalol in chronic hypertension during pregnancy. Am J Obstet Gynecol 1990;
162(4):960-966.
(101) Steyn DW, Odendaal HJ. Randomised controlled trial of ketanserin and aspirin in prevention of preeclampsia. Lancet 1997; 350(9087):1267-1271.
(102) Weitz C, Khouzami V, Maxwell K, Johnson JW. Treatment of hypertension in pregnancy with
methyldopa: a randomized double blind study. Int J Gynaecol Obstet 1987; 25(1):35-40.
(103) Blake S, MacDonald D. The prevention of the maternal manifestations of pre-eclampsia by intensive
antihypertensive treatment. Br J Obstet Gynaecol 1991; 98(3):244-248.
(104) Bott-Kanner G, Hirsch M, Friedman S, Boner G, Ovadia J, Merlob P et al. Antihypertensive therapy
in the management of hypertension in pregnancy - a clinical double-blind study of pindolol. Clin
Exper Hypertens Pregn 1992; B11:207-220.
(105) Cruickshank DJ, Campbell D, Robertson AA, MacGillivray I. Intra-uterine growth retardation and
maternal labetalol treatment in a random allocation controlled study. J Obstet Gynaecol 1992;
12:223-227.
(106) Elhassan EM, Mirghani OA, Habour AB, Adam I. Methyldopa versus no drug treatment in the
management of mild pre-eclampsia. East Afr Med J 2002; 79(4):172-175.
(107) Ganzevoort W, Rep A, Bonsel GJ, Fetter WP, van Sonderen L, De Vries JI et al. A randomised
controlled trial comparing two temporising management strategies, one with and one without plasma
volume expansion, for severe and early onset pre-eclampsia. BJOG 2005; 112(10):1358-1368.
(108) Hogstedt S, Lindeberg S, Axelsson O, Lindmark G, Rane A, Sandstrom B et al. A prospective
controlled trial of metoprolol-hydralazine treatment in hypertension during pregnancy. Acta Obstet
Gynecol Scand 1985; 64(6):505-510.
(109) Kahhale S, Zugaib M, Carrara W, Paula FJ, Sabbaga E, Neme B. Estudio comparativo de gestantes
hipertensas cronicas tratadas e nao tratadas com betabloqueador pindolol [Comparative study of
chronic hypertensive pregnant women treated and non-treated with pindolol]. Ginecol Obstet Brasil
1985; 8(2):85-89.
(110) Leather HM, Humphreys DM, Baker P, Chadd MA. A controlled trial of hypotensive agents in
hypertension in pregnancy. Lancet 1968; 2(7566):488-490.
(111) Li CY, Lao TT, Yu KM, Wong SP, Leung CF. The effect of labetalol on mild pre-eclampsia.
Proceedings of 7th Word Congress of Hypertension in Pregnancy 1990;191.
(112) MENZIES DN. CONTROLLED TRIAL OF CHLOROTHIAZIDE IN TREATMENT OF
EARLY PRE-ECLAMPSIA. Br Med J 1964; 5385:739-742.
(113) Odendaal HJ, Schabort I, Pattinson RC. Prazosin for the treatment of hypertension in pregnancy: a
randomized control trial. Oxford Database of Perinatal Trials 1991; Version 1.2(Disk Issue 6).
CHIPS Trial Protocol (Version 16 November 2011)
Page 23 of 30
(114) Phippard AF, Fischer WE, Horvath JS, Child AG, Korda AR, Henderson-Smart D et al. Early blood
pressure control improves pregnancy outcome in primigravid women with mild hypertension. Med J
Aust 1991; 154(6):378-382.
(115) Pickles CJ, Symonds EM, Broughton PF. The fetal outcome in a randomized double-blind controlled
trial of labetalol versus placebo in pregnancy-induced hypertension. Br J Obstet Gynaecol 1989;
96(1):38-43.
(116) Plouin PF, Breart G, Llado J, Dalle M, Keller ME, Goujon H et al. A randomized comparison of
early with conservative use of antihypertensive drugs in the management of pregnancy-induced
hypertension. Br J Obstet Gynaecol 1990; 97(2):134-141.
(117) Redman CW. Fetal outcome in trial of antihypertensive treatment in pregnancy. Lancet 1976;
2(7989):753-756.
(118) Rubin PC, Butters L, Clark D, Sumner D, Belfield A, Pledger D et al. Obstetric aspects of the use in
pregnancy-associated hypertension of the beta-adrenoceptor antagonist atenolol. Am J Obstet
Gynecol 1984; 150(4):389-392.
(119) Rudnicki M, Frolich A, Rasmussen WF, McNair P. The effect of magnesium on maternal blood
pressure in pregnancy-induced hypertension. A randomized double-blind placebo-controlled trial.
Acta Obstet Gynecol Scand 1991; 70(6):445-450.
(120) Sibai BM, Barton JR, Akl S, Sarinoglu C, Mercer BM. A randomized prospective comparison of
nifedipine and bed rest versus bed rest alone in the management of preeclampsia remote from term.
Am J Obstet Gynecol 1992; 167(4 Pt 1):879-884.
(121) Walker J. Intrauterine growth retardation and maternal labetalol treatment in a random allocation
controlled study [MD Thesis]. University of Glasgow, Scotland, 1992.
(122) Wichman K, Ryden G, Karlberg BE. A placebo controlled trial of metoprolol in the treatment of
hypertension in pregnancy. Scand J Clin Lab Invest 1984; 169:90-95.
(123) Wide-Swensson DH, Ingemarsson I, Lunell NO, Forman A, Skajaa K, Lindberg B et al. Calcium
channel blockade (isradipine) in treatment of hypertension in pregnancy: a randomized placebocontrolled study. Am J Obstet Gynecol 1995; 173(3 Pt 1):872-878.
(124) Sibai BM, Gonzalez AR, Mabie WC, Moretti M. A comparison of labetalol plus hospitalization
versus hospitalization alone in the management of preeclampsia remote from term. Obstet Gynecol
1987; 70(3 Pt 1):323-327.
(125) Magee LA, von Dadelszen P, Chan S, Gafni A, Gruslin A, Helewa ME et al. The CHIPS (Control of
Hypertension In Pregnancy Study) Pilot Trial. 15th World Congress of the ISSHP, Portugal [abstract]
2006.
(126) von Dadelszen P, Ornstein MP, Bull SB, Logan AG, Koren G, Magee LA. Fall in mean arterial
pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis. Lancet 2000;
355(9198):87-92.
(127) Steer PJ, Little MP, Kold-Jensen T, Chapple J, Elliott P. Maternal blood pressure in pregnancy, birth
weight, and perinatal mortality in first births: prospective study. BMJ 2004; 329(7478):1312.
CHIPS Trial Protocol (Version 16 November 2011)
Page 24 of 30
(128) Chen XK, Wen SW, Smith G, Yang Q, Walker M. Pregnancy-induced hypertension and infant
mortality: Roles of birthweight centiles and gestational age. BJOG 2007; 114(1):24-31.
(129) McCowan LM, Pryor J, Harding JE. Perinatal predictors of neurodevelopmental outcome in smallfor-gestational-age children at 18 months of age. Am J Obstet Gynecol 2002; 186(5):1069-1075.
(130) Plouin PF, Breart G, Llado J, Dalle M, Keller ME, Goujon H et al. A randomized comparison of
early with conservative use of antihypertensive drugs in the management of pregnancy-induced
hypertension. Br J Obstet Gynaecol 1990; 97(2):134-141.
(131) Bolte AC, van Eyck J, Kanhai HH, Bruinse HW, van Geijn HP, Dekker GA. Ketanserin versus
dihydralazine in the management of severe early-onset preeclampsia: maternal outcome. Am J Obstet
Gynecol 1999; 180(2 Pt 1):371-377.
(132) Brown MA, Buddle ML, Farrell T, Davis GK. Efficacy and safety of nifedipine tablets for the acute
treatment of severe hypertension in pregnancy. Am J Obstet Gynecol 2002; 187(4):1046-1050.
(133) Casavilla F, Ruda Vega H. Prospective and randomized study on mepindolol and alpha-methyldopa
efficacy in arterial hypertension (AH) treatment during pregnancy. Proceedings of the World
Congress of Gynaecology and Obstetrics, Brazil 1988;183.
(134) el Qarmalawi AM, Morsy AH, al Fadly A, Obeid A, Hashem M. Labetalol vs. methyldopa in the
treatment of pregnancy-induced hypertension. Int J Gynaecol Obstet 1995; 49(2):125-130.
(135) Ellenbogen A, Jaschevatzky O, Davidson A, Anderman S, Grunstein S. Management of pregnancyinduced hypertension with pindolol--comparative study with methyldopa. Int J Gynaecol Obstet
1986; 24(1):3-7.
(136) Faneite PJ, Gonzalez X, Salazar G. Evaluacion de antihipertensiovos en embarazadas: Mepindolol y
alfametildopa. Estudio Prospectivo y randomizado [Evaluation of antihypertensives in pregnancy:
Prospective randomized study of mepindolol and alpha methyldopa]. Revista de Obstetricia y
Ginecologia de Venezuela 1988;139-143.
(137) Fenakel K, Fenakel G, Appelman Z, Lurie S, Katz Z, Shoham Z. Nifedipine in the treatment of
severe preeclampsia. Obstet Gynecol 1991; 77(3):331-337.
(138) Fidler J, Smith V, Fayers P, de Swiet M. Randomised controlled comparative study of methyldopa
and oxprenolol in treatment of hypertension in pregnancy. Br Med J (Clin Res Ed) 1983;
286(6382):1927-1930.
(139) Gallery ED, Ross MR, Gyory AZ. Antihypertensive treatment in pregnancy: analysis of different
responses to oxprenolol and methyldopa. Br Med J (Clin Res Ed) 1985; 291(6495):563-566.
(140) Hall DR, Odendaal HJ, Steyn DW, Smith M. Nifedipine or prazosin as a second agent to control
early severe hypertension in pregnancy; a randomised controlled trial. Br J Obstet Gynaecol 2000;
107:759-765.
(141) Hjertberg R, Faxelius G, Lagercrantz H. Neonatal adaptation in hypertensive pregnancy--a study of
labetalol vs hydralazine treatment. J Perinat Med 1993; 21(1):69-75.
CHIPS Trial Protocol (Version 16 November 2011)
Page 25 of 30
(142) Horvath JS, Phippard A, Korda A, Henderson-Smart DJ, Child A, Tiller DJ. Clonidine
hydrochloride--a safe and effective antihypertensive agent in pregnancy. Obstet Gynecol 1985;
66(5):634-638.
(143) Jannet D, Carbonne B, Sebban E, Milliez J. Nicardipine versus metoprolol in the treatment of
hypertension during pregnancy: a randomized comparative trial. Obstet Gynecol 1994; 84(3):354-359.
(144) Kahhale S, Alves EA, Takiuti NH, Zugaib M. Efficacy and safety of isradipina and atenolol in
hypertensive disorders in pregnancy. Proceedings of the 11th World Congress of the ISSHP, Japan
1998;98.
(145) Laivuori HM, Laakso M, Tikkanen MJ, Cacciatore B, Ylikorkala RO, Kaaja RJ. Short-term metabolic
effects of isradipine and metoprolol in pre-eclampsia. J Hypertens 1999; 17(8):1189-1194.
(146) Lamming GD, Broughton PF, Symonds EM. Comparison of the alpha and beta blocking drug,
labetalol, and methyl dopa in the treatment of moderate and severe pregnancy-induced hypertension.
Clin Exp Hypertens 1980; 2(5):865-895.
(147) Lardoux H, Blazquez G, Leperlier E, Gerard J. [Randomized, comparative study on the treatment of
moderate arterial hypertension during pregnancy: methyldopa, acebutolol, labetalol]. Arch Mal Coeur
Vaiss 1988; 81 Spec No:137-140.
(148) Livingstone I, Craswell PW, Bevan EB, Smith MT, Eadie MJ. Propranolol in pregnancy three year
prospective study. Clin Exp Hypertens B 1983; 2(2):341-350.
(149) Marlettini MG, Crippa S, Morselli-Labate AM, Contarini A, Orlandi C. Randomized comparison of
calcium antagonists and beta-blockers in the treatment of pregnancy-induced hypertension. Curr
Ther Res 1990; 48(4):684-694.
(150) Montan S, Ingemarsson I, Marsal K, Sjoberg NO. Randomised controlled trial of atenolol and
pindolol in human pregnancy: effects on fetal haemodynamics. BMJ 1992; 304(6832):946-949.
(151) Montan S, Anandakumar C, Arulkumaran S, Ingemarsson I, Ratnam S. Randomised controlled trial
of methyldopa and isradipine in preeclampsia--effects on uteroplacental and fetal hemodynamics. J
Perinat Med 1996; 24(2):177-184.
(152) Neri I, Valensise H, Facchinetti F, Menghini S, Romanini C, Volpe.A. 24-hour ambulatory blood
pressure monitoring: a comparison between transdermal glyceryl-trinitrate and oral nifedipine.
Hypertens Pregn 1999; 18:107-113.
(153) Oumachigui A, Verghese M, Balachander J. A comparative evaluation of metoprolol and methyldopa
in the management of pregnancy induced hypertension. Indian Heart J 1992; 44(1):39-41.
(154) Paran E, Holzberg G, Mazor M, Zmora E, Insler V. Beta-adrenergic blocking agents in the treatment
of pregnancy-induced hypertension. Int J Clin Pharmacol Ther 1995; 33(2):119-123.
(155) Plouin PF, Breart G, Maillard F, Papiernik E, Relier JP. Comparison of antihypertensive efficacy and
perinatal safety of labetalol and methyldopa in the treatment of hypertension in pregnancy: a
randomized controlled trial. Br J Obstet Gynaecol 1988; 95(9):868-876.
(156) Redman CWG. A controlled trial of the treatment of hypertension in pregnancy: labetalol compared
with methyldopa. Excerpta Medica, 1978.
CHIPS Trial Protocol (Version 16 November 2011)
Page 26 of 30
(157) Rosenfeld JB, Bott-Kanner G, Boner G, Nissenkorn A, Friedman S, Ovadia J et al. Treatment of
hypertension during pregnancy with hydralazine monotherapy or with combined therapy with
hydralazine and pindolol. Eur J Obstet Gynecol Reprod Biol 1986; 22:197-204.
(158) Rudnicki M, Frolich A, Pilsgaard K, Nyrnberg L, Moller M, Sanchez M et al. Comparison of
magnesium and methyldopa for the control of blood pressure in pregnancies complicated with
hypertension. Gynecol Obstet Invest 2000; 49:231-235.
(159) Thorley KJ. Randomised trial of atenolol and methyldopa in pregnancy related hypertension. Clin
Exp Hypertens 1984; B3:168.
(160) Voto LS, Lapidus AM, Neira J, Magulies M. Tratamiento de la hipertension en el embarazo: atenolol
versus alfa metildopa. Obstetrico Ginecologia Latino-Americanas 1985; 43(9-10):335-341.
(161) Voto LS, Zin C, Neira J, Lapidus AM, Margulies M. Ketanserin versus alpha-methyldopa in the
treatment of hypertension during pregnancy: a preliminary report. J Cardiovasc Pharmacol 1987; 10
Suppl 3:S101-S103.
(162) Bortolus R, Ricci E, Chatenoud L, Parazzini F. Nifedipine administered in pregnancy: effect on the
development of children at 18 months. Br J Obstet Gynaecol 2000; 107(6):792-794.
(163) Reynolds B, Butters L, Evans J, Adams T, Rubin PC. First year of life after the use of atenolol in
pregnancy associated hypertension. Arch Dis Child 1984; 59(11):1061-1063.
(164) Cockburn J, Moar VA, Ounsted M, Redman CW. Final report of study on hypertension during
pregnancy: the effects of specific treatment on the growth and development of the children. Lancet
1982; 1(8273):647-649.
(165) Report of the National High Blood Pressure Education Program Working Group on High Blood
Pressure in Pregnancy. Am J Obstet Gynecol 2000; 183(1):S1-S22.
(166) Brown MA, Hague WM, Higgins J, Lowe S, McCowan L, Oats J et al. The detection, investigation
and management of hypertension in pregnancy: executive summary. Aust N Z J Obstet Gynaecol
2000; 40(2):133-138.
(167) Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutical trials. J Chronic Dis
1967; 20(8):637-648.
(168) Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: increasing the value of clinical research for
decision making in clinical and health policy. JAMA 2003; 290(12):1624-1632.
(169) Willan AR, Pinto EM. The value of information and optimal clinical trial design. Stat Med 2005;
24(12):1791-1806.
(170) Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutical trials. J Chronic Dis
1967; 20(8):637-648.
(171) Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: increasing the value of clinical research for
decision making in clinical and health policy. JAMA 2003; 290(12):1624-1632.
(172) Willan AR, Pinto EM. The value of information and optimal clinical trial design. Stat Med 2005;
24(12):1791-1806.
CHIPS Trial Protocol (Version 16 November 2011)
Page 27 of 30
(173) Magee LA, von Dadelszen P, Bohun CM, Rey E, El Zibdeh M, Stalker S et al. Serious perinatal
complications of non-proteinuric hypertension: an international, multicentre, retrospective cohort
study. J Obstet Gynaecol Can 2003; 25(5):372-382.
(174) Report of the National High Blood Pressure Education Program Working Group on High Blood
Pressure in Pregnancy. Am J Obstet Gynecol 2000; 183(1):S1-S22.
(175) Brown MA, Hague WM, Higgins J, Lowe S, McCowan L, Oats J et al. The detection, investigation
and management of hypertension in pregnancy: executive summary. Aust N Z J Obstet Gynaecol
2000; 40(2):133-138.
(176) Magee LA. Fetal growth restriction. Lancet 2000; 355:1367-1368.
(177) Schwartz D, Lellouch J. Explanatory and pragmatic attitudes in therapeutical trials. J Chronic Dis
1967; 20(8):637-648.
(178) Moutquin JM, Garner PR, Burrows RF, Rey E, Helewa ME, Lange IR et al. Report of the Canadian
Hypertension Society Consensus Conference: 2. Nonpharmacologic management and prevention of
hypertensive disorders in pregnancy. CMAJ 1997; 157(7):907-919.
(179) Bartha JL, Gonzalez-Bugatto F, Fernandez-Macias R, Gonzalez-Gonzalez NL, Comino-Delgado R,
Hervias-Vivancos B. Metabolic syndrome in normal and complicated pregnancies. Eur J Obstet
Gynecol Reprod Biol 2007.
(180) Girouard J, Giguere Y, Moutquin JM, Forest JC. Previous hypertensive disease of pregnancy is
associated with alterations of markers of insulin resistance. Hypertension 2007; 49(5):1056-1062.
(181) Newstead J, von Dadelszen P, Magee LA. Preeclampsia and future cardiovascular risk. Expert Rev
Cardiovasc Ther 2007; 5(2):283-294.
(182) Helewa ME, Burrows RF, Smith J, Williams K, Brain P, Rabkin SW. Report of the Canadian
Hypertension Society Consensus Conference: 1. Definitions, evaluation and classification of
hypertensive disorders in pregnancy. CMAJ 1997; 157(6):715-725.
(183) Demianczuk NN, Van Den Hof MC, Farquharson D, Lewthwaite B, Gagnon R, Morin L et al. The
use of first trimester ultrasound. J Obstet Gynaecol Can 2003; 25(10):864-875.
(184) Martin JN, Jr., Thigpen BD, Moore RC, Rose CH, Cushman J, May W. Stroke and severe
preeclampsia and eclampsia: a paradigm shift focusing on systolic blood pressure. Obstet Gynecol
2005; 105(2):246-254.
(185) Brown MA, Buddle ML, Farrell T, Davis GK. Efficacy and safety of nifedipine tablets for the acute
treatment of severe hypertension in pregnancy. Am J Obstet Gynecol 2002; 187(4):1046-1050.
(186) Zhang B, Schmidt B. Do we measure the right end points? A systematic review of primary outcomes
in recent neonatal randomized clinical trials. J Pediatr 2001; 138(1):76-80.
(187) Wingert A. Canadian Neonatal Network admissions for babies of hypertensive mothers. Personal
communication July 31, 2007.
(188) Collins J. Which randomized controlled trials are relevant to clinical practice? Obstet Gynecol 2005;
106(2):216-218.
CHIPS Trial Protocol (Version 16 November 2011)
Page 28 of 30
(189) Ross S. Composite outcomes in randomized clinical trials: arguments for and against. Am J Obstet
Gynecol 2007; 196(2):119-6.
(190) Sibai BM. Preeclampsia as a cause of preterm and late preterm (near-term) births. Semin Perinatol
2006; 30(1):16-19.
(191) Nystrom K, Axelsson K. Mothers' experience of being separated from their newborns. J Obstet
Gynecol Neonatal Nurs 2002; 31(3):275-282.
(192) Haut C, Peddicord K, O'Brien E. Supporting parental bonding in the NICU: a care plan for nurses.
Neonatal Netw 1994; 13(8):19-25.
(193) McGrath JM. Building relationships with families in the NICU: exploring the guarded alliance. J
Perinat Neonatal Nurs 2001; 15(3):74-83.
(194) Lee SK, Anderson L. BC Perinatal Services Costing Project: Report on costs in the neonatal intensive
care unit. Centre for Healthcare Innovation and Improvement 2004.
(195) Kirkby S, Greenspan JS, Kornhauser M, Schneiderman R. Clinical outcomes and cost of the
moderately preterm infant. Adv Neonatal Care 2007; 7(2):80-87.
(196) Lee SK, McMillan DD, Ohlsson A, Pendray M, Synnes A, Whyte R et al. Variations in practice and
outcomes in the Canadian NICU network: 1996-1997. Pediatrics 2000; 106(5):1070-1079.
(197) Richardson DK, Corcoran JD, Escobar GJ, Lee SK. SNAP-II and SNAPPE-II: Simplified newborn
illness severity and mortality risk scores. J Pediatr 2001; 138(1):92-100.
(198) Wingert A. Canadian Neonatal Network admissions for babies of hypertensive mothers. Personal
communication July 31, 2007.
(199) Hayter MA, Anderson L, Claydon J, Magee LA, Little R, Liston RM et al. Variations in early and
intermediate neonatal outcomes for inborn infants admitted to a Canadian NICU and born of
hypertensive pregnancies. JOGC 2004; submitted July 2004; MS# pending.
(200) Lee SK, McMillan DD, Ohlsson A, Pendray M, Synnes A, Whyte R et al. Variations in practice and
outcomes in the Canadian NICU network: 1996-1997. Pediatrics 2000; 106(5):1070-1079.
(201) Kramer MS, Platt RW, Wen SW, Joseph KS, Allen A, Abrahamowicz M et al. A new and improved
population-based Canadian reference for birth weight for gestational age. Pediatrics 2001;
108(2):E35.
(202) Kramer MS, Platt RW, Wen SW, Joseph KS, Allen A, Abrahamowicz M et al. A new and improved
population-based Canadian reference for birth weight for gestational age. Pediatrics 2001;
108(2):E35.
(203) Fetus and Newborn Committee CPS. Routine screening cranial ultrasound examinations for the
prediction of long term neurodevelopmental outcomes in preterm infants. Paed Child Health 2001;
6(1):39-43.
(204) Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF et al. Wholebody hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;
353(15):1574-1584.
CHIPS Trial Protocol (Version 16 November 2011)
Page 29 of 30
(205) Walsh MC, Kliegman RM, Fanaroff AA. Necrotizing enterocolitis: a practitioner's perspective.
Pediatr Rev 1988; 9(7):219-226.
(206) Gafni A, Goeree R, Myhr TL, Hannah ME, Blackhouse G, Willan AR et al. Induction of labour
versus expectant management for prelabour rupture of the membranes at term: an economic
evaluation. TERMPROM Study Group. Term Prelabour Rupture of the Membranes. CMAJ 1997;
157(11):1519-1525.
(207) Sibai BM, Barton JR, Akl S, Sarinoglu C, Mercer BM. A randomized prospective comparison of
nifedipine and bed rest versus bed rest alone in the management of preeclampsia remote from term.
Am J Obstet Gynecol 1992; 167(4 Pt 1):879-884.
(208) Wide-Swensson DH, Ingemarsson I, Lunell NO, Forman A, Skajaa K, Lindberg B et al. Calcium
channel blockade (isradipine) in treatment of hypertension in pregnancy: a randomized placebocontrolled study. Am J Obstet Gynecol 1995; 173(3 Pt 1):872-878.
(209) Magee LA, von Dadelszen P, Chan S, Gafni A, Gruslin A, Helewa M et al. The Control of
Hypertension In Pregnancy Study pilot trial. BJOG 2007; 114(6):770, e13-770, e20.
(210) Sibai BM, Barton JR, Akl S, Sarinoglu C, Mercer BM. A randomized prospective comparison of
nifedipine and bed rest versus bed rest alone in the management of preeclampsia remote from term.
Am J Obstet Gynecol 1992; 167(4 Pt 1):879-884.
(211) Wide-Swensson DH, Ingemarsson I, Lunell NO, Forman A, Skajaa K, Lindberg B et al. Calcium
channel blockade (isradipine) in treatment of hypertension in pregnancy: a randomized placebocontrolled study. Am J Obstet Gynecol 1995; 173(3 Pt 1):872-878.
(212) Magee LA, von Dadelszen P, Chan S, Gafni A, Gruslin A, Helewa M et al. The Control of
Hypertension In Pregnancy Study pilot trial. BJOG 2007; 114(6):770, e13-770, e20.
(213) Wingert A. Canadian Neonatal Network admissions for babies of hypertensive mothers. Personal
communication July 31, 2007.
(214) Hernandez AV, Steyerberg EW, Habbema JD. Covariate adjustment in randomized controlled trials
with dichotomous outcomes increases statistical power and reduces sample size requirements. J Clin
Epidemiol 2004; 57(5):454-460.
(215) Spilker B, Cramer JA. Patient recruitment in clinical trials. New York: Raven Press, 1992.
(216) Helewa ME, Burrows RF, Smith J, Williams K, Brain P, Rabkin SW. Report of the Canadian
Hypertension Society Consensus Conference: 1. Definitions, evaluation and classification of
hypertensive disorders in pregnancy. CMAJ 1997; 157(6):715-725.
(217) Thompson SG, Warn DE, Turner RM. Bayesian methods for analysis of binary outcome data in
cluster randomized trials on the absolute risk scale. Stat Med 2004; 23(3):389-410.
(218) Magee LA, von Dadelszen P, Chan S, Gafni A, Gruslin A, Helewa M et al. The Control of
Hypertension In Pregnancy Study pilot trial. BJOG 2007; 114(6):770, e13-770, e20.
(219) WinBUGS Version 1.2 User Manual. Cambridge: MRC Biostatistics Unit, 1999.
CHIPS Trial Protocol (Version 16 November 2011)
Page 30 of 30