B Monitoring Gestational Hypertension PDF 6836186127

National Institute for Health and Care
Excellence
FINAL
Hypertension in Pregnancy
[B] Evidence review for monitoring gestational
hypertension
NICE guideline NG133

Evidence reviews
June 2019
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These evidence reviews were developed

by the National Guideline Alliance hosted
by the Royal College of Obstetricians and
Gynaecologists
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Contents
Disclaimer
The recommendations in this guideline represent the view of NICE, arrived at after careful
consideration of the evidence available. When exercising their judgement, professionals are
expected to take this guideline fully into account, alongside the individual needs, preferences
and values of their patients or service users. The recommendations in this guideline are not
mandatory and the guideline does not override the responsibility of healthcare professionals
to make decisions appropriate to the circumstances of the individual patient, in consultation
with the patient and/or their carer or guardian.
Local commissioners and/or providers have a responsibility to enable the guideline to be
applied when individual health professionals and their patients or service users wish to use it.
They should do so in the context of local and national priorities for funding and developing
services, and in light of their duties to have due regard to the need to eliminate unlawful
discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing
in this guideline should be interpreted in a way that would be inconsistent with compliance
with those duties.
NICE guidelines cover health and care in England. Decisions on how they apply in other UK
countries are made by ministers in the Welsh Government, Scottish Government, and
Northern Ireland Executive. All NICE guidance is subject to regular review and may be
updated or withdrawn.
Copyright
© NICE 2019. All rights reserved. Subject to Notice of Rights.
ISBN: 978-1-4731-3434-8
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Monitoring gestational hypertension
Contents
Contents .............................................................................................................................. 4
Review question: What is the best strategy (including frequency) for monitoring
gestational hypertension in women?...................................................................... 5
Introduction ........................................................................................................... 5
Summary of the protocol ....................................................................................... 5
Methods and process ............................................................................................ 6
Clinical evidence ................................................................................................... 6
Summary of clinical studies included in the evidence review ................................. 7
Quality assessment of clinical studies included in the evidence review ................. 8
Economic evidence ............................................................................................... 8
Evidence statements ............................................................................................. 8
Comparison 1. Management based on Korotkoff 4 (K4) sounds versus K5
sounds ....................................................................................................... 8
Comparison 2a. Home monitoring versus hospital monitoring ............................... 9
Comparison 2b: Home blood pressure telemonitoring (obstetrician updated;
intevention) versus home blood pressure monitoring (obstetrician not
updated; control) ........................................................................................ 9
Comparison 3. Hospital bedrest versus home normal activity .............................. 10
Comparison 4: Less-tight versus tight control of blood pressure .......................... 11
The committee’s discussion of the evidence ........................................................ 12
Refeence ............................................................................................................. 15
Appendices ........................................................................................................................ 17
Appendix A – Review protocol ...................................................................................... 17
Appendix B – Literature search strategies .................................................................... 25
Health economics search strategies .................................................................... 32
Appendix C – Clinical evidence study selection ............................................................ 42
Appendex D – Clinical evidence tables ......................................................................... 43
Appendix E – Forest plots............................................................................................. 61
Appendix F – GRADE tables ........................................................................................ 62
Appendix G – Economic evidence study selection ........................................................ 71
Appendix H – Economic evidence tables ...................................................................... 72
Appendix I – Health economic evidence profiles ........................................................... 73
Appendix J – Health economic analysis........................................................................ 74
Appendix K – Excluded studies .................................................................................... 75
Clinical studies .................................................................................................... 75
Economic studies ................................................................................................ 79
Appendix L – Research recommendations ................................................................... 81
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Review question: What is the best strategy (including

frequency) for monitoring gestational hypertension in
women?
Introduction
Gestational hypertension is high blood pressure in a pregnant woman after 20 weeks’
gestation, and it can lead to complications for both the woman (such as severe hypertension
or progression to pre-eclampsia) and for her baby (including intra-uterine growth retardation,
preterm delivery and admission to a neonatal unit). It is therefore important that women with
gestational hypertension are monitored carefully, with appropriate initiation of
antihypertensive treatment if required.
The aim of this review is to update the recommendations on the best strategy to be followed
when monitoring a woman with gestational hypertension, to optimise care and outcomes and
to reduce the likelihood of adverse events.
Summary of the protocol

Table 1 summarises the population, intervention, comparator, and outcome (PICO)
characteristics of this review.
Table 1: Summary of protocol (PICO table)

Population Pregnant women with gestational hypertension
Intervention Tests in woman for monitoring:
 Blood pressure
 Monitoring target for blood pressure
 Haematological:
o Platelets
o Coagulation/clotting screen
 Renal function:
o Creatinine
 Liver function:
o Transaminases
 Urine testing for proteinuria:
o Dipstick
o Proteinuria (protein/creatinine ratio, PCR)
o Albuminuria (albumin/creatinine ratio, ACR)
o 24 hour urine collection
 Placental growth factor (PlGF)
 Soluble fms-like tyrosine kinase 1 / placental growth factor
(sFLT1/PlGF)
 Ultrasound for growth estimates
 Cardiotocography / Electronic Fetal Monitoring (CTG / EFM)
 Place of monitoring (inpatient compared to outpatient)
Comparison  Testing (followed by treatment, if appropriate) versus not testing
 Single testing (followed by treatment, if appropriate) versus
repeated testing (followed by treatment, if appropriate)
 Different schedules of testing frequency (e.g. weekly versus
monthly)
 Any versus PCR/ACR
 One test compared to a different test
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Outcome Outcomes for babies:

 Critical outcomes:
o Perinatal mortality
- Stillbirth (include if reported as part of perinatal mortality)
- Neonatal death up to 7 days (include if reported as part of
perinatal mortality)
o Small-for-gestational age (birthweight<10th centile)
 Important outcomes:
o Gestational age at delivery
o Admission to neonatal unit
Outcomes for women:

 Critical outcomes
o Severe hypertension (systolic BP ≥ 160 and/or diastolic BP ≥
110 mmHg)
 Important outcomes
o Progression to pre-eclampsia
o Placental abruption
o Mode of birth
o Maternal death
ACR: albumin:creatinine ratio; BP: blood pressure; CTG: cardiotocography; EFM: electronic fetal monitoring;
mmHg: millimetres of mercury; PCR: protein:creatinine ratio; PlGF: placental growth factor; sFLT1: soluble fms-
like tyrosine kinase 1
For full details see the review protocol in appendix A.
Methods and process

This evidence review was developed using the methods and process described in
Developing NICE guidelines: the manual 2014. Methods specific to this review question are
described in the review protocol in appendix A.
Declaration of interests were recorded according to NICE’s 2018 conflicts of interest policy
(see Register of interests).
Clinical evidence
Included studies
Six randomised controlled trials (RCTs) were included in this review (Brown 1998, Cartwright
1992, Crowther 1992, Denolle 2008, Magee 2007, Magee 2015). The majority of included
studies considered different interventions, and were therefore not suitable for meta-analysis.
The only studies suitable for meta-analysis were Magee 2007 and Magee 2015, which were
reports of the pilot data and full data from the Control of Hypertension in Pregnancy Study
(CHIPS).
The clinical studies included in this evidence review are summarised in Table 2.
See also the literature search strategy in appendix B and study selection flow chart in
appendix C.
Excluded studies
Studies not included in this review with reasons for their exclusions are provided in appendix
K.
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Summary of clinical studies included in the evidence review

Table 2 provides a brief summary of the included studies.
Table 2: Summary of included studies

Study Population Intervention Comparator Outcomes
Brown 1998 N=220 Management Management  Perinatal
based on K4 based on K5 mortality
RCT Diastolic blood pressure sounds sounds  SGA<10th
≥90mmHg, as measured centile
Australia with Korotkoff 4 (K4)  GA at birth
sound  Severe
hypertension
GA: ≥20 weeks  Pre-
eclampsia
 Maternal
death
Cartwright N=99 (67 analysed) Oscillometric Hospital  GA at birth
1992 method of home monitoring  Mode of birth
hypertensive enough to blood pressure
RCT be admitted under normal monitoring
obstetric standards
England
GA:~ ≥35weeks
Crowther N=218 Hospital bedrest Home normal  Perinatal
1992 activity mortality
BP>140/90mmHg but no  SGA<10th
RCT proteinuria (or only a centile
trace on urine dip testing)  GA at birth
Zimbabwe  Admission to
GA: 28-38 weeks neonatal unit
 Severe
hypertension
 Pre-
eclampsia
 Mode of birth
Denolle N=57 (48 analysed) Home (HBPT) Home  GA at birth
2008 monitoring - monitoring -  Mode of birth
Recently discovered obstetrician obstetrician not
RCT hypertension (mean of 3 updated in real updated
office BP measurements) time
France ≥140/90mmHg but (for 7 days only)
<180/105mmHg (for 7 days only)
GA: 18 weeks
Magee N=132 (84 with GH; Less tight control Tight control of  Perinatal
2007 48 with pre-existing of BP BP mortality
hypertension) (target dBP (target dBP  SGA<10th
RCT 100mmHg) 85mmHg) centile
Pre-existing or  Admission to
Multi- gestational hypertension: neonatal unit
country/ dBP 90-109mmHg  Severe
international hypertension
(Canada) GA: 20-33+6 weeks
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Study Population Intervention Comparator Outcomes

 Pre-
eclampsia
 Placental
abruption
 Mode of birth
Magee N=1030 (987 analysed); Less tight control Tight control of Subgroup
2015 251 with GH of BP (target BP (target dBP analysis for
pre-existing or gestational dBP 100mmHg) 85mmHg) women with
RCT hypertension: gestational
dBP 90-105mmHg (not hypertension
on antihypertensives) or only:
Multi-
dBP 85-105mmHg (on  SGA<10th
country/
antihypertensives) centile
international
(Canada)  Severe
GA: 14-33+6 weeks hypertension
 Pre-
eclampsia
BP: blood pressure; dBP: diastolic blood pressure; GA: gestational age; GH: gestational hypertension; HBPT:
home blood pressure telemonitoring; K: Korotkoff; mmHg: millimetres of mercury; RCT: randomised controlled
trial, SGA: small for gestational age
See appendix D for the full evidence tables.
Quality assessment of clinical studies included in the evidence review

See appendix F for the full GRADE tables.
Economic evidence
No economic evidence on the cost effectiveness interventions for chronic hypertension was
identified by the systematic search of the economic literature undertaken for this guideline.
Economic modelling was not undertaken for this question because other topics were agreed
as higher priorities for economic evaluation.
Evidence statements
Comparison 1. Management based on Korotkoff 4 (K4) sounds versus K5 sounds
Outcomes for babies
Critical outcomes
Small-for-gestational age
 One randomised controlled trial (n=220) provided very low quality evidence to show no
clinically important difference in the number of babies born small-for-gestational age
between women whose blood pressure was recorded using K4 sounds and those whose
blood pressure was recorded using K5 sounds.
Important outcomes
Gestational age at birth

 One randomised controlled trial (n=220) provided moderate quality evidence to show no
clinically important difference in the gestational age at birth for babies born to women
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whose blood pressure was monitored using K4 sounds, compared to those whose blood
pressure was monitored using K5 sounds.
Outcomes for women
Critical outcomes
Severe hypertension (systolic BP ≥160 and/or diastolic BP ≥110 mmHg)

 One randomised controlled trial (n=220) provided low quality evidence to show a clinically
important increase in the incidence of severe hypertension for women whose blood
pressure was monitored using K4 sounds, as compared to those whose blood pressure
was monitored using K5 sounds.
Important outcomes
Maternal death
maternal deaths in women whose BP was recorded using either K4 sounds or K5 sounds.
Comparison 2a. Home monitoring versus hospital monitoring
Outcomes for babies
Important outcomes

clinically important difference in the gestational age at birth for babies of women who
underwent home monitoring, compared to those who were monitored in hospital.
Outcomes for women
Important outcome
Mode of birth
clinically important difference in the number of women having a spontaneous vaginal birth
when home monitoring was used compared to hospital monitoring.
Comparison 2b: Home blood pressure telemonitoring (obstetrician updated;

intevention) versus home blood pressure monitoring (obstetrician not updated;
control)
Outcomes for babies
Important outcomes

clinically important difference in the gestational age at birth for babies born to women in
whom home blood pressure telemonitoring was used (and the obstetrician was aware of
the results) when compared to women in whom the results of home monitoring were not
known by the obstetrician.
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Outcomes for women
Important outcomes
Mode of birth (caesarean birth)

 One randomised controlled trial (n=48) provided low quality evidence to show no clinically
important difference in the rate of caesarean birth for women in whom home blood
pressure monitoring was used (and the obstetrician was aware of the results) when
compared to women in whom the results of home monitoring were not known by the
obstetrician.
Comparison 3. Hospital bedrest versus home normal activity
Outcomes for babies
Critical outcomes
Perinatal mortality
clinically important difference in the perinatal mortality rate between women who were
admitted to hospital for bedrest, and those who were not admitted to hospital.
between women who were admitted to hospital for bedrest, and those who were not
admitted to hospital.
Important outcomes

clinically important difference in the gestational age at birth of babies born to women who
were admitted to hospital for bedrest, and those who were not admitted to hospital.
Preterm birth (<37 weeks)

important reduction in the number of babies born preterm (<37 weeks) for women who
were admitted to hospital for bedrest, as compared to women who were not admitted to
hospital.

clinically important difference in the number of babies born preterm (<34 weeks) for
women who were admitted to hospital for bedrest, as compared to women who were not
Admission to neonatal unit

clinically important difference in the number of babies needing admission to a neonatal
unit, when comparing women who were admitted to hospital for bedrest to women who
were not admitted to hospital.
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Outcomes for women
Critical outcomes
Severe hypertension
important reduction in the number of episodes of severe hypertension for women who
were admitted to hospital for bedrest, as compared to women who were not admitted to
hospital.
Important outcomes
Progression to pre-eclampsia
clinically important difference in the number of women developing pre-eclampsia, when
comparing women who were admitted to hospital for bedrest to women who were not
Induction of labour
 One randomised controlled trial (n=218) provided moderate quality evidence to show a
clinically important increase in the number of women who had induction of labour for those
who were admitted to hospital for bedrest, as compared to women who were not admitted
to hospital.
Mode of birth (Caesarean birth)

clinically important difference in the number of women giving birth by caesarean section
when those admitted to hospital for bedrest were compared to women who were not
Comparison 4: Less-tight versus tight control of blood pressure
Outcomes for babies
Critical outcomes
Stillbirth
stillbirths for women who had less-tight or tight control of their blood pressure.
Neonatal death
clinically important difference in neonatal deaths between women who had less-tight
compared to tight control of their blood pressure.
 Two randomised controlled trials (n=380) provided very low quality evidence to show no
between women who had less-tight compared to tight control of their blood pressure.
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Important outcomes

 One randomised controlled trial (n=131) provided low quality evidence to show no
clinically important difference in gestational age at birth for babies born to women who had
less-tight compared to tight control of their blood pressure.

clinically important difference in the number of babies born preterm (<37 weeks) to women
who had less-tight compared to tight control of their blood pressure.

 One randomised controlled trial (n=131) provided low quality evidence to show no
clinically important difference in the number of babies admitted to a neonatal unit for
women who had less-tight compared to tight control of their blood pressure.
Outcomes for women
Critical outcome
Severe hypertension
 Two randomised controlled trials (n=380) provided low quality evidence to show no
clinically important difference in the incidence of severe hypertension between women
who had less-tight compared to tight control of their blood pressure.
Important outcomes
 Two randomised controlled trials (n=379) provided moderate quality evidence to show no
clinically important difference in the number of women who developed pre-eclampsia
between women who had less-tight compared to tight control of their blood pressure.
Placental abruption
occurrence of placental abruption in women who had less-tight or tight control of their
blood pressure.
Mode of birth (caesarean birth)

clinically important difference in the incidence of caesarean birth for women who had less-
tight or tight control of their blood pressure.
See appendix E for Forest plots
The committee’s discussion of the evidence
Interpreting the evidence
The outcomes that matter most

The aim of this review was to update the recommendations on the investigations and
monitoring that should take place in women who have been diagnosed with gestational
hypertension. As gestational hypertension and its treatment can have an impact on the baby,
and lead to adverse outcomes for women if not treated, the outcomes were divided into
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outcomes for babies and outcomes for women. For babies, gestational hypertension can be
associated with intra-uterine growth restriction, stillbirth or preterm birth (particularly if it
progresses to pre-eclampsia) so the critical outcomes were perinatal mortality (which
included stillbirth and neonatal death up to 7 days) and babies small for gestational age at
birth. The important outcomes were gestational age at birth and admission to the neonatal
unit. For the woman, the main aim of monitoring is to avoid maternal complications by
ensuring that blood pressure is controlled, and so the critical outcome was severe
hypertension (defined as systolic blood pressure ≥ 160 and/or diastolic blood pressure ≥ 110
mmHg). The main concerns with gestational hypertension are that it may progress to pre-
eclampsia or lead to placental abruption so these were selected as the important outcomes.
Mode of birth was also considered important to determine if the pregnancy led to a normal
vaginal birth or required a planned birth. Maternal death is a rare consequence of
undiagnosed and inadequately treated gestational hypertension, so was included as an
important outcome too.
The quality of the evidence

For all the outcomes the quality of evidence ranged from very low to moderate, except for the
comparison of home blood pressure monitoring compared to hospital monitoring where it
ranged from very low to low. The quality of the evidence was downgraded for all outcomes
because of indirectness – the studies did not make it clear if all the included women had
gestational hypertension or chronic hypertension, or in some studies pre-eclampsia. The
CHIPS study included a population of woman with chronic hypertension or gestational
hypertension. Only the subgroup of women with gestational hypertension were included in
the meta-analysis from the main trial, providing directly relevant information to this population
of women. However, the CHIPS pilot data (contributing to the meta-analysis and providing
data for more outcomes than the main CHIPS trial alone) included 64% of women with
gestational hypertension and 36% with chronic hypertension. All relevant data from this pilot
study were included, but the quality of the evidence was downgraded for indirectness. the
committee recognised that analysing results from a sub-group (women with gestational
hypertension) in a trial of women with hypertension during pregnancy (both chronic and
gestational) might mean that there is insufficient power to show sub-group differences.
Where there was no reason to consider that the sub-group would respond differently to the
larger group of women with pregnancy hypertension, the committee took this into
consideration when making recommendations.
The evidence for the majority of outcomes was also downgraded for imprecision as many of
the estimates had wide confidence intervals, and crossed one or both of the minimally
important difference boundaries.
Benefits and harms

The comparison of management based on K4 sounds compared to management based on
K5 sounds showed no difference in the outcomes for babies, but detected an increased
incidence of severe hypertension in women with the K4 sounds. However, the committee
agreed that the use of K4 sounds had already now been superceded by use of K5 sounds in
clinical practice and therefore did not think it was necessary to make a recommendation
relating to this.
For the comparison of home versus hospital monitoring of blood pressure, and home
monitoring with the consultant aware of the results compared to home monitoring with the
consultant not aware, there was no difference in any of the outcomes reported. The
committee therefore agreed that they did not have enough evidence to recommend that
either home or hospital monitoring should take precedence. The committee were aware of an
ongoing study comparing home versus hospital blood pressure monitoring for pregnant
women (The BUMP study) which will address this, so did not make a research
recommendation.
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The comparison of hospital bedrest versus normal home activity showed that hospital
bedrest decreased the number of women with severe hypertension and the incidence of
preterm birth, but increased the incidence of women who underwent induction of labour.
However, the committee noted that this study had been conducted in Zimbabwe where
overall standards of maternity care were likely to be very different to the UK setting and that it
was therefore very difficult to extrapolate from these results. The committee agreed, based
on their clinical experience, that it was not necessary to admit women with gestational
hypertension for hospital bed-rest. The committee therefore chose to adopt the
recommendation from the previous guideline which stated this.
The comparison of tight versus less-tight blood pressure control from the CHIPS and CHIPS
pilot study showed no difference in any of the outcomes for the sub-group of women with
gestational hypertension. However, the committee were aware that in the combined study
population (which included women with chronic hypertension too) the rate of severe
hypertension had been lower in the tight control group. As tight control did not increase the
risk of adverse effects on babies, the committee agreed it would therefore be acceptable to
adopt the tight control blood pressure target from CHIPS, of a diastolic blood pressure of 85
mmHg. The systolic blood pressure target of 135 mmHg was adopted from the NICE clinical
guideline on hypertension in adults. The committee discussed that these targets were also
the same as they had recommended for women with chronic hypertension and that it made
sense for clinical consistency to have the same blood pressure targets for both groups.
The committee simplified the table from the previous NICE guideline for the management of
pregnancy with gestational hypertension and agreed that, based on their clinical experience
and knowledge, women only need to be stratified into those with hypertension, and those
with severe hypertension. The committee had no evidence on which to base changes in the
frequency of monitoring for blood pressure, proteinuria or blood tests, so adapted the
recommendations from the previous guideline, amending some of the recommendations
based on their clinical experience and expertise. However, the committee noted that the
management table did not include guidance on how often to monitor fetal growth (this is
covered in a separate section of the guideline and no new evidence was found on this as
part of this review).They agreed that it was important to include this in the table to ensure it
was not omitted from the ongoing monitoring of women and their babies, and so they added
this information, based on the recommendations already in section 1.6 of the guideline. As
no evidence had been found, the committee made a research recommendation as well.
As with the blood pressure targets, the committee agreed there should be consistency of the
pharmacologic treatments used for any type of hypertension in pregnancy and so they
amended the wording of the previous recommendations: they retained labetalol as first
choice as it is specifically licensed for use in pregnancy with nifedipine and then methyldopa
as alternatives. They recommended a choice from these three medicines based on side
effect profiles, fetal effects, and the woman’s preferences.
The committee noted that since the previous guideline had been published, NICE had
produced diagnostic guidance on the use of placental growth factor (PlGF) monitoring to help
rule-out pre-eclampsia in women between 20+0 and 34+6 weeks. Since gestational
hypertension can progress to pre-eclampsia, the committee agreed that a cross-reference to
this guidance should be included.
Cost effectiveness and resource use

No relevant studies were identified in a systematic review of the economic evidence. The
committee agreed that the recommendations would not have a major overall impact on
current clinical practice and so were unlikely to lead to any significant change in resource use
in the NHS as whole.
Changes to blood pressure tagets aimed to simplify the previous guidance and make it more
clinically appropriate. It is thought that the recommmednations already reflect current practice
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for most units and so there should not be significant changes at a national level. However,
there may be some change in resources at a local level for those units which use different
blood pressure targets to those that have been recommended.
Other factors the committee took into account

The committee were aware of the findings from a recently updated Cochrane systematic
review and meta-analysis on antihypertensive treatment in pregnancy, which indicated that
beta-blockers and calcium channel blockers were more effective than methyldopa at
preventing severe hypertension. The Cochrane review included a mixed population of
women with any hypertension during pregnancy and so did not meet the protocol criteria for
inclusion in this evidence report (which included women with gestational hypertension only).
However, the committee agreed that it would be appropriate to recommend methyldopa as a
third-line option, after labetalol and nifedipine, based on the findings of the Cochrane review
and their experience of the side-effect profile of methyldopa.
Refeence
Brown et al., 1998
Brown, M. A., Buddle, M. L., Farrell, T., Davis, G., Jones, M., Randomised trial of
management of hypertensive pregnancies by Korotkoff phase IV or phase V, Lancet
(London, England), 352, 777-81, 1998
Cartwright et al., 1992
Cartwright,W., Dalton,K.J., Swindells,H., Rushant,S., Mooney,P., Objective measurement of

anxiety in hypertensive pregnant women managed in hospital and in the community, British
Journal of Obstetrics and Gynaecology, 99, 182-185, 1992
Crowther 1992
Crowther,C.A., Bouwmeester,A.M., Ashurst,H.M., Does admission to hospital for bed rest

prevent disease progression or improve fetal outcome in pregnancy complicated by non-
proteinuric hypertension?, British Journal of Obstetrics and Gynaecology, 99, 13-17, 1992
Denolle 2008
Denolle, T., Weber, J. L., Calvez, C., Getin, Y., Daniel, J. C., Lurton, O., Cheve, M. T.,
Marechaud, M., Bessec, P., Carbonne, B., Razafintsalama, T., Diagnosis of white coat
hypertension in pregnant women with teletransmitted home blood pressure, Hypertension in
Pregnancy, 27, 305-13, 2008
Magee 2007
Magee, L. A., Von Dadelszen, P., Chan, S., Gafni, A., Gruslin, A., Helewa, M., Hewson, S.,
Kavuma, E., Lee, S. K., Logan, A. G., McKay, D., Moutquin, J. M., Ohlsson, A., Rey, E.,
Ross, S., Singer, J., Willan, A. R., Hannah, M. E., The control of hypertension in pregnancy
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study pilot trial, BJOG: An International Journal of Obstetrics and Gynaecology, 114, 770-
e20, 2007
Magee 2015
Magee, L. A., von Dadelszen, P., Rey, E., Ross, S., Asztalos, E., Murphy, K. E., Menzies, J.,
Sanchez, J., Singer, J., Gafni, A., Gruslin, A., Helewa, M., Hutton, E., Lee, S. K., Lee, T.,
Logan, A. G., Ganzevoort, W., Welch, R., Thornton, J. G., Moutquin, J. M., Less-tight versus
tight control of hypertension in pregnancy, New England Journal of Medicine, 372, 407-17,
2015
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Appendices
Appendices
Appendix A – Review protocol
Table 3: Review protocol
Field (based on PRISMA-P) Content
Key area in the scope Assessment of women who present with or develop
hypertension without proteinuria during pregnancy (gestational
hypertension)
Actual review questions What is the best strategy (including frequency) for monitoring
gestational hypertension in women?
Type of review question Intervention review (investigations and monitoring)
Objective of the review To update the recommendations in CG107 (2010) for the
investigation and monitoring of gestational hypertension –
surveillance has identified that this should be updated in light of
the confidential enquiry into maternal deaths (with regards to
treatment thresholds and targets), and the CHIPS study
Eligibility criteria – population/disease/condition/issue/domain Pregnant women with gestational hypertension
Test in mother Tests in mother for monitoring:
 Blood pressure
 Monitoring target for BP
 Haematological:
o Platelet
o Coagulation/clotting screen
 Renal function:
o Creatinine
 Liver function:
o Transaminases
 Urine testing:
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Appendices

o Dipstick
o Proteinuria (protein/creatinine ratio, PCR)
o Albuminuria (albumin/creatinine ratio, ACR)
o 24 hour urine collections
 PlGF (placental growth factor)
 sFLT1/PlGF (soluble fms-like tyrosine kinase 1 / placental
growth factor)
 Ultrasound
 CTG / EFM (Electronic Fetal Monitoring)
 Place of monitoring (inpatient compared to outpatient)
Eligibility criteria – comparator(s)/control or reference (gold) standard  Testing (followed by treatment, if appropriate) vs not testing
(monitoring review)  Single testing (followed by treatment, if appropriate) vs
repeated testing (followed by treatment, if appropriate)
 Different schedules of testing frequency (e.g. weekly versus
monthly)
 Any vs PCR (protein: creatinine ratio)/ACR
(albumin:creatinine ratio)
 One test compared to a different test
Outcomes and prioritisation Outcomes for the baby:
(monitoring review) Critical outcomes:
 Perinatal mortality
o Stillbirth (include if reported as part of perinatal mortality)
o Neonatal death up to 7 days (include if reported as part of
perinatal mortality)
 Small-for-gestational age (BW<10th centile)
Important outcomes:
 Gestational age at delivery
 Admission to neonatal unit
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Appendices
Outcomes for the women:

Critical outcome:
 Severe hypertension (SBP ≥ 160 and/or DBP ≥ 110 mmHg)
Important outcomes:
 Progression to pre-eclampsia
 Placental abruption
 Mode of birth
 Maternal death
Eligibility criteria – study design Only published full text papers in English language
 Systematic reviews of RCTs
 RCTs
 Comparative cohort studies (only if RCTs unavailable or
limited data to inform decision making)
Conference abstracts of RCTs will only be considered if no
evidence is available from full published RCTs (only for critical
outcomes and if no evidence from RCTs or comparative cohort
studies available and are recent i.e., in the last 2 years-authors
will be contacted for further information)
Exclusion criteria
Proposed stratified, sensitivity/sub-group analysis, or meta-regression Stratify by mild/moderate/severe hypertension
Stratify for gestational age:
- <34 weeks
- 34+0 to 36+6 weeks
- >=37+0 weeks
Selection process – duplicate screening/selection/analysis Duplicate screening/selection/analysis will be undertaken for

this review on at least 10% of records and where possible all
19
FINAL
Appendices

records. Included and excluded studies will be cross checked
with the committee and with published systematic reviews
when available.
Data management (software) (monitoring review) If pairwise meta-analyses are undertaken, they will be
performed using Cochrane Review Manager (RevMan5).
‘GRADE’ will be used to assess the quality of evidence for
each outcome.
STAR will be used for bibliographies/citations, text mining, and
study sifting, data extraction and quality assessment/critical
appraisal.
Information sources – databases and dates Sources to be searched: Medline, Medline In-Process,
CCTR, CDSR, DARE, HTA and Embase.
Limits (e.g. date, study design): Study design limited to
Systematic Reviews, RCTs and Comparative Cohort Studies.
Apply standard animal/non-English language filters. No date
limit.
Supplementary search techniques: No supplementary
search techniques were used.
Key papers (from surveillance report):
 Magee LA, von Dadelszen P, Rey E, Ross S, Asztalos E,
Murphy KE, Menzies J, Sanchez J, Singer J, Gafni A, Gruslin
A. Less-tight versus tight control of hypertension in
pregnancy. New England Journal of Medicine. 2015 Jan
29;372(5):407-17.
 Wilkinson H. Saving mothers’ lives. Reviewing maternal
deaths to make motherhood safer: 2006–2008. BJOG: An
International Journal of Obstetrics & Gynaecology. 2011 Oct
1;118(11):1402-3. (surveillance report stated that this study
is unlikely to impact on the guideline recommendations)
See appendix B for full strategies.
20
FINAL
Appendices

Identify if an update This is an update. Studies meeting the current protocol criteria
and previously included in the 2010 guideline (CG107) will be
included in this update.
Author contacts  Developer: National Guideline Alliance
NGA-enquiries@RCOG.org.uk
Highlight if amendment to previous protocol Items added in this protocol:
 tests added: PlGF (placental growth factor); sFLT1/PlGF
(soluble fms-like tyrosine kinase 1 / placental growth factor);
Ultrasound and CTG / EFM (Electronic Fetal Monitoring)
 for the comparisons, it was stated that the test should be
compared with PCR (protein creatinine ratio)/ACR (albumin
creatinine ratio) should be measured.
Tests removed from the previous protocol:
 Interventions removed: blood pressure and dipstick as part of
the interventions
The population, comparisons and outcomes are the same as in

the 2010 protocol for this review question.
Search strategy – for one database For details please see appendix B
Data collection process – forms/duplicate Studies included in the previous guideline (CG107) that meet
the inclusion criteria of this protocol will be re-extracted in a
standardised evidence table and published as appendix D
(clinical evidence tables) or H (economic evidence tables)
Data items – define all variables to be collected For clinical evidence tables (appendix D), the following data
items will be collected: full reference, study ID, type of study,
objective country/ies where the study was carried out, inclusion
criteria, exclusion criteria, methods, results and limitations.
Methods for assessing bias at outcome/study level Appraisal of methodological quality:
21
FINAL
Appendices

 The methodological quality of each study will be assessed
using an appropriate checklist:
- Systematic review and Meta-analyses – ROBIS
- Randomised controlled trials – Cochrane risk of bias tool
- Newcastle-Ottowa scale for cohort studies
For details please see section 6.2 of Developing NICE
guidelines: the manual
The risk of bias across all available evidence will evaluated for
each outcome using an adaptation of the ‘Grading of
Recommendations Assessment, Development and Evaluation
(GRADE) toolbox’ developed by the international GRADE
working group http://www.gradeworkinggroup.org/
Studies included in the previous guideline (CG107) that meet
the inclusion criteria of this protocol will be assessed with the
above mentioned checklists (as appropriate) and outcomes will
be evaluated using GRADE.
Criteria for quantitative synthesis For details please see section 6.4 of Developing NICE
guidelines: the manual
Methods for quantitative analysis – combining studies and exploring Synthesis of data:
(in)consistency  Meta-analysis will be conducted where appropriate using
Review Manager/ STATA.
Minimum important differences
 Default values will be used of: 0.8 and 1.25 for RR of
dichotomous outcomes; 0.5 times SD of the control group for
continuous outcomes, unless more appropriate values are
identified by the guideline committee or in the literature.
Double sifting, data extraction and methodological quality
assessment:
 Sifting, data extraction, appraisal of methodological quality
and GRADE assessment will be performed by the systematic
reviewer. Quality control will be performed by the senior
22
FINAL
Appendices

systematic reviewer. Dual quality assessment and data
extraction will be performed.
How the evidence included in the previous guideline will
be incorporated with the new evidence
 Studies meeting the current protocol criteria and previously
included in the previous guideline (CG107) will be included in
this update. The methods for quantitative analysis –
combining studies and exploring (in)consistency- will be the
same as for the new evidence (see above).
Meta-bias assessment – publication bias, selective reporting bias For details please see section 6.2 of Developing NICE
guidelines: the manual.
Confidence in cumulative evidence For details please see sections 6.4 and 9.1 of Developing
NICE guidelines: the manual
Rationale/context – what is known For details please see the introduction to the evidence review
in the full guideline.
Describe contributions of authors and guarantor A multidisciplinary committee developed the guideline. The
committee was convened by the National Guideline Alliance
and chaired by Sarah Fishburn in line with section 3 of
Developing NICE guidelines: the manual.
Staff from the National Guideline Alliance undertook systematic
literature searches, appraised the evidence, conducted meta-
analysis and cost-effectiveness analysis where appropriate,
and drafted the guideline in collaboration with the committee.
For details please see the methods chapter of the full
guideline.
Sources of funding/support The National Guideline Alliance is funded by NICE and hosted
by the Royal College of Obstetricians and Gynaecologists
Name of sponsor The National Guideline Alliance is funded by NICE and hosted
by the Royal College of Obstetricians and Gynaecologists
Roles of sponsor NICE funds the National Guideline Alliance to develop
guidelines for the NHS in England.
23
FINAL
Appendices

PROSPERO registration number Not registered with PROSPERO
CDSR: Cochrane Database of Systematic Reviews; CCTR: Cochrane Controlled Trials Register; CI: confidence interval; DARE: Database of Abstracts of Reviews of Effects;
GRADE: Grading of Recommendations Assessment, Development and Evaluation; HTA: Health Technology Assessment; NICE: National Institute for Health and Care
Excellence; NGA: National Guideline Alliance; RCT: randomised controlled trial; RoB: risk of bias; ROBIS: Risk of Bias in Systematic Reviews; SD: standard deviation;
24
Appendix B – Literature search strategies
Databases: Medline; Medline EPub Ahead of Print; and Medline In-Process & Other
Non-Indexed Citations
Date of last search: 23/03/18
# Searches
1 META-ANALYSIS/
2 META-ANALYSIS AS TOPIC/
3 (meta analy* or metanaly* or metaanaly*).ti,ab.
4 ((systematic* or evidence*) adj2 (review* or overview*)).ti,ab.
5 (reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab.
6 (search strategy or search criteria or systematic search or study selection or data extraction).ab.
7 (search* adj4 literature).ab.
8 (medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation
index or bids or cancerlit).ab.
9 cochrane.jw.
10 or/1-9
11 randomized controlled trial.pt.
12 controlled clinical trial.pt.
13 pragmatic clinical trial.pt.
14 randomi#ed.ab.
15 placebo.ab.
16 randomly.ab.
17 CLINICAL TRIALS AS TOPIC/
18 trial.ti.
19 or/11-18
20 COHORT STUDIES/
21 (cohort adj3 (study or studies)).ti,ab.
22 (Cohort adj3 analy$).ti,ab.
23 FOLLOW-UP STUDIES/
24 (Follow$ up adj3 (study or studies)).ti,ab.
25 LONGITUDINAL STUDIES/
26 longitudinal$.ti,ab.
27 PROSPECTIVE STUDIES/
28 prospective$.ti,ab.
29 RETROSPECTIVE STUDIES/
30 retrospective$.ti,ab.
31 OBSERVATIONAL STUDY/
32 observational$.ti,ab.
33 or/20-32
34 HYPERTENSION, PREGNANCY-INDUCED/
35 PREGNANCY/ and HYPERTENSION/
36 PRE-ECLAMPSIA/
37 HELLP SYNDROME/
38 ((pregnan$ or gestation$) adj5 hypertensi$).ti.
39 preeclamp$.ti,ab.
40 pre eclamp$.ti,ab.
41 HELLP.ti,ab.
42 tox?emi$.ti,ab.
43 or/34-42
44 BLOOD PRESSURE DETERMINATION/
45 BLOOD PRESSURE MONITORING, AMBULATORY/
46 ((investigat$ or monitor$ or test$) adj5 blood adj3 pressure?).ti.
47 ((investigat$ or monitor$ or test$) adj5 blood adj3 pressure?).ab. /freq=2
48 BLOOD PRESSURE/ and (Optimal$ or Target? or Goal?).ti,ab.
49 ((Optimal$ or Target? or Goal? or Aim$) adj5 blood adj3 pressure?).ti,ab.
50 exp PLATELET FUNCTION TESTS/
51 ((investigat$ or monitor$ or test$) adj5 platelet?).ti,ab.
52 (bleed$ adj3 time?).ti,ab.
53 (clot? adj3 retract$).ti,ab.
54 (mean adj3 platelet? adj3 vol$).ti,ab.
55 (platelet? adj3 (count? or number?)).ti.
25
(June 2019)
# Searches
56 (platelet? adj3 (count? or number?)).ab. /freq=2
57 *BLOOD PLATELETS/ and (investigat$ or monitor$ or test$).ti,ab.
58 exp BLOOD COAGULATION TESTS/
59 ((investigat$ or monitor$ or test$) adj5 (coagulat$ or clot$)).ti,ab.
60 (screen$ adj5 (coagulat$ or clot$)).ti,ab.
61 international normali?ed ratio?.ti,ab.
62 (partial$ adj3 thromboplatin adj3 time?).ti,ab.
63 (cephalin kaolin adj3 coagulat$ adj3 time?).ti,ab.
64 (prothrombin adj3 time?).ti,ab.
65 thromb?elastograph$.ti,ab.
66 (thrombin adj3 time?).ti,ab.
67 (whole adj3 blood adj3 (coagulat$ or clot$) adj3 time?).ti,ab.
68 KIDNEY FUNCTION TESTS/
69 ((investigat$ or monitor$ or test$) adj5 (renal or kidney?) adj3 function?).ti,ab.
70 *CREATININE/ and (investigat$ or monitor$ or test$).ti,ab.
71 ((investigat$ or monitor$ or test$) adj5 creatinine).ti,ab.
72 LIVER FUNCTION TESTS/
73 ((investigat$ or monitor$ or test$) adj5 liver adj3 function?).ti,ab.
74 *TRANSAMINASES/ and (investigat$ or monitor$ or test$).ti,ab.
75 ((investigat$ or monitor$ or test$) adj5 transaminases).ti,ab.
76 URINALYSIS/
77 urinalysis.ti,ab.
78 ((investigat$ or monitor$ or test$) adj5 urine).ti,ab.
79 REAGENT STRIPS/
80 (dipstick? or dip-stick?).ti,ab.
81 *PROTEINURIA/ and (investigat$ or monitor$ or test$).ti,ab.
82 ((investigat$ or monitor$ or test$) adj5 proteinuria).ti,ab.
83 ((spot$ or ratio$) adj5 protein$ adj3 creatinine).ti,ab.
84 *ALBUMINURIA/ and (investigat$ or monitor$ or test$).ti,ab.
85 ((investigat$ or monitor$ or test$) adj5 albuminuria).ti,ab.
86 ((spot$ or ratio$) adj5 creatinine adj3 albumin$).ti,ab.
87 (("24" or twenty four) adj2 (hour? or hr?) adj5 urin$).ti,ab.
88 (24h$ adj5 urin$).ti,ab.
89 *PLACENTA GROWTH FACTOR/ and (investigat$ or monitor$ or test$).ti,ab.
90 ((investigat$ or monitor$ or test$) adj5 (placenta? growth factor or PLGF)).ti,ab.
91 ((soluble fms-like tyrosine kinase-1 or sFLT1) adj5 (placenta? growth factor or PLGF)).ti,ab.
92 exp *ULTRASONOGRAPHY/ and (investigat$ or monitor$ or test$).ti,ab.
93 ((investigat$ or monitor$ or test$) adj5 (ultrasonograph$ or sonograph$ or ultrasound or sonogram?)).ti,ab.
94 ((investigat$ or monitor$ or test$) adj5 (fetal or fetus$) adj3 (grow$ or size?)).ti,ab.
95 ((ultrasonograph$ or sonograph$ or ultrasound or sonogram?) adj5 (fetal or fetus$) adj3 (grow$ or size?)).ti,ab.
96 ((investigat$ or monitor$ or test$) adj5 (amniotic fluid? or liquor) adj3 volume$).ti,ab.
97 ((ultrasonograph$ or sonograph$ or ultrasound or sonogram?) adj5 (amniotic fluid? or liquor) adj3 volume$).ti,ab.
98 ((investigat$ or monitor$ or test$) adj5 doppler? adj3 arter$).ti,ab.
99 ((ultrasonograph$ or sonograph$ or ultrasound or sonogram?) adj5 doppler? adj3 arter$).ti,ab.
100 CARDIOTOCOGRAPHY/
101 cardiotocogra$.ti,ab.
102 CTG.ti,ab.
103 ELECTROCARDIOGRAPHY/
104 electrocardiogra$.ti,ab.
105 ECG.ti,ab.
106 EKG.ti,ab.
107 FETAL MONITORING/
108 UTERINE MONITORING/
109 HEART RATE, FETAL/ and (monitor$ or assess$).ti,ab.
110 exp FETAL HEART/ and (monitor$ or assess$).ti,ab.
111 FETAL DISTRESS/ and (monitor$ or assess$).ti,ab.
112 (electr$ adj5 (f?etal or f?etus$ or uter$) adj5 (heart$ or monitor$ or assess$)).ti,ab.
113 EFM.ti,ab.
114 ((nonstress or non-stress) adj3 test$).ti,ab.
115 NST.ti,ab.
116 ((investigat$ or monitor$ or test$) adj5 place?).ti,ab.
117 INPATIENTS/ and (investigat$ or monitor$ or test$).ti,ab.
118 ((investigat$ or monitor$ or test$) adj5 inpatient?).ti,ab.
119 OUTPATIENTS/ and (investigat$ or monitor$ or test$).ti,ab.
26
(June 2019)
# Searches
120 ((investigat$ or monitor$ or test$) adj5 outpatient?).ti,ab.
121 or/44-120
122 ((frequen$ or regular$ or routine$) adj5 (investigat$ or monitor$ or test$)).ti,ab.
123 ((repetition or repeat$ or rate? or amount?) adj3 (investigat$ or monitor$ or test$)).ti,ab.
124 (number? adj3 test$).ti,ab.
125 or/122-124
126 MONITORING, PHYSIOLOGIC/
127 ((investigat$ or monitor$ or test$) adj5 (pregnan$ or gestation$) adj5 hypertensi$).ti.
128 43 and 121
129 43 and 125
130 43 and 126
131 or/127-130
132 limit 131 to english language
133 LETTER/
134 EDITORIAL/
135 NEWS/
136 exp HISTORICAL ARTICLE/
137 ANECDOTES AS TOPIC/
138 COMMENT/
139 CASE REPORT/
140 (letter or comment*).ti.
141 or/133-140
142 RANDOMIZED CONTROLLED TRIAL/ or random*.ti,ab.
143 141 not 142
144 ANIMALS/ not HUMANS/
145 exp ANIMALS, LABORATORY/
146 exp ANIMAL EXPERIMENTATION/
147 exp MODELS, ANIMAL/
148 exp RODENTIA/
149 (rat or rats or mouse or mice).ti.
150 or/143-149
151 132 not 150
152 10 and 151
153 19 and 151
154 33 and 151
155 or/152-154
Databases: Embase; and Embase Classic

# Searches
1 SYSTEMATIC REVIEW/
2 META-ANALYSIS/
3 (meta analy* or metanaly* or metaanaly*).ti,ab.
4 ((systematic or evidence) adj2 (review* or overview*)).ti,ab.
5 (reference list* or bibliograph* or hand search* or manual search* or relevant journals).ab.
6 (search strategy or search criteria or systematic search or study selection or data extraction).ab.
7 (search* adj4 literature).ab.
8 (medline or pubmed or cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinahl or science citation
index or bids or cancerlit).ab.
9 ((pool* or combined) adj2 (data or trials or studies or results)).ab.
10 cochrane.jw.
11 or/1-10
12 random*.ti,ab.
13 factorial*.ti,ab.
14 (crossover* or cross over*).ti,ab.
15 ((doubl* or singl*) adj blind*).ti,ab.
16 (assign* or allocat* or volunteer* or placebo*).ti,ab.
17 CROSSOVER PROCEDURE/
18 SINGLE BLIND PROCEDURE/
19 RANDOMIZED CONTROLLED TRIAL/
20 DOUBLE BLIND PROCEDURE/
27
(June 2019)
# Searches
21 or/12-20
22 COHORT ANALYSIS/
23 (cohort adj3 (study or studies)).ti,ab.
24 (Cohort adj3 analy$).ti,ab.
25 FOLLOW UP/
26 (Follow$ up adj3 (study or studies)).ti,ab.
27 LONGITUDINAL STUDY/
28 longitudinal$.ti,ab.
29 PROSPECTIVE STUDY/
30 prospective$.ti,ab.
31 RETROSPECTIVE STUDY/
32 retrospective$.ti,ab.
33 OBSERVATIONAL STUDY/
34 observational$.ti,ab.
35 or/22-34
36 MATERNAL HYPERTENSION/
38 PREECLAMPSIA/
39 HELLP SYNDROME/
43 HELLP.ti,ab.
44 tox?emi$.ti,ab.
45 or/36-44
46 *BLOOD PRESSURE MONITORING/
49 *BLOOD PRESSURE/ and (Optimal$ or Target? or Goal?).ti,ab.
51 exp *BLOOD CLOTTING PARAMETERS/
58 *THROMBOCYTE/ and (investigat$ or monitor$ or test$).ti,ab.
59 *BLOOD CLOTTING TEST/
69 *KIDNEY FUNCTION TEST/
71 *CREATININE URINE LEVEL/
74 *LIVER FUNCTION TEST/
76 *AMINOTRANSFERASE/ and (investigat$ or monitor$ or test$).ti,ab.
78 *URINALYSIS/
81 *TEST STRIP/
83 *PROTEIN URINE LEVEL/
28
(June 2019)
# Searches
92 *PLACENTAL GROWTH FACTOR/ and (investigat$ or monitor$ or test$).ti,ab.
95 exp *ECHOGRAPHY/ and (investigat$ or monitor$ or test$).ti,ab.
103 *CARDIOTOCOGRAPHY/
105 CTG.ti,ab.
106 *ELECTROCARDIOGRAPHY/
107 *FETUS ELECTROCARDIOGRAPHY/
109 ECG.ti,ab.
110 EKG.ti,ab.
111 *FETUS MONITORING/
112 *UTERINE ACTIVITY MONITORING/
113 *FETUS HEART RATE/ and (monitor$ or assess$).ti,ab.
114 *FETUS HEART/ and (monitor$ or assess$).ti,ab.
115 *FETUS DISTRESS/ and (monitor$ or assess$).ti,ab.
117 EFM.ti,ab.
119 NST.ti,ab.
121 *HOSPITAL PATIENT/ and (investigat$ or monitor$ or test$).ti,ab.
123 *OUTPATIENT/ and (investigat$ or monitor$ or test$).ti,ab.
125 or/46-124
129 or/126-128
130 *MONITORING/
131 *PHYSIOLOGIC MONITORING/
133 45 and 125
134 45 and 129
135 45 and 130
136 45 and 131
137 or/132-136
139 letter.pt. or LETTER/
140 note.pt.
141 editorial.pt.
142 CASE REPORT/ or CASE STUDY/
144 or/139-143
146 144 not 145
147 ANIMAL/ not HUMAN/
148 NONHUMAN/
29
(June 2019)
# Searches
149 exp ANIMAL EXPERIMENT/
150 exp EXPERIMENTAL ANIMAL/
151 ANIMAL MODEL/
152 exp RODENT/
154 or/146-153
155 138 not 154
156 11 and 155
157 21 and 155
158 35 and 155
159 or/156-158
Databases: Cochrane Central Register of Controlled Trials; Cochrane Database of

Systematic Reviews; Database of Abstracts of Reviews of Effects; and Health
Technology Assessment
# Searches
1 MeSH descriptor: [HYPERTENSION, PREGNANCY-INDUCED] this term only
2 MeSH descriptor: [PREGNANCY] this term only
3 MeSH descriptor: [HYPERTENSION] this term only
4 #2 and #3
5 MeSH descriptor: [PRE-ECLAMPSIA] this term only
6 MeSH descriptor: [HELLP SYNDROME] this term only
7 ((pregnan* or gestation*) near/5 hypertensi*):ti
8 preeclamp*:ti,ab
9 pre eclamp*:ti,ab
10 HELLP:ti,ab
11 tox?emi*:ti,ab
12 #1 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11
13 MeSH descriptor: [BLOOD PRESSURE DETERMINATION] this term only
14 MeSH descriptor: [BLOOD PRESSURE MONITORING, AMBULATORY] this term only
15 ((investigat* or monitor* or test*) near/5 blood near/3 pressure?):ti,ab
16 MeSH descriptor: [BLOOD PRESSURE] this term only
17 (Optimal* or Target? or Goal?):ti,ab
18 #16 and #17
19 ((Optimal* or Target? or Goal? or Aim*) near/5 blood near/3 pressure?):ti,ab
20 MeSH descriptor: [PLATELET FUNCTION TESTS] explode all trees
21 ((investigat* or monitor* or test*) near/5 platelet?):ti,ab
22 (bleed* near/3 time?):ti,ab
23 (clot? near/3 retract*):ti,ab
24 (mean near/3 platelet? near/3 vol*):ti,ab
25 (platelet? near/3 (count? or number?)):ti,ab
26 MeSH descriptor: [BLOOD PLATELETS] this term only
27 (investigat* or monitor* or test*):ti,ab
28 #26 and #27
29 MeSH descriptor: [BLOOD COAGULATION TESTS] explode all trees
30 ((investigat* or monitor* or test*) near/5 (coagulat* or clot*)):ti,ab
31 (screen* near/5 (coagulat* or clot*)):ti,ab
32 “international normali?ed ratio?”:ti,ab
33 (partial* near/3 thromboplatin near/3 time?):ti,ab
34 (cephalin kaolin near/3 coagulat* near/3 time?):ti,ab
35 (prothrombin near/3 time?):ti,ab
36 thromb?elastograph*:ti,ab
37 (thrombin near/3 time?):ti,ab
38 (whole near/3 blood near/3 (coagulat* or clot*) near/3 time?):ti,ab
39 MeSH descriptor: [KIDNEY FUNCTION TESTS] this term only
40 ((investigat* or monitor* or test*) near/5 (renal or kidney?) near/3 function?):ti,ab
41 MeSH descriptor: [CREATININE] this term only
43 #41 and #42
30
(June 2019)
# Searches
44 ((investigat* or monitor* or test*) near/5 creatinine):ti,ab
45 MeSH descriptor: [LIVER FUNCTION TESTS] this term only
46 ((investigat* or monitor* or test*) near/5 liver near/3 function?):ti,ab
47 MeSH descriptor: [TRANSAMINASES] this term only
49 #47 and #48
50 ((investigat* or monitor* or test*) near/5 transaminases):ti,ab
51 MeSH descriptor: [URINALYSIS] this term only
52 urinalysis:ti,ab
53 ((investigat* or monitor* or test*) near/5 urine):ti,ab
54 MeSH descriptor: [REAGENT STRIPS] this term only
55 (dipstick? or dip-stick?):ti,ab
56 MeSH descriptor: [PROTEINURIA] this term only
58 #56 and #57
59 ((investigat* or monitor* or test*) near/5 proteinuria):ti,ab
60 ((spot* or ratio*) near/5 protein* near/3 creatinine):ti,ab
61 MeSH descriptor: [ALBUMINURIA] this term only
63 #61 and #62
64 ((investigat* or monitor* or test*) near/5 albuminuria):ti,ab
65 ((spot* or ratio*) near/5 creatinine near/3 albumin*):ti,ab
66 (("24" or “twenty four”) near/2 (hour? or hr?) near/5 urin*):ti,ab
67 (24h* near/5 urin*):ti,ab
68 MeSH descriptor: [PLACENTA GROWTH FACTOR] this term only
70 #68 and #69
71 ((investigat* or monitor* or test*) near/5 (placenta? growth factor or PLGF)):ti,ab
72 ((soluble fms-like tyrosine kinase-1 or sFLT1) near/5 (placenta? growth factor or PLGF)):ti,ab
73 MeSH descriptor: [ULTRASONOGRAPHY] explode all trees
75 #73 and #74
76 ((investigat* or monitor* or test*) near/5 (ultrasonograph* or sonograph* or ultrasound or sonogram?)):ti,ab
77 ((investigat* or monitor* or test*) near/5 (fetal or fetus*) near/3 (grow* or size?)):ti,ab
78 ((ultrasonograph* or sonograph* or ultrasound or sonogram?) near/5 (fetal or fetus*) near/3 (grow* or size?)):ti,ab
79 ((investigat* or monitor* or test*) near/5 (amniotic fluid? or liquor) near/3 volume*):ti,ab
80 ((ultrasonograph* or sonograph* or ultrasound or sonogram?) near/5 (amniotic fluid? or liquor) near/3 volume*):ti,ab
81 ((investigat* or monitor* or test*) near/5 doppler? near/3 arter*):ti,ab
82 ((ultrasonograph* or sonograph* or ultrasound or sonogram?) near/5 doppler? near/3 arter*):ti,ab
83 MeSH descriptor: [CARDIOTOCOGRAPHY] this term only
84 cardiotocogra*:ti,ab
85 CTG:ti,ab
86 MeSH descriptor: [ELECTROCARDIOGRAPHY] this term only
87 electrocardiogra*:ti,ab
88 ECG:ti,ab
89 EKG:ti,ab
90 MeSH descriptor: [FETAL MONITORING] this term only
91 MeSH descriptor: [UTERINE MONITORING] this term only
92 MeSH descriptor: [HEART RATE, FETAL] this term only
93 MeSH descriptor: [FETAL HEART] explode all trees
94 MeSH descriptor: [FETAL DISTRESS] this term only
95 #92 or #93 or #94
96 (monitor* or assess*):ti,ab
97 #95 and #96
98 (electr* near/5 (f?etal or f?etus* or uter*) near/5 (heart* or monitor* or assess*)):ti,ab
99 EFM:ti,ab
100 ((nonstress or non-stress) near/3 test*):ti,ab
101 NST:ti,ab
102 ((investigat* or monitor* or test*) near/5 place?):ti,ab
103 MeSH descriptor: [INPATIENTS] this term only
105 #103 and #104
106 ((investigat* or monitor* or test*) near/5 inpatient?):ti,ab
107 MeSH descriptor: [OUTPATIENTS] this term only
31
(June 2019)
# Searches
109 #107 and #108
110 ((investigat* or monitor* or test*) near/5 outpatient?):ti,ab
111 #13 or #14 or #15 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #28 or #29 or #30 or #31 or #32 or #33
or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #43 or #44 or #45 or #46 or #49 or #50 or #51 or #52 or #53 or
#54 or #55 or #58 or #59 or #60 or #63 or #64 or #65 or #66 or #67 or #70 or #71 or #72 or #75 or #76 or #77 or #78
#100 or #101 or #102 or #105 or #106 or #109
112 ((frequen* or regular* or routine*) near/5 (investigat* or monitor* or test*)):ti,ab
113 ((repetition or repeat* or rate? or amount?) near/3 (investigat* or monitor* or test*)):ti,ab
114 (number? near/3 test*):ti,ab
115 #112 or #113 or #114
116 MeSH descriptor: [MONITORING, PHYSIOLOGIC] this term only
117 ((investigat* or monitor* or test*) near/5 (pregnan* or gestation*) near/5 hypertensi*):ti,ab
118 #12 and #111
119 #12 and #115
120 #12 and #116
121 #117 or #118 or #119 or #120
Health economics search strategies

Databases: Medline; Medline EPub Ahead of Print; and Medline In-Process & Other
Non-Indexed Citations
# Searches
1 ECONOMICS/
2 VALUE OF LIFE/
3 exp "COSTS AND COST ANALYSIS"/
4 exp ECONOMICS, HOSPITAL/
5 exp ECONOMICS, MEDICAL/
6 exp RESOURCE ALLOCATION/
7 ECONOMICS, NURSING/
8 ECONOMICS, PHARMACEUTICAL/
9 exp "FEES AND CHARGES"/
10 exp BUDGETS/
11 budget*.ti,ab.
12 cost*.ti,ab.
13 (economic* or pharmaco?economic*).ti,ab.
14 (price* or pricing*).ti,ab.
15 (financ* or fee or fees or expenditure* or saving*).ti,ab.
16 (value adj2 (money or monetary)).ti,ab.
17 resourc* allocat*.ti,ab.
18 (fund or funds or funding* or funded).ti,ab.
19 (ration or rations or rationing* or rationed).ti,ab.
20 ec.fs.
21 or/1-20
22 HYPERTENSION, PREGNANCY-INDUCED/
24 PRE-ECLAMPSIA/
25 HELLP SYNDROME/
29 HELLP.ti,ab.
30 tox?emi$.ti,ab.
31 or/22-30
32 BLOOD PRESSURE DETERMINATION/
33 BLOOD PRESSURE MONITORING, AMBULATORY/
32
(June 2019)
# Searches
36 BLOOD PRESSURE/ and (Optimal$ or Target? or Goal?).ti,ab.
38 exp PLATELET FUNCTION TESTS/
45 *BLOOD PLATELETS/ and (investigat$ or monitor$ or test$).ti,ab.
46 exp BLOOD COAGULATION TESTS/
56 KIDNEY FUNCTION TESTS/
60 LIVER FUNCTION TESTS/
62 *TRANSAMINASES/ and (investigat$ or monitor$ or test$).ti,ab.
64 URINALYSIS/
67 REAGENT STRIPS/
77 *PLACENTA GROWTH FACTOR/ and (investigat$ or monitor$ or test$).ti,ab.
80 exp *ULTRASONOGRAPHY/ and (investigat$ or monitor$ or test$).ti,ab.
88 CARDIOTOCOGRAPHY/
90 CTG.ti,ab.
91 ELECTROCARDIOGRAPHY/
93 ECG.ti,ab.
94 EKG.ti,ab.
95 FETAL MONITORING/
96 UTERINE MONITORING/
97 HEART RATE, FETAL/ and (monitor$ or assess$).ti,ab.
98 exp FETAL HEART/ and (monitor$ or assess$).ti,ab.
99 FETAL DISTRESS/ and (monitor$ or assess$).ti,ab.
33
(June 2019)
# Searches
101 EFM.ti,ab.
103 NST.ti,ab.
105 INPATIENTS/ and (investigat$ or monitor$ or test$).ti,ab.
107 OUTPATIENTS/ and (investigat$ or monitor$ or test$).ti,ab.
109 or/32-108
113 or/110-112
114 MONITORING, PHYSIOLOGIC/
116 31 and 109
117 31 and 113
118 31 and 114
119 or/115-118
121 LETTER/
122 EDITORIAL/
123 NEWS/
124 exp HISTORICAL ARTICLE/
125 ANECDOTES AS TOPIC/
126 COMMENT/
127 CASE REPORT/
129 or/121-128
131 129 not 130
132 ANIMALS/ not HUMANS/
133 exp ANIMALS, LABORATORY/
134 exp ANIMAL EXPERIMENTATION/
135 exp MODELS, ANIMAL/
136 exp RODENTIA/
138 or/131-137
139 120 not 138
140 21 and 139
Databases: Embase; and Embase Classic

# Searches
1 HEALTH ECONOMICS/
2 exp ECONOMIC EVALUATION/
3 exp HEALTH CARE COST/
4 exp FEE/
5 BUDGET/
6 FUNDING/
7 RESOURCE ALLOCATION/
8 budget*.ti,ab.
9 cost*.ti,ab.
10 (economic* or pharmaco?economic*).ti,ab.
11 (price* or pricing*).ti,ab.
12 (financ* or fee or fees or expenditure* or saving*).ti,ab.
13 (value adj2 (money or monetary)).ti,ab.
14 resourc* allocat*.ti,ab.
34
(June 2019)
# Searches
15 (fund or funds or funding* or funded).ti,ab.
16 (ration or rations or rationing* or rationed).ti,ab.
17 or/1-16
18 MATERNAL HYPERTENSION/
20 PREECLAMPSIA/
21 HELLP SYNDROME/
25 HELLP.ti,ab.
26 tox?emi$.ti,ab.
27 or/18-26
28 *BLOOD PRESSURE MONITORING/
31 *BLOOD PRESSURE/ and (Optimal$ or Target? or Goal?).ti,ab.
33 exp *BLOOD CLOTTING PARAMETERS/
40 *THROMBOCYTE/ and (investigat$ or monitor$ or test$).ti,ab.
41 *BLOOD CLOTTING TEST/
51 *KIDNEY FUNCTION TEST/
53 *CREATININE URINE LEVEL/
56 *LIVER FUNCTION TEST/
58 *AMINOTRANSFERASE/ and (investigat$ or monitor$ or test$).ti,ab.
60 *URINALYSIS/
63 *TEST STRIP/
65 *PROTEIN URINE LEVEL/
74 *PLACENTAL GROWTH FACTOR/ and (investigat$ or monitor$ or test$).ti,ab.
77 exp *ECHOGRAPHY/ and (investigat$ or monitor$ or test$).ti,ab.
35
(June 2019)
# Searches
85 *CARDIOTOCOGRAPHY/
87 CTG.ti,ab.
88 *ELECTROCARDIOGRAPHY/
89 *FETUS ELECTROCARDIOGRAPHY/
91 ECG.ti,ab.
92 EKG.ti,ab.
93 *FETUS MONITORING/
94 *UTERINE ACTIVITY MONITORING/
95 *FETUS HEART RATE/ and (monitor$ or assess$).ti,ab.
96 *FETUS HEART/ and (monitor$ or assess$).ti,ab.
97 *FETUS DISTRESS/ and (monitor$ or assess$).ti,ab.
99 EFM.ti,ab.
101 NST.ti,ab.
103 *HOSPITAL PATIENT/ and (investigat$ or monitor$ or test$).ti,ab.
105 *OUTPATIENT/ and (investigat$ or monitor$ or test$).ti,ab.
107 or/28-106
111 or/108-110
112 *MONITORING/
113 *PHYSIOLOGIC MONITORING/
115 27 and 107
116 27 and 111
117 27 and 112
118 27 and 113
119 or/114-118
121 letter.pt. or LETTER/
122 note.pt.
123 editorial.pt.
124 CASE REPORT/ or CASE STUDY/
126 or/121-125
128 126 not 127
129 ANIMAL/ not HUMAN/
130 NONHUMAN/
131 exp ANIMAL EXPERIMENT/
132 exp EXPERIMENTAL ANIMAL/
133 ANIMAL MODEL/
134 exp RODENT/
136 or/128-135
137 120 not 136
138 17 and 137
Database: Cochrane Central Register of Controlled Trials
36
(June 2019)
# Searches
1 MeSH descriptor: [ECONOMICS] this term only
2 MeSH descriptor: [VALUE OF LIFE] this term only
3 MeSH descriptor: [COSTS AND COST ANALYSIS] explode all trees
4 MeSH descriptor: [ECONOMICS, HOSPITAL] explode all trees
5 MeSH descriptor: [ECONOMICS, MEDICAL] explode all trees
6 MeSH descriptor: [RESOURCE ALLOCATION] explode all trees
7 MeSH descriptor: [ECONOMICS, NURSING] this term only
8 MeSH descriptor: [ECONOMICS, PHARMACEUTICAL] this term only
9 MeSH descriptor: [FEES AND CHARGES] explode all trees
10 MeSH descriptor: [BUDGETS] explode all trees
11 budget*:ti,ab
12 cost*:ti,ab
13 (economic* or pharmaco?economic*):ti,ab
14 (price* or pricing*):ti,ab
15 (financ* or fee or fees or expenditure* or saving*):ti,ab
16 (value near/2 (money or monetary)):ti,ab
17 resourc* allocat*:ti,ab
18 (fund or funds or funding* or funded):ti,ab
19 (ration or rations or rationing* or rationed):ti,ab
20 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or
#19
24 #22 and #23
28 preeclamp*:ti,ab
29 pre eclamp*:ti,ab
30 HELLP:ti,ab
31 tox?emi*:ti,ab
38 #36 and #37
48 #46 and #47
37
(June 2019)
# Searches
63 #61 and #62
69 #67 and #68
72 urinalysis:ti,ab
78 #76 and #77
83 #61 and #62
90 #88 and #89
95 #93 and #94
105 CTG:ti,ab
108 ECG:ti,ab
109 EKG:ti,ab
115 #112 or #113 or #114
117 #115 and #116
119 EFM:ti,ab
121 NST:ti,ab
125 #123 and #124
38
(June 2019)
# Searches
129 #127 and #128
or #99 or #100 or #101 or #102 or #103 or #104 or #105 or #106 or #107 or #108 or #109 or #110 or #111 or #117 or
#118 or #119 or #120 or #121 or #122 or #125 or #126 or #129 or #130
135 #132 or #133 or #134
138 #32 and #131
139 #32 and #135
140 #32 and #136
141 #137 or #138 or #139 or #140
142 #20 and #141
Databases: Health Technology Assessment; and NHS Economic Evaluation Database

# Searches
4 #2 and #3
8 preeclamp*:ti,ab
9 pre eclamp*:ti,ab
10 HELLP:ti,ab
11 tox?emi*:ti,ab
18 #16 and #17
28 #26 and #27
39
(June 2019)
# Searches
43 #41 and #42
49 #47 and #48
52 urinalysis:ti,ab
58 #56 and #57
63 #61 and #62
70 #68 and #69
75 #73 and #74
85 CTG:ti,ab
88 ECG:ti,ab
89 EKG:ti,ab
95 #92 or #93 or #94
97 #95 and #96
99 EFM:ti,ab
101 NST:ti,ab
40
(June 2019)
# Searches
105 #103 and #104
109 #107 and #108
#100 or #101 or #102 or #105 or #106 or #109
115 #112 or #113 or #114
118 #12 and #111
119 #12 and #115
120 #12 and #116
121 #117 or #118 or #119 or #120
41
(June 2019)
Appendix C – Clinical evidence study selection
Titles and abstracts

identified, N=2681
Full copies retrieved Excluded, N=2638

and assessed for (not relevant population,
eligibility, N=43 design, intervention,
comparison, outcomes,
unable to retrieve)
Publications included Publications excluded

in review, N=6 from review, N=37
(refer to excluded
studies list)
42
(June 2019)
Appendex D – Clinical evidence tables
Table 4: Clinical evidence tables
Study details Participants Interventions Methods Outcomes and Results Comments
Full citation Sample size Interventions Details Results Limitations

n= 220 (Group K4 = 103, Group Test using K4 sounds vs Diagnoses Outcomes for the baby Risk of Bias assessed using
Brown, M. A., K5 = 117) test using K5 sounds Pre-eclampsia: diagnosed Perinatal mortality: K4 (20 per Cochrane ROB tool
Buddle, M. L., All completed the trial Management based on according to Australasian 1000 cases, 19%)*, K5 (20 per Selection bias: LOW
Farrell, T., diastolic blood pressure Society for the Study of 1000 cases, 17%)*, p=0.90 (ns)
Davis, G., recording using K4 (muffling) Hypertension in
Jones, M.,  Random sequence
or K5 (disappearance) of Pregnancy, and 300mg Small for gestational age (<10th
Randomised Characteristics generation Intervention was
Korotkoff sounds. protein in a 24-hr urine centile): K4 (n=10/103, 10%), K5
trial of Age: 29±5yrs (both K4 and K5) Clinical management randomly assigned to
collection or spot-urine (n=14/117, 12%), p=0.59 (ns)
management of Gestation at study entry: individual pregnant women
according to standard protein:creatinine>30mg/
hypertensive 35±4wks (both K4 and K5) from computer generated list
protocol used in the two mmol. Gestational age at birth: K4
pregnancies by DBP at study entry: 95±5mmHg participating obstetrics of random numbers (LOW)
Gestational Hypertension: 37±3 wks, K5 37±3 wks p=0.56
Korotkoff phase (both K4 and K5) - severe units. SBP≥160mmHg, or isolated "de-novo" (new) (ns)  Allocation concealment
IV or phase V, diastolic hypertension at study DBP≥90mmHg, or both hypertension in second Randomization was
Lancet (London, entry: K4 n=34/103 (33%); K5 received long-term half of pregnancy, which Admission to neonatal unit: not determined before the start
England), 352, n=20/117 (17%) antihypertensive therapy returned to normal within reported of the study and maintained
777-81, 1998 SBP at study entry: 3-months post-natally. *These are values reported in centrally in a closed file...
140±12mmHg (K4), Essential (chronic) the paper, but do not make randomization was stratified
Ref Id 139±11mmHg (K5) hypertension: sense (20/1000 cases is not before the study (LOW)
Gestational hypertension: cause hypertension present ~20%, it is ~2%), it is
787637 of hypertension noted, not before pregnancy or unclear which value is correct Performance bias: HIGH
reported - unclear whether diagnosed in first half of from the available data
Country/ies women had Essential (Chronic) pregnancy, with no
where the Hypertension, Gestational Outcomes for the woman:
 Blinding of
obvious secondary cause.
study was Hypertension, or any proteinuria participants: Baby &
Management Severe hypertension:
carried out at baseline. Maternal outcomes: Patients,
According to protocol of severe diastolic hypertension:
doctors, and midwives were
Australia treatment in two obstetrics K4 (n=34/103 [33%]), K5
all aware of the random
unit, established over 10 (n=20/117 [17%]), p=0.006
allocation (HIGH)
Study type years. (significant)
Inclusion criteria  Blinding of
Prospective SBP≥160mmHg or severe systolic hypertension:
DBP≥90mmHg, or both, reported as no significant personnel: Baby & Maternal
randomised
 Pregnant women with K4 received long-term difference between groups outcomes: Patients, doctors,
study
diastolic blood pressure antihypertensive therapy and midwives were all aware
43
≥90mmHg after 20 weeks (oxyprenolol, methyldopa, "any severe hypertension": K4 of the random allocation
gestation. hydralazine). Acute (n=39/103, 38%), K5 (n=30/117, (HIGH)
 BP remained above severe episodes treated 26%), p=0.051
Aim of the with nefidipine or need for antihypertensive
90mmHg after overnight Detection bias - Blinding of
study hydralizine. treatment: K4 (n=89/103, 86%),
rest in hospital, or as outcome assessment: Baby &
Assess the use average reading over a 4- Sample size/power K5 (n=98/117, 84%), p=0.58
of Korotkoff Maternal outcomes: Endpoint
hour stay in day calculation (ns) assessment by researcher... not
sound phase IV assessment. Accepted that more
(K4) or phase V involved in the conduct of the
episodes of severe Progression to pre-eclampsia**: study. Blinded endpoint study
(K5) for diastolic hypertension pre-eclampsia**: K4 (n=57/103, (LOW)
management of Cause of hypertension was would be detected using 55%), K5 (n=56/117, 48%),
hypertensive recorded but not used for Attrition bias - Incomplete
K4 than K5 p=0.27 (ns) outcome data (for each
pregnancies inclusion/exclusion.
sound. Therefore, proteinuric PE**: K4 (n=42/103, outcome): Baby & Maternal
assumed that K4 sound 41%), K5 (n=48/117, 41%), outcomes: Analysis by intention-
Exclusion criteria would give greater p=0.97 (ns) to-treat (LOW)
None reported underlying prevalence of Reporting bias - Selective
Study dates
severe hypertension Placental abruption: not reported reporting: No access to protocol
Not reported
(25%) than K5 sound (UNCLEAR)
(20% prevalence). Mode of birth: not reported
Therefore, calculated a
Source of need for 100 participants Maternal death: none (K4 and
funding per group, but for an SD K5) Other information
Not reported of 600g in birthweight, a **these values indicate total
need of 110 per group, for number with PE or proteinuric
80% power (for 5% PE, it is unclear whether this
significance).therefore developed during the trial, or
sample size of total these women had the conditions
n=220. at baseline (proportions with
Statistical analyses proteinuria were not reported at
Intention to treat. baseline)
Continuous data:
Student's T-test, or Mann-
Witney test
Categorical data: Chi-
squared tests.
Equivalence testing: study
aimed to disprove a
difference (between K4
and K5) of >10%
(arbitrary definition of
44
equivalence) in
"detectable" severe
hypertension.

Recruited and randomized n=99 BP and urine proteinuria Cambridge blood Hospital: n=36; Home: n=31 Risk of Bias assessed using
Cartwright,W., pregnant hypertensive women monitoring setting (HOSP pressure system (HOME Baby outcomes: Cochrane ROB tool
Dalton,K.J., (Hospital group: 49; Home admission and monitoring, or monitoring) Perinatal mortality: not reported Selection bias:
Swindells,H., group: 50) self-monitoring at HOME) Standard Dinamap
Rushant,S., Analysis conducted on n=67 - No information provided for (1846SX) blood pressure Small for gestational
Mooney,P.,  Random sequence
(Hospital: 36; Home: 31) either group regarding urine monitor, linked to a age: birthweight 3.3±0.5 kg
Objective generation Randomised to
proteinuria testing, despite BP computer with three (HOSP); 3.9±1.5 kg (HOME)
measurement of two groups using a specially
cut-off relying on patient-response
anxiety in adapted computer software
presence/absence of buttons. Fully automated, Gestational age at
hypertensive Characteristics package which included
proteinura. takes 10 BP readings over birth: 39.9±1.4 weeks (HOSP);
pregnant Age: HOSP 29±4.3 years; stratification for obstetrician
HOSP 10 minutes. Downloads 39.7±1.5 weeks (HOME)
women HOME 28.5±4.7 years and parity (LOW)
admission/monitoring: Conve to the linked hospital-
managed in Gestational age at referral: ntional BP monitoring - BP based server. Admission to neonatal unit: not  Allocation
hospital and in HOSP 35.7±4.5 weeks; HOME measured every 4-hrs using Referring clinicians set a reported concealment Not possible
the community, 37.1±5.4 weeks mercury sphygmonometer or cut-off or "level of alert" Woman outcomes: (not reported) (HIGH)
British Journal DBP at referral: HOSP 92.1±6.7 Dinamap automated for high BP Severe hypertension:
of Obstetrics mmHg; HOME 92.4±5.6 mmHg recorder. Subsequent care (165/105mmHg w/o SBP during monitoring Performance bias:
and SBP at referral: HOSP by hospital-based midwives proteinuria, 126.6±10.7mmHg (HOSP);
Gynaecology, 142±13.1 mmHg; HOME and obstetricians. 155/100mmHg with 137.5±9.6mmHg (HOME)
99, 182-185, 145.6±10 mmHg  Blinding of
HOME self-monitoring: used proteinuria). High DBP during monitoring
1992 Gestational participants: Baby &
the Cambridge blood readings triggered an alert 77.2±11.5mmHg (HOSP);
hypertension: Maternal outcomes: Patients
pressure system; 10 BP to the research team, who 74.1±7.2mmHg (HOME)
Ref Id unclear on type of hypertension aware of the random
readings over a 10 minute alerted the relevant
women had (gestational, allocation; could not be
period, alerting the clinicians midwife/clinician for rapid Progression to pre-
175760 essential/chronic, pre- concealed, possible to affect
if high, re-tested after 30min response. Clinicians eclampsia: not reported
eclampsia), as reported only as outcome due to
rest, admitted to hospital if phoned woman with high
Country/ies "pregnant hypertensive women" stress/anxiety from group
remains high. Testing reading, and asked to re- Placental abruption: not reported
where the allocation "at randomisation,
frequency not reported. take BP after 30mins
study was the woman's reaction to
rest. Hospital admission Mode of birth: normal vaginal
carried out allocation was assessed..."
arranged if still above cut- delivery n=21/31 (68% HOSP);
Inclusion criteria (HIGH)
England off. n=19/36 (54% HOME)
Women identified during routine
Exit from study/end-  Blinding of
antenatal checks as being personnel: Baby & Maternal
point* Maternal death: not reported
45
hypertensive enough to be outcomes: Personnel aware
Study type admitted under normal obstetric of the random allocation;
Prospective  women in HOSP
could not be concealed,
standards.
randomized returned home as BP
unlikely to affect outcomes
controlled trial was "settled"
(LOW)
 women in HOME had
Exclusion criteria five consecutive BP <
140-90mmHg w/o Detection bias - Blinding of
Aim of the proteinura, or outcome assessment: Baby &
study  Women in hospital group <135/85mmHg with Maternal outcomes: Endpoint
Assess anxiety returned home if blood proteinura (one self-assessment by women
in hypertensive pressure "settled". session=10readings (anxiety - not relevant to this
women when  Women in home group had in 10mins) review); objective measures
monitored at BP readings <140/90mmHg recorded (LOW)
 women in HOME had
home or in w/o proteinuria, or Attrition bias - Incomplete
high average BP for
hospital <135/85mmHg with outcome data (for each
admission
proteinuria outcome): Baby & Maternal
(≥165/105mmHg w/o
 Women in home group had outcomes: Only 67/99 datasets
proteinura, ≥155/100
BP readings analysed, reasons for exclusion
mmHg with
Study dates >165/105mmHg w/o given; however of exclusions
proteinura)
Not reported proteinuria, or n=6 from HOME were admitted to
 women in either hospital due to severe
>155/100mmHg with group admitted to
proteinuria (Admitted to hypertension, and so biases the
delivery unit result by not reporting on women
hospital)
Source of who needed additional
funding  Women admitted to
delivery unit *women remained in the treatment/different
Health allocated management management (HIGH)
Promotion group (HOME/HOSP) Reporting bias - Selective
Research Trust despite repeated reporting: No access to protocol
"episodes" of (UNCLEAR)
hypertension
n=6 women in HOME
admitted to hospital due to
high BP readings - Other information
excluded from analysis
Monitoring duration similar
between groups: HOSP
(n=31) 4.9±9.5 days;
HOME (n=36) 4.6±5.3
days
46

n=218 (HOSP 110; BEDREST : Hospital bed-rest Diagnoses/definitions Outcomes for babies: Risk of Bias assessed using
Crowther,C.A., HOME/control 108) as much as possible, Severe hypertension: Perinatal mortality: Cochrane ROB tool
Bouwmeester,A ambulation around the ward BP≥160/90mmHg BEDREST stillbirth n=2/110; Selection bias:
.M., was acceptable. Clinic staff Severe proteinuria: HOME death in early neonatal
Ashurst,H.M., kept 4h record of BP, and Albustix test ≥3+ period n=1/108
Does admission Characteristics  Random sequence
tested urine daily. Preterm: <37 completed
to hospital for Age: BEDREST 28.9±6.6 years; HOME (CONTROL): normal generation Block
weeks gestation at birth Small for gestational age (<10th
bed rest prevent HOME 28.7±6.3 years randomization was used,
activities at home, no Low birthweight: <2500g centile): BEDREST n=15/110
disease Gestational age at entry: stratified into three groups.
restrictions Small for gestational age: (14%); HOME n=15/108 (14%);
progression or BEDREST 35.3±2.6 weeks; Women randomized by
advised. Instructions <10th centile by local OR=0.98 [0.45-2.11]
improve fetal HOME 34.6±3.0 weeks opening consecutively
provided for daily urine singleton standards
outcome in DBP at entry: numbered, opaque, sealed
proteinuria test at home. Power calculation Birthweight BEDREST 3.08±0.5
pregnancy BEDREST 97.8±5.3 mmHg; envelopes in the correct
Both groups: recorded fetal Detecting progression of kg; HOME 3.06±0.54 kg
complicated by HOME 97.4±5.0 mmHg stratification group (LOW)
movements for a 2-hr period disease using proteinuria,
non-proteinuric SBP at entry: every morning, reviewed based on previous Gestational age at  Allocation
hypertension?, BEDREST 150.7±10.8 mmHg; weekly (BEDREST on ward, population, was estimated birth: BEDREST 38.3±1.5 concealment Researchers
British Journal HOME 150.9±11.6 mmHg HOME in anatenatal clinic). at 30% at weeks; HOME 38.2±1.9 weeks involved in treatment
of Obstetrics Proteinuria trace: delivery. Therefore, a trial allocation were not involved
and BEDREST n=28/110 (26%); size of n=220 needed for Preterm birth <37wks in randomization
Gynaecology, HOME n=16/108 (15%) an 80% chance of BEDREST n=13/110; HOME schedule. (LOW)
99, 13-17, 1992 Sub-group data of statistically significant n=24/108; OR=0.48 [0.24-0.97]
Multigravidae women with difference if frequency of Performance bias:
Ref Id Chronic hypertension (not proteinuria was reduced Preterm birth <34wks BEDREST
gestational hypertension): using the intervention n=2/110; HOME n=4/108;
164977 BEDREST n=15/110 (14%);  Blinding of
(admission to hospital for OR=0.5 [0.1-2.5]
HOME n=18/108 (17%) participants: Maternal
bedrest). Admission to neonatal
Country/ies Gestational age at entry: outcomes: Masking was not
Statistical analyses* unit: BEDREST n=10/110
where the BEDREST 34.3±2.9 weeks; possible for BP
Student's T test to (9.1%); HOME n=12/108
study was HOME 33.7±3.0 weeks measurements and
compare means; OR to (11.1%); OR=0.80 [0.29-2.13]
carried out proteinuria
compare frequencies; Outcomes for women:
assessment (HIGH); Baby
Zimbabwe there were no interim Severe hypertension
outcomes: any outcomes
analyses. (≥160/110mmHg): BEDREST n=
Inclusion criteria unaffected by knowledge of
Study type *n=3/110 allocated to 25/110 (23%); HOME n=42/108
allocation (LOW)
Randomized HOSP BEDREST group (39%); OR=0.47 [0.26-0.83]
 Singleton pregnancy did not attend for  Blinding of
controlled trial
bedrest and n=5/110 Progression to pre-eclampsia: personnel: Baby & Maternal
47
 BP>140/90mmHg but no recorded absence Development of outcomes: Personnel
proteinuria (or only a trace (5.6±2.4 days absent) proteinuria BEDREST n=69/110 deciding on treatment
on Albustix testing) from HOSP, but still (63%); HOME n=69/108 (64%); (admission to NICU etc)
Aim of the included in analysis based OR=0.95 [0.55-1.65] unaware of management
study  28-38 weeks gestation.
on group Development of severe allocation (LOW)
Test whether allocation; n=53/108 of proteinuria (3+
admission to HOME group admitted for Albustix) BEDREST n=24/110 Detection bias - Blinding of
hospital for rest BP≥160/110mmHg or (22%); HOME n=34/108 (32%); outcome assessment: Baby &
is useful in Exclusion criteria
proteinuria≥1+, but OR=0.61 [0.32-1.16] Maternal outcomes: objective
management of analysed in allocated
non-proteinuric measures recorded (LOW)
 Symptomatic HOME group. Placental abruption: not reported Attrition bias - Incomplete
hypertension Randomization
 DBP≥110mmHg outcome data: Baby & Maternal
during Block randomization Mode of birth:
pregnancy  Caesarian section scar outcomes: Analysed according to
stratified by labour-induced BEDREST
 Antepartum haemorrhage allocation at randomization
n=42/110 (38%); HOME despite non-compliance (non-
during pregnancy.
n=42/108 (39%); OR=0.97
 primigravidae compliance was rare) (LOW)
[0.56-1.67] Reporting bias - Selective
Study dates  multigravidae with Caesarean section BEDREST reporting: No access to protocol
1985-1986 chronic hypertension n=23/110 (21%); HOME (UNCLEAR)
(BP≥160/90mmHg n=16/108 (15%); OR=1.51
before 20weeks [0.76-3.02]
gestation)
Source of
funding  multigravidae without Maternal death: not reported Other information
University of chronic hypertension
Zimbabwe and
The Sims Black End of intervention
Trust Both groups instructed to
attend hospital
immediately if labour
started, or if:
 proteinura ≥1+
(Albustix testing)
 fetal movements
were reduced or
ceased
 symptoms developed
of pre-eclampsia (eg.
headache, problem
48
with eyesight,
abdominal pain)
 any other problem
that concerned the
women.
 BP≥160/110mmHg
Labour was induced at 40

weeks if not yet started
spontaneously.

n=57 monitored BP and urine at One week (7 days) of BP Recruited across 8 Rarely reported as Risk of Bias assessed using
Denolle, T., home, results sent automatically monitoring at home for all hospitals. HBPT/HOME vs CONTROL, Cochrane ROB tool
Weber, J. L., to central unit. participants, measured before Management instead reported as white coat Selection bias:
Calvez, C., n=48 analyzed (HBPT/HOME breakfast and after Women taught to hypertension vs true
Getin, Y., group n=24; CONTROL group dinner. Urine checked daily measure BP at home hypertension as calculated
Daniel, J. C.,  Random sequence
n=24) using urine dipsticks. using an automatic through teletransmitted home
Lurton, O., generation After central
Intervention group (HBPT) oscillometric device BP readings.
Cheve, M. T., randomization, the [machine]
readings were sent (OMRON 705C) validated Outcomes for babies:
Marechaud, M., transmitted the results every
automatically to obstetrician for use in pregnancy. BP Perinatal mortality: not reported
Bessec, P., Characteristics day to the obstetrician or
who managed women results were transmitted to for HBPT v CONTROL
Carbonne, B., Age: combined 27±3 years stored them (LOW)
accordingly, control group a centralized centre "TAM
Razafintsalama, (range 22 to 35 years) readings were stored centrally Telesante". Small for gestational age (<10th  Allocation
T., Diagnosis of Gestational age: combined (obstetrician not informed, BP measured over 7 centile): not reported for HBPT v concealment Not reported
white coat 29±5 weeks (range 18 to 36 managed accordingly). days: 3 times before CONTROL (UNCLEAR)
hypertension in weeks) breakfast, 3 times after
pregnant SBP: HBPT/HOME dinner, while seated. Gestational age at Performance bias:
women with 119±14mmHg; CONTROL TAM Telesante birth: HBPT 38±1 weeks;
teletransmitted 116±12mmHg transmitted results to the CONTROL 37±8 weeks*
home blood DBP: HBPT/HOME  Blinding of
obstetrician (HBPT/HOME
pressure, 77±11mmHg; CONTROL participants: Baby &
group) or stored them Admission to neonatal unit: not
Hypertension in 74±10mmHg Maternal outcomes: Not
centrally (CONTROL). reported for HBPT v CONTROL
Pregnancy, 27, reported (UNCLEAR)
HBPT group: if
305-13, 2008 teletransmitted Outcomes for women:  Blinding of
BP>160/100mmHg (mean personnel: Baby & Maternal
Inclusion criteria
49
Pregnant women (from 18 of three successive Severe hypertension outcomes: Obstetricians
Ref Id weeks gestation) with recently readings), the obstetrician (≥160/90mmHg): not reported or were aware of allocation as
discovered hypertension (mean was immediately alerted HBPT v CONTROL they received updated data
375983 of 3 office BP measurements) by TAM Telesante. for intervention group (HIGH)
≥140/90mmHg but Both groups: told to Progression to pre-
Country/ies <180/105mmHg contact obstetrician if eclampsia: not reported for
where the Detection bias - Blinding of
urine dipstick HBPT v CONTROL outcome assessment: Baby &
study was showed ≥1+, or had
carried out Maternal outcomes: Not reported,
abnormal symptoms. Placental abruption: not but objective outcomes
Exclusion criteria After 7 days, the both reported for HBPT v CONTROL unaffected (LOW)
France
groups visited the Attrition bias - Incomplete
Study type  Albuminuria obstetrician. Mode of birth: Caesarean outcome data (for each
Randomized  History of hypertension Diagnostic Outcome: section: HBPT n=1/24; outcome): Baby & Maternal
trial (previous pregnancy or White coat hypertension CONTROL n=3/24 outcomes: n=9/57 patients
non-gestational (WCH) in HBPT group: excluded from analyses; valid
hypertension) after 7 days (one week), Maternal death: not reported for reasons stated (LOW)
mean (average) HBPT v CONTROL Reporting bias - Selective
 Undergoing treatment for
BP<117/73mmHg before
Aim of the reporting: No access to protocol
hypertension *potential error in data reporting (UNCLEAR)
study 28 weeks gestation (or
Assess the  Chronic disease <121/81mmHg after 28 - SD of control group was
diagnosis and weeks gestation). reported as 8 weeks, thought
prognosis of If diagnosed with WCH, likely to be a typographical error.
white coat there was a change in Interpret with caution. Other information
hypertension obstetric management
detected by (simplified, and delayed
home blood the next appointment).
pressure CONTROL group: WCH
monitoring diagnosis not possible,
(determine the and obstetric
incidence of management was
WCH compared maintained as before.
to true Statistical Analyses
hypertension) Excluded the first two
days of measurements
(allow for familiarisation).
BP monitoring was
Study dates validated if 22 of 30
Not reported measurements had been
teletransmitted (5 days, 6
measurements/day).
50
n=9/57 excluded from
Source of analysis: n=3/4
funding hospitalised (and treated)
la Direction des as a result of TAM
hopitaux/CNEH- Telesante alert to
Fentre obstetrician (HBPT
Telemedicine, group), n=3 delivered
and the Club during monitoring week,
des Jeunes n=2 unable/did not
Hypertensiologu complete BP monitoring.
es, and the
Societe de
Nephrologie de
l'Ouest

n=132 randomized (TIGHT Treatment with Multicentre (14 Outcomes for babies: Risk of Bias assessed using
Magee, L. A., n=66; LESS n=66) antihypertensive medication participating centres), Perinatal mortality: Stillbirth (n=0 Cochrane ROB tool
Von Dadelszen, (study preference: labetalol open randomised trial, in both groups); Neonatal death Selection bias:
P., Chan, S., 100-200mg 2/day, max with prognostic LESS n=0, TIGHT n=1/65
Gafni, A., 1200mg/day), aiming for stratification for type on
Gruslin, A., Characteristics  Random sequence
different BP treatment targets non-proteinuric Small for gestational age (<10th
Helewa, M., Age: LESS 33.6±5.0 years; generation Randomized
(less tight [DBP 100mmHg] or hypertension. centile): LESS n=20/66 (30.3%);
Hewson, S., TIGHT 33.3±5.8 years using permuted blocks of
tight control [DBP 85mmHg]) All aspects of care TIGHT n=19/65 (29.2%)
Kavuma, E., Gestational age at study entry: variable size and a toll-free
dictated by local practice,
Lee, S. K., LESS 28.1±4.7 weeks; TIGHT centrally controlled
except BP Gestational age at birth: LESS
Logan, A. G., 27.9±5.8 weeks computerized randomization
control. Changes in 36.9±3.0 weeks; TIGHT
McKay, D., SBP at study entry: LESS service (LOW)
antihypertensive 36.3±3.3 weeks
Moutquin, J. M., 142.6±10.2mmHg; TIGHT medication were noted in  Allocation
Ohlsson, A., 142.4±11.7mmHg participant's diary. GA <37weeks: LESS n=24/66 concealment Not reported
Rey, E., Ross, DBP at study entry: LESS BP assessed using (36.4%); TIGHT n=26/65 (40%) (UNCLEAR)
S., Singer, J., 94.5±5.2mmHg; TIGHT Kortokoff phase 5 (K5)
Willan, A. R., 95.9±5.4mmHg sounds. Admission to neonatal Performance bias:
Hannah, M. E., Gestational hypertension: LESS Management unit: LESS n=15/66 (22.7%);
The control of n=42/66 (63.6%); TIGHT Treatment goal (LESS or TIGHT n=22/65 (34.4%)
hypertension in n=42/66 (63.6%)  Blinding of
TIGHT) applied from
pregnancy participants: Baby &
randomisation to delivery. Outcomes for women:
study pilot trial,
51
BJOG: An LESS tight group [DBP Severe hypertension: LESS Maternal outcomes: Not
International Inclusion criteria 100mmHg]: n=38/66 (57.6%); TIGHT reported (UNCLEAR)
Journal of n=26/65 (40%)  Blinding of
Obstetrics and  personnel: Baby & Maternal
Pre-existing or gestational  DBP 95-99mmHg
Gynaecology, hypertension (DBP 90- Progression to pre-eclampsia: outcomes: Clinicians were
consideration given to
114, 770-e20, 109mmHg) LESS n=41/66 (62.1%); TIGHT aware of allocation as
decreasing dose or
2007 n=34/65 (52.3%) they managed care
 live foetus stopping
depending on group
Ref Id  20-33(+6) weeks gestation antihypertensive
Placental abruption: n=0 in birth allocation; clinician
 Included women on medication on women
groups compliance high (LOW)
788307 antihypertensives if they fit already being
the eligibility criteria. treated.
Mode of birth: C-section LESS
Country/ies  DBP<95mmHg, n=35/65 (53%); TIGHT n=37/65
Detection bias - Blinding of
where the antihypertensive outcome assessment: Baby &
(56.9%)
study was medication definitely Maternal outcomes: BP
carried out decreased/stopped in measured by masked team
Exclusion criteria Maternal death: Not reported
treated women, and member where possible. Other
Canada, not started in outcomes objectively measured
Australia, New  DBP<85mmHg untreated women. using maternal and infant charts
Zealand, & UK  SBP>170mmHg  DBP 101-105mmHg, (LOW)
 proteinuria consideration to Attrition bias - Incomplete
Study type outcome data (for each
 contra-indication to either sdtarting
Randomized outcome): Baby & Maternal
study arm antihypertensives, or
Controlled Trial outcomes: Analysis by intention-
 delivery anticipated in <1 increasing dose.
(Pilot) to-treat (LOW)
week  DBP>105mmHg,
Reporting bias - Selective
 known lethal or major fetal antihypertensive
reporting: No access to protocol,
anomaly medication definitely
but extensive reporting of
Aim of the started/increasing
 active labour.
dose.
outcomes (UNCLEAR/LOW)
study
Determine
whether "less TIGHT group [DBP
tight" (aim of 85mmHg]: Other information
DBP≤100mmHg
) control versus
"tight" (aim of  DBP 80-84mmHg
DBP≤85mmHg) consideration given to
control of decreasing dose or
nonsevere stopping
maternal antihypertensive
hypertension medication on women
52
can decrease already being
risk of adverse treated.
perinatal  DBP<80mmHg,
outcome and antihypertensive
maternal medication definitely
complications. decreased/stopped in
treated women, and
not started in
untreated women.
Study dates
April 2003 - Dec
 DBP 86-90mmHg,
2004 consideration to
starting
antihypertensives, or
increasing dose.
Source of  DBP>90mmHg,
funding antihypertensive
Canadian medication definitely
Institutes of started/increasing
Health dose.
Research
(MCT-59755) Antihypertensive
medication: study
preference was labetalol
100-200mg 2/day, max
1200mg/day. Case-by-
case assessment to
account for other co-
morbidities (eg severe
asthma).
Other antihypertensives
could be used EXCEPT
ACE-inhibitors,
angiotensin receptor
agonists, or atenolol.
Study visits
3 study visits: 28, 32, 36
weeks gestation (BP
taken as mean of 3
readings each visit)
53
BP taken 3 times, 5 min
apart, after 15mins of rest
in seated position, back
and arm supported.
BP taken by
(preferentially):
 research team
member blinded to
DBP target group
allocation
 coordinator using
validated automatic
device
 coordinator
performing
standardised
unmasked DBP
measurement
Statistical Analyses
Analysis by intention to
treat (ITT).
To allow for the imbalance
of repeated BP
measurements (some
recruited after 28 weeks
gestation, or delivered
before 36 weeks), used a
general linear model
(random effects) for
individual patient, and
fixed effects for treatment
group and time point.
Power calculation for
sample size
n=60 per group based on
80% power to achieve 5%
significance if DBP
54
differed between groups
by 6.4mmHg. Calculation
based on data from
previous meta-analyses of
antihypertensive drug vs
placebo/no therapy: mean
decrease of
6.4±11.4mmHg
associated with increase
in small-for-gestational
age. Assumed loss to
follow-up of 10%,
therefore sample size of
n=66 per group (total 132
pregnant women).

n=1030 recruited (LESS n= 519; Treatment with Similar methods to CHIPS aOR=adjusted Odds Ratio (see Risk of Bias assessed using
Magee, L. A., TIGHT n=511) antihypertensive medication Pilot study (Magee 2007), Methods for adjustments) Cochrane ROB tool
von Dadelszen, n=987* in analysis (LESS (study preference: labetalol though recruitment from Selection bias:
P., Rey, E., n=493; TIGHT n=488) 100-200mg 2/day, max 14weeks gestation (pilot Outcomes for babies:
Ross, S., *n=43 excluded from analysis 1200mg/day), aiming for study from 20 weeks), Perinatal mortality: total LESS
Asztalos, E.,  Random sequence
owing to concerns regarding different BP treatment targets and time-points from BP n=14/493 (2.8%); TIGHT
Murphy, K. E., informed consent and data generation Randomization s
(less tight [DBP 100mmHg] or collection (14-20;20;21- n=11/488 (2.3%); aOR=1.25
Menzies, J., tratified to centre and type of
integrity tight control [DBP 85mmHg]) 28;29-33;34-40 weeks, [0.56-2.81]
Sanchez, J., hypertension (pre-existing or
Pilot study only at 28, 32, stillbirth LESS n=12/493 (2.4%);
Singer, J., gestational) performed in
36 weeks) TIGHT n=7/488 (1.4%)
Gafni, A., permuted blocks of random
Multicentre, open neonatal death LESS n=2/493
Gruslin, A., Characteristics size (2 or 4) by site
randomised trial, with (0.4%); TIGHT n=4/488 (0.8%)
Helewa, M., Age: LESS 34±5.7 years; coordinators at a central site,
prognostic stratification for
Hutton, E., Lee, TIGHT 33.7±5.8 years using a toll-free centrally
type on non-proteinuric Small for gestational age (<10th
S. K., Lee, T., Gestational age at study controlled computerized
hypertension. centile): LESS n=79/491
Logan, A. G., entry: LESS 23.7±6.3 weeks; randomization service (LOW)
All aspects of care (16.1%); TIGHT n=96/488
Ganzevoort, W., TIGHT 24.2±6.3 weeks dictated by local practice, (19.7%); aOR=0.78 [0.56-1.08]  Allocation
Welch, R., SBP at study entry: LESS except BP concealment Sequence
Thornton, J. G., 140.4±9.7mmHg; TIGHT control. Changes in Gestational age at birth: LESS generated by a programmer,
Moutquin, J. M., 139.7±9.8mmHg antihypertensive 36.8±3.4 weeks; TIGHT secured and available only to
Less-tight 37.2±3.1 weeks system manager, telephone
55
versus tight DBP at study entry: LESS medication were noted in line was password protected
control of 92.6±4.8mmHg; TIGHT participant's diary. Admission to neonatal unit: (LOW)
hypertension in 92.2±5.2mmHg BP assessed using LESS n=141/493 (29.4%);
pregnancy, New Gestational hypertension: LESS Kortokoff phase 5 (K5) TIGHT n=139/488 (29%); Performance bias:
England Journal n=126/497 (25.4%); TIGHT sounds. aOR=1.00 [0.75-1.33]
of Medicine, n=125/490 (25.5%) Randomization
372, 407-17, BP measurement taken Outcomes for women:  Blinding of
2015 by healthcare professional Severe hypertension: LESS participants: Baby &
4hrs apart, or at two n=200/493 (40.6%); TIGHT Maternal outcomes: Not
Ref Id Inclusion criteria consecutive outpatient n=134/488 (27.5%); aOR=1.80 reported (UNCLEAR)
visits, within one week [1.34-2.38]  Blinding of
377652 before personnel: Baby & Maternal
 pre-existing or gestational
hypertension randomization. Both BP Progression to pre- outcomes: Clinicians were
Country/ies measurements had to be eclampsia: LESS n=241/493 aware of allocation as
where the  DBP 90-105mmHg (not on
antihypertensives) or DBP elevated. Stratified (48.9%); TIGHT n=223/488 they managed care
study was according to centre and (45.7%); aOR=1.14 [0.88-1.47] depending on group
carried out 85-105mmHg (on
antihypertenives) type of hypertension, 1:1 allocation; clinician
to LESS or TIGHT group. Placental abruption: LESS compliance was high (LOW)
Canada,  live foetus Diagnoses n=11/493 (2.2%); TIGHT
Argentina,  gestational age 14-33(+6) Pre-existing hypertension: n=11/488 (2.3%); aOR=0.94 Detection bias - Blinding of
Brazil, Chile, weeks DBP≥90mmHg before 20 [0.40-2.21] outcome assessment: Baby &
France, Israel,
(+0) weeks gestation. Maternal outcomes: BP
Jordan,
Gestational hypertension: Mode of birth: C-section LESS measured by masked team
Malaysia, New
DBP≥90mmHg at 20 (+0) n=231/493 (47%); TIGHT member where possible. Other
Zealand, South Exclusion criteria weeks gestation or after. n=250/488 (51.4%); aOR=0.81 outcomes objectively measured -
Africa, The
Management [0.63-1.04] taken from mother and infant
Netherlands,
Treatment goal (LESS or
UK, USA  severe systolic charts (LOW)
TIGHT) applied from Maternal death: n=0 (both Attrition bias - Incomplete
hypertension
Study type (within 4-weeks) post- groups) outcome data (for each
(SBP≥160mHg at
Randomized randomisation to delivery. outcome): Baby & Maternal
randomization)
controlled trial Women seen by maternity FOR GESTATIONAL outcomes: Analysis by intention-
 proteinuria (≥0.3g/d) care provider within 4 HYPERTENSION WOMEN
 use of ACE inhibitors (after to-treat. One site excluded 43
weeks after ONLY women due to concern regarding
14weeks gestation) randomization. After Primary perinatal outcome consent and data integrity (LOW)
Aim of the  contra-indication to either which, women were seen (pregnancy loss or high level Reporting bias - Selective
study arm of trial or to pregnancy according to schedule by neonatal care for >48hr): LESS reporting: Outcomes reported
Determine prolongation local practice. BP n=41/124 (33.9%); TIGHT according to protocol (LOW)
whether "less  known multiple gestation readings collected by site n=45/125 (36%)
tight" control  known lethal or major fetal coordinator in person or
(target DBP anomaly by phone at: 14-20 weeks,
56
100mmHg) vs  plan to terminate 20 weeks, 21-28 weeks, Small for gestational age
"tight" control pregnancy 29-33 weeks, and 34-40 (<10th centile): LESS n=28/124 Other information
(target DBP  prior participation in CHIPS weeks gestation. (22.6%); TIGHT n=25/125 (20%)
85mmHg) of main trial LESS tight group [DBP Secondary maternal outcome
non-severe 100mmHg]: (one/more serious maternal
maternal complications (including
hypertension death)): LESS n=8/124 (6.5%);
 DBP 95-99mmHg
TIGHT n=2/125 (1.6%)
will decrease
fetal/neonatal Severe hypertension post-
decreasing dose or
risk without randomization: LESS n=41/124
stopping
increasing (33.1%); TIGHT n=38/125
antihypertensive
maternal risk. (30.4%)
medication on women
Pre-eclampsia: LESS n=65/123
already being
(52.8%); TIGHT n=68/125
treated.
(54.4%)
Study dates  DBP<95mmHg,
26 March 2009 antihypertensive
- 2 August 2012 medication definitely
decreased/stopped in
treated women, and
not started in
Source of untreated women.
funding  DBP 101-105mmHg,
Canadian consideration to
Institute of sdtarting
Health antihypertensives, or
Research increasing dose.
(MCT-87522)
 DBP>105mmHg,
antihypertensive
medication definitely
started/increasing
dose.
TIGHT group [DBP

85mmHg]:
 DBP 80-84mmHg
decreasing dose or
57
stopping
antihypertensive
medication on women
already being
treated.
 DBP<80mmHg,
antihypertensive
decreased/stopped in
treated women, and
not started in
untreated women.
 DBP 86-90mmHg,
consideration to
starting
antihypertensives, or
increasing dose.
 DBP>90mmHg,
antihypertensive
started/increasing
dose.
Antihypertensive
medication: study
preference was labetalol
100-200mg 2/day, max
1200mg/day. Case-by-
case assessment to
account for other co-
morbidities (eg severe
asthma).
Other antihypertensives
could be used EXCEPT
ACE-inhibitors,
angiotensin receptor
agonists, or atenolol.
No medication provided
by the study.
58
Statistical analyses
Analysis by intention to
treat (ITT).
To allow for the imbalance
of repeated BP
measurements, used
a mixed-effect logistic-
regression model (random
effects) for individual
patient (unit of analysis:
individual woman), and
fixed effects for treatment
group and time point.
aOR (adjusted Odds
Ratio) adjusted for:
 stratification factors:
type of hypertension
(gestational vs pre-
existing), and centre
 use of
antihypertensive
therapy at
randomization
 previous
BP≥160/110mmHg
during this pregnancy
 gestational diabetes
 weeks of gestation at
randomization
Power calculation for

sample size
Calculated a need of
n=514 per group based
on 80% power to achieve
5% (p<0.05) significance
assuming primary
59
outcome (neonatal
morbidity) rates of 33% in
TIGHT and 25% in LESS,
with a crossover rate of
10%, assumed loss to
follow-up of 1%, and two
interim analyses.
Secondary outcome
statistical significance set
at p<0.01, and p<0.001
for other outcomes.
60
Appendix E – Forest plots
No forest plots were generated for comparisons 1-3, as no meta-analyses were performed.
Comparison 4. Less-tight versus tight control of BP
Figure 1: Small-for-gestational age (BW<10th centile)

Less tight control Tight control Risk Ratio Risk Ratio
Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Magee 2007 (CHIPS pilot) 20 66 19 65 43.5% 1.04 [0.61, 1.75]

Magee 2015 (CHIPS main) 28 124 25 125 56.5% 1.13 [0.70, 1.82]
Total (95% CI) 190 190 100.0% 1.09 [0.76, 1.55]
Total events 48 44
Heterogeneity: Chi² = 0.06, df = 1 (P = 0.81); I² = 0%
0.01 0.1 1 10 100
Test for overall effect: Z = 0.47 (P = 0.64)
Favours LESS TIGHT Favours TIGHT CONTROL
Figure 2: Severe hypertension (sBP ≥ 160 and/or dBP ≥ 110 mmHg)


Magee 2015 (CHIPS main) 41 124 38 125 59.1% 1.09 [0.76, 1.57]
Total (95% CI) 190 190 100.0% 1.23 [0.95, 1.59]
Total events 79 64
0.01 0.1 1 10 100
Figure 3: Progression to pre-eclampsia


Magee 2015 (CHIPS main) 65 123 69 125 66.6% 0.96 [0.76, 1.20]
Total (95% CI) 189 190 100.0% 1.03 [0.86, 1.24]
Total events 106 103

0.01 0.1 1 10 100
61
(June 2019)
Appendix F – GRADE tables
Comparison 1: Management based on K4 (intervention) or K5 (control) sounds
Table 5: Clinical evidence profile. Comparison 1. Management based on K4 sounds versus K5 sounds
Quality assessment Number of women Effect
Quality Importance
Number Management Management
Risk of Other Relative
of Design Inconsistency Indirectness Imprecision based on K4 based on K5 Absolute
bias considerations (95% CI)
studies sounds sounds
SGA <10th centile
No 23 fewer per
RR 0.81
1 (Brown Randomised serious No serious 10/103 14/117 1000 (from 74
Serious1 Very serious2 None (0.38 to VERY LOW CRITICAL
1998) trials risk of inconsistency (9.7%) (12%) fewer to 90
1.75)
bias more)
Gestational age at birth (weeks) (Better indicated by higher values)
No
MD 0 higher
1 (Brown Randomised serious No serious No serious
Serious1 None 103 117 - (0.79 lower to MODERATE IMPORTANT
1998) trials risk of inconsistency imprecision3
0.79 higher)
bias
Severe hypertension
209 more per

RR 2.22
1 (Brown Randomised No serious No serious 39/103 20/117 1000 (from 67
Serious4 Serious 1
None (1.39 to LOW CRITICAL
1998) trials inconsistency imprecision (37.9%) (17.1%) more to 434
3.54)
more)
Maternal death
No
1 (Brown Randomised serious No serious No serious 0/103 0/117 Not
Serious1 None Not calculable MODERATE IMPORTANT
1998) trials risk of inconsistency imprecision (0%) (0%) calculable
bias
62
1 The quality of the evidence was downgraded by 1 level as it was unclear whether women had essential (chronic) hypertension, gestational hypertension, or any proteinuria at
baseline
2 The quality of the evidence was downgraded by 2 levels as the 95% CI crosses 2 default MID thresholds (0.8 and 1.25)
3 MID calculated as =+/-1.5 weeks (0.5*SD of control [K5] group)
4 The quality of the evidence was downgraded by 1 level as there was no blinding of participants or personnel
63
Comparison 2a: Home monitoring versus hospital monitoring
Table 6: Clinical evidence profile. Comparison 2a. Dinamap home monitoring versus hospital monitoring
Quality Importance
Dinamap
Number of Risk of Other Hospital Relative
Design Inconsistency Indirectness Imprecision home Absolute
studies bias considerations monitoring (95% CI)
monitoring
MD 0.2 lower (0.9

1 (Cartwright Randomised No serious VERY
Serious1 Serious2 Serious3 None 31 36 - lower to 0.5 IMPORTANT
1992) trials inconsistency LOW
higher)
Mode of birth - spontaneous vaginal birth
RR 0.78 149 fewer per

1 (Cartwright Randomised No serious 19/36 21/31 VERY
Serious1 Serious2 Serious4 None (0.53 to 1000 (from 318 IMPORTANT
1992) trials inconsistency (52.8%) (67.7%) LOW
1.15) fewer to 102 more)
1 The quality of the evidence was downgraded by 1 level due to incomplete outcome data (6 participants in the home monitoring group admitted to hospital due to severe
hypertension, and excluded from analyses)
2 The quality of the evidence was downgraded by one level as it was unclear which type of hypertension women had (gestational, essential/chronic, pre-eclampsia)
3 The quality of the evidence was downgraded by 1 level as the 95% CI crosses 1 MID threshold (MID=+/-0.7 [0.5*SD in control group; SD=1.4])
4 The quality of the evidence was downgraded by 1 level as the 95% CI crosses 1 default MID threshold (0.8)
64
Comparison 2b: Home blood pressure telemonitoring (obstetrician updated) versus home monitoring (ostetrician not updated)
Table 7: Clinical evidence profile. Comparison 2b. Home blood pressure telemonitoring (obstetrician updated) versus home
monitoring (obstetrician not updated)
Quality Importance
Home (HBPT)
Number Home monitoring
Risk of Other monitoring Relative
of Design Inconsistency Indirectness Imprecision (Obstetrician not Absolute
bias considerations (Obstetrician (95% CI)
studies updated)
updated)
1 Randomised No No serious No serious Very None 24 24 - MD 1 higher LOW IMPORTANT

(Denolle trials serious inconsistency indirectness serious1 (2.23 lower to
2008) risk of 4.23 higher)
bias
Mode of birth – caesarean section
1 Randomised No No serious No serious Very None 1/24 3/24 RR 0.33 84 fewer per LOW IMPORTANT
(Denolle trials serious inconsistency indirectness serious2 (4.2%) (12.5%) (0.04 to 1000 (from 120
2008) risk of 2.98) fewer to 248
bias more)
1 The quality of the evidence was downgraded by 2 levels due to a likely typographical error in the article, resulting in inappropriate assessment of imprecision. The SD of the
control group was reported as 8 weeks, and this was felt to be unlikely for the outcome ‘gestational age at delivery’. Although the calculated 95% CI does not cross the
boundaries for the MID (MID=+/-4 [MID=0.5*SD of control group; SD=8 weeks]) the rating for imprecision should be interpreted with caution because of this.
65
Comparison 3: Hospital bedrest versus home normal activity
Table 8: Clinical evidence profile. Comparison 3. Hospital bedrest versus home normal activity
Quality Importance
Home
Design Inconsistency Indirectness Imprecision normal Absolute
studies bias considerations bedrest (95% CI)
activity
Perinatal mortality
1 (Crowther Randomised No serious No serious Serious1 Very serious2 None 2/110 1/108 RR 1.96 9 more per 1000 VERY LOW CRITICAL
1992) trials risk of bias inconsistency (1.8%) (0.93%) (0.18 to (from 8 fewer to
21.34) 188 more)
SGA <10th centile
1 (Crowther Randomised No serious No serious Serious1 Very serious2 None 15/110 15/108 RR 0.98 3 fewer per 1000 VERY LOW CRITICAL
1.91) 126 more)
1 (Crowther Randomised No serious No serious Serious1 No serious None 110 108 - MD 0.1 higher MODERATE IMPORTANT
1992) trials risk of bias inconsistency imprecision3 (0.35 lower to 0.55
higher)
Preterm birth <37weeks
1 (Crowther Randomised No serious No serious Serious1 Serious5 None 13/110 24/108 RR 0.53 104 fewer per LOW CRITICAL
1992) trials risk of bias inconsistency (11.8%) (22.2%) (0.29 to 1000 (from 2 fewer
0.99) to 158 fewer)
Preterm birth <34weeks
1 (Crowther Randomised No serious No serious Serious1 Very serious2 None 2/110 4/108 RR 0.49 19 fewer per 1000 VERY LOW CRITICAL
2.62) 60 more)
66
Quality Importance
Home
Design Inconsistency Indirectness Imprecision normal Absolute
studies bias considerations bedrest (95% CI)
activity
1 (Crowther Randomised No serious No serious Serious1 Very serious2 None 10/110 12/108 RR 0.82 20 fewer per 1000 VERY LOW IMPORTANT
1.81) 90 more)
Severe hypertension (>160/110mmhg)
1 (Crowther Randomised No serious No serious Serious1 Serious4 None 25/110 42/108 RR 0.58 163 fewer per LOW CRITICAL
1992) trials risk of bias inconsistency (22.7%) (38.9%) (0.38 to 1000 (from 43
0.89) fewer to 241
fewer)
Progression to pre-eclampsia (proteinuria)
1 (Crowther Randomised No serious No serious Serious1 No serious None 69/110 69/108 RR 0.98 13 fewer per 1000 MODERATE IMPORTANT
1992) trials risk of bias inconsistency imprecision (62.7%) (63.9%) (0.80 to 1.2) (from 128 fewer to
128 more)
Induction of labour
1 (Crowther Randomised No serious No serious Serious1 No serious None 42/110 16/108 RR 2.58 234 more per MODERATE IMPORTANT
1992) trials risk of bias inconsistency imprecision (38.2%) (14.8%) (1.55 to 1000 (from 81
4.30) more to 489 more)
1 (Crowther Randomised No serious No serious Serious1 Very serious2 None 23/110 16/108 RR 1.41 61 more per 1000 VERY LOW IMPORTANT
2.52) 225 more)
1 The quality of the evidence was downgraded by 1 level as women with chronic hypertension were also included in analysis (not exclusively gestational hypertension): 14% of
those admitted to hospital and 17% of the home monitoring group.
3 MID calculated as =+/-0.95 (MID=0.5*SD in control group [SD=1.9])
4 The quality of the evidence was downgraded by 1 level as the 95% CI crosses 1 default MID thresholds (0.8)
67
Comparison 4: Less-tight versus tight control of BP
Table 9: Clinical evidence profile. Comparison 4. Less-tight versus tight control of BP
Quality Importance
Less-tight Tight
Number of Risk of Other Relative
Design Inconsistency Indirectness Imprecision control of control of Absolute
studies bias considerations (95% CI)
BP BP
Stillbirth
1 (Magee Randomised No No serious Serious1 No serious None 0/66 0/65 Not Not calculable MODERATE CRITICAL
2007) trials serious inconsistency imprecision (0%) (0%) calculable
risk of
bias
Neonatal death
1 (Magee Randomised No No serious Serious1 Very serious2 None 0/66 1/65 RR 0.33 10 fewer per 1000 VERY LOW CRITICAL
2007) trials serious inconsistency (0%) (1.5%) (0.01 to (from 15 fewer to
risk of 7.92) 106 more)
bias
SGA <10th centile
2 (Magee Randomised No No serious Serious1 Very serious2 None 48/190 44/190 RR 1.09 21 more per 1000 VERY LOW CRITICAL
2007; Magee trials serious inconsistency (25.3%) (23.2%) (0.76 to (from 56 fewer to
2015) risk of 1.55) 127 more)
bias
1 (Magee Randomised No No serious Serious1 Serious3 None 66 65 - MD 0.6 higher LOW IMPORTANT
2007) trials serious inconsistency (0.48 lower to
risk of 1.68 higher)
bias
Preterm birth <37 weeks
1 (Magee Randomised No No serious Serious1 Very serious2 None 24/66 26/65 RR 0.91 36 fewer per 1000 VERY LOW CRITICAL
2007) trials serious inconsistency (36.4%) (40%) (0.59 to (from 164 fewer to
1.41) 164 more)
68
Quality Importance
Less-tight Tight
Number of Risk of Other Relative
Design Inconsistency Indirectness Imprecision control of control of Absolute
studies bias considerations (95% CI)
BP BP
risk of
bias
1 (Magee Randomised No No serious Serious1 Serious4 None 15/66 22/65 RR 0.67 112 fewer per LOW IMPORTANT
2007) trials serious inconsistency (22.7%) (33.8%) (0.38 to 1000 (from 210
risk of 1.18) fewer to 61 more)
bias
Progression to severe hypertension
2 (Magee Randomised No No serious Serious1 Serious5 None 79/190 64/190 RR 1.23 77 more per 1000 LOW CRITICAL
2007; Magee trials serious inconsistency (41.6%) (33.7%) (0.95 to (from 17 fewer to
2015) risk of 1.59) 199 more)
bias
2 (Magee Randomised No No serious Serious1 No serious None 106/189 103/190 RR 1.03 16 more per 1000 MODERATE IMPORTANT
2007; Magee trials serious inconsistency imprecision (56.1%) (54.2%) (0.86 to (from 76 fewer to
2015) risk of 1.24) 130 more)
bias
Placental abruption
1 (Magee Randomised No No serious Serious1 No serious None 0/66 0/65 Not Not calculable MODERATE IMPORTANT
2007) trials serious inconsistency imprecision (0%) (0%) calculable
risk of
bias
1 (Magee Randomised No No serious Serious1 Very serious2 None 35/65 37/65 RR 0.95 28 fewer per 1000 VERY LOW
2007) trials serious inconsistency (53.8%) (56.9%) (0.69 to (from 176 fewer to
risk of 1.29) 165 more)
bias
69
1 The quality of the evidence was downgraded by 1 level as Magee 2007 included a mixed population of women (64% gestational hypertension, 36% with pre-existing/chronic
hypertension)
3 The quality of the evidence was downgraded by 1 level as the 95% CI crosses 1 MID threshold (MID=+/-1.65 [MID=0.5*SD in control group; SD=3.3])4
70
Appendix G – Economic evidence study selection
71
(June 2019)
Appendix H – Economic evidence tables
No health economic evidence was identified for this review.
72
Appendix I – Health economic evidence profiles
No health economic evidence was identified for this review.
73
FINAL
Appendices
Appendix J – Health economic analysis

No health economic analysis was conducted for this review.
74
(June 2019)
FINAL
Appendices
Appendix K – Excluded studies

Clinical studies
Table 10: Clinical excluded studies with reasons for exclusion

Study Reason for Exclusion
Allen, D. G., Craig, C. J., Management of No relevant outcomes
patients with a diastolic blood pressure of 90
mmHg in the third trimester of pregnancy, South
African Medical Journal. Suid-Afrikaanse
Tydskrif Vir Geneeskunde, 66, 910-2, 1984
Barton,J.R., Stanziano,G.J., Jacques,D.L., Unmatched cohorts, same management
Bergauer,N.K., Sibai,B.M., Monitored outpatient
management of mild gestational hypertension
remote from term in teenage pregnancies,
American Journal of Obstetrics and Gynecology,
173, 1865-1868, 1995
Benedetto, C., Marozio, L., Zonca, M., Giarola, Cannot separate gestational hypertension (GH)
M., Maula, V., Melzi, E., Chiarolini, L., Ciochetto, and pre-eclampsia (PE) data. Control group are
D., Micheletti, L., Coppo, F., 24h monitoring of normotensive
blood pressure in pregnancy: clinical
advantages, Chronobiologia, 21, 113-6, 1994
Bhide, Amarnath, Sankaran, Srividhya, Moore, Unmatched cohorts
Jessica, Khalil, Asma, Furneaux, Eleanor,
Ambulatory blood pressure measurements in
mid-pregnancy and development of
hypertensive pregnancy disorders, Hypertension
in Pregnancy, 33, 159-67, 2014
Condon, N., Martinez, F., Fetal doppler Abstract only
evaluation and perinatal outcomes in the
absence of fetal growth restriction, Obstetrics
and Gynecology, 129, 185S, 2017
Eguchi, K., Ohmaru, T., Ohkuchi, A., Hirashima, Cannot separate data for PE and GH at baseline
C., Takahashi, K., Suzuki, H., Kario, K.,
Matsubara, S., Suzuki, Mitsuaki, Ambulatory BP
monitoring and clinic BP in predicting small-for-
gestational-age infants during pregnancy,
Journal of Human Hypertension, 30, 62-7, 2016
El Guindy, Alaa A., Nabhan, Ashraf F., A Essential hypertension and gestational
randomized trial of tight vs. less tight control of hypertension - no subgroup analysis and <2/3
mild essential and gestational hypertension in population are relevant for this review question.
pregnancy, Journal of Perinatal Medicine, 36, Cannot separate data
413-8, 2008
Frusca, T., Soregaroli, M., Platto, C., Enterri, L., Unmatched cohorts - PE versus GH
Lojacono, A., Valcamonico, A., Uterine artery
velocimetry in patients with gestational
hypertension, Obstetrics and Gynecology, 102,
136-40, 2003
Fukushima, Teiichiro, Berumen, Maria, Vargas, Cannot separate data for PE/CH/GH -
Noemi, Zadeh, Neda, Hon, Edward H., The observational study of a population of pregnant
effects of cardiovascular dynamics monitoring in women with preeclampsia and
the outpatient management of pregnancy chronic/gestational hypertension.
75
(June 2019)
FINAL
Appendices

hypertension, American Journal of Obstetrics
and Gynecology, 186, 1207-5, 2002
Ganzevoort, Wessel, Rep, Annelies, Bonsel, Cannot separate data at baseline for GH only:
Gouke J., Fetter, Willem P. F., van Sonderen, "all hypertensive disorders": ~30% chronic
Loekie, De Vries, Johanna I. P., Wolf, Hans, hypertension (CH) ~3% eclampsia ~ 45% PE
Petra investigators, 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 : an international journal
of obstetrics and gynaecology, 112, 1358-68,
2005
Giannubilo, S. R., Cecchi, S., Bezzeccheri, V., Abstract only
Landi, B., Battistoni, G. I., Vitali, P., Tranquilli, A.
L., Outpatient management of pregnancy
complicated by hypertensive disorders,
Pregnancy Hypertension, 1, S32-S33, 2010
Heazell, Alexander Ep, Whitworth, Melissa, Wrong population - not GH (just "high risk
Duley, Lelia, Thornton, Jim G, Use of preganancies")
biochemical tests of placental function for
improving pregnancy outcome, Cochrane
Database of Systematic Reviews, 2015
Hirtenlehner, K., Huber, A., Strohmer, H., No intervention between matched cohorts (twin
Zeisler, H., Husslein, P., Langer, M., Reduction compared to triplet pregnancy)
of preeclampsia in multiple pregnancies by a
dedicated monitoring protocol, Journal of the
Society for Gynecologic Investigation, 10, 418-
22, 2003
Knuist, M., Bonsel, G. J., Zondervan, H. A., Unmatched cohorts; No intervention
Treffers, P. E., Intensification of fetal and
maternal surveillance in pregnant women with
hypertensive disorders, International Journal of
Gynecology and Obstetrics, 61, 127-133, 1998
Lanssens, Dorien, Vandenberk, Thijs, Smeets, Cannot separate GH data from other gestational
Christophe Jp, De Canniere, Helene, hypertensive disorders
Molenberghs, Geert, Van Moerbeke, Anne, van
den Hoogen, Anne, Robijns, Tiziana, Vonck,
Sharona, Staelens, Anneleen, Storms, Valerie,
Thijs, Inge M., Grieten, Lars, Gyselaers, Wilfried,
Remote Monitoring of Hypertension Diseases in
Pregnancy: A Pilot Study, JMIR mHealth and
uHealth, 5, e25, 2017
Magee, L. A., Von Dadelszen, P., Rey, E., Ross, Abstract only
S., Asztalos, E., Murphy, K. E., Menzies, J.,
Sanchez, J., Singer, J., Gafni, A., Gruslin, A.,
Helewa, M., Hutton, E., Lee, S. K., Logan, A. G.,
Ganzevoort, W., Welch, R., Thornton, J. G.,
Moutquin, J. M., The control of hypertension in
pregnancy study (CHIPS) randomized controlled
trial, Pregnancy Hypertension, 5, 2, 2015
Magee, L. A., Von Dadelszen, P., Singer, J., CHIPS trial - post hoc analysis, already counted
Lee, T., Rey, E., Ross, S., Asztalos, E., Murphy, in included study list
K. E., Menzies, J., Sanchez, J., Gafni, A.,
76
(June 2019)
FINAL
Appendices

Helewa, M., Hutton, E., Koren, G., Lee, S. K.,
Logan, A. G., Ganzevoort, W., Welch, R.,
Thornton, J. G., Moutquin, J. M., The CHIPS
randomized controlled trial (control of
hypertension in pregnancy study), Hypertension,
68, 1153-1159, 2016
Marko, Kathryn I., Krapf, Jill M., Meltzer, Andrew Not GH population
C., Oh, Julia, Ganju, Nihar, Martinez, Anjali G.,
Sheth, Sheetal G., Gaba, Nancy D., Testing the
Feasibility of Remote Patient Monitoring in
Prenatal Care Using a Mobile App and
Connected Devices: A Prospective
Observational Trial, JMIR research protocols, 5,
e200, 2016
McCauley, M., Dornan, J., A cheap and efficient Abstract only
test to help with detection and monitoring of
patients with pre-eclampsia, Archives of Disease
in Childhood: Fetal and Neonatal Edition, 97,
A62, 2012
Murray, Noreen, Homer, Caroline S. E., Davis, Prospective observational study - no intervention
Gregory K., Curtis, Julie, Mangos, George,
Brown, Mark A., The clinical utility of routine
urinalysis in pregnancy: a prospective study,
The Medical journal of Australia, 177, 477-80,
2002
Nabhan,Ashraf F., Elsedawy,Maged M., Tight Cochrane review of 2 studies already included
control of mild-moderate pre-existing or non- from STAR: (1) CHIPs (Magee 2007) (2) El
proteinuric gestational hypertension, Cochrane Guindy 2008
Database of Systematic Reviews, -, 2011
Naef, R. W., 3rd, Perry, K. G., Jr., Magann, E. Chronic hypertension, not gestational
F., McLaughlin, B. N., Chauhan, S. P., Morrison, hypertension
J. C., Home blood pressure monitoring for
pregnant patients with hypertension, Journal of
Perinatology, 18, 226-9, 1998
Nathan, H. L., Hezelgrave, N. L., Widmer, M., Protocol only
Chappell, L. C., Shennan, A. H., Setting and
techniques for monitoring blood pressure during
pregnancy, Cochrane Database of Systematic
Reviews, 2017, CD012739, 2017
Pahwa, M. B., Seth, S., Khosla, A., Significance Letter to the Editor - no intervention
of urine protein/creatinine ratio in pregnancy-
induced hypertension, Clinica Chimica Acta,
382, 145-147, 2007
Pattinson,R.C., Norman,K., Odendaal,H.J., The Cannot separate GH data. most women with PE.
role of Doppler velocimetry in the management
of high risk pregnancies, British Journal of
Obstetrics and Gynaecology, 101, 114-120,
1994
Pauli, J. M., Lauring, J. R., Stetter, C. M., Intervention was the publication of a paper about
Repke, J. T., Botti, J. J., Ural, S. H., Ambrose, GH management (HYPITAT)
A., Management of gestational hypertension -
77
(June 2019)
FINAL
Appendices

The impact of HYPITAT, Journal of Perinatal
Medicine, 41, 415-420, 2013
Preethi, D. S., Rai, L., Nambiar, M. J., Kumar, Unavailable
P., Pai, M. V., Amin, S. V., Role of laboratory
investigations to assess maternal and perinatal
outcome in hypertensive mothers, International
Journal of Infertility and Fetal Medicine, 8, 18-
23, 2017
Rey, Evelyne, Morin, Francine, Boudreault, Prospective observational study of "all
Jocelyne, Pilon, Francine, Vincent, Dominique, subgroups of preg hypertensive women".
Ouellet, Doris, Blood pressure assessments in unmatched cohort, no mention of GH (PE v CH
different subtypes of hypertensive pregnant v WCH)
women: office versus home patient- or nurse-
measured blood pressure, Hypertension in
Pregnancy, 28, 168-77, 2009
Rhodes, Catharine A., Beevers, D. Gareth, No relevant outcomes reported
Churchill, David, A randomized trial of
ambulatory blood pressure monitoring versus
clinical blood pressure measurement in the
management of hypertension in pregnancy. A
feasibility study, Pregnancy Hypertension, 11,
142-144, 2018
Ross-McGill, H., Hewison, J., Hirst, J., Not GH (wrong population)
Dowswell, T., Holt, A., Brunskill, P., Thornton, J.
G., Antenatal home blood pressure monitoring: a
pilot randomised controlled trial, BJOG: An
International Journal of Obstetrics &
Gynaecology, 107, 217-21, 2000
Shahbazian, Nahid, Shahbazian, Heshmatollah, Unmatched cohorts (WCH v GH v
Mohammadjafari, Razieh, Mousavi, Mahsan, normotensive)
Ambulatory monitoring of blood pressure and
pregnancy outcome in pregnant women with
white coat hypertension in the third trimester of
pregnancy, Journal of nephropharmacology, 2,
5-9, 2013
Shields, Laurence E., Wiesner, Suzanne, Klein, Wrong population: severe pre-eclampsia
Catherine, Pelletreau, Barbara, Hedriana, hypertension
Herman L., Use of Maternal Early Warning
Trigger tool reduces maternal morbidity,
American Journal of Obstetrics and Gynecology,
214, 527.e1-527.e6, 2016
Spinapolice, Rx, Feld, S, Harrigan, Jt, Effective Gestational hypertension and/or pre-eclampsia
prevention of gestational hypertension in as outcome measure. intervention is advice to
nulliparous women at high risk as identified by increase daily rest. same management in both
the rollover test, American Journal of Obstetrics grops
and Gynecology, 146, 166-168, 1983
Tucker, Katherine L., Taylor, Kathryn S., Not GH at baseline - any high risk
Crawford, Carole, Hodgkinson, James A.,
Bankhead, Clare, Carver, Tricia, Ewers,
Elizabeth, Glogowska, Margaret, Greenfield,
Sheila M., Ingram, Lucy, Hinton, Lisa, Khan,
Khalid S., Locock, Louise, Mackillop, Lucy,
McCourt, Christine, Pirie, Alexander M.,
78
(June 2019)
FINAL
Appendices

Stevens, Richard, McManus, Richard J., Blood
pressure self-monitoring in pregnancy:
examining feasibility in a prospective cohort
study, BMC Pregnancy and Childbirth, 17, 442,
2017
Vicente Bertagnolli, T., Souza Rangel Machado, Wrong population - diagnosed PE only
M. D., Ferreira, C. J. H., Machado, J. S. R.,
Duarte, G., Cavalli, R. C., Safety of a physical
therapy protocol for women with preeclampsia: a
randomized controlled feasibility trial,
Hypertension in Pregnancy, 1-9, 2018
Waugh, J., Halligan, A., Shennan, A., Thornton, Abstract only/ letter/ correspondence
J. G., Antenatal home blood pressure
monitoring: A pilot randomised controlled trial [3]
(multiple letters), British Journal of Obstetrics
and Gynaecology, 107, 1180-1181, 2000
Westergaard, H. B., Langhoff-Roos, J., All relevant references checked and excluded at
Lingman, G., Marsal, K., Kreiner, S., A critical abstract level
appraisal of the use of umbilical artery Doppler
ultrasound in high-risk pregnancies: Use of
meta-analyses in evidence-based obstetrics,
Ultrasound in Obstetrics and Gynecology, 17,
466-476, 2001
Economic studies
Table 11: Economic excluded studies with reasons for exclusion

Study Reason for exclusion
Duckworth S, Chappell LC, Seed PT, Mackillop Considers different topic - diagnosis of pre-
L, Shennan AH, Hunter R. Placental Growth eclampsia in women with suspected pre-
Factor (PlGF) in Women with Suspected Pre- eclampsia.
Eclampsia Prior to 35 Weeks' Gestation: A
Budget Impact Analysis. PloS one, 11(10),
e0164276. 2016
Frampton GK, Jones J, Rose M, Payne L. Considers different topic - diagnosis of pre-
Placental growth factor (alone or in combination eclampsia in women with suspected pre-
with soluble fms-like tyrosine kinase 1) as an aid eclampsia.
to the assessment of women with suspected
pre-eclampsia: systematic review and economic
analysis. Health Technol Assess;20(87) 2016
Frusca T, Gervasi MT, Paolini D, Dionisi M, Different population (women with suspected pre-
Ferre F, Cetin I. Budget impact analysis of sFlt- eclampsia)
1/PlGF ratio as prediction test in Italian women
with suspected preeclampsia, The Journal of
Maternal-Fetal & Neonatal Medicine, 30:18,
2166-2173 2017
Hadker N, Garg S, Costanzo C, Miller JD, Van More applicable version of study using UK costs
Der Helm W, Foster T, Creeden J. Financial is available (Hadker 2010)
impact of a novel preeclampsia diagnostic test
vsstandard care: A decision-analytic modeling
79
(June 2019)
FINAL
Appendices
Study Reason for exclusion

analysis from a german health care payer
perspective. Value in Health 12(7) 2009
Hadker N, Garg S, Costanzo C, Miller JD, Foster Considers different topic - diagnosis of pre-
T, Van der Helm W, Creeden J. Financial impact eclampsia in women with suspected pre-
of a novel pre-eclampsia diagnostic test versus eclampsia.
standard practice: a decision-analytic modeling
analysis from a UK healthcare payer
perspective, Journal of Medical Economics,
13:4, 728-737 2010
Hunter R, Duckworth S, Seed P, Shennan A, Considers different topic - diagnosis of pre-
Chappell L. Budget impact analysis of maternal eclampsia in women with suspected pre-
plasma PIGF concentrations in women with eclampsia.
suspected pre-eclampsia: The potential for
improved health service usage. Pregnancy
Hypertens. Apr;3(2):85 2013
Meads CA, Cnossen JS, Meher S, Juarez- Considers different topic - prediction and
Garcia A, ter Riet G, Duley L, Roberts TE, Mol prevention of pre-eclampsia.
BW, Van der Post JA, Leeflang MM, Barton PM,
Hyde CJ, Gupta JK, Khan KS. Methods of
prediction and prevention of pre-eclampsia:
systematic reviews of accuracy and
effectiveness literature with economic modelling.
Health Technol Assess;12(6). 2008
Schnettler WT, Dukhovny D, Wenger J, Considers different topic - diagnosis of pre-
Salahuddin S, Ralston SJ, Rana S. Cost and eclampsia in women with suspected pre-
resource implications with serum angiogenic eclampsia.
factor estimation in the triage of pre-eclampsia.
BJOG, 120(10), 1224-32. 2013
Sheehan E, Thilaganathan B, Bhide A, Khalil A. Available as abstract only (poster presentation)
Evaluation of home monitoring of hypertension
in pregnancy. BJOG, 123 (Supplement 1). pp.
29-30 2016
Vatish M, Strunz‐McKendry T, Hund M, Considers different topic - diagnosis of pre-
Allegranza D, Wolf C, Smare C. sFlt‐1/PlGF eclampsia in women with suspected pre-
ratio test for pre‐eclampsia: an economic eclampsia.
assessment for the UK. Ultrasound Obstet
Gynecol, 48: 765-771. 2016
Xydopoulos G, Perry H, Sheehan E, Not specific enough to population of interest -
Thilaganathan B, Fordham R, Khalil A. Home only 30% of patients have gestational
blood‐pressure monitoring in a hypertensive hypertension in one of the study arms.
pregnant population: cost minimisation study.
Ultrasound Obstet Gynecol. 2019
80
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FINAL
Appendices
Appendix L – Research recommendations
In women with hypertensive disorders of pregnancy, what is the optimal fetal

monitoring strategy to detect small for gestational age infants?
Why this is important

Women with hypertensive disorders in pregnancy (including chronic hypertension,
gestational hypertension, pre-eclampsia) are at varying risk of adverse fetal and perinatal
outcomes including fetal growth restriction, preterm birth and stillbirth during pregnancy and
neonatal morbidity and mortality after birth. The evidence base for recommending an optimal
fetal monitoring strategy for women with hypertensive disorders is sparse.
Table 12: Research recommendation rationale

Research In women with hypertensive disorders of pregnancy, what is the optimal
question fetal monitoring strategy to detect small for gestational age infants?
Importance to Women with hypertensive disorders in pregnancy are at a greater risk of
‘patients’ or the adverse fetal outcomes and perinatal outcomes. Women frequently cite
population concerns about the wellbeing of their unborn baby as an additional stressor
during pregnancy.
Relevance to NICE The 2010 NICE guidelines found that there was minimal evidence on the use
guidance of fetal biometry and conflicting evidence on use of umbilical artery Doppler in
pregnancies complicated by hypertensive disorders. No further evidence was
found during surveillance in preparation for the 2019 update and the evidence
gap remains.
Relevance to the The fetal and neonatal complications of hypertensive disorders in pregnancy
NHS are costly to the woman and the health service in medical, psychosocial and
financial terms. The uncertainty over optimal fetal monitoring strategies for
these women leads to potential under-diagnosis of fetuses at risk and/ or
potential unnecessary monitoring and intervention.
National priorities The Department of Health and Social Care Single Departmental Plan (May
2018) aims to reduce the 2010 rate of neonatal deaths and brain injuries in
babies that occur during or soon after birth by 20% by 2020 and 50% by 2025
Current evidence Lack of evidence; some low or very low quality evidence available.
base
Equality Unborn babies in women with hypertension in pregnancy are entitled to
effective and safe monitoring to minimise risk of mortality and short and long
term morbidity.
Table 13: Research recommendation modified PICO table

Criterion Explanation
Population Women with hypertensive disorders of pregnancy (to include chronic
hypertension in pregnancy, gestational hypertension and pre-
eclampsia)
Intervention Fetal monitoring strategies (to include ultrasound)
Prognostic or risk factor N/A
Comparator Different fetal monitoring strategies
Outcome Small for gestational age infants
Neonatal mortality
81
(June 2019)
FINAL
Appendices
Criterion Explanation
Neonatal morbidity
Study design The design could either be a randomised controlled trial of different
fetal monitoring strategies or a prospective cohort study to evaluate
which fetal monitoring strategy best identifies subsequent adverse
outcomes.
Timeframe Minimum duration of follow-up: To primary discharge of woman and
baby.
Consideration should be given to use of consent for longer term follow
up using routinely collected data.
82
(June 2019)

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National Institute for Health and Care

NICE guideline NG133

These evidence reviews were developed

Review question: What is the best strategy (including

Summary of the protocol

Table 1: Summary of protocol (PICO table)

Outcome Outcomes for babies:

Outcomes for women:

For full details see the review protocol in appendix A.

Methods and process

Summary of clinical studies included in the evidence review

Table 2: Summary of included studies

Study Population Intervention Comparator Outcomes

See appendix D for the full evidence tables.

Quality assessment of clinical studies included in the evidence review

Comparison 1. Management based on Korotkoff 4 (K4) sounds versus K5 sounds

Outcomes for babies

Gestational age at birth

Outcomes for women

Severe hypertension (systolic BP ≥160 and/or diastolic BP ≥110 mmHg)

Comparison 2a. Home monitoring versus hospital monitoring

Outcomes for babies

Gestational age at birth

Outcomes for women

Comparison 2b: Home blood pressure telemonitoring (obstetrician updated;

Outcomes for babies

Gestational age at birth

Outcomes for women

Mode of birth (caesarean birth)

Comparison 3. Hospital bedrest versus home normal activity

Outcomes for babies

Gestational age at birth

Preterm birth (<37 weeks)

Preterm birth (<34 weeks)

Admission to neonatal unit

Outcomes for women

Mode of birth (Caesarean birth)

Comparison 4: Less-tight versus tight control of blood pressure

Outcomes for babies

Gestational age at birth

Preterm birth (<37 weeks)

Admission to neonatal unit

Outcomes for women

Mode of birth (caesarean birth)

The committee’s discussion of the evidence

Interpreting the evidence

The outcomes that matter most

The quality of the evidence

Benefits and harms

Cost effectiveness and resource use

Other factors the committee took into account

Brown et al., 1998

Cartwright et al., 1992

Cartwright,W., Dalton,K.J., Swindells,H., Rushant,S., Mooney,P., Objective measurement of

Crowther,C.A., Bouwmeester,A.M., Ashurst,H.M., Does admission to hospital for bed rest

Field (based on PRISMA-P) Content

Field (based on PRISMA-P) Content