State of the Art REVIEW

BMJ: first published as 10.1136/bmj-2022-071653 on 30 June 2023. Downloaded from http://www.bmj.com/ on 5 November 2023 at Universidad del Rosario. Protected by copyright.
Hypertensive disorders of pregnancy
Pensée Wu,1,2,3 Marcus Green,4 Jenny E Myers5
A b s t ra c t
1
School of Medicine, Keele
Hypertensive disorders of pregnancy (HDP) are one of the most commonly
University, Newcastle-under- occurring complications of pregnancy and include chronic hypertension, gestational
Lyme, UK
2
Academic Department of hypertension, and pre-eclampsia. New developments in early pregnancy screening
Obstetrics and Gynaecology,
University Hospital of North
to identify women at high risk for pre-eclampsia combined with targeted aspirin
Midlands, Stoke-on-Trent, UK prophylaxis could greatly reduce the number of affected pregnancies. Furthermore,
3
Department of Obstetrics
and Gynecology, College of recent advances in the diagnosis of pre-eclampsia, such as placental growth
Medicine, National Cheng Kung
University, Tainan, Taiwan
factor based testing, have been shown to improve the identification of those
4
Action on Pre-eclampsia, pregnancies at highest risk of severe complications. Evidence from trials has refined
Evesham, UK
5
Maternal and Fetal Health
the target blood pressure and timing of delivery to manage chronic hypertension
Research Centre, University of and pre-eclampsia with non-severe features, respectively. Importantly, a wealth of
Manchester, Manchester, UK
Correspondence to: P Wu epidemiological data now links HDP to future cardiovascular disease and diabetes
[email protected] decades after an affected pregnancy. This review discusses the current guidelines
Cite this as: BMJ 2023;381:e071653
http://dx.doi.org/10.1136/ and research data on the prevention, diagnosis, management, and postnatal follow-
bmj‑2022‑071653
up of HDP. It also discusses the gap in knowledge regarding the long term risks for
Series explanation: State of the
Art Reviews are commissioned cardiovascular disease following HDP and illustrates the importance of improving
on the basis of their relevance
to academics and specialists
adherence to postnatal guidelines to monitor hypertension and the need for more
in the US and internationally. research focused on primary prevention of future cardiovascular disease in women
For this reason they are written
predominantly by US authors identified as being at high risk because of HDP.

Introduction analyses, randomised controlled trials (RCTs), large

Hypertensive disorders of pregnancy (HDP) are the size of study), direct relevance to the topic, and year
leading causes of maternal morbidity and mortality of publication, with preference given to more recent
worldwide.1 The International Society for the Study publications. We also assessed relevant international
of Hypertension in Pregnancy (ISSHP) has updated professional guidelines and conducted hand
the definition of HDP: chronic hypertension, white searching for relevant articles in the bibliography of
coat hypertension, masked hypertension, gestational the studies found by the search criteria. We included
hypertension, and pre-eclampsia.2 This review is earlier references if a strong case existed for their
aimed at specialists providing maternity services inclusion owing to their relevance.
and gives an overview of the prevention, diagnosis,
management, postnatal sequelae, and follow-up of Epidemiology
HDP. We highlight the latest evidence on screening The prevalence of HDP varies according to region,
for and diagnosis of pre-eclampsia and the long term with a global prevalence of 116 per 100 000 women
consequences of HDP. of childbearing age.3 Regionally, Africa had the
highest prevalence of HDP (335 per 100 000 women
Sources and selection criteria of childbearing age), followed by Southeast Asia and
We searched Medline and Embase databases for the Middle East, whereas the Western Pacific region
studies published between January 2013 and had the lowest prevalence of HDP (16 per 100 000
December 2022, using synonyms of hypertensive women of childbearing age).3 Worldwide, 18.1
disorders of pregnancy (“hypertensive pregnancy million incident cases of HDP were estimated for
disorders” or “hypertension in pregnancy”) or pre- 2019, with HDP thought to be responsible for 27 800
eclampsia (“preeclampsia” or “pre-eclampsia” or deaths in women of childbearing age, a reduction of
“EPH” or “pregnancy toxemia” or “edema-proteinuria- 30% since 1990.4 Moreover, HDP is estimated to be
hypertension gestos”) or pregnancy induced present in 200 000 pregnancies ending in stillbirths
hypertension (“pregnancy-induced hypertension” or every year worldwide.5
“gestational hypertension”) or “chronic hypertension
in pregnancy” or “eclampsia” or “HELLP syndrome”. Classification of HDP
We predefined the priority of the studies to be included The ISSHP defines hypertension in pregnancy as a
on the basis of quality (systematic reviews and meta- systolic blood pressure (sBP) ≥140 mm Hg and/or

the bmj | BMJ 2023;381:e071653 | doi: 10.1136/bmj-2022-071653 1

 State of the Art REVIEW

BMJ: first published as 10.1136/bmj-2022-071653 on 30 June 2023. Downloaded from http://www.bmj.com/ on 5 November 2023 at Universidad del Rosario. Protected by copyright.
Box 1: ISSHP classification of hypertensive disorders of pregnancy
Pre-pregnancy or <20 weeks’ gestation
Chronic hypertension:
• Hypertension pre-pregnancy or <20 weeks’ gestation
White coat hypertension:
• BP ≥140/90 mm Hg in clinic, but BP <135/85 mm Hg with home or ambulatory BP monitoring
Masked hypertension:
• BP <140/90 mm Hg in clinic, but BP ≥135/85 mm Hg outside clinic
≥20 weeks’ gestation
Gestational hypertension:
• Hypertension de novo ≥20 weeks’ gestation without proteinuria or other features suggestive of pre-eclampsia
Pre-eclampsia:
• Gestational hypertension with ≥1 new onset conditions of organ or uteroplacental dysfunction:
○○Proteinuria
○○Other maternal end organ dysfunction, including:
• Neurological complications (eg, eclampsia, altered mental status, blindness, stroke, clonus, severe headaches, or persistent visual scotomata)
• Pulmonary oedema
• Haematological complications (eg, platelet count <150 000/μL, disseminated intravascular coagulation, haemolysis)
• Acute kidney injury (such as creatinine ≥90 μmol/L or 1 mg/dL)
• Liver involvement (eg, elevated transaminases such as ALT or AST >40 IU/L) with or without right upper quadrant or epigastric abdominal pain)
• Uteroplacental dysfunction (eg, placental abruption, angiogenic imbalance, fetal growth restriction, abnormal umbilical artery Doppler
waveform analysis, or intrauterine fetal death)
○○With severe features (according to ACOG):
• Systolic BP ≥160 mm Hg or diastolic BP ≥110 mm Hg on two occasions at least 4 hours apart
• Thrombocytopenia
• Impaired liver function
• Renal insufficiency
• Pulmonary oedema
• New onset headache unresponsive to medication and not accounted for by alternative diagnoses and visual disturbances
Superimposed pre-eclampsia on chronic hypertension:
• Chronic hypertension with development of new proteinuria and/or organ or uteroplacental dysfunction(s) with the conditions listed above

Adapted from ISSHP 2021 guideline.2

ACOG=American College of Obstetrics and Gynecology; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BP=blood pressure;
ISSHP=International Society for the Study of Hypertension in Pregnancy.

a diastolic blood pressure (dBP) ≥90 mm Hg, with hypertension. White coat hypertension should be
sBP ≥160 mm Hg and/or a dBP ≥110 mm Hg defined monitored with regular blood pressure surveillance
as severe hypertension.2 The use of an automated and/or home or 24 hour ambulatory blood pressure
device validated in pregnancy and pre-eclampsia is monitoring, as it is associated with an increased risk
preferable for the measurement of blood pressure; of pre-eclampsia.9 10 For masked hypertension, as
a list of suitable devices is available online.6 It is the blood pressure seems to be normal in clinic, the
good practice to confirm the diagnosis with repeated diagnosis is usually sought only when unexplained
measures of blood pressure, ideally over several features of organ damage from hypertension are
hours or days. Ideally, the diagnosis would be present. Diagnosis is confirmed by home or 24 hour
confirmed by ambulatory monitoring, which is the ambulatory blood pressure monitoring.11
gold standard outside of pregnancy, but for logistical Gestational hypertension (often previously referred
reasons the diagnosis in pregnancy is usually to as pregnancy induced hypertension) is defined as
confirmed by repeated hospital or clinic based de novo hypertension after 20 weeks’ gestation. Pre-
measurements. Self-monitoring of blood pressure eclampsia is a multisystem disease characterised
is now increasingly common in the management of by widespread endothelial dysfunction, and the
HDP. The BUMP trials confirmed that this practice definition requires at least two features of the syndrome
was acceptable to women and not associated with to be present (see box 1). In addition to hypertension
increased risk of adverse outcomes.7 8 (de novo or chronic), proteinuria is the most frequent
The ISSHP has refined the classification of HDP over additional sign of endothelial dysfunction and
the years (box 1).2 Chronic hypertension is defined as therefore most often used to make the diagnosis.
hypertension present before pregnancy or diagnosed The clinical diagnosis is based on the presence
before 20 weeks’ gestation. The modified definitions of signs/symptoms including vasoconstriction
include white coat hypertension and masked (hypertension), increased capillary permeability

2 doi: 10.1136/bmj-2022-071653 | BMJ 2023;381:e071653 | the bmj

 State of the Art REVIEW

BMJ: first published as 10.1136/bmj-2022-071653 on 30 June 2023. Downloaded from http://www.bmj.com/ on 5 November 2023 at Universidad del Rosario. Protected by copyright.
primiparity, assisted reproduction and short duration
Box 2: Major and moderate risk factors for pre-eclampsia in National Institute for
of sperm exposure, and extremes of maternal age.20
Health and Care Excellence guideline30
A meta-analysis including 25 356 688 women
Major analysed 40 studies from Europe and 30 from North
• HDP during previous pregnancy America.21 Previous HDP, chronic hypertension,
• Chronic kidney disease and antiphospholipid syndrome were associated
• Autoimmune disease—eg, SLE or APS with the highest absolute risk of pre-eclampsia.
• Diabetes—type 1, type 2 However, in terms of population attributable risk,
• Chronic hypertension obesity and nulliparity (11%) accounted for the
Moderate largest population risk.22 Similar data have also
• Nulliparity been collated from low income and middle income
• Age ≥40 years settings, with data from 276 388 mothers and their
• Pregnancy interval >10 years infants analysed by investigators at the World Health
• BMI ≥35 at first clinic visit Organization.23 The prevalence of pre-eclampsia/
• Family history of pre-eclampsia eclampsia in this study population was 4%, and
• Multi-fetal pregnancy the odds ratios for development of the condition
associated with body mass index ≥35, nulliparity,
APS=antiphospholipid syndrome; BMI=body mass index; HDP=hypertensive and chronic hypertension were 3.90 (95% confidence
disorders of pregnancy; SLE=systemic lupus erythematosus interval 3.52 to 4.33), 2.04 (1.92 to 2.16), and 7.75
(6.77 to 8.87), respectively.
No treatment is available for pre-eclampsia or
(proteinuria, peripheral oedema, cerebral oedema, fetal growth restriction once they have developed.24
liver congestion, pulmonary oedema), and abnormal To prevent maternal complications and fetal death,
endothelial/platelet interactions (thrombocytopenia, intensive surveillance and iatrogenic preterm birth
disseminated intravascular coagulation). are the mainstay of management.2 For decades,
Pre-eclampsia is strongly associated with aspirin has been considered an effective preventive
placental dysfunction; placental damage and/or treatment for pre-eclampsia.25 26 A range of effective
stress is thought to precede the development of aspirin dosages (50 to 150 mg) for prevention of pre-
the maternal condition.12 Recognising the strong eclampsia have been presented in meta-analyses.27-29
association between chronic placental insufficiency The current guidelines from the National Institute
and particularly preterm pre-eclampsia, the presence for Health and Care Excellence (NICE) recommend
of objective features of placental dysfunction, aspirin for women with one high risk factor or two
including fetal growth restriction, oligohydramnios, moderate risk factors for pre-eclampsia (box 2).30
abnormal umbilical artery, or maternal uterine The algorithm from the Fetal Medicine Foundation
artery Doppler, are also accepted features of the pre- (FMF) (https://www.fetalmedicine.org/research/
eclampsia syndrome (box 1). The combination of assess/preeclampsia/first-trimester) incorporates
placental dysfunction and hypertension is therefore maternal risk factors, blood pressure, placental
usually considered to satisfy a clinical diagnosis biomarkers (pregnancy associated plasma protein A
of pre-eclampsia although this combination is not (PAPP-A) and protein placental growth factor (PlGF)),
included in the American College of Obstetricians and uterine artery Doppler. The FMF’s algorithm
and Gynecologists (ACOG) guideline definition.13 has been developed over a series of observational
The importance of distinguishing pre-eclampsia studies.31-33 In 2018 an independent prospective
from other HDP is very important in clinical cohort study reported a doubling of the detection
practice. Left unchecked, pre-eclampsia leads rate of preterm pre-eclampsia with the algorithm.
to severe adverse maternal outcomes including At a fixed screen positive rate of 10.3%, rates of
cerebrovascular haemorrhage, pulmonary oedema, preterm pre-eclampsia were 3.4% in women screen
acute kidney injury, hepatic rupture, placental positive using NICE criteria and 6.8% in women
abruption, and eclampsia.14-19 Prevention of these screen positive using the FMF’s algorithm; the test
severe, life threatening outcomes relies on early doubled the detection rate for preterm pre-eclampsia
diagnosis and intervention; early delivery is the only compared with the NICE guidelines (41% to 82%).33
current treatment. The consequences of inaccurate Although several trials had already shown a
classification of HDP therefore include missed reduction in preterm pre-eclampsia with aspirin,25 26
diagnoses and avoidable adverse outcomes, as well the ASPRE trial confirmed a significant reduction
as inappropriate iatrogenic preterm births leading to in risk when aspirin was used in conjunction with
significant neonatal morbidity. the FMF’s algorithm.34 In this RCT, 11% of the
population were screen positive, of whom 60% were
Risk factors and prevention randomised to aspirin 150 mg daily or placebo. Rates
The maternal and pregnancy characteristics of preterm pre-eclampsia were 4.3% in the placebo
associated with an increased risk of pre-eclampsia group and 1.6% in the treatment group (odds ratio
have been reported in many cohort studies and 0.38, 0.20 to 0.74). Moreover, the effectiveness of
include a previous history of HDP, nulliparity, aspirin is greatest in preventing births at <32 weeks’
family history, obesity, pre-existing medical disease, gestation,35 when the consequences of pre-eclampsia

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State of the Art REVIEW

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Healthy pregnancy Pre-eclampsia

PIGF TGF-β

sFlt-1 sENG

Flt-1 ENG

Fig 1 | In healthy pregnancy, soluble FMS-like tyrosine kinase 1(Flt-1) binds to placental growth factor (PlGF) and endoglin (ENG) binds to
transforming growth factor β (TGF-β). In pre-eclampsia, soluble Flt-1 (sFlt-1) is cleaved off Flt-1 and competes with Flt-1 to bind to PlGF. Also soluble
ENG (sENG) is cleaved off ENG and competes with ENG to bind to TGF-β

are most severe. First trimester screening using the cost effectiveness of calcium supplementation in
FMF’s algorithm combined with aspirin seems to preventing pre-eclampsia in the UK.
outperform NICE screening, particularly in first time
mothers and women from Black and minority ethnic Recent advances in diagnosis
backgrounds.36 37 The clinical presentation is heterogeneous and
Despite the ASPRE trial, the FMF’s algorithm has frequently atypical, leading to ambiguity in the
not been widely adopted in the UK although ISSHP classification of HDP in both clinical practice and
and the International Federation of Gynecology and research studies. Unsurprisingly, a diagnosis based
Obstetrics now recommend combined screening on highly variable clinical observations such as
with the FMF algorithm where possible.2 38 blood pressure and proteinuria, and which relies
Concerns about cost effectiveness and the logistics on parameters with poor diagnostic accuracy
of implementation, given the low prevalence of (eg, fetal ultrasonography and urine protein
the disease, are commonly cited as barriers among measurement),43 44 is often inaccurate. Transient
obstetricians. Only limited external validation of and sustained gestational hypertension is common
this screening test has been conducted.39 However, in pregnancy, particularly towards term and
in a single site study in London, its adoption led to intrapartum. The distinction between a transient
a reduction in preterm pre-eclampsia by 80%.36 excursion in blood pressure above 140/90 mm Hg
To date, multimodal screening for pre-eclampsia and the diagnosis of a syndrome attributable to
using the FMF’s algorithm has not been endorsed endothelial dysfunction therefore continues to pose
by the National Screening Committee; the updated a frequent diagnostic challenge. The diagnosis of
statement concluded that evidence supports clinical pre-eclampsia is even more complicated in women
effectiveness for early pregnancy screening combined who have chronic hypertension and/or other
with aspirin prophylaxis, but insufficient evidence medical or obstetric disorders that are associated
“of harms and benefits of a screening programme in with the development of hypertension, proteinuria,
this population” is available.40 compromised kidney function (eg, diabetes, chronic
Implementation of the FMF’s algorithm could kidney disease), abnormal liver function (eg,
achieve an absolute risk reduction in the rate of obstetric cholestasis), or abnormal haematology
preterm pre-eclampsia of 0.4%,33 which equates to (gestational thrombocytopenia). Although many
around 17 cases per year of preterm pre-eclampsia studies have attempted to adjudicate the diagnosis
avoided in an average maternity unit (4500 births per of pre-eclampsia, the use of clinical definitions is
annum). Given the significant cost of implementation limited and inevitably many pre-eclampsia research
(approximately £170 000 ($210 000; €196 000) studies will have inaccuracies.
per year—£38 per pregnancy) and the logistical Progress towards a more accurate diagnostic test
challenges of introducing the test, further evidence for pre-eclampsia was accelerated by the discovery of
to evaluate cost effectiveness is likely to be needed an abnormal angiogenic imbalance in pre-eclampsia.
before routine implementation can be recommended The initial study identified very high concentrations
in the UK. of the protein soluble FMS-like tyrosine kinase
Calcium supplementation has also shown 1 (sFlt) in the placentas of women with pre-
promise in Cochrane systematic reviews for the eclampsia.45 This observation was followed by a
prevention of HDP, particularly in areas with second study that showed high concentrations of the
low dietary calcium.41 42 The ongoing CaPE RCT antiangiogenic protein sFlt and low concentrations of
(ISRCTN12033893), expected to complete in the proangiogenic PlGF in the maternal circulation of
2025, is investigating the clinical effectiveness and women before clinical diagnosis of pre-eclampsia.46

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 State of the Art REVIEW

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Screening Prophylaxis Diagnosis Medication Delivery Postnatal

Standard care Using factors in Aspirin PlGF based If BP ≥140/90 <34 weeks’ BP surveillance
NICE guideline to testing mm Hg, start gestation: expectant minimum of once
screen for antihypertensive management with between days 3 and
pre-eclampsia medication plan to guide earlier 5 and on alternate
(labetalol, birth if suspected days until normal
Uterine artery nifedipine, maternal/fetal
Doppler at 20-24 methyldopa, compromise―eg, If abnormal BP on
weeks’ gestation in hydralazine) sustained, refractory day 3-5, medication
women with chronic severe hypertension, review at 2 weeks
hypertension/ Magnesium deteriorating
previous HDP to sulphate for seizure haematology/
Annual
screen for early prophylaxis biochemistry,
surveillance and
onset FGR non-reassuring fetal
diet/lifestyle advice
surveillance
Corticosteroids if
(abnormal
planning preterm
CTG/Doppler)
delivery

34-37 weeks’
gestation:
consideration of
early birth following
discussion of
PHOENIX trial

>37 weeks’
gestation: offer birth

Additional care Multimodal first Calcium

offered variably trimester screening
In UK using FMF
algorithm: maternal
risk factors, first
trimester uterine
artery Doppler,
biochemical
screening
(PAPP-A/PlGF)

Fig 2 | Standard care according to National Institute for Health and Care Excellence guidance in the UK.30 61 62 BP=blood pressure;
CTG=cardiotocography; FGR=fetal growth restriction; FMF=Fetal Medicine Foundation; PAPP-A=pregnancy associated plasma protein A;
PlGF=placental growth factor

The association between this angiogenic marker studies, the NICE Diagnostic Assessment Panel
imbalance and a clinical diagnosis of pre-eclampsia made a recommendation that PlGF based testing
has been consistently reproduced in many subsequent should be offered to women presenting with clinical
studies.47 48 Furthermore, a relation between the signs suggestive of pre-eclampsia before 37 weeks’
severity of the clinical features of the disease and gestation. This recommendation was recently
the scale of the angiogenic imbalance has also been updated following a review of further evidence
observed.49 50Figure 1 illustrates the angiogenic showing the clinical utility of PlGF based testing
markers in the pathophysiology of pre-eclampsia.51 as an adjunct to the diagnosis of pre-eclampsia.54
Two large prospective observational studies have The PARROT trial, a multicentre cluster randomised
since confirmed the accuracy of a high sFlt to PlGF step wedged study, showed that a clinical diagnosis
ratio or a low PlGF concentration as a diagnostic was made more promptly (median 4 days to 2 days)
marker for pre-eclampsia presenting before 37 when PlGF based testing (Quidel) was incorporated
weeks’ gestation.52 53 On the basis of these two into the diagnosis and that severe, rare adverse

the bmj | BMJ 2023;381:e071653 | doi: 10.1136/bmj-2022-071653 5

State of the Art REVIEW

BMJ: first published as 10.1136/bmj-2022-071653 on 30 June 2023. Downloaded from http://www.bmj.com/ on 5 November 2023 at Universidad del Rosario. Protected by copyright.
maternal outcomes were avoided.55 An embedded cardiovascular examination, renal function tests,
cost utility study also confirmed that PlGF based proteinuria assessment, and diabetes screen should
testing was associated with cost savings associated be offered. Women with chronic hypertension are
with fewer outpatient attendances, reduced numbers at risk of developing superimposed pre-eclampsia,
of ultrasound scans, and reduced neonatal unit bed and most guidelines recommend starting aspirin
days in the intervention arm.56 A single centre study for prevention.27 63 64 A recent meta-analysis
also confirmed that inclusion of the sFlt to PlGF concluded that low dose aspirin did not reduce
ratio test (Roche Diagnostics) was associated with the risk of superimposed pre-eclampsia in women
improved diagnostic accuracy and improved triage with chronic hypertension. However, a significant
of women at the highest risk to high surveillance reduction in all preterm birth was seen.65 This may
pathways.57 reflect inaccuracies in the diagnosis of preterm pre-
Funding from NHS England following adoption of eclampsia in women with chronic hypertension.
PlGF based testing by the NHS Accelerated Access A Cochrane systematic review on antihypertensive
Collaborative and Innovation Technology Payment treatments for women with mild to moderate
programmes has resulted in widespread adoption hypertension during pregnancy (n=3485) was
of PlGF based testing in English maternity units; a inconclusive on the treatment benefits for reducing
sustained effort is needed to ensure that testing is adverse outcomes such as pre-eclampsia (risk
available to women across the UK. The recent NICE ratio 0.92, 95% confidence interval 0.75 to 1.14;
guidance includes several alternatives for PlGF n=2851), small for gestational age infant (0.96, 0.78
based testing, and to date comparison between the to 1.18; n=2686), and preterm birth (0.96, 0.83 to
available assays has not suggested that any of the 1.12; n=2141), except for the reduction in severe
available tests have superior diagnostic accuracy.58 hypertension (0.49, 0.40 to 0.60; n=2558).66 The
In clinical practice, PlGF based testing has most mainstay of management in women with chronic
impact as part of the ongoing, holistic assessment hypertension includes maintenance of a safe blood
of women in whom a confident clinical diagnosis is pressure, surveillance of fetal growth, and early
not possible. This includes women with borderline detection of pre-eclampsia, which affects up to
hypertension, but more importantly women with 25% of women.67 The threshold for instigation of
chronic hypertension and other chronic medical antihypertensive treatment in chronic hypertension
conditions for whom preterm birth is often offered has long been debated; recent evidence has shown
and justified by a clinical suspicion of developing pre- significant maternal benefits without additional
eclampsia. A lack of consistency between the clinical concerns about fetal growth. The CHIPS RCT
diagnosis and the biochemical diagnosis has been (n=987; 75% with chronic hypertension), showed
reported,59 and as experience of using PlGF based no difference in severe composite maternal or
testing develops, the greatest clinical impact is likely neonatal outcomes (pregnancy loss/high level
to be in women with clinical features that confound neonatal care: odds ratio 1.02, 0.77 to 1.35; serious
the diagnosis.60 For example, a cohort study (n=979) maternal complications: 1.74, 0.79 to 3.84) between
in a real world clinical setting showed that low PlGF less tight control (target dBP<100 mm Hg) and tight
concentrations are associated with increased rates control (target dBP<85 mm Hg), with the exception
of preterm birth within two weeks (standardised of an increased risk of severe hypertension (odds
survival difference −0.43, 95% confidence interval ratio 1.80, 1.34 to 2.38) in the less tight control
−0.76 to −0.09) irrespective of the clinical diagnosis, group.68 More recently, the CHAP RCT (n=2408
as well as increased risk of early onset pre-eclampsia women with chronic hypertension) reported that a
(odds ratio 58.2, 32.1 to 105.4) and stillbirth (15.9, target blood pressure <140/90 mm Hg, compared
7.6 to 33.3).60 In summary, PlGF based testing helps with no medication unless blood pressure was
to inform the frequency and location of surveillance ≥160/105 mm Hg, led to a reduction in adverse
for women with HDP by adding confidence to the composite outcomes including pre-eclampsia with
exclusion of disease and justifying close surveillance severe features, preterm birth, abruption, and
in those with an intermediate or positive test. The fetal or neonatal death (risk ratio 0.82, 0.74 to
evidence supports the test as a short term (up to 0.92), without harming fetal growth (birth weight
four weeks) diagnostic test; it should not be used to <10th centile: 1.04, 0.82 to 1.31).69 NICE guidance
guide timing of birth following a diagnosis of pre- recommends treatment for all HDP if blood pressure
eclampsia. exceeds 140/90 mmHg.30
Data on the timing of delivery for women with
Antepartum management chronic hypertension that is well controlled are
Chronic hypertension limited. Cohort studies suggest that delivery between
Figure 2 shows a summary of standard care 38 and 39+6 weeks’ gestation is optimal for the fetus
according to NICE guidance in the UK. In women with in women not taking antihypertensive drugs.70 71
hypertension before 20 weeks, clinical judgment However, other studies have shown that delivery
should determine whether investigations (eg, beyond 39 weeks is associated with increased risk
renal imaging, echocardiography, catecholamines) of developing superimposed pre-eclampsia.72 73
for secondary hypertension are justified; as a Therefore, most guidelines recommend delivery
minimum, a detailed medical history, clinical between 38 and 39 weeks’ gestation,2 74-78

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 State of the Art REVIEW

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cardiovascular
Pre-existing

risk factors
disease
risk sive
tic
e ne erten ancy
ad Car d g yp regn
to
hyp apta diac are n h r
tio Sh wee s of p scula
e t r
dis rten ns be orde iova
ord sive
pre ers dis card
d
gn
an f
o an ease
cy dis

Ma
lar infl terna
scu
Va ction am l
ma
un
dysf tio
n
Placental
ischaemia

Fig 3 | Potential underlying mechanisms for association between hypertensive disorders of pregnancy (HDP) and future cardiovascular disease (CVD).
Adapted with permission from Wu et al. Eur Cardiol Rev 2021 118

whereas others suggest offering delivery from 37 The optimal timing of delivery for women with
weeks’ gestation,79 particularly if maintenance gestational hypertension remains unclear, as no data
antihypertensive treatment is used.30 74 The WILL from a large trial are available specifically for this
trial (ISRCTN77258279), completing in 2024, group. The HYPITAT RCT randomised women with
is attempting to close this gap in knowledge by gestational hypertension (n=496) and pre-eclampsia
comparing birth at 38+0 to 38+3 weeks’ gestation with non-severe features (n=246) to induction of
with usual care, usually birth after 39 weeks’ labour or expectant management.84 Induction of
gestation, in women with chronic or gestational labour at 37 weeks’ gestation was associated with a
hypertension.80 reduction in composite adverse maternal outcomes
including pre-eclampsia with severe features and
Gestational hypertension eclampsia (risk ratio 0.71, 0.59 to 0.86), without
Approximately 10-25% of women with gestational differences in rates of caesarean delivery (0.75,
hypertension will develop pre-eclampsia,81 and 0.55 to 1.04) or neonatal complications (0.75, 0.45
the risk is highest in those who present at earlier to 1.26), compared with expectant management.
gestations (<34 weeks).82 83 Predicting which However, the intervention group had worse
women will develop pre-eclampsia at the time of neurodevelopment outcomes at age of 2 years (odds
presentation on the basis of clinical features alone is ratio 0.48, 0.24 to 0.96).85 On the other hand, a large
not possible, but the addition of PlGF based testing retrospective observational study of women with
allows surveillance to be targeted to those at highest gestational hypertension (n=228 668) found that a
risk of developing pre-eclampsia.30 54 The threshold later delivery gestation between 38 and 39 weeks’
for antihypertensive treatment in the NICE guidelines gestation balances the lowest maternal and fetal risk
is the same as that for chronic hypertension and pre- of morbidity and mortality.86 The rate of maternal
eclampsia (≥140/90 mm Hg).30 63 morbidity/mortality at 38 weeks was 89.9 (95%

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State of the Art REVIEW

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Table 1 | Prevalence of recurrent hypertensive disorders of pregnancy

Type of hypertension in affected pregnancy

Prevalence in future pregnancy Any hypertension Pre-eclampsia Gestational hypertension
Any hypertension ~21% ~20% ~22%
Pre-eclampsia ~14% ~16%; birthed 28-34 weeks’ gestation ~33%; ~7%
birthed 34-37 weeks’ gestation 23%
Gestational hypertension ~9% ~6-12% ~11-15%
Chronic hypertension NA ~2% ~3%
Adapted from National Institute for Health and Care Excellence guideline.30

confidence interval 68.1 to 111.8) per 1000 live Fetal monitoring

births, whereas the rate of fetal morbidity/mortality The suggested frequency of third trimester scans
at 38 weeks was 10.5 (2.8 to 18.2) per 1000 live should be dictated by the clinical presentation
births. and fetal wellbeing assessments. Most guidelines
recommend a minimum of four weekly
Pre-eclampsia assessment in women with controlled chronic
Pre-eclampsia with non-severe features can progress hypertension in the absence of concerns about fetal
to pre-eclampsia with severe features within days. wellbeing.2 13 30 74 87 98
Therefore, many national guidelines recommend a
minimum of twice weekly blood pressure monitoring Intrapartum management
and blood testing.2 13 30 87 The externally validated Control of blood pressure and prevention of seizures
fullPIERS or PREP prognostic models referred to in are central to peripartum management of HDP. Given
the NICE guidance may be used to identify women the significant risk of cerebrovascular haemorrhage
at risk of adverse maternal outcomes and help with associated with untreated hypertension in pre-
making a decision on place of care and threshold for eclampsia,99 100 guidelines recommend that women
intervention.30 88-90 Studies have shown that PlGF with severe hypertension (≥160/110 mm Hg)
based testing can also predict adverse maternal should be treated as inpatients, using intravenous
outcomes.55 57 91 Treatment of hypertension for labetalol, oral nifedipine, or intravenous hydralazine
women with pre-eclampsia with non-severe features as necessary.63 Women with sustained severe
at ≥140/90 mm Hg is recommended by most hypertension in the context of pre-eclampsia, or
guidelines,2 63 92 93 with the exception of the ACOG with symptoms consistent with end organ disease
which advocates a treatment threshold of ≥160/110 (headache, visual disturbance, epigastric pain,
mm Hg.13 vomiting), should be treated with intravenous
For pre-eclampsia with severe features at a magnesium sulfate for seizure prophylaxis. Most
previable gestation, termination of pregnancy should national guidelines emphasise that decisions
be considered owing to the high risks of maternal on mode of delivery should be dictated by usual
complications. Between 24 and 34 weeks’ gestation, obstetric considerations.63
a Cochrane systematic review (n=748) showed that
expectant care until 34 weeks’ gestation may be Eclampsia
associated with less fetal morbidity if no maternal or Without magnesium sulfate prophylaxis, the rate of
fetal indication for immediate delivery is present.94 seizures in women with pre-eclampsia with severe
Babies whose mothers were in the intervention features is four times higher than in those with pre-
group (delivery within 24-48 hours of presenting eclampsia with non-severe features.13 The Magpie
with pre-eclampsia with severe features) had more RCT (n=10 141) showed a reduction in eclamptic
intraventricular haemorrhage (risk ratio 1.94, 1.15 seizures (58% (95% confidence interval 40% to
to 3.29) and respiratory distress (2.30, 1.39 to 3.81) 71%) reduction),101 and a Cochrane systematic
and needed more ventilation (1.50, 1.11 to 2.02). For review (n=1396) showed a reduction in maternal
pre-eclampsia with non-severe features between 34 death (risk ratio 0.59, 0.38 to 0.92) and recurrent
and 37 weeks’ gestation, the PHOENIX RCT (n=901) eclamptic seizures (0.43, 0.33 to 0.55) with the use
showed that induction of labour within 48 hours of intravenous magnesium sulfate.102 Magnesium
was associated with reduced adverse composite sulfate also has a role in fetal neuroprotection for
maternal morbidity (risk ratio 0.86, 0.79 to 0.94), preterm birth.103 104
increased likelihood of vaginal birth, and reduced
magnesium sulfate administration but increased Antihypertensive agents
composite perinatal adverse outcome, primarily Recommended antihypertensive agents for HDP
composed of increased neonatal unit admission include labetalol, modified release nifedipine (12
(1.25, 1.05 to 1.48).95 These findings are consistent hourly), and methyldopa. For the treatment of mild
with subsequent individual participant data meta- to moderate hypertension, a Cochrane systematic
analyses.96 97 Once at or beyond 37 weeks’ gestation, review (n=2774) concluded that labetalol and
delivery is recommended on the basis of the HYPITAT nifedipine were preferable to methyldopa for the
findings.84 avoidance of severe hypertension (risk ratio 0.70, 0.56

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to 0.88).66 For pre-eclampsia with severe features, a longer acting, once daily drugs are also likely to
network meta-analysis including 46 studies reported be advantageous.30 Diuretics may decrease milk
similar efficacy between intravenous labetalol, oral production and therefore should be avoided.
nifedipine, and intravenous hydralazine.105 In a low
resource setting, an RCT (n=2307) showed that oral Postnatal follow-up
nifedipine led to significantly better blood pressure Short term management
control than oral methyldopa.106 The Giant PANDA Postpartum blood pressure is often higher than
study (ISRCTN12792616), completing in 2024, is blood pressure during pregnancy, and a sustained
recruiting in the UK and will compare oral labetalol risk of cerebrovascular haemorrhage exists in
with oral nifedipine in women with HDP; a subgroup the postpartum period.100 Poorly controlled
analysis to investigate the impact of self-reported hypertension is a frequent cause of postnatal
ethnicity will be included. readmission, so proactive management is likely to
Labetalol is a mixed α and β adrenoreceptor be beneficial. Blood pressure is commonly highest
blocker. Current UK guidance advises neonatal three to five days after birth and should be measured
surveillance for hypoglycaemia following exposure at least once during this period. We consider it good
to labetalol,107 although little definitive evidence practice to anticipate an increase in blood pressure
is available to guide this practice. Nifedipine is a if primary hospital discharge occurs before day 3-5
calcium channel antagonist and can cause maternal and to have a lower threshold for antihypertensive
headache and tachycardia.108 Nicardipine has treatment during the first two weeks after birth.
also been evaluated in a retrospective case series Normalisation of blood pressure in the early
(n=830).109 It was shown to be effective in lowering weeks after HDP is very important to avoid the rare
sBP ≥160 mmHg and/or dBP ≥110 mmHg in 77% of occurrence of cerebrovascular accidents. It may also
study participants within two hours of treatment. have significant benefits for future cardiovascular
Methyldopa acts by stimulating α2 receptors in the health by reducing the effects of hypertensive cardiac
brainstem and decreasing the central sympathetic remodelling.116 117
output. Although methyldopa has a good safety
profile, studies have shown that it may be marginally Long term implications
less effective than labetalol or nifedipine and often Cardiovascular disease
causes side effects.66 110-112 Hydralazine, an arterial Figure 3 illustrates the potential underlying
vasodilator, is indicated only in severe hypertension. mechanisms underpinning the association between
In a meta-analysis (n=893), hydralazine was HDP and future cardiovascular disease.116 The
more effective than labetalol in treating severe association between HDP and increased long term
hypertension (risk ratio 0.29, 0.08 to 1.04) but was risk of developing cardiovascular disease is now
linked with more adverse maternal and perinatal well established and discussed in several reviews
outcomes (maternal hypotension: 3.29, 1.50 to 7.23; of meta-analyses.119 120 Pre-eclampsia is associated
placental abruption: 4.17, 1.19 to 14.28; caesarean with a twofold increase in risk of coronary heart
section: 1.30, 1.08 to 1.59; maternal oliguria: 4.00, disease, stroke, and death from cardiovascular
1.22 to 12.50; 1 minute Apgar score <7: 2.70, 1.27 disease and a fourfold increase in risk of heart
to 5.88).113 failure,121 122 with recurrent pre-eclampsia having
Amlodipine, as an alternative calcium channel the highest risk.123 Gestational hypertension
blocker and doxazosin/prazosin (α-adrenegic is associated with a 1.8-fold increase in risk of
receptor blockers) are frequently used to treat HDP, coronary heart disease, heart failure, and composite
although limited published evidence supports their cardiovascular disease and a 1.4-fold increase in
use as first line options. Owing to teratogenicity, risk for composite cardiovascular disease.124 125
renin-angiotensin-aldosterone inhibitors are Although the relative risk is highest within the first
contraindicated during pregnancy114; some year postpartum, the cardiovascular risks of women
international guidelines also recommend against with HDP persist decades after the pregnancy,
diuretics, atenolol, and thiazides during pregnancy.63 when the absolute risks are greater than those
immediately postpartum.121 126
Postnatal antihypertensive treatment Pre-eclampsia is also associated with an up to
All antihypertensive drugs are detectable at low 3.9-fold increase in risk of hypertension and a 1.3-
concentrations in breast milk,115 but they are fold increase in risk of dyslipidaemia.122 127 The
considered safe to prescribe in the context of SNAP-HT pilot trial showed that self-management
breast feeding.30 Calcium channel blockers and of blood pressure in the puerperium resulted in
angiotensin converting enzyme (ACE) inhibitors, lower dBP at six months and 3.6 years,116 128 even
such as captopril and enalapril, are all considered without antihypertensive treatment. As a follow-
safe for breastfeeding women.74 ACE inhibitors up study, the recently completed POP-HT trial is
have the disadvantage of requiring dose titration adequately powered to formally assess whether this
and monitoring of renal function; adequate blood self-management is associated with blood pressure
pressure treatment may require an additional agent reduction at six to nine months.129 The BP-PRESELF
until a satisfactory dose is reached. Adherence is trial included women who were 12 years after their
also a consideration in the postnatal period, and index pregnancy with pre-eclampsia or haemolysis,

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elevated liver enzymes, and low platelets (HELLP) Counselling for next pregnancy
syndrome.130 It showed that home blood pressure Risk of recurrence
monitoring reduces blood pressure at one year A meta-analysis of individual patient data reported
follow-up. a 20% recurrence rate of HDP.151 The risk of
Women with a history of pre-eclampsia have recurrence increases with concomitant HELLP
higher left ventricular mass index and relative wall syndrome, preterm delivery, or small for gestational
thickness, as well as mild diastolic dysfunction age infant. Women with previous pre-eclampsia
postnatally.131 132 The PICK-UP feasibility trial are equally likely to develop either pre-eclampsia
showed that enalapril treatment following pregnancy (14%) or gestational hypertension (14%), whereas
affected by preterm pre-eclampsia may lead to women with previous gestational hypertension are
improved cardiac remodelling and diastolic function more likely to develop gestational hypertension
at six months postpartum.117 (26%) than pre-eclampsia.152 Table 1 illustrates the
likelihood of recurrence of HDP.30
Diabetes
HDP are associated with type 2 diabetes, even Management for next pregnancy
without coexisting gestational diabetes, with an up If the hypertension has not resolved within
to 2.6-fold and 2.2-fold increase in risk of diabetes three months postpartum, investigations for
for pre-eclampsia and gestational hypertension, secondary hypertension should be considered. If
respectively, in meta-analyses.133-135 Pre-eclampsia women are taking ACE inhibitors or angiotensin
itself is associated with an up to 4.3-fold increase in II receptor blockers, a plan should be made to
risk of developing metabolic syndrome.127 136 137 switch antihypertensive drugs before or as soon
as pregnancy is diagnosed, as some studies have
Other conditions reported increased risk of congenital malformations
Meta-analyses have shown the association between with first trimester exposure, compared with both
HDP and long term kidney disease. Pre-eclampsia is non-exposure and exposure to other antihypertensive
associated with up to 6.4-fold and 2.1-fold increase drugs.153 154 Low dose aspirin should be offered from
in risk of end stage kidney disease and chronic 12 weeks’ gestation to reduce the risk of recurrence
kidney disease, respectively.138 139 By contrast, of pre-eclampsia in these women at high risk.
gestational hypertension is associated with a 3.6- Women with other risk factors that are modifiable,
fold increase in risk of end stage kidney disease and a such as poor glycaemic control or obesity, should be
1.5-fold increase in risk of chronic kidney disease.138 encouraged to lose weight, eat healthily, and reduce
Overall, HDP are associated with a 1.4-fold increase salt and excessive caffeine intake. Although stopping
in risk of dementia,140 with pre-eclampsia being smoking improves other pregnancy outcomes, it
associated with a 2.6-fold increase in risk of vascular does not decrease the recurrence rate of HDP.155 156
dementia.141 Pre-eclampsia has been associated Women should also be counselled about the risk of
with a 1.5-fold and 1.8-fold increase in risk of developing recurrent HDP and what that means to
venous thromboembolism and premature mortality, their planned pregnancy care. A systematic review
respectively.122 HDP lead to lower scores for health (n=77 561) showed a small increase in risk (odds
related quality of life in the postpartum period ratio 1.10, 1.02 to 1.19) of recurrent pre-eclampsia
compared with postpartum haemorrhage.142 143 A with an inter-pregnancy interval of more than four
meta-analysis (n=893), including studies conducted years.157
up to 40 years after the affected pregnancy, showed
that pre-eclampsia is associated with development of Guidelines
more severe depression outside the perinatal period Diagnosis and management
(standardised mean difference 0.18, 95% confidence Five international guidelines are available (WHO’s
interval 0.05 to 0.31; P=0.007).144 2011 guideline,158 the Society of Obstetric Medicine
of Australia and New Zealand’s 2014 guideline,159 the
Lack of awareness about cardiovascular risk European Society of Cardiology’s 2018 guideline,160
Recent studies show that healthcare professionals the International Federation of Gynecology and
are aware of the long term risks for cardiovascular Obstetrics’ 2021 guideline,161 and the ISSHP’s 2021
disease after HDP, with most counselling women guideline2), with the ISSHP guideline having the
about their increased cardiovascular risks.145 146 shortest cycle for guideline update. These guidelines
However, this rising awareness has not translated agreed on the definitions of HDP, prevention of
into knowledge among women, with fewer than half pre-eclampsia with low dose aspirin, treatment
being aware of their risk and having received heart of severe hypertension, use of magnesium sulfate
health advice.147 148 Maternal HDP was suggested to for prevention of eclampsia, and delivery for pre-
be an opportunity for cardiovascular screening and eclampsia by term. The areas of disagreement are the
early intervention 20 years ago,149 but its potential definition of “severe” pre-eclampsia; target blood
has not been realised. More resources are urgently pressure when hypertension is not severe; timing
needed to improve adherence to postnatal guidelines of delivery for women with chronic hypertension,
and improve the long term cardiovascular health of gestational hypertension, or pre-term pre-
this high risk population.150 eclampsia; and use of magnesium sulfate for fetal

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neuroprotection when pre-eclampsia is not “severe.” trial is under way in South Africa. Phase 3 trials are
Similar findings were reported in a systematic review ongoing for treatment of pre-eclampsia to evaluate
that identified 17 national and international clinical beetroot juice (NCT05241327) and recombinant
practice guidelines on hypertension in pregnancy.63 antithrombin γ (NCT04182373), which are due to
complete in May and July 2023, respectively.170 171
Postnatal screening for cardiovascular disease and Another phase 3 trial (ACTRN12618000216213)
diabetes to assess broccoli spout extract has been registered
What to screen for but not yet started.172 Other therapeutic approaches
In a review of guidelines, eight of the 16 guidelines have been studied, albeit in early phase clinical
identified recommended follow-up beyond the trials only. For example, increasing vasodilator
immediate postpartum period,162 but no consensus nitric oxide concentrations through infusion of a
existed about who to monitor more closely, the nitric oxide donor (S-nitrosoglutathione) was shown
duration and frequency of follow-up, and what to reduce the augmentation index, a measure of
parameters to screen for.162 Guidelines from cardiology small blood vessel tone, by 6% at 30 μg/min in
societies are more detailed than those from the a phase 1 study including six women with pre-
obstetrics and gynaecology communities, with some eclampsia at <32 weeks’ gestation.173 Melatonin
recommending annual blood pressure monitoring was shown to extend the diagnosis-to-delivery
and assessment of cardiovascular and metabolic risk interval by a mean of 6 (standard error 2.3) days
factors including lipids, fasting blood glucose, and and reduce the need for antihypertensive agents
body mass index,160 163 whereas others recommend in a phase 1 study involving 68 women with pre-
periodic monitoring.75 164 165 Of 13 US guidelines or eclampsia at <37 weeks’ gestation (20 treated; 48
society recommendation publications relevant to control).174 The results of a pharmacokinetics study
primary care based cardiovascular risk management of sulfasalazine (ACTRN12617000226303) are yet
in the year following pregnancy outcome, eight to be reported.174 175 Another pilot study evaluated
included recommendations specifically for HDP.166 plasmapheresis to remove sFlt-1 in 11 women
These include early postnatal follow-up in primary with pre-eclampsia at <32 weeks’ gestation.176
care or cardiology outpatient settings,167 close The pregnancies continued for eight to 15 days,
monitoring to ensure that hypertension resolves compared with only three days in 22 women in the
within 12 weeks postpartum,142 and, for women who control group. Administration of recombinant PlGF
had preterm pre-eclampsia, annual cardiovascular siRNA to silence sFlt-1 or angiotensinogen genes has
risk assessment.163 A prediction model including shown promise in pre-clinical studies.177-180
demographic, clinical, and echocardiographic
variables has been developed to identify women with Conclusions
HDP with persistent hypertension at three months Globally, HDP are a major cause of maternal and
postpartum.143 fetal morbidity and mortality. The development of
more accurate screening tools coupled with targeted
Advice on lifestyle modification aspirin prophylaxis could significantly reduce
In a systematic review of national and international cases of preterm pre-eclampsia. Placental growth
clinical practice guidelines for HDP, 11 of the 17 factor based testing has been shown to improve the
identified guidelines suggested lifestyle counselling accuracy of diagnosis of pre-eclampsia in women
for cardiovascular risk reduction.63 These include with HDP and identify those women at highest risk
guidelines from the ACOG, the American Heart of complications. Future research may offer further
Association, NICE, and the European Society of
Cardiology.30 160 165 167 Lifestyle modifications Glossary of abbreviations
include exercise, healthy eating, maintaining healthy
• ACE—angiotensin converting enzyme
weight, and smoking cessation. A systematic review
• ACOG—American College of Obstetricians and
found only two intervention trials for cardiovascular
Gynecologists
risk reduction in women who had HDP.144 The
• dBP—diastolic blood pressure
authors concluded that limited evidence suggested
• FMF—Fetal Medicine Foundation
that lifestyle intervention may be effective. A recent
• HDP—hypertensive disorders of pregnancy
trial suggests that web based interventions have
• HELLP—haemolysis, elevated liver enzymes, and low
high acceptability among women who had pre-
platelets
eclampsia.168
• ISSHP—International Society for the Study of
Hypertension in Pregnancy
Emerging treatments
• NICE—National Institute for Health and Care
The PI2 trial, involving 180 women with pre-eclampsia
Excellence
at <32 weeks’ gestation in South Africa, randomised
• PAPP-A—pregnancy associated plasma protein A
women to metformin or placebo and showed that
• PlGF—placental growth factor
metformin prolonged gestation by 7.6 days compared
• RCT—randomised controlled trial
with placebo.169 Although the difference was not
• sBP—systolic blood pressure
statistically significant, no serious adverse events
• sFlt—soluble FMS-like tyrosine kinase 1
relating to the intervention were reported169; a larger

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