2021 - Magee - The 2021 ISSHP Classification

Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 27 (2022) 148–169
Contents lists available at ScienceDirect
Pregnancy Hypertension: An International

Journal of Women's Cardiovascular Health
journal homepage: www.elsevier.com/locate/preghy
The 2021 International Society for the Study of Hypertension in Pregnancy

classification, diagnosis & management recommendations for
international practice☆
Laura A Magee a, *, Mark A. Brown b, David R. Hall c, Sanjay Gupte d, Annemarie Hennessy e,
S. Ananth Karumanchi f, Louise C. Kenny g, Fergus McCarthy h, Jenny Myers i, Liona C. Poon j,
Sarosh Rana k, Shigeru Saito l, Anne Cathrine Staff m, n, Eleni Tsigas o, Peter von Dadelszen a
a
Department of Women and Children’s Health, School of Life Course Sciences, King’s College London, UK
b
Departments of Renal Medicine & Medicine, St. George Hospital & University of New South Wales, Sydney, Australia
c
Department of Obstetrics & Gynaecology, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa
d
Secretary General, World Organization Gestosis, Gupte Hospital, Pune, India
e
School of Medicine, Western Sydney University and South Western Sydney Local Health District, Sydney, Australia
f
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
g
Faculty of Health & Life Sciences, University of Liverpool and INFANT Centre, Cork University Maternity Hospital, Cork, Ireland
h
Department of Obstetrics and Gynaecology, University College Cork, Cork, Ireland
i
Maternal & Fetal Health Research Centre, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
j
Department of Obstetrics and Gynaecology, Chinese University of Hong Kong, Chair of Hypertension in Pregnancy Subcommittee FIGO Pregnancy and NCD Committee,
Hong Kong
k
Department of Obstetrics and Gynecology/Division of Maternal Fetal Medicine, University of Chicago, Chicago, IL, USA
l
Department of Obstetrics and Gynecology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Japan
m
Faculty of Medicine, University of Oslo, and Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway
n
Global Pregnancy Collaboration (Member, Steering and Executive Committees), USA
o
Preeclampsia Foundation, USA
A R T I C L E I N F O A B S T R A C T
Keywords: All units managing hypertensive pregnant women should maintain and review uniform departmental manage
Hypertension ment protocols and conduct regular audits of maternal & fetal outcomes.
Pregnancy The cause(s) of pre-eclampsia and the optimal clinical management of the hypertensive disorders of pregnancy
Pre-eclampsia
remain uncertain; therefore, we recommend that every hypertensive pregnant woman be offered an opportunity
Outcome
Maternal
to participate in research, clinical trials and follow-up studies.
Perinatal
Abbreviations: ABPM, ambulatory 24-hour blood pressure monitoring; ACR, albumin:creatinine ratio; AKI, acute kidney injury; ART, assisted reproductive
technology; BID, twice daily; BMI, body mass index; BP, blood pressure; CKD, chronic kidney disease; FGR, fetal growth restriction; FIGO, International Federation of
Gynecology and Obstetrics; GPP, good practice point; HBPM, home blood pressure monitoring; HDP, hypertensive disorder of pregnancy; HELLP syndrome, Hae
molysis, Elevated Liver enzymes, Low Platelet syndrome; ISSHP, International Society for the Study of Hypertension in Pregnancy; ISUOG, International Society for
Ultrasound in Obstetrics and Gynecology; IV, intravenous; LA, long-acting; MgSO4, magnesium sulphate; MR, modified release; NICU, neonatal intensive care unit;
PA, prolonged action; PlGF, placental growth factor; QAM, every morning; QID, four times daily; QPM, every evening; OR, odds ratio; PrCr, protein:creatinine ratio;
RCT, randomised controlled trial; RR, relative risk; sFlt-1, soluble fms-like tyrosine kinase-1; TID, three times daily; WHO, World Health Organization; XL, extended-
release.
☆
This document has been endorsed by World Organization Gestosis and the Japanese Society for the Study of Hypertension in Pregnancy.
* Corresponding author at: Department of Women and Children’s Health, School of Life Course Sciences, King’s College London, Becket House, 1 Lambeth Palace
Road, Room BH.05.11, London SE1 7EU, UK.
E-mail address: laura.a.magee@kcl.ac.uk (L.A. Magee).
https://doi.org/10.1016/j.preghy.2021.09.008
Received 28 September 2021; Accepted 30 September 2021
Available online 9 October 2021
2210-7789/© 2021 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.
L.A. Magee et al. Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 27 (2022) 148–169
Recommendations Women at increased risk of pre-eclampsia*

18. Low-dose aspirin is recommended (⊕⊕⊕⊕/Strong), to be taken
Diagnosis of hypertension and proteinuria at bedtime (⊕⊕⊕O/Strong), preferably before 16 weeks and dis
1. Blood pressure (BP) should be measured using standardised continued by 36 weeks (⊕⊕⊕O/Strong).
technique, including women’s position (sitting, feet flat on floor), cuff 19. After multivariable screening, aspirin should be given at a dose of
size (‘large’ if the mid-upper arm circumference is ≥33 cm), Korotkoff V 150 mg/night (⊕⊕⊕⊕/Strong).
for the diastolic BP (dBP), and arm used (both, at least initially) (⊕⊕⊕O/ 20. After screening with clinical risk factors and BP, aspirin should be
Strong). given at a dose of 100–162 mg/d (⊕⊕⊕O/Strong).
2. BP taken in pregnancy or postpartum, in any setting, should be Management
measured using a device validated for use in pregnancy and pre- Place of care
eclampsia (⊕⊕⊕O/Strong). 21. Women with pre-eclampsia or severe hypertension should be
3. Hypertension should be defined as a systolic BP (sBP) ≥ 140 assessed and managed in hospital, before carefully-selected cases are
mmHg and/or dBP ≥ 90 mmHg, based on an average of at least two considered for outpatient care (GPP).
measurements (⊕⊕⊕⊕, Strong). Antihypertensive therapy
4. BP should be repeated to confirm true hypertension; if hyperten 22. Hypertension in pregnancy should be treated with antihyper
sion is severe (sBP ≥ 160 and/or dBP ≥ 110 mmHg), then repeat within tensive therapy, irrespective of the underlying HDP (⊕⊕⊕O/Strong).
15 min; otherwise, repeat in at least 4 h or on two consecutive outpatient 23. Severe hypertension in pregnancy (i.e., sBP ≥ 160 mmHg or dBP
visits (Good practice point, GPP). ≥ 110 mmHg) requires urgent antihypertensive therapy, in a monitored
5. Quantitative proteinuria testing for pre-eclampsia should be per setting (⊕⊕OO/Strong).
formed as part of the work-up for women suspected of having pre- 24. The target BP for antihypertensive therapy should be a dBP of 85
eclampsia or at high-risk of developing it (⊕⊕⊕⊕, Strong). mmHg, regardless of sBP (⊕⊕⊕⊕/Strong).
6. Proteinuria should be defined as ≥ 30 mg/mmol urinary protein: 25. Non-severe hypertension should be treated with the first-line
creatinine ratio (PrCr) in a spot (random) urine sample, or albumin: agents oral methyldopa, labetalol, or nifedipine (⊕⊕⊕O/Strong).
creatinine ratio (ACR) ≥ 8 mg/mmol, or ≥ 0.3 g/d in a complete 24-hour 26. Severe hypertension should be treated with the first-line agents
urine collection, or ≥ 2 + by urinary dipstick if confirmatory testing is oral nifedipine, oral labetalol, intravenous (IV) labetalol, or IV hydral
not available (⊕⊕⊕O/Strong). azine (⊕⊕⊕O/Strong).
Classification Plasma volume expansion
7. The hypertensive disorders of pregnancy (HDPs) should be clas 27. Plasma volume expansion is not recommended routinely for
sified according to the criteria presented in Table 1. women with pre-eclampsia. (⊕⊕⊕O/Strong).
8. The ISSHP does not suggest routine testing for secondary causes of Magnesium sulphate
hypertension in the absence of clinical clues to these conditions (⊕⊕OO/ 28. Women with eclampsia should receive magnesium sulphate to
Strong). prevent recurrent seizures (⊕⊕⊕⊕/Strong).
9. Women with white-coat hypertension should undertake regular 29. Women with pre-eclampsia who have proteinuria and severe hy
home BP monitoring (HBPM) (⊕⊕⊕O/Strong). pertension, or hypertension with neurological signs or symptoms, should
10. Pre-eclampsia should not be classified as ‘mild’ or ‘severe’ in an receive magnesium sulphate for eclampsia prevention (⊕⊕⊕⊕/Strong).
ongoing pregnancy (⊕⊕⊕O /Strong). Timed birth
See Table 1 and text. 30. Indications for delivery with any HDP at any gestational age
11. An elevation in BP should not be used to make a diagnosis of pre- (⊕⊕⊕O/Strong) include:
eclampsia superimposed on chronic hypertension (⊕⊕OO/Strong).
12. To the assessment of women suspected of having pre-eclampsia • Abnormal neurological features (such as eclampsia, severe intrac
(<37 weeks), we recommend adding evaluation of angiogenic imbal table headache or repeated visual scotomata);
ance, when available, as a marker of uteroplacental dysfunction to be • Repeated episodes of severe hypertension despite maintenance
used in conjunction with other clinical tests. (⊕⊕⊕O/Strong). treatment with three classes of antihypertensive agents;
Prediction of pre-eclampsia • Pulmonary oedema;
13. At minimum, women should be screened for clinical risk markers • Progressive thrombocytopenia or platelet count <50 × 109/L;
of pre-eclampsia risk at antenatal care booking (GPP). • Transfusion of any blood product;
14. If testing is available, after appropriate counselling, women • Abnormal and rising serum creatinine;
should be screened at 11–14 weeks for preterm pre-eclampsia risk, using • Abnormal and rising liver enzymes;
a combination of clinical risk factors, BP, uterine artery pulsatility index, • Hepatic dysfunction (INR > 2 in absence of DIC or warfarin), hae
and PlGF, as available, even if they have been already been identified as matoma or rupture
having clinical ‘high-risk’ factors (⊕⊕⊕O/Strong). • Abruption with evidence of maternal or fetal compromise; or
Prevention of pre-eclampsia • Non-reassuring fetal status (including death)
All women in pregnancy
15. Unless there are contraindications, all women should exercise in 31. A decision to deliver should not be based solely upon the degree
pregnancy to reduce the likelihood of gestational hypertension and pre- of either proteinuria (⊕⊕OO/Strong) or hyperuricaemia (⊕⊕OO/
eclampsia (⊕⊕⊕O/Strong). Strong).
16. For women with dietary intake of calcium (<900 mg/day), oral (See Table 7 for recommendations according to gestational age.)
calcium supplementation of at least 500 mg/d is recommended (⊕⊕OO/ Antenatal corticosteroids
Weak). 32. Do not administer corticosteroids to hasten resolution of Hae
17. Women should NOT receive low-molecular-weight heparin*, molysis Elevated Liver enzyme Low Platelet (HELLP) syndrome
vitamins C or E, or folic acid for pre-eclampsia prevention (⊕⊕⊕O/ (⊕⊕⊕O/Strong)
Strong). Postpartum care
* This recommendation relates to use of heparin for pre-eclampsia pre 33. For women with antepartum hypertension, BP should be moni
vention. and not for other indications, such as thromboprophylaxis in anti tored at least once on days 3–7 postpartum when it is likely to be highest
phospholipid antibody syndrome. after birth (GPP).
149
34. Antihypertensive therapy administered antepartum should be 2. Methods

continued after birth. Also, consideration should be given to adminis
tering antihypertensive therapy for any hypertension diagnosed before The guideline was developed by maternity care providers, a patient
six days postpartum (⊕⊕OO/Weak) representative, and researchers (from obstetrics, internal medicine,
35. The target dBP for postpartum antihypertensive treatment should health care administration) who are knowledgeable about the HDP and
be 85 mmHg, as antenatally (⊕⊕OO/Weak) guideline development. The literature reviewed included the previous
36. Non-steroidal anti-inflammatory drugs (NSAIDs) for postpartum (2018) ISSHP guideline, all other national and international pregnancy
analgesia may be used in women with pre-eclampsia if other analgesics hypertension guidance and references, updated literature searches
are ineffective, and there is no acute kidney injury (AKI) or other risk covering articles until Dec 2020, and subsequently-published literature
factors for it (⊕⊕OO/Weak) known to the authors.
37. Breastfeeding is recommended (⊕⊕⊕O/Strong) We replicated the search strategy used previously for guideline
38. Counselling should be provided about the risks of gestational development [3] (Table S1, restricting articles to those published in
hypertension (at least 4%) or pre-eclampsia (at least 15%) in future English and French). We prioritised randomised controlled trials (RCTs)
pregnancy (GPP) and systematic reviews (if available) for therapies and evaluated sub
39. At 3 months postpartum, all women should be reviewed to ensure stantive clinical outcomes for mothers (death; serious morbidity,
that BP, urinalysis, and any laboratory abnormalities have normalised. If including eclampsia, HELLP (Haemolysis, Elevated Liver enzymes, Low
proteinuria or hypertension persist, then appropriate referral for further Platelet) syndrome, and other major end-organ complications; severe
investigations should be initiated (GPP). hypertension; placental abruption; preterm delivery; Caesarean de
40. At 6 months postpartum, where possible, all women should be livery; maternal adverse effects of drug therapies or other interventions;
reviewed again, at which point we suggest that BP ≥ 120/80 mmHg lead and long-term health) and babies (perinatal death, stillbirth and
to discussion of lifestyle change (⊕⊕⊕O/Weak) neonatal death; small for gestational age infants; NICU (neonatal
41. Following hypertensive pregnancy, particularly pre-eclampsia, intensive care unit) care; serious neonatal morbidity, and long-term
counselling should be provided about the heightened health risks for paediatric health and neurodevelopment). All authors graded the qual
the mother (particularly cardiovascular) and the offspring (⊕⊕⊕O/ ity of the evidence and their recommendations, using GRADE (Level of
Strong) evidence/Strength of recommendation, Table S1), or designated rec
42. We recommend calculating lifetime (not 10-year) cardiovascular ommendations as GPPs.
risk scores to estimate cardiovascular risk in these women (⊕⊕⊕O/ The recommendations are organised into the following sections:
Strong) classification, diagnosis of hypertension and proteinuria, prediction of
43. Annual medical review following hypertensive pregnancy is pre-eclampsia, prevention of pre-eclampsia, management, and post
recommended for the first 5–10 years postpartum (⊕⊕⊕O/Weak) partum care. Within each section, any advice specific to a specific hy
44. Following hypertensive pregnancy, all women and their offspring pertensive disorder(s) is highlighted, to avoid repetition inherent in
should adopt a healthy lifestyle that includes eating well, exercising, presenting the information for each of chronic hypertension, gestational
aiming for ideal body weight, living smoke-free, and aiming for BP < hypertension, and pre-eclampsia.
120/80 mmHg (⊕⊕⊕⊕/Strong) This document was reviewed by the Executive Council of the ISSHP
and the Preeclampsia Foundation.
1. Introduction
3. Recommendations and supporting text
The HDPs are leading causes of maternal and perinatal mortality and
morbidity worldwide. >99% of HDP-related maternal deaths occur in 3.1. Diagnosis of hypertension and proteinuria
under-resourced settings, worldwide, while perinatal death and
maternal morbidity remain major challenges for health care providers. Recommendations
The International Society for the Study of Hypertension in Pregnancy 1. BP should be measured using standardised technique, including
(ISSHP) is committed to providing global leadership through up-to-date, women’s position (sitting, feet flat on floor), cuff size (‘large’ if the mid-
evidence-based guidance for the diagnosis, prediction, prevention, and upper arm circumference is ≥ 33 cm), Korotkoff V for the diastolic BP
management of the HDPs. While we recognise that not all guidance can (dBP), and arm used (both, at least initially) (⊕⊕⊕O/Strong).
be implemented in all settings even in well-resourced settings, options 2. BP taken in pregnancy or postpartum, in any setting, should be
for management in less-resourced settings are discussed separately. Our measured using a device validated for use in pregnancy and pre-
guidelines align with the International Federation of Gynecology and eclampsia (⊕⊕⊕O/Strong).
Obstetrics (FIGO), and as much as possible, with the World Health Or 3. Hypertension should be defined as a systolic BP (sBP) ≥ 140
ganization (WHO), as the other international organisations providing mmHg and/or dBP ≥ 90 mmHg, based on an average of at least two
pregnancy hypertension guidelines. measurements (⊕⊕⊕⊕, Strong).
The current document represents an update of the 2018 guidance 4. BP should be repeated to confirm true hypertension; if hyperten
following review of intervening published evidence [1,2]. Compared sion is severe (sBP ≥ 160 and/or dBP ≥ 110 mmHg), then repeat within
with 2018, we now grade the quality of the evidence and strength of 15 min; otherwise, repeat in at least 4 h or on two consecutive outpatient
recommendations, although where evidence is lacking, we continue to visits (GPP).
provide practical advice in the form of ‘good practice points’ (GPPs). 5. Quantitative proteinuria testing for pre-eclampsia should be per
Also, we now outline auditable standards and research formed as part of the work-up for women suspected of having pre-
recommendations. eclampsia or at high-risk of developing it (⊕⊕⊕⊕, Strong).
Importantly, the ISSHP recommends that each unit has a specific 6. Proteinuria should be defined as ≥ 30 mg/mmol urinary protein:
policy as to management guidelines that are to be followed so that there creatinine ratio (PrCr) in a spot (random) urine sample, or albumin:
is uniform practice within each unit. In addition, each unit should strive creatinine ratio (ACR) ≥ 8 mg/mmol, or ≥0.3 g/d in a complete 24-hour
to record and evaluate their maternal and fetal outcomes to ensure that urine collection, or ≥2+ by urinary dipstick if confirmatory testing is not
their policies and guidelines remain appropriate at all times. available (⊕⊕⊕O/Strong).
The definitions of hypertension and proteinuria have not changed
since the 2018 guideline.
150
BP measurement hypertension (see ‘Classification/Chronic hypertension’), diabetes,

BP in pregnancy should be measured using the standardised tech human immunodeficiency virus or hepatitis C virus infection, sickle cell
nique, as outside pregnancy. BP should be measured in both arms at trait, malignancy, autoimmune disease, nephrolithiasis, recurrent uri
least initially, and, thereafter, in the same arm for consistency, choosing nary tract infections, or a family history of CKD. Any woman who sub
the arm with the higher BP. sequently has a pregnancy complication associated with CKD, such as
BP should be measured with a device validated for use in pregnancy pre-eclampsia or FGR, should be evaluated. (See ‘Postpartum care’.)
and pre-eclampsia (and by extension, for six weeks postpartum) [4]. After antenatal care booking, the value of performing dipstick pro
Mercury sphygmomanometry is no longer available. While aneroid de teinuria screening at all antenatal appointments for low-risk normo
vices are used commonly, they may over- or under-estimate BP [5], and tensive women has been questioned [11]. Dipstick proteinuria testing
they need to be regularly calibrated. Liquid-crystal sphygmom has low diagnostic accuracy, being neither sensitive nor specific at the 1
anometery [6] is the best alternative, but, if unavailable, an automated + level [12]. The majority (i.e., at least two-thirds) of women who
device validated in pregnancy and pre-eclampsia is preferable; a list of present with proteinuria without hypertension do not develop pre-
suitable devices is available online [7]. eclampsia as pregnancy progresses [13–16]. Furthermore, the costs of
Once BP is found to be elevated in a clinical setting (i.e., clinic/office, screening all women so frequently are substantial [13,15,17]. Under
obstetrical day unit, or hospital inpatient), and there is no evidence of taking dipstick proteinuria (manual or automated) screening at all
pre-eclampsia, ‘out-of-office’ BP monitoring (i.e., at home, by 24-hour antenatal appointments, particularly for women with chronic hyper
ambulatory BP monitoring [ABPM] that takes BP regularly, or in a tension or who are normotensive but otherwise at increased risk of pre-
pharmacy) is advised. This will identify any element of white-coat hy eclampsia, is common practice. As such, where resources allow and as
pertension, confirm the diagnosis of hypertension, and ideally, there suited to local context, proteinuria screening after booking may be un
after, monitor changes in BP and response to antihypertensive dertaken to identify concerns about pre-eclampsia earlier [16].
treatment. Also, it is wise to check a woman’s home BP device (against a Quantitative proteinuria testing (by urinary PrCr, ACR, or 24-hour
calibrated device in the office) before she begins home BP monitoring urine collection) should be performed when pre-eclampsia is sus
(HBPM) and intermittently thereafter. ABPM remains the gold standard pected, including: ≥1 + dipstick proteinuria in women with hyperten
for BP assessment, but it is less commonly used, especially in pregnancy sion and rising BP and in women with normal BP, but symptoms or signs
because of availability, convenience and women’s preferences. suggestive of pre-eclampsia. A PrCr ratio of ≥30 mg/mmol (0.3 mg/mg)
is considered to be abnormal [18–21], but the test may occasionally give
Hypertension a false negative result, usually at <400 mg/day proteinuria [20]. A 24-
Hypertension in pregnancy continues to be defined as a clinic sBP ≥ hour urine collection offers no advantage [21], and should be reserved
140 mmHg and/or a dBP ≥ 90 mmHg, with sBP ≥ 160 mmHg and/or a to confirm nephrotic syndrome and define the need for thrombopro
dBP ≥ 110 mmHg defined as severe hypertension. While the American phylaxis. A urinary ACR ≥ 8 mg/mmol (71 mg/g) is considered to be
Heart Association and American College of Cardiology have redefined abnormal based on its association with a definition of pre-eclampsia that
hypertension outside pregnancy as 130/80 mmHg (‘stage 1′ hyperten included the need for more intensive monitoring and/or magnesium
sion), with 140/90 as ‘stage 2’ hypertension, these definitions have not sulphate [21]. If confirmatory testing for dipstick proteinuria is not
been adopted in pregnancy, even in the United States. While stage 1 may available, then dipstick proteinuria of ≥2+ (>1g/L) provides a reason
be associated with an increased risk of adverse pregnancy outcomes [8], able assessment of true proteinuria [22–23].
it has not been shown that implementing a lower diagnostic threshold Importantly, a decision to deliver should not be based upon the de
for hypertension in pregnancy would improve outcomes or be cost- gree of proteinuria alone (see ‘Management/Timing of birth’, below).
effective [9]. Proteinuria is not independently predictive of adverse maternal
Hypertension should be diagnosed based on at least two readings, outcome. While absolute levels of proteinuria correlate with adverse
averaged to reflect the BP for the visit. If BP values are >10 mmHg perinatal outcomes [24–28], the predictive value of heavy (4 + dipstick)
different, a third measurement should be taken, and the second and third proteinuria is limited to settings without advanced fetal surveillance
measurements used. capacity. (Please see ‘Management/Maternal monitoring and Manage
BP measured out-of-office is generally lower than in the clinic setting ment/Fetal monitoring’ for details.)
among hypertensive women, but there is wide variation [10]. (Use of
out-of-office BP values to guide antihypertensive therapy is discussed 3.2. Classification
under ‘Management/Antihypertensive therapy’, below.)
Recommendations
Proteinuria 7. The HDPs should be classified according to the criteria presented
Proteinuria may be detected qualitatively, by urinary dipstick testing in Table 1.
(manual or automated), or quantitatively, by PrCr, ACR, or 24-hour 8. The ISSHP does not suggest routine testing for secondary causes of
urine collection. While testing in pregnancy is focused on detecting hypertension in the absence of clinical clues to these conditions (⊕⊕OO/
the proteinuria of pre-eclampsia, detecting underlying CKD that is Strong).
associated with adverse pregnancy and long-term outcomes in preg 9. Women with white-coat hypertension should undertake regular
nancy and long-term is important. For CKD detection, a microscopic HBPM (⊕⊕⊕O/Strong).
urinalysis of the urine sediment is an important second component, to 10. Pre-eclampsia should not be classified as ‘mild’ or ‘severe’ in an
detect red or white blood cells and casts. In pregnancy, a third compo ongoing pregnancy (⊕⊕⊕O /Strong).
nent not covered by these guidelines, is routine screening for asymp See Table 1 and text.
tomatic bacteriuria by urine culture. 11. An elevation in BP should not be used to make a diagnosis of pre-
At antenatal care booking, screening for proteinuria may identify eclampsia superimposed on chronic hypertension (⊕⊕OO/Strong).
early CKD, leading to management in pregnancy to optimise outcomes, 12. To the assessment of women suspected of having pre-eclampsia
and after pregnancy to slow or prevent progression to end-stage kidney (<37 weeks), we recommend adding evaluation of angiogenic imbal
disease. However, urinary dipstick testing for proteinuria is a poor test ance, when available, as a marker of uteroplacental dysfunction to be
for this purpose. We suggest a case-finding approach in early pregnancy, used in conjunction with other clinical tests. (⊕⊕⊕O/Strong).
as advocated outside pregnancy, with proteinuria testing (ideally albu The classification of the HDPs places women into meaningful prog
minuria) and microscopic urinalysis for women with dipstick haema nostic groups (Table 1). This classification differs from our 2018 guid
turia or CKD risk factors, particularly Aboriginal ethnicity, chronic ance in that women with chronic hypertension can now be diagnosed
151
Table 1 Table 2
Classification of the HDPs. Chronic hypertension – diagnostic testing and monitoring.
Type of hypertensive Definition DIAGNOSIS MONITORING
disorder
All women with chronic hypertension The frequency of follow-up should be
Pre-pregnancy or at < 20 weeks should have the following tests guided by BP level and other individual
Chronic hypertension Hypertension detected pre-pregnancy or before 20 performed at first diagnosis in risks of adverse outcome (GPP).
weeks’ gestation pregnancy, to provide a baseline
Essential Hypertension without a known secondary cause reference should suspicion arise later in
Secondary Hypertension with a known secondary cause (e.g., pregnancy of superimposed pre-
renal disease) eclampsia (GPP):
White-coat hypertension sBP ≥ 140 and/or dBP ≥ 90 mmHg when measured in • Urine microscopy and urinary protein
the office or clinic, and BP < 135/85 mmHg using excretion (ideally, by PrCr or ACR)
HBPM or ABPM readings • Full blood count for platelet count (and
Masked hypertension BP that is <140/90 mmHg at a clinic/office visit, but haemoglobin);
≥135/85 mmHg at other times outside the clinic/ • Serum creatinine; and
office • Liver enzymes [AST or ALT).
≥20 weeks Additional testing can be performed if
Gestational hypertension Hypertension arising de novo at ≥ 20 weeks’ gestation abnormalities are detected, such as other
in the absence of proteinuria or other findings electrolytes, and renal ultrasound if serum
suggestive of pre-eclampsia creatinine or urinary dipstick testing are
Transient gestational Hypertension arising at ≥20 weeks’ gestation in the abnormal, LDH and a blood film (for
hypertension clinic, which resolves with repeated BP readings schistocytes) if haemolysis is suspected, or
Pre-eclampsia* 24-hour urine collection (for proteinuria)
De novo Pre-eclampsia (de novo) is gestational hypertension and serum albumin if nephrotic syndrome
accompanied by one or more of the following new- is suspected. If resources are limited, pri
onset conditions at ≥20 weeks’ gestation: oritise evaluation of urinary protein
1. Proteinuria excretion and serum creatinine.
2. Other maternal end-organ dysfunction, including:
• Neurological complications (e.g., eclampsia, ACR (albumin:creatinine ratio), ALT (alanine aminotransferase), AST (aspartate
altered mental status, blindness, stroke, clonus, aminotransferase), BP (blood pressure), GPP (good practice point), LDH (lactate
severe headaches, or persistent visual scotomata) dehydrogenase), PrCr (protein:creatinine ratio).
• Pulmonary oedema
• Haematological complications (e.g., platelet count
hypertension are due to essential hypertension, usually accompanied by
< 150,000/μL, DIC, haemolysis)
• AKI (such as creatinine ≥ 90 μmol/L or 1 mg/dL) a family history of hypertension and often by overweight or obesity.
• Liver involvement (e.g., elevated transaminases Unless there are clues to a secondary cause of hypertension, the ISSHP
such as ALT or AST > 40 IU/L) with or without does not recommend routine investigations (e.g., renal ultrasound).
right upper quadrant or epigastric abdominal pain)
Chronic hypertension is best managed by ‘tight’ control of BP (see
3. Uteroplacental dysfunction (e.g., placental
abruption, angiogenic imbalance, fetal growth
‘Management/Antihypertensive therapy’, below).
restriction, abnormal umbilical artery Doppler White-coat hypertension is common (≈30% of chronic hypertension)
waveform analysis, or intrauterine fetal death). and associated with an increased risk of pre-eclampsia [31–32]. HBPM is
Superimposed on chronic Among women with chronic hypertension, necessary to manage white-coat hypertension, as it is reasonable to
hypertension development of new proteinuria, another maternal
withhold antihypertensive therapy when home BP values are normal. In
organ dysfunction(s), or evidence of uteroplacental
dysfunction (as above). the absence of severe hypertension (≥160/110 mmHg), we suggest
relying on average BP over several days, rather than acting on single
ABPM (ambulatory 24-hour BP monitoring), AKI (acute kidney injury), ALT
readings [33].
(alanine aminotransferase), AST (aspartate aminotransferase), BP (blood pres
Masked hypertension is probably less common in pregnancy, but
sure), dBP (diastolic BP), DIC (disseminated intravascular coagulation), HBPM
(home BP monitoring), HDPs (hypertensive disorders of pregnancy), sBP (sys much less is known about this compared with white-coat hypertension.
tolic BP). It is typically diagnosed by HBPM or ABPM that is initiated when there is
* Some components of the definition will require use of locally-accepted defi evidence of hypertensive target organ damage in the mother (e.g., un
nitions (such as fetal growth restriction) and clinical judgement. Also, the term explained CKD, or left ventricular cardiac hypertrophy) or uteropla
‘severe pre-eclampsia’ should not be used in clinical practice, as all women with cental dysfunction, but there is no apparent hypertension in clinic.
pre-eclampsia are at risk of developing severe features.
Gestational hypertension
with superimposed pre-eclampsia if they have evidence of uteropla Transient gestational hypertension resolves with repeated BP mea
cental dysfunction; this was previously excluded from the diagnosis of surements, such as those taken over the course of several hours in a Day
superimposed pre-eclampsia as a known complication of chronic Assessment Unit. This is not the same as white-coat hypertension, which
hypertension. is associated in early pregnancy with completely normal out-of-office BP
measurements. Transient gestational hypertension is associated with a
Chronic hypertension 40% risk of subsequent true gestational hypertension or pre-eclampsia
Chronic hypertension should be confirmed by HBPM or ABPM if at [34], warranting additional monitoring throughout the remainder of
all possible, to exclude white-coat hypertension which is common (as pregnancy, ideally including HBPM.
discussed below). If access to the appropriate equipment and in Persistent gestational hypertension is associated with outcomes that
structions is not possible, or women are not willing, then at minimum, are dependent on the gestational age at which hypertension develops
elevated BP should be confirmed after repeated measurements over after 20 weeks’. About 25% of women who present with gestational
hours at the same visit, or on two consecutive antenatal visits [29]. hypertension at <34 weeks’ will progress to pre-eclampsia and have
Chronic hypertension is associated with an excess of adverse poorer outcomes [35].
maternal and fetal outcomes, including superimposed pre-eclampsia When a woman presents for antenatal care at ≥20 weeks, without
(see below) [30]. knowledge of prior BP values, and she is found to be hypertensive, she
Diagnostic testing and ongoing monitoring of women with chronic should be managed in pregnancy as if she has gestational hypertension
hypertension are presented in Table 2. Most cases of chronic or pre-eclampsia, unless, or until the balance of evidence shows
152
Table 3 Proteinuria is not mandatory for the diagnosis, but it is commonly

Gestational hypertension – diagnostic testing and monitoring. present (in up to 75% of cases) [40]. Also, among women with protei
DIAGNOSIS ONGOING SURVEILLANCE nuric renal disease, an increase in proteinuria during pregnancy is
insufficient to diagnose superimposed pre-eclampsia. Other manifesta
Women should undergo testing for pre- Antenatal contacts should occur at least
eclampsia to rule it out (⊕⊕⊕⊕). once weekly (GPP). Proteinuria testing tions of pre-eclampsia (such as severe headache) are also common in
Angiogenic markers (if available) should be performed at each subsequent pregnancy, but in the context of new-onset hypertension, it is safest to
could be performed; if normal, the antenatal visit (⊕⊕⊕O). The risk of consider such a woman to have pre-eclampsia and manage accordingly.
diagnosis of gestational hypertension adverse maternal outcomes increases Elevated serum uric acid corrected for gestational age has been associ
would be strengthened (⊕⊕⊕O). Fetal with earlier gestational age and/or the
ultrasound (where available) should onset/worsening of the following
ated with elevated perinatal risk and uteroplacental dysfunction
be performed to assess fetal growth, features that women should be informed [41–43], but it was not independently predictive of adverse maternal
amniotic fluid volume and umbilical to report between visits, according to the outcome in multivariable modelling [44]. Hyperreflexia is not a diag
artery Doppler (⊕⊕⊕O). If FGR is miniPIERS model (https://pre-empt. nostic criterion as it is non-specific, often present in otherwise well
detected, local/national fetal bcchr.ca/evidence/minipiers).(⊕⊕⊕⊕):
young women, and is highly subject to observer interpretation.
surveillance guidance should be • headache/visual disturbances
followed [1] (GPP). • chest pain/dyspnoea Diagnostic testing and ongoing monitoring of women with pre-
• vaginal bleeding with abdominal pain eclampsia are presented in Table 4.
• sBP (if self-monitoring)
• dipstick proteinuria (if self- Angiogenic imbalance
monitoring)
• pulse oximetry (if self-monitoring).
Angiogenic imbalance, as assessed by reduced PlGF (<5th centile for
Fetal ultrasound should be repeated at gestational age) or increased sFlt/PlGF ratio (e.g., >38 by the Roche
least monthly to assess fetal growth, assay), has been actively evaluated for its role in making an earlier
amniotic fluid volume and umbilical diagnosis of pre-eclampsia based on the presence of uteroplacental
artery Doppler (⊕⊕⊕O). If pre-eclampsia
dysfunction. (For prediction of pre-eclampsia, see ‘Prediction’ below).
is again suspected on clinical grounds,
the woman should be re-evaluated for Systematic review (33 studies, 9426 women) has confirmed that
pre-eclampsia (⊕⊕⊕⊕). angiogenic imbalance shows promise for prediction of adverse maternal
and perinatal outcomes, although there is substantial between-study
FGR (fetal growth restriction), GPP (good practice point), PIERS (Pre-eclampsia
Integrated Estimate of Risk Score), sBP (systolic blood pressure).
Table 4
otherwise. Pre-eclampsia: diagnostic testing and ongoing monitoring.
Diagnostic testing and ongoing monitoring of women with gesta DIAGNOSIS ONGOING SURVEILLANCE
tional hypertension are presented in Table 3. Where angiogenic marker Women should undergo comprehensive Women with pre-eclampsia
testing is available, the lack of angiogenic imbalance, as assessed by testing for pre-eclampsia (⊕⊕⊕⊕). superimposed on chronic hypertension
normal PlGF (≥5th centile for gestational age) or normal sFlt/PlGF ratio, Women suspected of having pre- should undergo the same surveillance as
suggests that there is no uteroplacental dysfunction. In the absence of eclampsia superimposed on chronic for women with de-novo pre-eclampsia
hypertension should undergo the same (⊕⊕⊕⊕). Once confirmed as significant,
other markers of pre-eclampsia (see below), a diagnosis of gestational
testing as for women with de-novo pre- proteinuria testing does not need to be
hypertension can be made. Rarely (<1%), these women will require eclampsia (⊕⊕⊕⊕). Maternal testing repeated (⊕⊕⊕O/Strong). Maternal
delivery for pre-eclampsia within the next 7–14 days, although some (up should include the following testing, at least twice weekly, should
to ≈20%) will evolve into pre-eclampsia at some point [36–38]. components of the fullPIERS model include re-evaluation of the following
(https://pre-empt.bcchr.ca/evidence/ components of the fullPIERS model
Appropriate investigations should be done after pregnancy to determine
fullpiers), which along with earlier (https://pre-empt.bcchr.ca/evidence/
if she has underlying chronic hypertension; this will generally be gestational age and the symptoms of fullpiers) (⊕⊕⊕O):
apparent because the BP will not have normalised within three months chest pain/dyspnoea, identify women • gestational age
after birth; see ‘Postpartum care’ for details. at increased risk of adverse maternal • chest pain or dyspnoea
outcomes (⊕⊕⊕⊕): • oxygen saturation
• oxygen saturation • platelet count
Pre-eclampsia
• platelet count • serum creatinine
Pre-eclampsia is the most dangerous of the HDPs; world-wide, each • serum creatinine • AST or ALT
year, pre-eclampsia is responsible for over 500,000 fetal and neonatal • AST or ALT Upon admission to delivery suite,
deaths and over 70,000 maternal deaths. Angiogenic markers (if available) could women with pre-eclampsia should have
be performed; if there is angiogenic a platelet count done, regardless of when
While the definition of pre-eclampsia has not changed (Table 1),
imbalance†, the diagnosis of pre- this was last performed (GPP). There is
further clarity has been provided by additional examples of other eclampsia would be strengthened insufficient evidence to recommend re-
maternal organ dysfunction (i.e., pulmonary oedema) and uteropla (⊕⊕⊕O). Fetal ultrasound should be evaluation with angiogenic markers
cental dysfunction (i.e., placental abruption, angiogenic imbalance). performed to assess fetal growth, amni (⊕OOO). Where available, fetal ultra
Given the international target audience, we rely on locally-accepted otic fluid volume and umbilical & uter sound should be performed once every
ine artery Doppler (⊕⊕⊕O). If FGR is two weeks to assess fetal growth, and at
definitions. ‘Other’ maternal organ dysfunction includes rarer compli
detected, ISUOG fetal surveillance guid least once every two weeks to assess
cations, such as ascites or Bell’s palsy. ance [2] should be followed (GPP). amniotic fluid volume and umbilical ar
Pre-eclampsia may develop or be recognised for the first time tery Doppler (⊕⊕⊕O). We recommend
intrapartum or early postpartum. Superimposed pre-eclampsia may that at <34 weeks when there is fetal
develop in ≈25% of women with chronic hypertension and even more growth restriction, Doppler velocimetry
of the ductus venosus be performed
women with underlying renal disease, including those with renal where available, to assess risk of adverse
transplants [39]. Pre-eclampsia can deteriorate rapidly and without perinatal outcome (⊕⊕⊕O/Strong). We
warning, which is why the ISSHP does not recommend classifying it as recommend against use of the biophysi
non-severe or severe. The HELLP syndrome (full or partial, with only cal profile to monitor fetuses at risk in
hypertensive pregnancy (⊕⊕⊕O/
some manifestations, such as elevated liver enzymes and low platelets) is
Strong).
a (serious) manifestation of pre-eclampsia and not a separate disorder.
Among women with chronic hypertension, rises in BP are insufficient ALT (alanine aminotransferase), AST (aspartate aminotransferase), FGR (fetal
to diagnose superimposed pre-eclampsia, as such rises are difficult to growth restriction), GPP (good practice point), ISUOG (International Society for
Ultrasound in Obstetrics and Gynecology), PIERS (Pre-eclampsia Integrated
distinguish from the usual increase in BP after 20 weeks’ gestation.
Estimate of Risk Score).
153
heterogeneity [45]. For example, among women with ‘suspected pre- encouraged to evaluate patient preferences, resources, outcomes, and
eclampsia’, angiogenic imbalance has high negative predictive value in costs associated with use of these markers in their own population.
ruling out: development of proteinuric pre-eclampsia within 7 days,
adverse maternal outcomes within 14 days [46], or delivery with pre- Maternal monitoring
eclampsia within 14 days [37–38] when suspected pre-eclampsia is For women with pre-eclampsia, maternal assessment should include
primarily related to hypertension (but not when FGR is a prominent BP and proteinuria, as well as the components of the fullPIERS (Pre-
reason [48]). Use of angiogenic markers to guide care may reduce eclampsia Integrated Estimate of Risk Score) model that is predictive of
adverse maternal outcomes (5% to 4%) [38], time-to-diagnosis of pre- adverse maternal outcome in hypertensive pregnancy and pre-eclampsia
eclampsia (by an average of 2 days) [38,49], identify women at specifically, when performed at least twice weekly [44,65]. The adverse
increased risk of peripartum severe maternal morbidity (including maternal outcomes are a composite derived from Delphi consensus and
postnatal hypertension) [50], and be cost-saving in the UK [51]. Similar similar to the later 14 core maternal outcomes in pre-eclampsia (Panel),
findings are emerging from less-resourced settings [52]. Prediction of reflecting one/more of:
adverse outcomes may be improved by combining angiogenic markers
with other clinical, routine laboratory, and ultrasonographic data • maternal death;
[53–55]. • neurological complications (eclampsia or posterior reversible en
There remain a number of challenges. cephalopathy syndrome; stroke, transient ischaemic attack, or
reversible ischaemic neurological deficit; Glasgow coma score <13);
• First, the term ‘suspected pre-eclampsia’ has been used for a broad • cardiorespiratory complications (infusion of a third parenteral anti
range of women. Those with new/worsening hypertension who un hypertensive drug; pulmonary oedema; positive inotropic support;
dergo investigations may receive a diagnosis of pre-eclampsia and myocardial ischaemia or infarction; oxygen saturation <90%; ≥50%
angiogenic imbalance may aid in identification of uteroplacental inspired oxygen for more than one hour; intubation other than for
dysfunction. Normotensive women with one/more of the symptoms Caesarean);
or signs characteristic of pre-eclampsia (e.g., FGR) cannot be diag • renal complications (acute renal sufficiency [creatinine >150 μmol/
nosed with pre-eclampsia, but angiogenic imbalance appears to L] with pre-existing renal disease, acute renal failure with pre-
identify those at increased risk of progression to pre-eclampsia. existing renal disease [creatinine >200 μmol/L], dialysis;
(Normotensive FGR is covered by specific guidance [56].) Other • hepatic (liver dysfunction or capsule haematoma or rupture);
manifestatons are non-specific and overlap with other conditions, • haematological (platelet count < 50 × 109 per L or transfusion of any
such as migraine. As such, the ISSHP advises that ‘suspected pre- blood product);
eclampsia’ be used for no more than 24 h to avoid confusion. • placental abruption;
• Second, women with ‘suspected pre-eclampsia’ have often been • other (severe ascites, Bell’s palsy).
studied where pre-eclampsia was defined only by gestational hy
pertension and proteinuria [37,47,57], or women with new dipstick The fullPIERS model includes: gestational age, chest pain/dyspnoea,
proteinuria did not necessarily undergo confirmatory testing for pulse oximetry, platelet count, serum creatinine, and AST or ALT [44].
proteinuria prior to enrolment [36,38]. As such, many women with By incorporating gestational age into the model, use of fullPIERS model
‘suspected pre-eclampsia’ would have already satisfied the current is not restricted to a specific gestational age range, like the PREP model
ISSHP broad definition of pre-eclampsia. It is possible that the ability developed for use in pre-eclampsia before 34 weeks [66]. fullPIERS does
of angiogenic markers to predict ‘delivery with pre-eclampsia within not include proteinuria; once confirmed as present, proteinuria testing
14 days’ may have been driven by the fact that many of the women does not need to be repeated. (Please see ‘BP and proteinuria’ for further
already had pre-eclampsia [36]. Alternatively, angiogenic markers details.) An online calculator is available (https://pre-empt.bcchr.ca/
may add further to risk stratification among women who already evidence/fullpiers).
meet diagnostic criteria for pre-eclampsia [58]. Further work is It is not known how, among women with pre-eclampsia, angiogenic
needed to define the added value of angiogenic markers across markers (performed once or serially) may add to fullPIERS for prediction
gestational ages. of adverse maternal outcomes, or to traditional fetal assessment for
• Third, our understanding about how best to use angiogenic markers prediction of adverse perinatal outcomes. However, there are some
is complicated by numerous assays and cut-off values (with PlGF promising publications [53,67].
varying with gestational age), and promotion as a test for pre- Without ready access to laboratory results, miniPIERS includes: sBP,
eclampsia rather than one for uteroplacental dysfunction that un dipstick proteinuria, parity, gestational age, and symptoms (headache/
derlies many cases of preterm pre-eclampsia, but also other related visual symptoms, chest pain/dyspnoea, abdominal pain with vaginal
conditions, like placental FGR [59]. bleeding); model performance is improved with addition of pulse ox
• Finally, we do not know how angiogenic markers add to prediction of imetry [68–69]; an online calculator is available (https://pre-empt.bcch
adverse outcomes based on routinely-collected data used in models r.ca/evidence/minipiers). With ready access to laboratory results,
[44,60], although a recent publication suggests that a multivariable fullPIERS includes: gestational age, chest pain/dyspnoea, pulse oxime
approach is important [53]. If reassessment for suspected pre- try, platelet count, serum creatinine, and AST or ALT [44]. While clonus
eclampsia is required, limited data suggested that ≈75% of PlGF reflects central nervous system irritability, the reproducibility of clonus
results remain similar [61]. testing (in the maternity setting) and its independent predictive value
for adverse outcome is uncertain. Uric acid has been associated with
These challenges aside, maternal circulating angiogenic markers are heightened risk of adverse maternal and fetal outcomes, particularly
increasingly part of investigations for pre-eclampsia, and real-time data when gestational age corrected, but the test was not independently
from a number of groups support clinical utility as a diagnostic and predictive of adverse maternal outcomes in fullPIERS [41].
prognostic tool [53,62]. As such, the ISSHP has moved to incorporate
angiogenic markers into investigations as another marker of uteropla Fetal monitoring
cental dysfunction, similar to angiogenic marker dysregulation in FGR, Although multiple methods of fetal surveillance are available, there
but not as a sole criterion for diagnosing pre-eclampsia. Angiogenic is no strategy of various methods and timings that has been recognised
markers may be particularly useful in the face of pre-existing protein to be superior in hypertensive pregnancy specifically. For the four fetal
uria, chronic hypertension or CKD [63–64]. As making a diagnosis of and four neonatal adverse outcomes in pre-eclampsia, see Panel [70].
pre-eclampsia is such an important clinical decision, all units are While serial FHR monitoring is common practice in hypertensive
154
pregnancy, the effectiveness of this approach in reducing adverse Table 5

outcome and the optimal frequency, if any, is undetermined. Where Clinical risk factors for pre-eclampsia identifiable in early pregnancy (modified
resources are limited, CTGs performed 6-hourly in inpatient women from Bartsch et al3)*.
have been used to monitor for placental abruption [71–72]. ‘High-risk’ factors (any one) ‘Moderate-risk’
As the fetus with growth restriction and/or reduced amniotic fluid factors (two or
volume is at particular risk of stillbirth and neonatal mortality and more)
morbidity, ultrasonographic assessment of fetal growth and liquor vol Prior pregnancy
ume is recommended. Given the shared origins of pre-eclampsia and history
Prior pre-eclampsia Prior placental
FGR [73], we recommend that care-providers follow current ISUOG
abruption
guidance for women with suspected FGR [56]. Doppler ultrasound of the Prior stillbirth
umbilical artery may reduce perinatal death and obstetric intervention Prior fetal growth
in high-risk pregnancies, but the evidence is not definitive [74]; it is restriction
important to note that near or at term, a normal umbilical artery Doppler Demographics
Pre-pregnancy BMI > 30 kg/m2 Maternal age >40
does not exclude fetal compromise. At ≤33+6 weeks in the presence of years
FGR, the addition of Doppler ultrasound of the ductus venosus may be Pre-existing
beneficial, as an absent or reversed a wave is associated with a sub medical
stantially increased risk for stillbirth [75]; neurodevelopmental out conditions
Chronic hypertension
comes among survivors is improved when timing of birth is based on
Pre-gestational diabetes mellitus
abnormal ductus venosus Doppler, short-term (computerised) fetal heart Chronic kidney disease (inc.
rate (FHR) variability, and/or spontaneous FHR decelerations [76–78]. kidney transplanted women)†
The biophysical profile is not recommended as it can be falsely Systemic lupus erythematosus/
reassuring in hypertensive and fetal growth-restricted pregnancies, and antiphospholipid antibody
syndrome†
an abnormal profile is a late finding [79–81].
This pregnancy
Without ready access to methods of fetal surveillance beyond FHR Assisted reproductive therapyǂ Nulliparity
monitoring, maternal characteristics (including 4 + dipstick protein Multifetal
uria) can be used to estimate perinatal risk at ≥32 weeks; before this pregnancy
time, perinatal risk is almost entirely driven by gestational age [82]. BMI (body mass index).
* Women are considered to be at increased risk if they have at one ‘high risk’
4. Prediction of pre-eclampsia factor or two or more ‘moderate risk’ factors.
†
These have been listed as ‘high’ (not ‘moderate’ risk factors3) because of the
Recommendations wider spectrum of chronic kidney disease and associated adverse outcomes than
13. At minimum, women should be screened for clinical risk markers evidenced in the included cohort studies [4].
ǂ
The risk of ART varies with the methods used, being highest among women
of pre-eclampsia risk at antenatal care booking (GPP).
receiving semen or oocyte donation and following frozen embryo transfer [5].
14. If testing is available, after appropriate counselling, women
should be screened at 11–14 weeks for preterm pre-eclampsia risk, using
a combination of clinical risk factors, BP, uterine artery pulsatility index, anticardiolipin antibodies), and fetoplacental endocrine function
and PlGF, as available, even if they have been already been identified as (including beta-hCG, pregnancy-associated plasma protein A [PAPP-A],
having clinical ‘high-risk’ factors (⊕⊕⊕O/Strong). placental protein 13 [PP13], and inhibin A). Ultrasonographic measures
No first or second trimester test or set of tests can reliably predict the have included uterine artery Doppler, placental vascularisation, and
development of all cases of pre-eclampsia, and combined first trimester single fetal umbilical artery indices. Multivariable, specialised models
testing (described above) does not predict development of pre-eclampsia have outperformed single factors or simple models [88].
at term when most cases develop. In the multi-ethnic UK population with an incidence of pre-eclampsia
Large-scale epidemiological studies have identified clinical risk fac of ≈3%, screening with a ‘triple test’ (of clinical risk factors plus BP,
tors for pre-eclampsia (Table 5). The strongest are prior pre-eclampsia serum PlGF, and uterine artery Doppler ultrasound) can identify the
(RR 8.4, 95% CI 7.1, 9.9) and chronic hypertension (RR 5.1, 95% CI largest proportion of women (≈80%) who will go on to develop preterm
4.0, 6.5). There is some disagreement as to whether some high-risk pre-eclampsia [89–90]. Identifying women in this way, and giving them
factors should be considered moderate-risk, such as obesity and those low-dose aspirin, reduces the incidence of preterm (but not term) pre-
who have conceived with ART based on risks alone [83]; however, these eclampsia [91]. An online calculator is available on the Fetal Medicine
risk factors are likely to be modifiable by aspirin and addressing by pre- Foundation website [92] and as an app through the App Store. (For
pregnancy weight loss the pre-eclampsia risk associated with obesity recommendations about aspirin, see ‘Prevention’ below.)
could have a substantial impact on pre-eclampsia incidence at the Only ≈10% of women who develop preterm pre-eclampsia have
population level [84]. Also, there is a wide spectrum of CKD that was not clinical risk factors [83]. However, a large proportion (43.9%) of women
reflected in the epidemiological studies included in the predictive ana with ‘strong’ clinical risk factors and the majority (70.7%) with ‘mod
lyses [84–85]. erate’ ones screen negative by the FMF algorithm, and their risk of pre-
Clinical measurements, and ultrasonographic and laboratory pa eclampsia is substantially lower (i.e., 0.65% and 0.42%, respectively)
rameters have been explored during early pregnancy as tools for pre [83]; ‘triple test’ screening, where available, should be undertaken with
dicting who will later develop pre-eclampsia [86–87]. According to clear objectives in mind, such as women’s reassurance, to guide aspirin
systematic reviews, well-studied clinical predictors have included de dosing, or a change in management, including surveillance.
mographics, past history, medical conditions, characteristics of current Screening beyond clinical factors should be considered in the context
pregnancy (like conception by ART or multifetal pregnancy), physio of the available health care resources, and discussed with the woman
logical variables (like BP), and the social determinants of health [83]. The detection rate of maternal factors alone (≈40% of European
(including nutrition). Laboratory measures have included maternal women and 25% in Asia [93] for preterm pre-eclampsia is inferior to
circulating angiogenic proteins (including PlGF, sFlt-1, and soluble maternal factors plus BP (just under 50%). A combination of maternal
endoglin), inflammation (including IFN-γ), lipid metabolism and risk factors, BP, and uterine artery Doppler can detect just over 75% of
oxidative stress (including ozone), cardiac function, renal function, women who will develop preterm pre-eclampsia [89]; the addition of
coagulation (including genetic thrombophilia testing and PlGF improves detection to 80% [94]. All approaches are poor at
155
identifying women who go on to develop term pre-eclampsia (≈40% carrying moderate loads, and household chores such as gardening or
detection) [89–90]. This multivariable approach to screening has also washing windows. Typically during these activities, a person can talk
been validated prospectively in mixed-European, Australian, Asian, but not sing, and notices that their heart rate has increased.
North and South American populations [93,95–100]. Exercise is contraindicated in all women with established pre-
All measurements - clinical, laboratory, or ultrasonographic - should eclampsia, and relatively contraindicated in women with gestational
be performed by individuals with adequate training and who undergo hypertension [104], but among those without contraindications, there
ongoing quality assurance assessment. This is a critical point given that are no significant adverse effects of exercise in pregnancy.
some ultrasound departments do not have staff specifically trained in
uterine artery Doppler assessment despite performing these tests on a 5.2. Calcium
frequent basis.
While the most effective screening strategy involves a number of Calcium administered from 20 weeks’ gestation is effective in
investigative tools, some consider screening to be complex and expen decreasing pre-eclampsia risk when administered at high (1.5–2.5 g/d)
sive; the costs of screening must be weighed against the short-term costs or low dose (<1 g/d) and to women at high or low risk of pre-eclampsia,
of preterm pre-eclampsia, likely driven by neonatal care unit costs but only among populations with low baseline intake of calcium (<900
[101], as well as the long-term implications of pre-eclampsia for the mg/d) [105–106]. Currently, there is no standardised method for
mother and offspring. The psychological implications of a false positive assessing dietary intake of calcium among individual women. The bulk
screening test for the mother have been raised as a potential concern of the evidence comes from women at high risk, administered high-dose
associated with multivariable screening; however, false positive calcium in low-intake populations, and there is a lack of understanding
screening results occurred as frequently with multivariable screening as about how baseline risk, individual calcium intake, and calcium dose
with clinical criteria, and women who declined to participate in the administered in pregnancy interact. An ongoing trial in the UK is
ASPRE trial were not concerned about being labelled as high risk [102]. addressing the question of very high-dose calcium administered to high-
It will be important to confirm the cost effectiveness of multivariable risk women in an on average, adequate calcium intake population (CaPE
screening for pre-eclampsia risk and intervention, contextualised to trial, NIHR127325).
population, disease prevalence, and models and costs of care. Given the In a RCT of 1355 women at high risk of pre-eclampsia based on
link between prediction and prevention, these issues are discussed disease in prior pregnancy, calcium supplementation (vs. placebo) of
further under, ‘Prevention’, for aspirin. 500 mg/day before pregnancy and until 20 weeks of the subsequent
pregnancy (with an increase in calcium to 1.5 g/d thereafter for all
5. Prevention of pre-eclampsia women), reduced the incidence of pre-eclampsia only when compliance
with tablets before 20 weeks (45.0%) was at least 80% (RR 0.66, 95% CI
All women in pregnancy 0.44, 0.98), and may have reduced the incidence of pregnancy loss or
pre-eclampsia (107/323, 33% vs. 126/310, 41%; RR 0.82, 95% CI 0.66,
Recommendations 1.00) [107]. These data serve to emphasise that low calcium intake
15. Unless there are contraindications, all women should exercise in should be addressed pre-pregnancy if possible, especially among high-
pregnancy to reduce the likelihood of gestational hypertension and pre- risk women among whom compliance is critical.
eclampsia ((⊕⊕⊕O/Strong). Calcium administration should be in addition to aspirin, as indicated.
16. For women with low dietary intake of calcium (<900 mg/day),
oral calcium supplementation of at least 500 mg/d is recommended 5.3. Aspirin
(⊕⊕OO/Weak).
17. Women should NOT receive low-molecular-weight heparin*, Women at increased risk of preterm pre-eclampsia benefit from
vitamins C or E, or folic acid for pre-eclampsia prevention (⊕⊕⊕O/ receiving low-dose aspirin. However, the magnitude of benefit depends
Strong). on how their risk is identified, the timing of initiation and dose of aspirin
* This recommendation relates to use of heparin for pre-eclampsia pre administered, and their adherence to aspirin as prescribed.
vention. And not for other indications, such as thromboprophylaxis in anti
phospholipid antibody syndrome. Method of risk identification
Women identified as being at increased risk of pre-eclampsia based
Women at increased risk of pre-eclampsia on clinical risk factors alone benefit from receiving low-dose aspirin
(75–162 mg/d), but the risk of pre-eclampsia (RR 0.90, 95% CI 0.84,
Recommendations 0.97) or pre-eclampsia with delivery at <34 weeks (RR 0.90, 95% CI
18. Low-dose aspirin is recommended (⊕⊕⊕⊕/Strong), to be taken 0.83, 0.98) is reduced by only ≈10%, based on an individual participant
at bedtime (⊕⊕⊕O/Strong), preferably before 16 weeks and dis data meta-analysis (31 trials, 32,217 women) [108]. However, meta-
continued by 36 weeks (⊕⊕⊕O/Strong). analyses have illustrated that benefit is related to initiation of aspirin
19. After multivariable screening, aspirin should be given at a dose of before 16 weeks and at higher dosage, and primarily to prevention of
150 mg/night (⊕⊕⊕⊕/Strong). preterm and more severe disease [109–111]. Women who book late for
20. After screening with clinical risk factors and BP, aspirin should be antenatal care may still benefit from aspirin started after 16 weeks,
given at a dose of 100–162 mg/d (⊕⊕⊕O/Strong). although the reduction in pre-eclampsia has been estimated to be non-
No treatment to date can prevent pre-eclampsia in all women, but significant [109].
there are approaches that reduce the risk. Women identified as being at increased risk of pre-eclampsia (of at
least 1%) can be identified by the FMF ‘triple test’ of multivariable
5.1. Exercise screening and their risk of preterm pre-eclampsia more than halved (OR
0.38, 95% CI 0.20, 0.74) by low-dose aspirin at a dose of 150 mg each
In RCTs, exercise reduces the risk of both gestational hypertension night, from 11 to 14 weeks until 36 weeks (or birth, if earlier) [91]. The
(OR 0.61, 95% CI 0.43, 0.85) and pre-eclampsia (OR 0.59, 95% CI 0.37, benefits were even greater when women complied with at least 90% of
0.90) (as well as gestational diabetes by a similar degree) [103–104]. To tablets (71% of women). However, the risk of term pre-eclampsia was
achieve these reductions, women must undertake at least 140 min per unchanged (OR 0.95, 95% CI 0.57, 1.57). No adverse effects of aspirin
week of moderate-intensity exercise, such as brisk walking, water aer were reported. However, in subgroup analyses, participants with
obics, stationary cycling with moderate effort, resistance training, chronic hypertension may not have benefited from a reduced risk of
156
preterm pre-eclampsia (aOR 1.29, 95% CI 0.33, 5.12), in contrast to target therapies more effectively in specific groups yielding more posi
other participants (aOR 0.27, 95% CI 0.12, 0.60; p = 0.055), even tive results.
among women with excellent adherence to aspirin (p = 0.002) [112].
Until this finding can be replicated, it would be prudent to recommend 6. Management
aspirin to women with chronic hypertension and discuss with them the
uncertainties. 6.1. Place of care
The cost-effectiveness of a multivariable screen and treat approach
has been demonstrated in Canada [113] and Israel [114], and supported Recommendations
by ASPRE data that estimated that the cost of screening would be out 21. Women with pre-eclampsia or severe hypertension should be
weighed by reduced length of neonatal intensive care unit stay (by US assessed and managed in hospital, before carefully-selected cases are
$560 per pregnancy screened) [115]. (Approximately 10% of pregnant considered for outpatient care (GPP).
women screened are screen-positive.) While multivariable screening has Pre-eclampsia can progress quickly, without warning. The level of BP
been challenged by analyses demonstrating the cost-effectiveness of itself is not a reliable way to stratify immediate risk in pre-eclampsia,
universal aspirin prophylaxis in pregnancy for all women [116–117] or because some women may develop serious maternal end-organ or ute
all nulliparous women [118], these studies did not all account for likely roplacental dysfunction at minimally elevated BP. However, when BP
lower adherence with aspirin, reduced effect size, and a potential in elevation is to 160/110 mmHg or above, women require urgent treat
crease in complications. ment in a monitored setting, given the further elevation in risk of
adverse maternal and fetal outcomes [130] and to ensure that antihy
Safety pertensive is effective in lowering BP. Wherever women with pre-
Low-dose aspirin has been widely regarded as safe in pregnancy, eclampsia receive care, resources should be available to undertake
although there are signals of small increases in bleeding risk; aspirin has emergent delivery and care for sick mothers and newborns [131];
not been associated with miscarriage. Risks, even at a 75 mg dose, but otherwise, transfer of care should be considered.
probably higher with increasing dosage [119] have been reported to Some care outside hospital can be considered for women with non-
include vaginal spotting [118,120], antepartum [121–122], intra severe hypertension or pre-eclampsia without maternal end-organ
partum [123], and postpartum haemorrhage [118,122–123], post involvement after their initial assessment (Table 1). Models of care
partum haematoma [123],and importantly, a small (0.06%) absolute could include serial visits to obstetrical day units or home care, but any
increase in neonatal intracranial hemorrhage [123], particularly after model should include regular (ideally daily) contact to monitor for
vaginal birth [123]. Many risks may be mitigated by discontinuing disease progression. Women considered for outpatient management
aspirin by 36 weeks based on the lack of effectiveness for prevention of should: be informed about concerning symptoms, including when and
term pre-eclampsia [124]. Risks of aspirin must be seen in the context of how to report them and be prepared to do so; be provided with HBPM
important maternal and perinatal risks of pre-eclampsia occurrence, and capability, if possible; live a reasonable distance from hospital; have
should dissuade care-providers from instituting universal aspirin pro ready access to maternal and fetal surveillance; and be cared for by an
phylaxis, especially as adverse effects of aspirin have been concentrated experienced and well-organised team.
in trials targeting low-risk women, even when aspirin was stopped
before birth, and in observational studies evaluating universal aspirin 6.2. Non-pharmacological therapy
prophylaxis.
There is insufficient evidence to recommend for or against restricted
Dose activity, in hospital or at home, for any HDP. A remotely-published,
The ISSHP recognises that different countries have different formu small trial (218 women) found that for women with gestational hyper
lations of aspirin, and it is not possible to cut enteric-coated tablets. In tension, some bedrest in hospital was superior to unrestricted activity at
RCTs, doses of 75–162 mg/day have been studied and there are no head- home [132] which, in a similar trial, was women preferred [133–134].
to-head trials of different aspirin doses. Aspirin at a dose <100 mg is not Concerns about thromboembolism risk should caution practitioners
recommended based on platelet insensitivity to aspirin in up to ≈40% of against recommending strict bed rest, due to the potential for harm in
women, particularly as pregnancy progresses and with higher BMI the absence of demonstrable benefit.
[125–126]; however, at least some component of non-responsiveness Uncontrolled hypertension of any type, and pre-eclampsia specif
may actually be non-adherence and a lack of exposure of platelets to ically, are absolute contraindications to exercise [104].
the aspirin [127]. A dose of 150 mg/day (or 162 mg based on two 81 mg
tablets of the available formulation) may be more effective, based on 6.3. Antihypertensive therapy
ASPRE [91].
Recommendations
5.4. Other preventative strategies 22. Hypertension in pregnancy should be treated with antihyper
tensive therapy, irrespective of the underlying HDP (⊕⊕⊕O/Strong).
There is insufficient information at this stage to recommend for or 23. Severe hypertension in pregnancy (i.e., sBP ≥ 160 mmHg or dBP
against other preventative strategies, such as oral magnesium, metfor ≥ 110 mmHg) requires urgent antihypertensive therapy, in a monitored
min, or statins although several trials are in progress. High-dose folic setting (⊕⊕OO/Strong).
acid, vitamin C, and vitamin E are not recommended [128]. 24. The target BP for antihypertensive therapy should be a dBP of 85
Low molecular weight heparin (LMWH) has received much attention mmHg, regardless of sBP (⊕⊕⊕⊕/Strong).
as a potential preventative strategy for pre-eclampsia and other condi 25. Non-severe hypertension should be treated with the first-line
tions related to uteroplacental dysfunction. A recent individual patient agents oral methyldopa, labetalol, or nifedipine (⊕⊕⊕O/Strong).
data meta-analysis including 963 women did not support use of LMWH, 26. Severe hypertension should be treated with the first-line agents
given no impact on the primary outcome, a composite of early pre- oral nifedipine, oral labetalol, IV labetalol, or IV hydralazine (⊕⊕⊕O/
eclampsia, FGR, and/or pregnancy loss [129]. (These data do not pre Strong).
clude use of LMWH and aspirin for other indications, such as throm
boprophylaxis in antiphospholipid antibody syndrome.) Like many Target BP
other interventions, the hope persists that with improved phenotyping Hypertension associated with chronic hypertension, gestational hy
of pre-eclampsia and related placental conditions, future trials will pertension, or pre-eclampsia requires treatment to reduce the likelihood
157
of developing severe maternal hypertension and other complications, on small, randomised trials [138]. The choice of antihypertensive agent
such as low platelets and elevated liver enzymes with symptoms based should be based on characteristics of the patient, contraindications to a
on the findings from the CHIPS trial [29]. While CHIPS enrolled women particular drug, and physician and patient preference. Caution should be
with chronic or gestational hypertension, almost half of women devel exercised when using labetalol or other beta-blockers in women with
oped pre-eclampsia and all stayed on their allocated BP control, for an asthma, particularly if not well-controlled, given the slight (about 0.5%)
average of two weeks before birth. In the CHIPS trial, severe hyperten increased risk of status asthmaticus [139]. For women with chronic
sion was similar to pre-eclampsia in being a surrogate marker for hypertension, no consistent association has been found between anti
adverse outcomes [135]. hypertensive agents and congenital malformations. However, there are
While not all national societies have adopted the results of CHIPS, lingering concerns that hypertension itself may be associated with an
the ISSHP endorses the perspective that, “To manage BP expectantly at increase in birth defects [140]. Beta-blockers, including labetalol, may
<160/110 mmHg, but emergently at ≥160/110 mmHg, is logically increase the risk of neonatal bradycardia and hypoglycaemia, and their
inconsistent” [136]. Increasing use of antihypertensive medication in use is deemed to warrant newborn blood glucose monitoring in some
hospitalised women with pre-eclampsia has been associated with a jurisdictions, such as the UK [141].
reduced incidence of stroke [137]. No firm conclusions can be drawn with regards to long-term child
The target BP for antihypertensive therapy should be a dBP of 85 outcomes given a paucity of relevant high-quality studies designed to
mmHg, as in CHIPS [29]. BP control resulted from use of a simple al examine exposure to antihypertensives [142]. Child outcomes at up to 5
gorithm in which antihypertensive drugs were reduced or ceased if dBP years of age were reassuring following exposure to nifedipine for
fell to ≤80 mmHg, and increased or started if dBP rose to >85 mmHg or tocolysis [143].
sBP were ≥160 mmHg (regardless of dBP, for safety) (Fig. 1). This Additional antihypertensive drugs should be used if target BP levels
simplified focus on dBP resulted in associated control of sBP, achieving a are not achieved with standard-dose monotherapy [144], at least to a
mean BP of 133/85 mmHg between randomisation and delivery. mid-range dose; add-on drugs should be from a different drug class
The approach to hypertension is the same for women with co- chosen from first-line or second-line options [144], Table 7 presents a
morbidities associated with hypertension, such as chronic renal dis suggested dosing escalation protocol. Less commonly-used but accept
ease. The only exception is white-coat hypertension unless women able second-line antihypertensive agents include other beta-blockers (e.
develop BP levels ≥160/110 mmHg in the office/hospital setting. g., metoprolol) [138]. Other potential agents are not usually first line
Among hypertensive women, out-of-office BP is usually lower than therapies, but are not contraindicated, based on limited trial data (e.g.,
office BP, but there is wide variation and no consensus about whether an amlodipine or diltiazem) or unproven concerns about maternal tachy
out-of-office BP target should be 130/80 mmHg (corresponding to an cardia when used alone (i.e., oral hydralazine), stillbirth in the setting of
office BP of 135/85 mmHg) or 135/85 mmHg (corresponding to an pre-eclampsia (i.e., prazosin), or theoretical hazards of reduced
office BP of 140/90 mmHg) [10]. At present, the ISSHP recommends maternal circulating volume (i.e., diuretics).
using similar target BP values for out-of-office and office BP, to minimise ISSHP recommendations are based on BP values, but there is po
the risk of low BP at home. An example of a monitoring strategy is tential in future to further personalise management, using demographic
presented in Table 6. (Black race) and haemodynamic parameters (lower heart rate and car
diac stroke volume, and higher peripheral vascular resistance).
Antihypertensive agents Together, these may identify women who respond better to nifedipine
Antihypertensive therapy is generally safe and benefits outweigh than labetalol [145], a particularly important group more often associ
risks. ated with severe hypertension and FGR, and more likely to respond to a
Initial antihypertensive therapy for non-severe hypertension in vasodilator (e.g., nifedipine). In contrast, women of non-Black race and
pregnancy should be monotherapy from the listed first-line drugs, based with higher heart rate and stroke volume, described as being
Fig. 1. Algorithm used in the CHIPS trial to achieve BP control (from Magee et al. Ultrasound Obstet Gynecol 2020; 56: 7–10). dBP (diastolic blood pressure), sBP
(systolic blood pressure). *If systolic BP (sBP) is ≥160 mmHg, increase dose of existing medication or start new antihypertensive medication to get sBP < 160 mmHg,
regardless of diastolic BP. Women require urgent treatment in a monitored setting.
158
Table 6
Suggested monitoring for hypertensive pregnant women with a target dBP of 85 mmHg (from Magee et al 2020 [138], modified from Dougall et al. BMJ Open 2020;10:
e034593. https://doi.org/10.1136/bmjopen-2019-034593).
BP (blood pressure), dBP (diastolic blood pressure).

* If at any time, sBP is ≥ 155 mmHg, BP should be considered very high and actions taken accordingly.
Table 7
Maintenance therapy and suggested dose titration of antihypertensive therapy for non-urgent control of hypertension in pregnancy (modified from Magee et al 2020)
[147].
LA (long-acting), MR (modified release), PA (prolonged action), XL (extended release).

* Starting doses are higher than generally recommended for adults given more rapid clearance in pregnancy.
† When a medication is at high (or maximum) dosage, consider using a different medication to treat any severe hypertension that may develop).
“hyperdynamic”, were more successfully treated with oral labetalol; in a unit admission was reduced by 60%, with no increase in FGR [146].
small observational study (84 women) of as haemodynamic-guided There are no relevant RCTs.
antihypertensive therapy for BP ≥ 140/90 mmHg guided by this Oral antihypertensives can be given in labour; if BP control is sub
model, antihypertensive management was altered for half of women, optimal, this may be due to reduced absorption because of gastrointes
and the incidence of severe hypertension requiring high dependency tinal motility and parenteral agents may be needed.
159
Angiotensin converting enzyme (ACE) inhibitors and angiotensin severe hypertension (without causing maternal or fetal adverse effects)
receptor blockers (ARBs) should not be used in women once pregnant in the majority (at least 75%) of women [159]. However, as single drugs,
based on fetotoxicity, manifest as fetal renal toxicity and its conse nifedipine PA and oral labetalol (compared with methyldopa) were less
quences, including stillbirth; the risk appears to be particularly high often associated with the need to administer a second agent (1% vs. 3%
with ARBs [147]. For women with chronic hypertension, these medi vs. 19%). While all women with severe hypertension have an obstetric
cations do not appear to be teratogenic [148–150], and in fact, prior urgency, oral therapy may facilitate earlier treatment while en route to a
associations with birth defects may have been due to the underlying monitored setting, or more timely treatment in that setting.
hypertension itself [151]. As such, it is acceptable to continue ACE Second-line agents include other beta-blockers, other calcium
inhibitors or ARBs until pregnancy is diagnosed if the drugs are channel blockers, and prazosin. [160]
administered for renoprotection, given that the risk of ACE inhibitor Local protocols should outline the nature and frequency of maternal
and ARB fetotoxicity may be greatest with exposure after 20 weeks and fetal monitoring in hypertensive pregnancy, as well as when to
[147]. However, as the literature is not uniformly reassuring, with repeat a dose of antihypertensive medication if BP is not well-controlled
reports of an excess of pregnant complications even when ACE in [161]. To harmonise protocols between medications and minimise the
hibitors and ARBs are stopped in early pregnancy [152], it is prudent to risk of maternal hypotension, a suggested approach is outlined in
switch to another antihypertensive pre-pregnancy, when clinically Table 8. Delayed treatment of severe hypertension has been associated
possible. with prior non-severe hypertension, lack of pre-eclampsia symptoms,
white race, presentation overnight, having labour-related symptoms,
Severe hypertension and later gestational age [162].
No trials have demonstrated that antihypertensive therapy is supe Antihypertensives, including nifedipine, can be used contempora
rior to placebo/no therapy for severe hypertension. However, such trials neously with magnesium sulphate (for eclampsia prevention or treat
would be unethical. Severe hypertension is a surrogate marker for ment) [163].
adverse maternal and perinatal outcomes [130] and there is consensus
that it should be treated. Treatment within 60 min may decrease the 6.4. Plasma volume expansion
incidence of severe maternal morbidity [153]. Advice to lower BP
gradually is based on exacerbation of cerebral ischaemia in stroke and Recommendations
an excess of adverse perinatal outcome among women treated with 27. Plasma volume expansion is not recommended routinely for
agents that lower BP quickly [154]. Nevertheless, success has been women with pre-eclampsia. (⊕⊕⊕O/Strong).
achieved without adverse effects when BP has been lowered within one Data on fluid management in pre-eclampsia are limited. A recent
hour [155]. systematic review (6 trials) showed that colloid volume expansion
The most commonly-recommended agents for treatment of severe reduced maternal BP, but no other benefits or harms were demonstrated
hypertension are IV labetalol, oral nifedipine, and IV hydralazine. [156] [164], unlike the largest trial in which multiple adverse effects were
By network meta-analysis (51 trials), each of these three medications demonstrated (i.e., Caesarean delivery, reduced pregnancy prolonga
achieved target BP in a similar number of women (32 trials, 3236 tion, and more frequent pulmonary oedema) [165]. For women with
women), although more quickly with nifedipine than IV hydralazine. pre-eclampsia, total fluid intake in labour is usually restricted to ≈80
[157] There was no difference in effectiveness between IV labetalol and mL/hour to minimise the risk of pulmonary oedema without increasing
either oral nifedipine or IV hydralazine, but more data were needed to the risk of acute kidney injury [166].
compare oral nifedipine and IV hydralazine. A second network meta-
analysis restricted to first-line agents (17 trials, 1591 women) found 6.5. Magnesium sulphate
that oral nifedipine more successfully treated severe hypertension than
IV hydralazine [158]. Recommendations
A recent, open-label RCT showed that, in low-resource settings, oral 28. Women with eclampsia should receive magnesium sulphate to
nifedipine (PA), labetalol, and methyldopa each successfully treated prevent recurrent seizures (⊕⊕⊕⊕/Strong).
Table 8
Suggested dose titration of antihypertensive therapy for urgent control of hypertension in pregnancy* (from Magee et al 2020) [164].
Caution T0 T 30 T 60 T 90 T 120 T 150 T 180 min
min min min min min
Labetalol (oral) ▪ Contra-indicated with uncontrolled 200 mg – 200 mg – 200 mg – Use alternative
Labetalol (IV intermittent) asthma or heart failure 10–20 20–40 40–80 40–80 40–80 40–80 from a different
▪ May cause neonatal bradycardia and mg mg‡ mg mg [29] mg mg§ drug class†
Labetalol (IV infusion) neonatal hypoglycaemia and warrants 0.5–2 → → → → →†
newborn screening in some jurisdictions mg/min
Nifedipine (oral tablet or capsule, ▪ May cause maternal headache and 10 mg 10 mg – 10 mg – 10 mg
either of which to be swallowed tachycardia
whole, NOT bitten or punctured)
Methyldopa (oral) ▪ Onset of action may be delayed 1000 mg – – – –
Hydralazine (IV) ▪ May increase risk of maternal 5 mg 5–10 5–10 5–10
hypotension, and maternal and fetal mg mg¶ mg¶
tachycardia
* When severe hypertension has resolved, switch to routine oral medication.

†
If nifedipine or hydralazine were the initial drug used, choose oral labetalol or oral methyldopa as the alternative.
‡
Double the initial dose of labetalol IV.
§
Do not exceed the maximum dose of IV labetalol, which is 300 mg total in a treatment course.
¶
Do not exceed the maximum dose of IV hydralazine of 20 mg.
160
29. Women with pre-eclampsia who have proteinuria and severe the monitoring of women and babies receiving this therapy.
hypertension, or hypertension with neurological signs or symptoms, The dosing regimens used in the Eclampsia and Magpie trials are
should receive magnesium sulphate for eclampsia prevention recommended, as outlined in Table 9, along with a protocol for moni
(⊕⊕⊕⊕/Strong). toring and treatment of toxicity. There are a few points worthy of
There is clear evidence that magnesium sulphate halves both the particular discussion. First, magnesium sulphate comes in different
incidence and recurrence of eclampsia [167–168]. The number-needed- concentrations and ampoules of different volume, and some sites have
to-treat (NNT) is ≈100 to prevent one seizure. However, it is contro the drug pre-mixed for administration; if mixing is required, this should
versial whether all women with pre-eclampsia should receive magne be done according to local protocols. Second, while alternative mag
sium sulphate, due to an elevated risk of Caesarean delivery, more nesium sulphate regimens (using lower doses or being more restricted in
maternal adverse effect risks, and higher costs (i.e., US$23,000 to pre duration) have been evaluated, data are currently insufficient to inform
vent one seizure if administered to all women with pre-eclampsia) clinical practice [170]. Unless there is renal impairment, standard doses
[169]. As the NNT is lower (≈50), it is reasonable in well-resourced should be used until further evidence is published on the effectiveness of
settings to restrict magnesium sulphate use to women with ‘severe’ administration that is reduced in dose or abbreviated in duration.
pre-eclampsia as defined by the Magpie trial: severe hypertension and at Finally, magnesium sulphate may be administered while women at
least 3 + of proteinuria, or slightly lower measurements (150/100 preterm gestational ages are being considered for expectant care; if in
mmHg and least 2 + of proteinuria) in the presence of at least two signs vestigations reveal that they do not require immediate birth, it is
or symptoms of “imminent eclampsia” (which was not defined but is reasonable to stop magnesium sulphate and re-evaluate its need when
taken to mean headache, visual symptoms, or clonus). Each unit should timed birth is considered or there is spontaneous onset of labour.
have a consistent policy concerning their use of magnesium sulphate and When not indicated for seizure prophylaxis or treatment, adminis
tration of magnesium sulphate for fetal neuroprotection should be
considered when delivery is imminent at ≤33+6 weeks [171].
Table 9
Magnesium sulphate dosing and monitoring (modified from Brown et al. 2018)
[2] 6.6. Timed birth
Dosing [168,171]
Recommendations
IV administration Combined IV and IM
30. Indications for delivery with any HDP at any gestational age
administration*
(⊕⊕⊕O/Strong) include:
Loading dose 4 g MgSO4 IV in 100 mL 4 g MgSO4 IV in 100 mL
normal saline, infused over normal saline, infused over 20
• Abnormal neurological features (such as eclampsia, severe intrac
20 min using an infusion min using an infusion device
device and 5 g IM into EACH buttock table headache or repeated visual scotomata);
(for a total of 10 g) • Repeated episodes of severe hypertension despite maintenance
Maintenance 1 g/hr IV in normal saline, 5 g IM into ONE buttock every treatment with three classes of antihypertensive agents;
using an infusion device 4 hrs
• Pulmonary oedema;
Duration Until 24 hrs after last eclamptic seizure or birth, whichever is
later • Progressive thrombocytopenia or platelet count <50 × 109/L;
• Transfusion of any blood product;
Monitoring
• Abnormal and rising serum creatinine;
Observations Signs of toxicityǂ
ǂ • Abnormal and rising liver enzymes;
Maternalł • Hepatic dysfunction (INR > 2 in absence of DIC or warfarin), hae
Upon Reflexes Decreased or absent matoma or rupture
completion of • Abruption with evidence of maternal or fetal compromise; or
loading dose
• Non-reassuring fetal status (including death)
Every 30 min BP Lower
Heart rate Lower or cardiac arrythmias
Respiratory rate <12/min for 15 min Recommendations
Pulse oximetry (if available) O2 saturation < 94% for 15 31. A decision to deliver should not be based solely upon the degree of
min
either proteinuria (⊕⊕OO/Strong) or hyperuricaemia (⊕⊕OO/Strong).
Every hr Urine output§ <30 mL/hr for 4 hrs¶
Reflexes Decreased or absent (See Table 10 for recommendations according to gestational age.)
Symptoms|| – Central nervous system (e.g., Indications for planned birth, regardless of gestational age, apply to
excessive drowsiness, slurred ‘complicated’ pre-eclampsia (i.e., involving end-organ complications
speech) that are associated with a heightened risk of maternal or perinatal
Neuromuscular (e.g., muscle
death) [172]. At present, angiogenic imbalance (i.e., maternal blood
–
weakness)
Fetal levels of sFLt-1 and/or PlGF) in itself is not an indication for delivery. If
≥26 wks Continuous cardiotocography timing allows, delivery should occur in a perinatal centre capable of
<26 wks Intermittent fetal heart rate caring for sick mothers and newborns.
auscultation every 30 min
Recommendations for timing of delivery based on gestational age are
*Administration can be switched to IV dosing by starting 1 g/hr (without a presented in Table 10.
loading dose) when the next dose of IM MgSO4 is due. Pre-viability, expectant care of pre-eclampsia is associated with very
ł
If toxicity is suspected, cease the MgSO4 infusion and take blood for serum Mg high perinatal mortality (>80%), as well as frequent maternal compli
level. If toxicity is clear, administer calcium gluconate 10% (10 mL in 100 mL cations (in 27–71% of cases) that may include death [173–174].
normal saline IV over 10 min). Termination of pregnancy should be discussed and patient values
ǂ
Monitoring of serum Mg levels is not necessary unless there is decreased renal
considered, along with transfer of care to a referral hospital.
function or signs of toxicity.
From viability to 33+6 weeks, the limited evidence favours expectant
§
Foley catheterisation is recommended.
¶
Decreased urine output is included because it increases the risk of toxicity. care when there is no clear indication for birth. By systematic review (6
||
Symptoms of toxicity should be distinguished from well-known side effects, trials, 748 women), interventionist (vs. expectant) care was associated
which include: flushing of the skin, a metallic taste in the mouth, sweating, with earlier gestational age at birth by ≈10 days (mean − 9.91 days, 95%
nausea and vomiting, heaviness in the chest, palpitations, and lowering of the BP CI − 16.37, − 3.45), similar maternal outcomes (but very wide CIs), but
initially. more neonatal morbidity (i.e., intraventricular haemorrhage [RR 1.94,
161
Table 10 6.7. Antenatal corticosteroids

Recommendations for timing of birth.
Gestational Pre-eclampsia Gestational Chronic Recommendations
age hypertension hypertension 32. Do not administer corticosteroids to hasten resolution of HELLP
Termination of syndrome (⊕⊕⊕O/Strong)
pregnancy should be Antenatal corticosteroids, in a single course, should be administered
Pre-viability
discussed (⊕⊕OO/ to women with HDPs in line with recommendations for any woman at
Weak) <34+0 weeks who is at risk of birth within the next 7 days, to reduce
Expectant
management should
neonatal death and neonatal morbidity, respiratory distress, and intra
be considered, but ventricular haemorrhage [186]. This is true in all settings where
Viability to only in hospitals gestational age can be accurately assessed [187]. A single repeat course
33þ6 where very preterm of steroids can be administered prior to 34 weeks if the woman remains
weeks infants and sick
Expectant care is Expectant care is pregnant at least 7 days (WHO) to 14 days (ACOG) after the initial
mothers can be
cared for (⊕⊕⊕O/
recommended recommended course, and she remains at high risk of preterm birth within the next 7
unless there is an unless there is an days [188]. Corticosteroids can be administered between 34+0 and 36+6
Weak)
indication for birth indication for birth
At 34+0-36+6 weeks,
((⊕⊕OO/Strong) (⊕OOO/Strong)
weeks in women with pre-eclampsia or gestational hypertension at risk
initiation of delivery for delivery, among women with singleton pregnancies who have not
should be discussed
as it decreases
received steroids before and are non-diabetic [189].
maternal but Steroids should not be specifically administered for HELLP syn
34þ0 to 36þ6
increases neonatal drome. While they may transiently improve platelet count and other
weeks
risk, particularly laboratory values in HELLP, they have not been proven to reduce
where antenatal
adverse outcomes and they have common adverse effects, such as
corticosteroids are
not prescribed hyperglycaemia and further elevation of BP [190–191].
(⊕⊕⊕O/Strong)
Women who reach

Women who reach 6.8. Novel therapies
40+0 weeks should
40+0 weeks should
be offered delivery
Initiation of delivery
be offered delivery
(⊕⊕OO/Strong)
Currently, there is no treatment for pre-eclampsia other than timed
≥37þ0 (⊕⊕OO/Strong) birth. Many therapies are being (e.g., statins, metformin) evaluated, at
is recommended Initiation of
weeks Women at 37+0
(⊕⊕⊕⊕/Strong) delivery may be various gestational ages or stages of disease, for their theoretically
–39+6 weeks may
offered at 38+0 to positive effects on the pathogenesis of pre-eclampsia, particularly
be offered delivery
39+6 weeks
(⊕⊕OO/Weak) angiogenic imbalance and maternal systemic endothelial dysfunction
(⊕⊕OO/Weak)
and/or inflammation. A major barrier to progress is limited safety data,
but this is being addressed by repurposing drugs acceptable for use in
95% CI 1.15, 3.29], hyaline membrane disease [RR 2.30, 95% CI 1.39, pregnancy, as well as novel nanoparticle delivery systems adapted from
3.81], and ventilation [RR 1.50, 95% CI 1.11, 2.02]), despite fewer oncology [192].
babies being SGA (RR 0.38, 95% CI 0.24, 0.61) [175].
At 34+0-36+6 weeks, there are maternal benefits of delivery but also 7. Postpartum care
neonatal risks, particularly where antenatal corticosteroids are not
routinely administered at this gestational age. In the PHOENIX trial (UK) Recommendations
in which expectant care was associated with more neonatal unit 33. For women with antepartum hypertension, BP should be moni
admission, but not more neonatal respiratory illness, most (60%) tored at least once on days 3–7 postpartum when it is likely to be highest
women had received antenatal steroids [176], whereas in the HYPITAT after birth (GPP).
II trial in which immediate delivery was associated with more neonatal 34. Antihypertensive therapy administered antepartum should be
respiratory distress syndrome, only 1% of women had received steroids continued after birth. Also, consideration should be given to adminis
[177]. An individual patient data meta-analysis suggested that neonatal tering antihypertensive therapy for any hypertension diagnosed before
risk may not be increased from 36+0 weeks, also consistent with sub six days postpartum (⊕⊕OO/Weak)
group analyses in PHOENIX [176,178]. Nevertheless, child neuro 35. The target dBP for postpartum antihypertensive treatment should
development to the age of 5 years appears to be similar after either be 85 mmHg, as antenatally (⊕⊕OO/Weak)
interventionist or expectant care [179]. 36. Non-steroidal anti-inflammatory drugs (NSAIDs) for postpartum
RCT data for 50 women with chronic hypertension suggests that analgesia may be used in women with pre-eclampsia if other analgesics
initiation of delivery at 37+0 weeks is associated with an excess of are ineffective, and there is no AKI or other risk factors for it (⊕⊕OO/
neonatal morbidity [180]. Weak)
At term (≥37+0 weeks), women with pre-eclampsia should be 37. Breastfeeding is recommended (⊕⊕⊕O/Strong)
offered birth based on the results of the HYPITAT trial [181]. The 2/3 of 38. Counselling should be provided about the risks of gestational
women in HYPITAT who had gestational hypertension at term experi hypertension (at least 4%) or pre-eclampsia (at least 15%) in future
enced no reduction in poor maternal outcome (OR 0.81, 95% CI 0.63, pregnancy (GPP)
1.03), raising questions about whether these women benefit from timed 39. At 3 months postpartum, all women should be reviewed to ensure
birth [182]. Women with preterm gestational hypertension [183] or that BP, urinalysis, and any laboratory abnormalities have normalised. If
those with chronic hypertension [184–185] may benefit from timed proteinuria or hypertension persist, then appropriate referral for further
birth at 38+0-39+6 weeks, based on observational data; there is one investigations should be initiated (GPP).
ongoing trial (ISRCTN77258279). 40. At 6 months postpartum, where possible, all women should be
Decision aids and risk communication strategies should be used to reviewed again, at which point we suggest that BP ≥ 120/80 mmHg lead
support patient education and truly informed consent. to discussion of lifestyle change (⊕⊕⊕O/Weak)
41. Following hypertensive pregnancy, particularly pre-eclampsia,
counselling should be provided about the heightened health risks for
the mother (particularly cardiovascular) and the offspring (⊕⊕⊕O/
162
Strong) these women have an increased risk of subsequent SGA babies, even if
42. We recommend calculating lifetime (not 10-year) cardiovascular their BP remains normal. Recurrence risks will be further modified by
risk scores to estimate cardiovascular risk in these women (⊕⊕⊕O/ the presence of any additional risk factors, such as earlier-onset or more
Strong) complicated pre-eclampsia (which at its most extreme, can be associated
43. Annual medical review following hypertensive pregnancy is with recurrence in up to 50% of women).
recommended for the first 5–10 years postpartum (⊕⊕⊕O/Weak)
44. Following hypertensive pregnancy, all women and their offspring
should adopt a healthy lifestyle that includes eating well, exercising, 7.3. Long-term health risks
aiming for ideal body weight, living smoke-free, and aiming for BP <
120/80 mmHg (⊕⊕⊕⊕/Strong) The long-term risks of pre-eclampsia, and gestational hypertension,
are now well-established [210]. These women have greater propensity
7.1. Short-term considerations to developing cardiovascular disease risk factors (like hypertension),
diabetes mellitus (a cardiovascular disease ‘equivalent’), cardiovascular
Women may develop pre-eclampsia or pre-eclampsia complications disease (including stroke or death) [211–212], in addition to venous
(including eclampsia) for the first time postpartum; therefore, BP mea thromboembolic disease (VTE), vascular dementia, and CKD.
surement and control should be offered to all women postpartum. BP How best to decrease these cardiovascular risks is a challenge,
peaks around days 3–7 after delivery, following redistribution of related to suboptimal engagement of women, high attrition, and a lack
extravascular fluid [193]. As the highest BP values may occur after of evidence that shows that intervention following hypertensive preg
women leave the monitored inpatient setting, and postpartum hyper nancy reduces long-term events. However, many risk factors for long-
tension may be the commonest indication for postnatal hospital read term cardiovascular and metabolic disease are modifiable and related
mission [194], it is important to have in place a BP monitoring and to healthy lifestyle (i.e., healthy eating and physical activity) and good
treatment plan. control of risk factors (i.e., smoking cessation, achieving a normal BMI
Antihypertensive therapy should target a similar BP goal as before and BP) [213].
delivery. First, there are no fetal concerns postpartum, by definition. Following hypertensive pregnancy, all women should be offered
Second, approximately half of strokes and half of eclampsia occur after lifestyle advice according to international guidelines (e.g. https://www.
birth [195]. Third, most antihypertensive agents (including the ACE heartfoundation.org.au and Diet and Physical Activity Guidelines for
inhibitors captopril, enalapril, and quinapril) are acceptable for use in Americans 2018, available from https://health.gov/dietaryguidelines/
breastfeeding; up-to-date information can be obtained in LactMed @NIH and https://health.gov/paguidelines/).
(www.ncb.nlm.nih.gov) [196]. A caveat is that many practitioners shy There is no evidence-based schedule of assessments for women
away from use of methyldopa, based on unsubstantiated concerns that it following hypertensive pregnancy, but the following has been proposed
may increase the risk of postnatal mental health problems [182]. Very and presented in a ‘My Health Beyond Pregnancy’ tool [214]:
limited data suggest similar efficacy in BP-lowering between agents
[197]. Fourth, good BP control in the months following a hypertensive • 6–12 weeks postpartum: for a simple cardiovascular screening with a
pregnancy may result in less aortic stiffness [198] and lower BP [199] general practitioner or obstetrician, to assess cardiovascular risk
(and therefore, cardiovascular risk) long-term; a recent randomised based on risk factors, physical activity and at minimum, BP. Of note,
controlled trial [199] found that self-management of postnatal hyper values that we use to define normal BP in the community are derived
tension to achieve good BP control in the first six weeks postpartum was from older and often male populations; ongoing studies will define a
associated with lower dBP at six months postpartum, when almost all new ‘normal’ range of BP for young women who have not had pre-
(>95%) of the women were taking no antihypertensive treatment. eclampsia. Lifestyle advice should be offered.
Finally, following pre-eclampsia, breastfeeding is associated with lower • 6 months postpartum: BP should be < 120/80 mmHg [215]; if higher
long-term maternal hypertension in observational studies [200–201]. than this, then women should be alerted to the fact that their BP is
NSAIDs may be used for postpartum analgesia if other analgesia is abnormal and encouraged to increase lifestyle measures to lower BP.
ineffective following hypertensive pregnancy as long as BP is controlled • 1 year post-partum: for a similar visit to the 6–12 week postpartum
and there is no AKI or risk factors for AKI, including CKD, sepsis, or visit, with additional testing of LDL, triglycerides and total choles
postpartum haemorrhage. When NSAIDs are prescribed, women with terol, fasting blood glucose, HbA1c, high sensitivity C-reactive pro
pre-eclampsia should have close monitoring of their BP, including home tein (CRP), and urinary albumin:creatinine ratio. Also, even with an
BP monitoring when possible. A case series of six women initially raised elevated lifetime risk of cardiovascular disease, young women may
concerns that postpartum use of NSAIDs following hypertensive preg have low 10-year cardiovascular risk scores using well-established
nancy may increase the risk of hypertensive urgency [202]. However, risk tools, and may be overlooked as being at high risk on that
subsequently-published literature has been reassuring. Retrospective basis [216]. Therefore, we do not recommend a sole reliance on such
cohort studies (involving 538 women, mostly with pre-eclampsia) have tools to predict cardiovascular risk in these women. Lifestyle advice
suggested that NSAIDs do not increase postpartum BP, antihypertensive should be offered. Referral to specialists and drug therapy for
dose or dose escalation, maternal complications, readmission rates, or hyperlipidaemia, abnormal glucose metabolism or high BP should
opioid use [203–205]. Two RCTs of ibuprofen vs. acetaminophen for follow local/national guidelines for primary prevention of cardio
postpartum analgesia have been reassuring, finding either no increase in vascular disease.
hypertension to six weeks postpartum [206] or an increase in BP ≥ 150/ • Annual medical review with a general practitioner for women at
100 mmHg but no increase in the incidence of severe hypertension highest risk (such as those with a family history of cardiovascular
[207]. disease or those with recurrent preterm pre-eclampsia), particularly
during the first 5–10 years after hypertensive pregnancy when car
7.2. Risks in a future pregnancy diovascular risk factors and disease appear most frequently [217].
If a hypertensive disorder of pregnancy recurs in subsequent preg The offspring of women with hypertensive pregnancy appear to be at
nancy, women with a history of gestational hypertension tend to have increased risk of cardiovascular disease and CKD. Consideration should
gestational hypertension (25%) rather than pre-eclampsia (4%), be given to monitoring them for hypertension. Parents should encourage
whereas women with prior pre-eclampsia may develop either gesta healthy lifestyle for their offspring to mitigate their increased cardio
tional hypertension (15%) or pre-eclampsia (15%) [208–209]. All of vascular disease risk [218–219].
163
8. Application of these guidelines to less health developed Table 11

countries Areas of agreement and disagreement in clinical practice guidelines for the
hypertensive disorders of pregnancy.
Less health developed countries have variably robust public and Areas of agreement Areas of disagreement
private health systems; private health care in the Western Cape, South Definitions of hypertension, proteinuria, The definition of ‘severe’ pre-eclampsia
Africa, differs greatly from maternity care in a refugee camp in northern chronic hypertension, gestational and use of the term.
Syria. In settings with overburdened and fragile health systems, where hypertension, and pre-eclampsia
most maternal-newborn care is provided by non-experts, the question Prevention of pre-eclampsia with low Target blood pressure when
dose aspirin & supplemental calcium hypertension is not severe
arises about how best to interpret and implement these
(if low calcium intake)
recommendations. Treatment of severe hypertension Timing of delivery for women with
In our opinion, all health systems should prioritise the provision of chronic hypertension, gestational
all elements of the Implementation Package (see below). Some practical hypertension, or preterm pre-eclampsia
points are expanded here. Use of magnesium sulphate for Use of magnesium sulphate for fetal
eclampsia & ‘severe’ pre-eclampsia neuroprotection when pre-eclampsia is
not ‘severe’
• Regular antenatal care, in addition to adequate obstetric support, is Use of antenatal corticosteroids to Post-partum maternal monitoring
important to reduce maternal and offspring mortality and morbidity. enhance fetal lung maturity at <34
• Access to the low-cost and validated Microlife CRADLE VSA BP de weeks’ gestation if delivery is likely
within the next 7 days
vice would provide accurate BP readings in pregnant and hyper
Delivery for pre-eclampsia at term
tensive pregnant women [220]. Oxytocin as an element of the active
• The Fetal Medicine Foundation model is more accurate than clinical management of the third stage of
risk factor assessment in identifying women at risk of preterm pre- labour
eclampsia, and aspirin (which is ubiquitous) reduces that risk.
• In countries with limited formularies, effective antihypertensives
may include beta-blockers that are not usually prescribed in more- Table 12
developed country settings (e.g., propranolol, metoprolol). Methyl Implementation priorities.
dopa is generally the cheapest antihypertensive medication that has Measure BP with a device validated for use in pregnancy and postpartum
been rigorously evaluated in both non-severe and severe pregnancy Assess the risk of pre-eclampsia at antenatal care booking and prescribe aspirin for
hypertension. Methyldopa, nifedipine (as a tocolytic), hydralazine women identified as being at increased risk.
and amlodipine are on the WHO List of Essential Medicines (2019) Treat hypertension (BP ≥ 140/90 mmHg) with antihypertensive therapy, antepartum
and postpartum
[221].
Define pre-eclampsia according to gestational hypertension with maternal, fetal, or
• The broad definition of pre-eclampsia should be used, especially placental complications, and not just by new proteinuria
where cost and access to toileting can limit the use of dipstick Assess the risk of adverse maternal outcomes in hypertensive women using the
screening for proteinuria. fullPIERS or miniPIERS models
• The miniPIERS model can identify risk of adverse outcomes using Deliver women with complicated pre-eclampsia regardless of gestational age (see
‘Management/Timing of birth’)
clinical symptoms and signs in hypertensive pregnant women, Time delivery from 37 weeks for women with uncomplicated pre-eclampsia
especially with the addition of accurate pulse oximetry. Use magnesium sulphate to treat eclampsia or pre-eclampsia with proteinuria and
• Magnesium sulphate is on the WHO List of Essential Medicines severe hypertension, or any hypertension with neurological signs or symptoms
(2019). However, supply chains can be unreliable and public health Measure BP postpartum, at least once on days 3–7 after hypertensive pregnancy
BP (blood pressure), PIERS (Pre-eclampsia Integrated Estimate of Risk Score)
system provision is not uniform.
• Measurement of BP in hypertensive women on postpartum days 3–6
may require task-sharing to community health workers, as achieved
in the Community-Level Interventions for Pre-eclampsia Trials Table 13
[222]. Research recommendations.
Evaluate whether routine proteinuria screening in normotensive women is associated
9. How our guidance compares with other international and with improved outcomes
Assess whether self-monitoring of BP reduces adverse pregnancy outcomes among
national guidance women with pregnancy hypertension, or those at high risk of pre-eclampsia
Incorporate women’s views into decisions about personalised risk stratification for
The ISSHP has the shortest cycle for guideline update in keeping with pre-eclampsia and associated prophylaxis with aspirin
our commitment to regular updates, in order to reduce confusion and Determine the cost-effectiveness of using a broad ISSHP definition of pre-eclampsia,
rather than a restrictive one based only on new hypertension and proteinuria
promote discussion about the most recent pregnancy hypertension
Investigate whether haemodynamic-guided antihypertensive therapy can achieve
research. maternal BP control and optimise perinatal outcomes
Compared with a previous systematic review of pregnancy hyper Establish whether angiogenic markers add prognostic value to the broad definition of
tension guidelines (2014) [223], there has been an increase in the pre-eclampsia or either the fullPIERS or miniPIERS modes for prediction of adverse
number of clinical practice guidelines (from 13 to 15) with all those short- and long-term maternal outcomes in pre-eclampsia
Establish mechanisms to engage women in cardiovascular risk reduction following
published within the last 10 years having been updated in part or in hypertensive pregnancy
whole [156]. Table 11 indicates that there remains broad agreement in a
number of areas, and where there is disagreement, consensus is building.
The key areas in which these guidelines differ are: incorporation of guide practice, rather than a clinical practice guideline per se.
angiogenic markers into the assessment of pre-eclampsia risk (i.e., 1st Table 12 presents an implementation package.
trimester screening) and assessment of suspected pre-eclampsia (after Table 13 presents research recommendations.
20–24 gestational weeks) as a marker of uteroplacental dysfunction, and
detailed advice about titration of antihypertensive therapy dose and 10. Future directions
polytherapy.
Guidelines focused on under-resourced settings include those of The ISSHP aims to update these recommendations every two years.
WHO 2011 and FIGO. IMPAC 2016 also provides pregnancy hyperten We invite feedback to info@isshp.org.
sion guidance, although it is a compilation of decision algorithms to
164
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Appendix A. Supplementary data
preeclampsia and its predictive role in maternal and neonatal outcomes,
Hypertens Pregnancy 38 (2019) 111–118.
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Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 27 (2022) 148–169

Contents lists available at ScienceDirect

Pregnancy Hypertension: An International

The 2021 International Society for the Study of Hypertension in Pregnancy

Recommendations Women at increased risk of pre-eclampsia*

34. Antihypertensive therapy administered antepartum should be 2. Methods

BP measurement hypertension (see ‘Classification/Chronic hypertension’), diabetes,

Table 3 Proteinuria is not mandatory for the diagnosis, but it is commonly

pregnancy, the effectiveness of this approach in reducing adverse Table 5

BP (blood pressure), dBP (diastolic blood pressure).

LA (long-acting), MR (modified release), PA (prolonged action), XL (extended release).

* When severe hypertension has resolved, switch to routine oral medication.

Table 10 6.7. Antenatal corticosteroids

Women who reach

8. Application of these guidelines to less health developed Table 11

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