Comment

Maternal deaths in the UK: pre-eclampsia deaths are avoidable

Being pregnant in the UK has never been safer. The
latest Condential Enquiries into Maternal Deaths
and Morbidity1 reported that fewer than one in
10 000 women died in or around pregnancy in the UK
during 201214 (241 women within the triennium),
the lowest rate recorded since such surveillance began
in 1952 in England and Wales. This maternal mortality
rate is lower than age-matched male death rates
(517 per 10 000 population for men aged 2044 years
in England and Wales, 2014) such that a man is more
likely to die while his partner is pregnant than she is.2
Several important messages emerge from the
latest Condential Enquiries into Maternal Deaths
and Morbidity: cardiac disease is the leading cause
of indirect maternal death, while thrombosis and
thromboembolism continues to feature as a major
issue and is the leading cause of direct deaths. Suicide
is, however, the leading cause of direct maternal
deaths within a year after the end of pregnancy.1
Two-thirds of maternal mortality is due to a medical
or mental health condition. Therefore, the need for
specialist care for women with pre-existing medical
25 Indirect causes of death
Direct causes of death
20
Rate per 100 000 maternities
and mental health problems is clearly still a vital
concern.
In addition to ongoing surveillance of triennial
maternal deaths, the report examined deaths related
to cardiovascular and hypertensive diseases, early
pregnancy problems, and critical care between
2009 and 2014. Indirect maternal deaths, related to
underlying conditions exacerbated by pregnancy, are
increasingly important and now represent 59% of total
maternal deaths; 153 women died from heart disease
between 2009 and 2014, representing about a third
of all maternal deaths.1 Specialist multidisciplinary care
for women with known heart disease, particularly with
prosthetic valves, together with prompt action when
women present with chest symptoms or breathlessness
remain key to avoiding further deaths. Health-
service provision must also focus on pre-pregnancy
counselling, and uptake of contraception and provision
of termination services to limit future mortality among
women with known heart disease. Other causes of
death both indirect and direct (resulting from obstetric
complications of pregnancy) have been stable, with the
exception of pre-eclampsia, which has substantially
reduced since the last report and is now the least
represented category (gure).
Only two women died from pre-eclampsia and
eclampsia during pregnancy in the UK during 201214.1

In the previous two reports, there were 19 and ten

15
maternal deaths from pre-eclampsia in 200608 and
200911, respectively.1 This reduction is remarkable
10 since hypertensive diseases have consistently been a
leading direct cause of death in pregnancy. Maternal
05 deaths from pre-eclampsia have been associated with
substandard care,3 suggesting they are avoidable. In the
0 latest Condential Enquiries into Maternal Deaths and
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The low rate of maternal deaths from pre-eclampsia

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Figure: Maternal mortality by cause from 2012 to 2014 in the UK in the UK is in stark contrast with the global setting
*Rate for direct sepsis (genital tract sepsis and other pregnancy related infections) is shown in pale and rate for where an estimated 40 000 women die each year from
indirect sepsis (inuenza, pneumonia, others) in dark bar. Rate for suicides is shown in pale and rate for indirect
psychiatric causes (drugs/alcohol) in dark bar. Source: MBRRACE-UK. Reproduced from Saving lives, improving this condition,4 which equates to about ve deaths
mothers caresurveillance of maternal deaths in the UK 201214 and lessons learned to inform maternity care
from the UK and Ireland Condential Enquiries into Maternal Deaths and Morbidity 200914.1 National Perinatal
every hour. The proportion of maternal deaths from
Epidemiology Unit, University of Oxford. hypertensive disorders of pregnancy is 28% in the

582 www.thelancet.com Vol 389 February 11, 2017


UK (201113),1 74% in the USA (201113),5 and
14% globally (2013).4
Deaths from hypertensive diseases of pregnancy are
largely due to treatable pathology, the elements of
which are important to dene if other countries are to
emulate the reduction in the UK. The largest triennial
fall in maternal deaths from these diseases in England
and Wales occurred between the 1950s (200 deaths)
and 1970s (fewer than 40 deaths); this reduction
was related to improved surveillance, diagnosis,
and timely delivery. From the 1980s onwards, the
condential enquiries showed that deaths in women
with hypertensive diseases of pregnancy were related
to pulmonary oedema and intracerebral events,
particularly haemorrhage. The subsequent introduction
of uid-restricting management protocols meant
pulmonary oedema was no longer a cause of maternal
death in the UK in 2002.6 Intracerebral haemorrhage
remained a fairly common cause of death, and
substandard care was often associated with inadequate
treatment of severe hypertension, a likely causative
factor.6
Have further improvements in management
caused this latest reduction in deaths? Pre-eclampsia
can be partly prevented by prophylactic use of
low-dose aspirin.7 Since 2010, aspirin has been
routinely recommended for higher risk women
by the UK National Institute for Health and Care
Excellence,8 which also underlines the judicious use
of antihypertensive medication with lower target
thresholds (now to less than 150/100 mm Hg). The
use of anticonvulsant therapies has increasingly
been introduced into practice for women with pre-
eclampsia in the past few decades, after trials showed
the ecacy of magnesium sulfate for the prevention
of eclamptic ts.9 More recently, planned delivery
from 37 weeks gestation has been shown to reduce
morbidity,10 and has become a standard of care in the
UK.8 The introduction of the UK National Health Service
evidence-based guidelines that have focused on the
systematic use of interventions may be the catalyst
that has reduced deaths from hypertensive diseases of
pregnancy.
The maternal deaths that remain still seem
to be largely avoidable, and are often related to
poor detection. However, we must guard against
complacency. Pre-eclampsia is only safe for the mother
www.thelancet.com Vol 389 February 11, 2017
Comment
if identied and well managed. However, as delivery
remains the mainstay of treatment, preterm birth
and its ensuing perinatal morbidity will continue
to be a challenge. The contribution of hypertensive
diseases of pregnancy to the 26 million stillbirths that
occur annually across the globe was highlighted in
the Lancets Ending Preventable Stillbirths Series.11 If
services are to impact on perinatal outcomes, therapies
that ameliorate established disease at early gestations
and safely maintain pregnancy will become increasingly
important. Novel therapies such as statins and other
drugs targeting various pathophysiological pathways
have been proposed and are under evaluation in clinical
trials.12
In the latest Condential Enquiries into Maternal
Deaths and Morbidity about a quarter of pregnant
women who died in 201214 were born outside
the UK, but maternal death rates were similar in
these women and those born in the UK (885 vs
787 per 100 000 maternities; relative risk 112;
95% CI 080156),1 even when their origins were from
a low-income setting, which suggests that universal
pregnancy care provision, rather than background
demographics, inuence the reduction of maternal
mortality rates. Antenatal care and many therapeutic
and management interventions for pregnancy
hypertensive disorders can be provided at relative
inexpensive cost and are potentially available in low-
income settings. The challenge is implementation.
*Andrew H Shennan, Marcus Green, Lucy C Chappell
Womens Health Academic Centre, Kings College London,
London SE1 7EH, UK (AHS, LCC); and Action on Pre-eclampsia,
Evesham, UK (MG)
andrew.shennan@kcl.ac.uk
MG is Chief Executive Ocer of Action on Pre-eclampsia and contributed to the
lay summary of the lastest Condential Enquiries into Maternal Deaths and
Morbidity. AHS and LCC declare no competing interests.
1 Knight M, Nair M, Tunell D, et al, eds, on behalf of MBRRACE-UK. Saving
lives, improving mothers caresurveillance of maternal deaths in the UK
201214 and lessons learned to inform maternity care from the UK and
Ireland Condential Enquiries into Maternal Deaths and Morbidity
200914. Oxford: National Perinatal Epidemiology Unit, University of
Oxford, 2016
2 Oce for National Statistics. Death registrations summary tablesEngland
and Wales. 2014. https://www.ons.gov.uk/
peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/
datasets/deathregistrationssummarytablesenglandandwales
referencetables (accessed Jan 5, 2017).
3 Shennan AH, Redman C, Cooper C, Milne F. Are most maternal deaths from
pre-eclampsia avoidable? Lancet 2012; 379: 168687.
4 WHO. World health statistics 2015. Geneva, Switzerland: World Health
Organization, 2015.
583
 Comment
5 Division of Reproductive Health National Center for Chronic Disease
Prevention and Health Promotion. Pregnancy mortality surveillance
system. 2016. https://www.cdc.gov/reproductivehealth/
maternalinfanthealth/pmss.html (accessed Jan 5, 2017).
6 Condential Enquiry into Maternal and Child Health. Why mothers die
20002002: the sixth report of the Condential Enquiries into Maternal
Death in the United Kingdom. London: Royal College of Obstetricians and
Gynaecologists Press, 2004.
7 Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for
preventing pre-eclampsia and its complications. Cochrane Database Syst Rev
2007; 2: CD004659.
8 National Institute for Health and Care Excellence. Hypertension in
pregnancy: the management of hypertensive disorders during
pregnancy. London: National Institute for Health and Care
Excellence, 2010.
Research misconduct and the INTERGROWTH-21st study
On Oct 20, 2016, a statement appeared on the WHO
website, announcing that An independent review
commissioned by WHO has found that research
ethics misconduct occurred in a study on foetal
growth standards.1 The study in question was the
INTERGROWTH-21st study, led by researchers at
the University of Oxford, UK, funded by the Bill &
Melinda Gates Foundation (BMGF), and reported
in several journals, including our own.25 Such a
judgment by the worlds foremost global health agency
was serious, casting damaging light on a study of
international importance.
On Nov 16, 2016, we wrote to Ian Smith, Executive
Director of the Oce of the WHO Director-General,
to request a copy of the review report, but were told
that it was condential and had been supplied only to
the University of Oxford, BMGF, and the UK General
Medical Council, which was considering whether to
open an investigation of its own.
We then wrote, on Nov 23, 2016, to the researchers,
Stephen Kennedy and Jos Villar at the University
of Oxford, to request their response to the reviews
ndings. We subsequently received a letter from the
Universitys Registrar, Ewan McKendrick, reiterating
the history of the dispute, which (as we were aware)
dates back to 2008 and has been the subject of
previous investigations by the University of Oxford,
the Committee on Publication Ethics (COPE), and
other journals. In brief, the dispute surrounds
allegations of plagiarism and disputes over intellectual
ownership concerning two research protocols with
joint origins: those of the International Fetal and
Newborn Growth Consortium for the 21st Century
584
9 Altman D, Carroli G, Duley L, et al. Do women with pre-eclampsia, and their
babies, benet from magnesium sulphate? The Magpie Trial: a randomised
placebo-controlled trial. Lancet 2002; 359: 187790.
10 Koopmans CM, Bijlenga D, Groen H, et al. Induction of labour versus
expectant monitoring for gestational hypertension or mild pre-eclampsia
after 36 weeks gestation (HYPITAT): a multicentre, open-label randomised
controlled trial. Lancet 2009; 374: 97988.
11 Lawn JE, Blencowe H, Waiswa P, et al. Stillbirths: rates, risk factors, and
acceleration towards 2030. Lancet 2016; 387: 587603.
12 Cottrell EC, Sibley CP. From pre-clinical studies to clinical trials: generation
of novel therapies for pregnancy complications. Int J Mol Sci 2015;
16: 1290724.
(INTERGROWTH-21st) and the WHO Multicentre
Study for the Development of Growth Standards from
Fetal Life to Childhood. Both protocols were drawn up
in response to a 1995 WHO Expert Committee report6
that recommended, among other things, Assessment
and development of fetal growth reference data
suitable for international applications. Both protocols
also built on the methods of the WHO Multicentre
Growth Reference Study,7 which produced growth
curves for children from birth to 5 years. Much of
the bases of the protocols are therefore in the public
domain. Kennedy and Villar are accused of having
plagiarised the WHO Multicentre Study protocol in
developing the INTERGROWTH-21st protocol and of
obtaining rival funding while still involved with the
WHO work.
McKendricks responses to us, on Nov 29, 2016, and
Dec 13, 2016, were robust. It is clear from this response
that the University of Oxford looked into these serious
allegations at a high level, methodically dissected
the claims, closely examined four pairs of protocols
at dierent stages of development, engaged with
the WHO Director-General, and retrieved supporting
documentation before concluding that the allegations
were unfounded. The Oxford researchers clearly stated
the methodological foundations of INTERGROWTH-
21st in their reports.
We were aware, however, that we had only heard
the Universitys version of events, and again pressed
WHO for their inquiry report. This document was
eventually shared with us in condence on Jan 16, 2017,
but we found it disappointingly insubstantial. We
have therefore concluded that its far-reaching judgment
www.thelancet.com Vol 389 February 11, 2017