Alyshah Abdul Sultan, Joe West, Laila J Tata, Kate M Fleming, Catherine Nelson-Piercy, Matthew J Grainge

Risk of first venous thromboemboIism in pregnant
women in hospitaI: popuIation based cohort study from

EngIand
OPEN ACCESS
Alyshah Abdul Sultan doctorate student
1
, Joe West associate professor
1
, Laila J Tata associate
professor
1
, Kate M Fleming lecturer
1
, Catherine Nelson-Piercy professor
2
, Matthew J Grainge
associate professor
1
1
Division of Epidemiology and Public Health, University of Nottingham, Clinical Sciences Building Phase 2, City Hospital, Nottingham NG5 1PB,
UK;
2
Womens Health Academic Centre, Guys and St Thomas Foundation Trust, St Thomas Hospital, London SE1 7EH, UK
Abstract
Objective To examine the potential for preventing venous
thromboembolism during and after antepartum hospital admissions in
pregnant women.
Design Cohort study using linked primary (Clinical Practice Research
Datalink) and secondary (Hospital Episode Statistics) care records.
Setting Primary and secondary care centres, England.
Participants 206 785 women aged 15-44 who had one or more
pregnancies from1997 up to 2010.
Main outcome measure Risk of first venous thromboembolism in
pregnant women admitted to hospital for one or more days for reasons
other than delivery or venous thromboembolism. Risk was assessed by
calculating the absolute rate of venous thromboembolismand comparing
these rates with those observed during follow-up time not associated
with hospital admission using a Poisson regression model to estimate
incidence rate ratios.
ResuIts Admission to hospital in pregnancy was associated with an
increased risk of venous thromboembolism(absolute rate 1752/100 000
person years; incidence rate ratio 17.5, 95% confidence interval 7.69 to
40.0) compared with time outside hospital. The rate of venous
thromboembolism was also high during the 28 days after discharge
(absolute rate 676; 6.27, 3.74 to 10.5). The rate during and after
admission combined was highest in the third trimester (961; 5.57, 3.32
to 9.34) and in those aged 35 years (1756; 21.7, 9.62 to 49.0). While
the absolute rate in the combined period was highest for those with three
or more days in hospital (1511; 12.2, 6.65 to 22.7), there was also a
fourfold increase (558; 4.05, 2.23 to 7.38) in the risk of venous
thromboembolismfor those admitted to hospital for less than three days.
ConcIusion The overall risk of first venous thromboembolismin pregnant
women increased during admissions to hospital not related to delivery,
and remained significantly higher in the 28 days after discharge. During
these periods need for thromboprophylaxis should receive careful
consideration.
Introduction
Venous thromboembolism is one of the leading causes of
maternal mortality in developed regions
1 2
and is also responsible
for many more non-fatal complications such as post-thrombotic
syndrome.
3
Around 50%of maternal venous thromboembolism
events occur during pregnancy, and there is a shortage of high
quality evidence regarding which women are at greatest risk.
Previous research has shown that obesity, cigarette smoking,
multiple gestations, and increased parity are associated with an
increased risk of antepartum venous thromboembolism.
4-7
Of
all potential risk factors, however, admission to hospital must
be considered as potentially the most important given that in
the general population the risk of venous thromboembolism
during admission is more than 100 times
8
the risk outside
hospital. Each year in the United Kingdom an estimated 25 000
deaths from venous thromboembolism are associated with
admissions to hospital.
9
It is not clear if the same magnitude of
risk exists for pregnant women. Also, the risk of venous
thromboembolism after discharge needs to be determined to
assess the need for thromboprophylaxis after admission.
Current guidelines fromthe Royal College of Obstetricians and
Gynaecologists
10
recommend that antenatal pharmacological
thromboprophylaxis should be considered in pregnant women
during admissions to hospital for stays of three or more days if
they also have two or more risk factors. Estimates of the absolute
risks of venous thromboembolism during and after antepartum
admissions, including those in women with no other medical
comorbidities or risk factors, however, are not available. Using
linked data sources from primary and secondary care we
determined the risk of first venous thromboembolismin pregnant
Correspondence to: A Abdul Sultan [email protected]
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BMJ 2013;347:f6099 doi: 10.1136/bmj.f6099 (Published 7 November 2013) Page 1 of 11
Research
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women admitted to hospital, while accounting for other maternal
risk factors and risk factors associated with pregnancy and
medical comorbidities.
Method
Study popuIation
We used the Clinical Practice Research Datalink (CPRD),
11
which is a large longitudinal UK database that contains
computerised primary care records of anonymised patients from
1987 onwards. About 98% of the UK population is registered
with general practitioners, who are responsible for nearly all of
a patients medical care. The database includes practices who
have been trained to record information with Vision software
and who have consented to be included in the database. All
patients within a consented practice are automatically included.
Around 50% of the CPRD practices are linked to data from
hospital episode statistics (HES),
12
which contains information
on all admissions to hospital in England, including all discharge
diagnoses and procedures. The anonymised patient identifiers
from CPRD and HES were linked by a trusted third party by
using the National Health Service (NHS) number, date of birth,
postcode, and sex.
13
Most patients were matched exactly
according to NHS number (over 90% of patients are linked in
this way), with the remaining patients linked probabilistically
on the basis of postcode, date of birth, and sex. As HES covers
only English hospitals, we excluded practices from Northern
Ireland, Wales, and Scotland. Previously data from the linked
portion of the CPRD have been shown to be similar in terms of
age, sex, and geographical distribution to data from the UK
population published by the Office for National Statistics
(ONS)
14
and the findings are generalisable. Both diagnoses of
venous thromboembolism
15
and birth
16
information in HES
maternity data are validated to external sources with reasonable
accuracy. We excluded pregnancies of women with previous
venous thromboembolism, regardless of whether those events
were diagnosed during pregnancy or not. Therefore, when
women developed a venous thromboembolismin one pregnancy,
we ignored person time resulting fromsubsequent pregnancies.
The study time period was defined from1997 up to 2010, during
which we identified women aged 15-44 registered within
CPRD-HES linked practices with no previous venous
thromboembolism who had at least one delivery resulting in
live or still birth.
Defining pregnancy and associated time
period
Person time for each woman with at least one pregnancy was
divided into antepartum(fromconception up to two days before
childbirth) and outside pregnancy (excluding one day before
childbirth up to 12 weeks afterwards, which was time associated
with the peripartum and postpartum; fig 1).
Admission to hospitaI
For each woman, we obtained information on admissions (other
than for delivery and not related to venous thromboembolism)
lasting for one or more days. For all admissions that involved
a venous thromboembolism event, two investigators (AAS and
JW) independently reviewed 30 days of electronic primary and
secondary data before and after the event to determine whether
the event was the cause or consequence of the admission.
Overall, there was good concordance between the investigators
(=0.8), with disagreement being resolved by consensus. We
considered admission to hospital as a time varying covariate
that was categorised into three states: admission (defined as
the time between the date of admission and date of discharge);
post-discharge (up to 28 days after discharge date), further
divided into weeks; and time outside admission (time not
associated with admission) (fig 1). Our choice of 28 days for
the period after discharge for most analyses was arbitrary but
was mainly based on recommendations of thromboprophylaxis
among patients undergoing knee surgery.
17
As such we also
ascertained the risk in the period from28 days to 10 weeks after
discharge to assess to what extent the risk in the longer term
based on the median duration of follow-up from hospital
discharge up till the date of delivery.
Information on other risk factors
We extracted information on womens demographic factors
such as body mass index (BMI) (most recent recording before
conception), smoking status (latest recording before the date of
delivery), and age (time varying) from their medical records
using primary care CPRD data. For each woman, we also
extracted information on characteristics associated with the
pregnancy (such as multiple gestations) and complications
associated with pregnancy (such as hyperemesis, antepartum
haemorrhage) using data fromboth primary and secondary care.
We defined women as having gestational diabetes or gestational
hypertension if the first medical code for the specified condition
(or three or more readings of high blood pressure with systolic
>140 mm Hg and/or diastolic >90 mm Hg recorded during
pregnancy for gestational hypertension) took place during
pregnancy, with no previous medical codes or prescription for
antidiabetic or antihypertensive drugs. Those with previous
medical codes or drug prescription for diabetes or hypertension
were classified as having pre-existing diabetes or hypertension.
We investigated common infections (urinary tract infection and
acute respiratory tract infections (including pneumonia, acute
bronchitis, chest infection, and influenza) recorded during
pregnancy (gestational). We also extracted information on other
comorbidities that are considered as risk factors in the current
RCOG guidelines; specifically cardiac disease, inflammatory
bowel disease, nephrotic syndrome, and varicose veins if
recorded at any time before the date of delivery.
Venous thromboemboIism
We defined venous thromboembolism as the recording of a
medical code relating to the diagnosis of pulmonary embolism
or deep vein thrombosis in HES or CPRD where there was
evidence of anticoagulation within 90 days of diagnosis or if
death occurred within 30 days of diagnosis. Based on this
definition 84% of cases have been previously validated in the
CPRD database when only medical codes in primary care were
used to define events.
15
StatisticaI anaIysis
Absolute rates of venous thromboembolismper 100 000 person
years and 95% confidence interval were calculated by dividing
the total number of events by the person years of follow-up. To
determine which factors were associated with an increased risk
of venous thromboembolism, we calculated incidence rate ratios
for each category of the risk factor for antepartum compared
with baseline using a Poisson regression model. Similar methods
were used to compare rates of venous thromboembolismduring
admission and the 28 days after discharge with time outside
hospital for antepartum (for comparative purposes this analysis
was repeated for time outside pregnancy). Initially, we
estimated the incidence rate ratio comparing the rate of venous
thromboembolismduring admission and after discharge to time
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outside hospital adjusted for age and calendar year. The
calculated incidence rate ratios were also adjusted for additional
risk factors found to be associated with increased risk of venous
thromboembolism. Women with missing information on BMI
were initially placed in a separate category for purposes of
presenting rates of venous thromboembolismaccording to BMI.
For the adjusted analyses of venous thromboembolism rate by
admission, we replaced missing values for BMI using
multivariate normal imputation. This involved regressing
existing BMI values on age and performing analyses on 10
imputed datasets before results were combined. Imputations
were carried out using actual BMI values, after which this
variable was categorised (with existing BMI categories) before
analysis. Asensitivity analysis was also conducted in which we
categorised missing BMI as a separate category and included
it in our regression analysis. We also fitted a clustering term to
take account of multiple pregnancies experienced by a woman.
The current RCOG guideline suggests pharmacological
thromboprophylaxis for pregnant women admitted to hospital
for three or more days with the presence of two or more risk
factors including obesity (BMI >30) and any significant
comorbidity. Therefore we also calculated the absolute and
relative rate for admission and after discharge restricting only
to pregnancies in women without those factors.
Subsequent subgroup analyses for antepartum combined the
admission and post-discharge periods because of the relatively
small number of venous thromboembolismevents that occurred
in either of these periods. These analyses included stratification
of results according to maternal age, BMI, trimester of
pregnancy, duration of hospital stay, and calendar year (before
and after 2004 based on the publication of first national guideline
for thromboprophylaxis during pregnancy). We also formally
tested for interaction between maternal age and admission by
fitting an interaction term between them and conducting a
likelihood ratio test at the 5% level of significance. Similarly,
we tested for an interaction between admission and BMI
category using the same methods. All statistical analysis was
conducted with Stata version 11.2.
ResuIts
Basic characteristics
A total of 206 785 women had 245 661 pregnancies resulting
in live or still birth during the study period. The median
follow-up for women in the study was 6.1 years (interquartile
range 2.0-10.2). Table 1 shows the basic characteristics of
women with those pregnancies .
Admission to hospitaI
Around 18% of womens pregnancies (42 256 pregnancies)
included at least one admission with 4.7% (11 472 ) of women
admitted more than once during an individual pregnancy. This
amounted to a total of 59 537 non-delivery periods of admission
that occurred during the antepartum period, of which 57% (33
560,), 22% (12 883), and 22% (13 094) concluded within one
day, two days, and three or more days, respectively. The overall
rate of antepartum admission was calculated to be 242/1000
pregnancies. This was much higher in the third trimester
(176/1000 pregnancies) than in the first and second trimester
(29/1000 and 37/1000 pregnancies, respectively). In total 16
137 (27%) antepartumperiods of admission occurred in women
with pre-existing medical risk factors (including cardiac disease,
varicose veins, pre-existing diabetes, hypertension, inflammatory
bowel disease, and nephrotic syndrome during pregnancy or
women with a BMI 30).
Venous thromboemboIism events
Initially, we identified 100 women who developed venous
thromboembolism during or within four weeks after admission
(of whom 35 women were pregnant at the time of diagnosis).
After the independent reviews, we classed 72 venous
thromboembolism events as being a consequence of the
admission, of which 46 and 26 occurred during the time outside
pregnancy and antepartumperiod, respectively. There were 176
venous thromboembolism events diagnosed during the
antepartum period, of which 15% (n=26) occurred when the
woman was an inpatient (occurring during or up to four weeks
after admission and when venous thromboembolism was not
the reason of admission).
Rate of venous thromboemboIismby maternaI
risk factors
Overall the rate of venous thromboembolism during the
antepartumperiod and time outside pregnancy was calculated
to be 112/100 000 and 32/100 000 person years, respectively.
We found high rates of antepartum venous thromboembolism
(more than two fold compared with their respective baseline)
in women who had gestational diabetes, gestational acute
systemic infection, hyperemesis, varicose veins, or cardiac
disease (table 2).
Rate of venous thromboemboIism by
admission and after admission
The risk of antepartum venous thromboembolism increased
during admission and after discharge, with absolute rates of
1752/100 000 and 676/100 000 person years, respectively (table
3). After adjustment for potential confounding factors
(including maternal age and calendar year), there was a 17.5-fold
(95% confidence interval 7.69 to 40.0) and a sixfold (3.74 to
10.5) increase in risk of venous thromboembolism during
admission and after discharge, respectively, compared with
outside hospital in the antepartum period. When we considered
only admissions in women with no associated pre-existing
medical comorbidity or BMI >30kg/m
2
, the magnitude of the
increase in relative risk associated with admission remained
similar. When we assessed risk associated with admission for
time outside pregnancy, we found that admission and
post-discharge corresponded to a 66-fold and a 33-fold increased
risk (after adjustment for age and calendar year), respectively,
compared with time outside admission (table 3). For the
antepartum period overall, we found the rate of venous
thromboembolism altered with duration of hospital stay (table
3). Those with a stay of less than three days had four times the
risk whereas those with stays of three or more days had over 12
times the risk of venous thromboembolism during
admission/after discharge compared with time outside hospital
in the antepartum period.
Variation of the risk by age, trimester, BMI,
and caIendar year
We also found the collective rate of venous thromboembolism
during admission and after discharge to be higher in the third
trimester of pregnancy (absolute rate 961/100 000 person years;
table 4). The rate increased with age, with the highest risk
among women aged 35 (1756/100 000 person years).
Furthermore, we observed a significant interaction between age
and admission (P=0.01). Our results highlighted that the
increased risk associated with admission and after discharge
remains broadly unaltered by womens BMI, as supported by
a non-significant test result for interaction between BMI
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category and admission (P=0.36). We also observed higher
absolute and relative rates of venous thromboembolism after
2004 during admission and after discharge. All our calculated
incidence rate ratios remained broadly similar when we
additionally adjusted for other risk factors significantly
associated with increased risk of venous thromboembolism
(model 2).
Rate of venous thromboemboIism in weeks
after hospitaI admission
The rate of venous thromboembolism after admission was
highest during the first two weeks after discharge (763/100 000
person years; incidence rate ratio 7.98, 95%confidence interval
4.50 to 14.1) (fig 2). The risk decreased after four weeks, with
an absolute rate of 387/100 000 person years (4.19, 4.57 to 11.6)
between five and 10 weeks after discharge.
Discussion
Main findings
Using nationally linked primary and secondary care data, we
have provided population level absolute and relative rates of
antepartum venous thromboembolism by admission to hospital
(including after discharge) while taking into account other risk
factors for venous thromboembolism. We found that 18% of
pregnant women were admitted to hospital at least once during
pregnancy (before the delivery admission). Most admissions
were of short duration and occurred during the third trimester.
While 85% of antepartum venous thromboembolism events
occurred in outpatients, the risk was 17-fold higher during
admission to hospital compared with time outside hospital.
We also found a higher rate of venous thromboembolismduring
the first 28 days after discharge, corresponding to a six fold risk
compared with baseline. While the rate of venous
thromboembolism during admission and after discharge was
particularly high for women with stays of three or more days,
there was also a fourfold increase in the risk of venous
thromboembolism for those admitted to hospital for less than
three days. The rate for admission/after discharge was also high
in all three trimesters and in women aged 35 years. The
association between admission and venous thromboembolism
remained when we restricted our analysis to women without
medical comorbidities including obesity, cardiac disease, and
varicose veins.
Strengths and Iimitations
Our study used an open cohort approach, with prospectively
collected data and information from linked primary and
secondary care data sources from all over England, covering
3% of the total UK population with a similar age and sex
distribution to the population as a whole.
14
Our finding should
be generalisable to the UK and other developed nations with
similar healthcare systems. The use of linked data enabled us
not only to obtain comprehensive information on risk factors
documented in either level of care (primary and secondary) but
gave us the opportunity to followpregnant women in and outside
hospital with accurate dates of admission and discharge. This
permitted us to calculate the absolute and relative rates of
antepartumvenous thromboembolismwith respect to admission
while taking into account other potential risk factors, which has
not been assessed previously in the literature. The completeness
of HES data and recording of diagnoses in different centres is
always a concern. The Department of Health, however, has
undertaken studies to assess the completeness of HES coverage,
which is reported to be high.
18
Moreover, a systematic review
of discharge coding in HES found that the median coding
accuracy rate for diagnostic codes is 91%.
19
As we used data
from both primary and secondary care, our prevalence of risk
factors such as diabetes in pregnancy, gestational hypertension,
and antepartum haemorrhage is similar to the expected
prevalence in the UK.
20-23
A limitation of this study is the relatively small number of
venous thromboembolism events either during or immediately
after admission. This not only gave us estimates with wide
confidence intervals but restricted our ability to stratify our
analysis by reason for admission. We also acknowledge that the
increased risk of venous thromboembolism during admission
could be caused by other well understood risk factors (such as
unmeasured comorbidities), leading to an overestimate in the
independent effect of admission. Our calculated estimates for
admission and after discharge, however, remained unchanged
when we excluded pregnant women with other known risk
factors. We also found that the increased rate of venous
thromboembolismdecreased in the weeks after discharge, which
should not have been the case if the effect was solely because
of other risk factors. Despite the fact that the risk of venous
thromboembolism was high in the later period after discharge
(five to 10 weeks), the decrease in the risk from around 1800
(during admission) to 387 per 100 000 person years shows some
longer term effect of admission on the incidence of venous
thromboembolism. While the cause of the association between
admission and venous thromboembolismis not clear, immobility
is often considered the main culprit.
4
Regardless of the reasons
for admission, pregnant women admitted to hospital for reasons
other than delivery represent a group at high risk as evident by
a fourfold increased risk in those with stays in hospital of less
than three days.
Our conclusions, in part, depend on two investigators agreeing
on whether the venous thromboembolism was a cause or
consequence of the hospital admission. To determine this, two
of the investigators carefully and independently reviewed 30
days of electronic primary and secondary data before and after
all venous thromboembolisms during the antepartum period.
Overall, agreement between investigators was high. When we
repeated analyses firstly accepting only cases when investigator
1 judged antepartum venous thromboembolism to be the
consequence of the admission (n=24 events) and secondly
accepting only cases judged by investigator 2 to be a
consequence (n=27 events), the impact on our effect estimates
was modest and our conclusions were unaltered on both
occasions. Subsequently we also involved a third investigator,
who independently agreed with the consensus assessment of
the other investigators for all cases.
We acknowledge that the diagnosis of venous thromboembolism
in pregnancy can be difficult and that leg swelling and calf pain
are common in the third trimester in women without deep vein
thrombosis. This could lead to a misclassification. Additionally,
D-dimer levels also increase with gestation,
2
with gestational
hypertension, and in preterm labour, leading to false positive
results if normal ranges for non-pregnant women are use, which
could add to this misclassification. In pregnancy, however,
venous thromboembolism is diagnosed only when there is
confirmatory imaging, and for our analysis we accepted only a
diagnosis made by a clinician if it was complemented by use
of anticoagulant therapy. One current drawback of UKsecondary
care data is the lack of information on heparin and warfarin
prescribed in hospital, which might have led to
underascertainment of cases using our definition of venous
thromboembolism. We believe, however, that the impact of this
limitation should be minimal as pregnant women with a
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diagnosis of venous thromboembolismare expected to be given
anticoagulation therapy throughout the remainder of their
pregnancy.
24
Therefore these prescriptions are likely to be
captured in the primary care data. Furthermore, the algorithm
used to define venous thromboembolism in our study has been
previously validated in primary care data with a positive
predicted value of 85%,
15
and our estimates of the incidence of
venous thromboembolism during the antepartum period are in
concordance with most recent studies published on this topic.
25
There could have been under ascertainment of deep vein
thrombosis during the time outside hospital compared with
during admission, when women would be closely monitored
for venous thromboembolism thus inflating our rate ratios for
that period. We believe venous thromboembolism events
occurring outside hospital, however, will be captured in primary
care data with a similar degree of ascertainment as pregnancy
is a known and established risk factor. It also is worth stating
that we were not able to consider certain risk factors such as
thrombophilia and anti-phospholipid syndrome, which are often
associated with increased risk. We believe that pragmatically
those risk factors cannot be used to predict venous
thromboembolism as routine screening for
thrombophilia/anti-phospholipid syndrome is not recommended
for pregnant women. Additionally the impact of those variables
on our estimates might be small as we considered only the first
venous thromboembolismwhereas most cases of thrombophilia
may be diagnosed after a venous thromboembolism event has
occurred.
Our increased absolute risk observed during admission and after
discharge to a certain extent advocates the use of
thromboprophylaxis measures during that period. Though it
could be argued that more liberal use of heparin might be
associated with a higher risk of osteoporosis, it should be noted
that low molecular weight heparin is now commonly used for
thromboprophylaxis during pregnancy and is considered to be
safe and effective. For instance, a systematic review
26
of 2777
pregnancies reported no increased risk of heparin induced
thrombocytopenia or osteoporosis associated with use of low
molecular weight heparin.
Our estimates for risk of venous thromboembolism during
admission and after discharge do not take into account that some
pregnant women might already be receiving thromboprophylaxis
during those periods. We believe, however, that since the first
RCOG guidelines for antenatal thromboprophylaxis were
published only in 2004 (updated 2009), the use of antenatal
thromboprophylaxis with low molecular weight heparin was
unusual before 2004 except for those women with previous
venous thromboembolism. We found that both absolute and
relative rates of venous thromboembolismhave increased since
2004, which should not be the case if those women were given
adequate pharmacological thromboprophylaxis. This does not
take into account the increasing ascertainment of less severe
venous thromboembolisms. Additionally, 67% of all pregnant
women diagnosed with antepartum pulmonary embolism
(between 2005 and 2006) in the UK did not receive
pharmacological thromboprophylaxis according to national
guidelines even though they qualified for thromboprophylaxis.
5
Despite these limitations, we believe a bespoke cohort study of
a similar size and scale to our study (using routine data) in which
women are followed up prospectively throughout pregnancy
would not be practically possible.
Finally in this study we have provided absolute risk expressed
as per 100 000 person years, which helps standardisation and
comparison. Another way of expressing those estimates might
be as risk per admission. For instance, 26 venous
thromboembolism events out of 59 537 hospital admissions
gives an overall rate of one per 2000 hospital admissions and
one per 1000 for those admitted for longer duration (three days
and more). Though this might be of potential clinical use, it
should be noted that these calculations are crude and do not take
into account the element of time associated with each hospital
episode.
Comparison with previous studies
To our knowledge this is the first study to assess the impact of
antepartum admission to hospital on the incidence of venous
thromboembolism during pregnancy. Therefore we cannot
directly compare our findings with those from other research.
Aprevious study carried out in Rochester, Minnesota, however,
showed an age adjusted 135-fold
8
increased risk of venous
thromboembolism among patients in hospital compared with
people outside hospital in the general population (including
men); in the present study to observed increase outside
pregnancy was 67-fold. While our confidence interval for this
estimate (36.3 to 120) does not include the value observed in
the Rochester study, this might not be surprising given that the
Rochester study was carried out in a much older population
(mean age 65), who would therefore be more likely to have
longer inpatient spells complicated by comorbidity .
CIinicaI impIications
We believe that this study has important implications in the way
pharmacological thromboprophylaxis is delivered to pregnant
women and hope that it will help targeting prophylaxis in three
ways. Firstly, we found a six fold increased risk of venous
thromboembolism in the 28 days after hospital discharge. This
suggests prudent consideration of all pregnant women during
that period in terms of assessment of risk of venous
thromboembolism. Secondly, at present RCOGguidelines advise
that prophylaxis should be considered for women at the time of
hospital admission provided that she has two or more risk factors
including obesity (BMI >30) and significant medical
comorbidity and is expected to be immobile for three or more
days. Our study showed that the risk of venous
thromboembolism during admission and after discharge
remained around 22-fold and eightfold, respectively, even in
women without such risk factors. Therefore pregnant women
might be at high risk of venous thromboembolism during
admission and for 28 days after discharge, particularly those
with longer stay in hospital. Our post hoc analysis found a higher
risk of venous thromboembolismamong pregnant women aged
35 years admitted to hospital. This should be investigated
further in future research. Finally, the risk of venous
thromboembolism remained increased fourfold (during
admission and 28 days after discharge) even in women who
stay in hospital for less than three days (rate equivalent to 0.4%
per year), which might also require careful consideration. It is
important to take into account the effectiveness of lowmolecular
weight heparin in term of costs involved in prophylaxis both
financial and also the tolerability surrounding a daily heparin
prescription as well as the well recognised side effects of allergy
and bleeding. For instance, the benefits would need to be
weighed against a risk of major haemorrhage, which is believed
to occur in 1% of pregnant women. Such a risk:benefit analysis
clearly goes beyond the scope of the present work; however,
we believe our presentation of population based risks of venous
thromboembolismin pregnant women admitted to hospital goes
some way to help clinicians involved in making decisions in
this area. In conclusion, we found that admission substantially
increases the risk of venous thromboembolism in pregnant
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women as has been found in other non-pregnant populations.
These findings support the National Institute of Clinical
Excellence guidelines on thromboprophylaxis among admitted
patients.
27
In light of this, careful consideration of which women
should receive prophylaxis during an antepartumadmission and
for how long is needed.
Contributors: AAS, JW, and MJG conceived the idea for the study, with
LJT and KMF also making important contributions to the design. AAS
carried out the data management and analysis and wrote the first draft
of the manuscript. CNP provided clinical input and interpretation at all
stages of the project. All authors were involved in the interpretation of
the data, contributed towards critical revision of the manuscript and
approved the final draft. AAS had full access to all of the data and MJG
had final responsibility for the decision to submit for publication. AAS
and MJG are guarantors.
Funding: AAS is funded by a scholarship awarded by the Aga Khan
Foundation. JW is funded by a University of Nottingham senior clinical
research fellowship, which also contributes to AASs funding.
Competing interests: All authors have completed the ICMJE uniform
disclosure form at www.icmje.org/coi_disclosure.pdf and declare: CNP
was co-developer of the currently available guidelines on VTE
prophylaxis in pregnancy issued by the Royal College of Obstetricians
and Gynaecologists (green top guideline 37a). CNP has also received
honorariums for lectures from Leo Pharma and Sanofi Aventis (makers
of tinzaparin and enoxaparin, low molecular weight heparins used in
obstetric thromboprophylaxis) and has received payment from Leo
Pharma for development of an educational slide kit about obstetric
thromboprophylaxis.
Ethical approval: This study was reviewed and approved by CPRD
Independent Scientific Advisory Committee (ISAC) Ref No 10_193R.
Declaration of transparency: AAS and MJG affirm that the manuscript
is an honest, accurate, and transparent account of the study being
reported; that no important aspects of the study have been omitted; and
that any discrepancies from the study as planned (and, if relevant,
registered) have been explained.
Data sharing: no additional data available
1 Saving Mothers Lives: Reviewing maternal deaths to make motherhood safer: 2006-2008.
Br J Obetet Gynaecol 2011;118:1-203.
2 Drife J. Thromboembolism. Br Med Bull 2003;67:177-90.
3 Wik H, Jacobsen A, Sandvik L, Sandset P. Prevalence and predictors for post-thrombotic
syndrome 3 to 16 years after pregnancy-related venous thrombosis: a population-based,
cross-sectional, case-control study. J Thromb Haemost 2012;10:840-7.
4 Jacobsen AF, Skjeldestad FE, Sandset PM. Ante- and postnatal risk factors of venous
thrombosis: a hospital-based case-control study. J Thromb Haemost 2008;6:905-12.
5 Knight M. Antenatal pulmonary embolism: risk factors, management and outcomes. Br J
Obstet Gynaecol 2008;115:453-61.
6 Larsen TB, Sorensen HT, Gislum M, Johnsen SP. Maternal smoking, obesity, and risk of
venous thromboembolism during pregnancy and the puerperium: a population-based
nested case-control study. Thromb Res 2007;120:505-9.
7 Simpson EL, Lawrenson RA, Nightingale AL, Farmer RD. Venous thromboembolism in
pregnancy and the puerperium: incidence and additional risk factors from a London
perinatal database. Br J Obstet Gynaecol 2001;108:56-60.
8 Heit JA, Melton LJ, Lohse CM, Petterson TM, Silverstein MD, Mohr DN, et al. Incidence
of venous thromboembolism in hospitalized patients vs community residents. Mayo Clin
Proc 2001;76:1102-10.
9 Department of Health. Venous thromboembolism prevention: a patient safety priority
(19/04/2013). www.kingsthrombosiscentre.org.uk/kings/12.pdf.
10 Royal College of Obstetricians and Gynaecologists. Reducing the risk of thrombosis and
embolism during pregnancy and the puerperium. Green-top Guideline No. 37a 2009.
11 Clinical Practice Research Database. (19/04/2013). www.cprd.com/intro.asp.
12 Hospital Episode Statistics. (19/04/2013). www.hesonline.nhs.uk.
13 Eaton SC, Williams TJ, Puri S, VanStaa T. The feasibility of linking the English Hospital
Episode Statistics to the GPRD. Pharmacoepidemiol Drug Saf 2008;17:S214.
14 Crooks C. Epidemiology of upper gastrointestinal bleeding studying its causes and
outcomes using case control studies and surivival analyses. [PhD thesis]. University of
Nottingham 2013.
15 Lawrenson R, Todd JC, Leydon GM, Williams TJ, Farmer RD. Validation of the diagnosis
of venous thromboembolism in general practice database studies. Br J Clin Pharmacol
2000;49:591-6.
16 Dattani N, Datta-Nemdharry P, Macfarlane A. Linking maternity data for England 2007:
methods and data quality. Health Stat Q 2012;53.
17 Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al. Prevention
of venous thromboembolism*: American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines. Chest 2008;133(6 suppl):381-453S.
18 Thompson A, Shaw M, Harrison G, Ho D, Gunnell D, Verne J. Patterns of hospital
admission for adult psychiatric illness in England: analysis of Hospital Episode Statistics
data. Br J Psychiatry 2004;185:334-41.
19 Campbell SE, Campbell MK, Grimshaw JM, Walker AE. A systematic reviewof discharge
coding accuracy. J Public Health 2001;23:205-11.
20 National Institute for Health and Clinical Excellence. Diabtes in pregnancy: Management
of diabetes and its complication from pre-conception to postnatal period. RCOG Press,
2008.
21 National Intitute for Health and Clinical Excellence. Diabetes in pregnancy: Management
of diabetes and its complications frompre-conception to the postnatal period. NICE, 2008.
22 Walker RL, Hemmelgarn B, Quan H. Incidence of gestational hypertension in the Calgary
Health Region from 1995 to 2004. Can J Cardiol 2009;25:e284-7.
23 Zhang J, Zeisler J, Hatch MC, Berkowitz G. Epidemiology of pregnancy-induced
hypertension. Epidemiol Rev 1997;19:218.
24 Royal College of Obstetricians and Gynaecologist. The acute management of thrombosis
and embolism during pregnancy and puerperium. Green-top guideline No. 37b. RCOG
Press, 2010.
25 Abdul Sultan A, Tata LJ, Grainge MJ, West J. The incidence of first venous
thromboembolism in and around pregnancy using linked primary and secondary care
data: a population based cohort study fromengland and comparative meta-analysis. Plos
One 2013;8:e70310.
26 Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and
treatment of venous thromboembolism in pregnancy: a systematic review of safety and
efficacy. Blood 2005;106:401-7.
27 National Institute for Health and Clinical Excellence. Venous thromboembolism: reducing
the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in
patients admitted to hospital. No. 92. NICE Publisher, 2010.
Accepted: 23 September 2013
Cite this as: BMJ 2013;347:f6099
This is an Open Access article distributed in accordance with the Creative Commons
Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute,
remix, adapt, build upon this work non-commercially, and license their derivative works
on different terms, provided the original work is properly cited and the use is
non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/.
RESEARCH
What is aIready known on the topic
Venous thromboembolism, which complicates one to two pregnancies in every 1000, is one of the leading direct causes of maternal
deaths in developed countries
Hospital admission is known to increase the risk of venous thromboembolism about 100-fold, and is responsible for more than 25 000
deaths each year in the United Kingdom
The magnitude of risk of venous thromboembolismduring antepartumadmission and after discharge in terms of absolute risk is unknown
What this paper adds
The study provides population based absolute and relative rates of venous thromboembolism during antepartum admission and after
discharge by using linked primary and secondary care data
There was a high relative rate of venous thromboembolism during inpatient admissions and in the 28 days after discharge, with a
particularly high rate among women admitted for three or more days
TabIes
TabIe 1| Characteristics of pregnancies in Iinked CPRD-HES data*. Figures are numbers (percentages) of pregnancies
No of pregnancies (n=245 661) VariabIe
No of admissions to hospital:
203 405 (83) 0
30 784 (13) 1
7470 (3) 2
4002 (2) 3
Demographic characteristics
Body mass index (BMI):
107 275 (44) Normal (18.5-24.9)
7733 (3) Underweight (<18.5)
45 132 (18) Overweight (25-29.9)
28 701 (12) Obese (30)
56 820 (23) Missing
Smoking status:
186 926 (76) Non-smoker
58 735 (24) Current smoker
Pregnancy associated characteristics and compIication
Diabetes:
3807 (2) Gestational diabetes
2739 (1) Pre-existing diabetes
Hypertension:
13 039 (6) Gestational hypertension
14 962 (6) Pre-existing hypertension
32 668 (13) Gestational acute systemic infection
8502 (3) Hyperemesis
11 614 (5) Antepartum haemorrhage
3564 (1) Multiple gestation
6244 (3) Varicose veins
2471 (1) Cardiac disease
1213 (<1) Inflammatory bowel disease
181 (<1) Nephrotic syndrome
*Pregnancies in 206 785 individual women. When women had more than one pregnancy, status of all above risk factors could potentially differ between pregnancies.
During antepartum period.
RESEARCH
TabIe 2| AbsoIute rate of venous thromboemboIism (VTE) per 100 000 person years and incidence rate ratios (IRR) during antepartum
period by potentiaI risk factors
IRR (95% CI) (unadjusted) Rate* (95% CI) No of VTE VariabIe
Demographic characteristics
Maternal age (years):
0.89 (0.61 to 1.29) 101 (74 to 139) 38 15-24
1.00 114 (94 to 138) 103 25-34
1.03 (0.70 to 1.52) 118 (85 to 164) 35 35-44
Body mass index (BMI):
1.00 85 (66 to 110) 61 Normal (18.5-24.9)
0.85 (0.64 to 2.09) 59 (19 to 185) 3 Underweight (<18.5)
1.29 (0.85 to 1.96) 120 (87 to 166) 37 Overweight (25-29.9)
1.76 (1.16 to 2.67) 178 (128 to 248) 35 Obese (30)
NA 130 (95 to 177) 40 Missing
Smoking status:
1.00 107 (90 to 127) 128 Non-smoker
1.18 (0.85 to 1.65) 127 (96 to 169) 48 Current smoker
Antepartum compIications|
2.05 (1.16 to 3.78) 222 (123 to 402) 11 Hyperemesis
1.63 (0.60 to 4.39) 181 (67 to 482) 4 Antepartum haemorrhage
2.02 (0.83 to 4.92) 223 (93 to 537) 5 Multiple gestation
3.30 (1.69 to 6.46) 361 (187 to 694) 9 Gestational diabetes
2.69 (1.81 to 3.98) 269 (188 to 358) 30 Gestational systemic infection
1.63 (0.94 to 2.83) 170 (100 to 287) 14 Gestational hypertension
MedicaI comorbidities|
2.35 (1.27 to 4.32) 253 (140 to 458) 11 Varicose veins
2.75 (1.13 to 6.70) 303 (126 to 728) 5 Cardiac disease
1.64 (1.03 to 2.74) 174 (110 to 277) 18 Pre-existing hypertension
*Rate per 100 000 person years.
Missing data imputed.
IRR compared with pregnancies without condition under study. Note: no VTE events were observed in pregnancies complicated by inflammatory bowel disease,
nephrotic syndrome, or pre-existing diabetes during antepartum period.
RESEARCH
TabIe 3| Rate of venous thromboemboIism (VTE) by admission to hospitaI and after hospitaI stay
IRR (95% CI)
Rate* (95% CI) No of VTE VariabIe Adjusted 2| Adjusted 1|
Antepartum overaII
1.00 1.00 97 (83 to 114) 150 Time outside hospital
17.5 (7.69 to 40.0) 18.2 (8.04 to 41.3) 1752 (787 to 3900) 6 Hospital admission
6.27 (3.74 to 10.5) 7.08 (4.41 to 11.3) 676 (436 to 1048) 20 After discharge
Pregnancies not compIicated by BMI >30 or major medicaI comorbidity
1.00 84 (69 to 101) 109 Time outside hospital
22.0 (8.97 to 54.3) 1821 (757 to 4375) 5 Hospital admission
7.56 (4.36 to 13.1) 623 (375 to 1034) 15 After discharge
Variation by duration of hospitaI stay (combining admission/after discharge)
Antepartum overall:
4.05 (2.23 to 7.38) 5.85 (3.37 to 10.1) 558 (331 to 943) 13 <3 days
12.2 (6.65 to 22.7) 15.7 (8.71 to 28.5) 1511 (858 to 2661) 13 3 days
Time outside pregnancy
1.00 28 (25 to 31) 326 Time outside hospital
66.2 (36.3 to 120) 1890 (1046 to 3412) 11 Hospital admission
32.3 (22.8 to 45.8) 911 (654 to 1269) 35 After discharge
IRR=incidence rate ratio.
*Rate calculated per 100 000 person years.
Adjusted for maternal age and calendar year when not stratified by them.
Adjusted for maternal age, calendaryear, BMI, gestational infection, cardiac disease, varicose vein, gestational diabetes, and hyperemesis.
Including varicose vein and cardiac disease.
RESEARCH
TabIe 4| Rate of first antepartum venous thromboemboIism (VTE) during hospitaI admission/after discharge stratified by trimester, age,
caIendar year and BMI
IRR (95% CI)
Rate* (95%CI) No of VTE VariabIe Adjusted 2| Adjusted 1|
Variation by antepartum trimester
Trimester 1 and 2:
8.43 (3.27 to 21.7) 7.61 (3.03 to 19.0) 449 (186 to 1078) 5 Admission/after discharge
Trimester 3:
Variation by caIendar year in admission/after discharge
1997-2003:
2004-10:
Variation by maternaI age (years)
15-24:
25-34:
35-44:
Variation by BMI
Normal BMI (18.5-24.9)
Overweight (25-29.9):
Obese (30):
IRR=incidence rate ratio.
*Rate calculated per 100 000 person years.
Adjusted for maternal age and calendar year when not stratified by them.
Adjusted for maternal age, calendaryear, BMI, gestational infection, cardiac disease, varicose vein, gestational diabetes, and hyperemesis when not stratified by
them.
RESEARCH
Figures
Fig 1 Division of antepartum person time into hospitalised time and time outside hospital
Fig 2 Rate of venous thromboembolism per 100 000 person years by weeks after discharge during antepartum period: 12
events in weeks 1-2 after discharge, 7 events in weeks 3-4 after discharge, and 12 events in weeks 5-10 after discharge
RESEARCH

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