1. For personal use. Only reproduce with permission from The Lancet Publishing Group.
RESEARCH LETTERS
Cost-effectiveness of screening for
the factor V Leiden mutation in
pregnant women
Peter Clark, Sara Twaddle, Isobel D Walker, Linda Scott,
Ian A Greer
The factor V Leiden (FVL) mutation is associated with vascular
complications in pregnancy, and routine screening of all
pregnant women has been suggested. We did a prospective,
unselected study in 967 pregnant women to evaluate the cost-
effectiveness of screening all women, or only those with a
personal or family history of venous thrombosis (n=113). When
anticoagulant prophylaxis was assumed to effect a 50%
reduction in vascular complications, we recorded an additional
management cost of UK£3768 with selective screening and
£39 841 with universal screening. This additional cost would
result in prevention of less than one and three vascular events,
respectively. Our findings, therefore, suggest that screening of
pregnant women for the FVL mutation is not cost-effective.
Lancet 2002; 359: 1919–20
The factor V Leiden (FVL) mutation is associated with
adverse vascular outcomes of pregnancy—eg, miscarriage,
intrauterine growth restriction, pre-eclampsia, and venous
thrombosis.1
In white populations, the FVL mutation is
common and, since treatment with anticoagulants can
prevent associated adverse effects,2
there is a need for
a formal prospective assessment of the benefits of
screening for such mutations in pregnant women.3
There
are two possible screening strategies: universal screening
of all women early in pregnancy, or selective screening
based on a personal or family (in a first degree relative)
history of venous thromboembolism (VTE). Our aim
was to establish whether or not either of these strategies
would be cost effective in reducing the incidence of all
pregnancy-related vascular complications.
We did an economic evaluation of screening (from the
perspective of the UK National Health Service [NHS]) for
the FVL mutation, in which we included the first 967
individuals recruited to the GOAL Pregnancy Study.4
The
study4
was approved by the local ethics committee, and
participants provided written consent. The researchers
recruited consecutive unselected individuals who attended
for antenatal care (962 [99·5%] white, 3 [0·3%] Afro-
Caribbean, 2 [0·2%] Chinese). At the first antenatal visit, a
detailed personal past medical and family history was
obtained, and FVL status was determined.4
Participants,
investigators, and doctors were not made aware of FVL
status until 6 weeks after delivery. 6 weeks post partum,
women in whom a complication such as miscarriage
(eight), stillbirth or neonatal death (15), VTE (one),
intrauterine growth restriction (45), or pre-eclampsia (18)
had occurred were identified. We ascertained additional
resources associated with the management of these women
retrospectively from case records, and applied costs
(table 1). 87 women had a vascular complication
associated with the FVL mutation,1,3
equalling an individ-
ual mean cost of management of UK£1816. This figure
results ina total cost to the NHS, for the management
of these women (n=967; in the absence of screening),
of £158 015.
We evaluated the two possible screening strategies for
identification of the presence of the FVL mutation: screening
only those women (n=113) with a personal history (1,
0·52%) or family history (13, 11·2%) of VTE, or screening
all pregnant women at presentation for antenatal care
(n=967). We assumed that enoxaparin prophylaxis, in
women identified with the FVL mutation, would have
resulted in a 50% reduction in the occurrence of, and cost
associated with, vascular complications.2
Although not
routine practice for the prevention of VTE, we assumed that
all individuals (in either strategy) identified as having the
FVL mutation would have been given enoxaparin
prophylaxis to prevent antenatal and postnatal vascular
complications from 12–40 weeks’ gestation until 6 weeks
post partum, at a cost of £33·08 per woman per week.
Identification of individuals heterozygous for the FVL
mutation would have incurred the cost (table 2) of an
activated protein C sensitivity ratio (£7·98 per test; done in
all women) and PCR analysis for the mutation (£25·00 per
test; done in all women with an abnormal activated
protein C sensitivity ratio).
In the selective screening strategy, the cost of testing for
the FVL mutation in the 113 women would have been
£1305 (table 2). The test would have identified three
women with the FVL mutation, only one of whom would
have had a vascular complication (a growth-restricted baby
in an individual with a family history of VTE). The total
cost of management of the selected strategy (in which
seven vascular complications arose in 113 women) would
THE LANCET • Vol 359 • June 1, 2002 • www.thelancet.com 1919
Area of resource Women with FH Women with Unit cost
or PMH no FH or PMH (UK£)
Daycare attendances 25 145 74·37*
Inpatient days 73 412 210·48*
Additional clinic attendances 14 39 17·21–
18·45*
Ultrasound 25 129 7·74*
Detailed ultrasound 19 105 19·78*
Doppler ultrasound 2 0 13·78*
Venogram 0 1 104*
Duration of subcutaneous 2 19 4·73†
heparin use (days)
Duration of intravenous 0 1 13·66†
heparin use (days)
TED stockings 0 5 3·35*
Cost of management 1571·91 1543·64 ··
(median, range) (£) (220·99– (17·21– ··
3267·99) 11 616·45)
TED=thromboembolic deterrent; FH=family history of factor V Leiden mutation;
PMH=personal history of factor V Leiden mutation. *NHS hospital trust cost.
†Cost listed in the British National Formulary. All costs are for 1999.
Table 1: Cost per woman and unit costs for the management of
complications
4 Loktionov A, O’Neill IK, Silvester KR, Cummings JH, Middleton SJ,
Miller R. Quantitation of DNA from exfoliated colonocytes isolated
from human stool surface as a novel noninvasive screening test for
colorectal cancer. Clin Cancer Res 1998; 4: 337–42.
5 Mukherjee G, Freeman A, Moore R, et al. Biologic factors and
response to radiotherapy in carcinoma of the cervix. Int J Gynecol
Cancer 2001; 11: 187–93.
MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge
CB2 2XZ, UK (R J Davies FRCS, A Freeman MD, L S Morris,
I S Scott DPhil, R A Laskey FRS, N Coleman FRCPath); Department of
Surgery, Addenbrooke’s NHS Trust, Hills Road, Cambridge
(R Miller FRCS); MRC Dunn Human Nutrition Unit, Wellcome
Trust/MRC Building, Cambridge (S Bingham PhD); and Department of
Metabolic Medicine, Imperial College School of Medicine,
Hammersmith Hospital, London (S Dilworth PhD).
Correspondence to: Dr Nicholas Coleman
(e-mail: nc109@cam.ac.uk)

2. For personal use. Only reproduce with permission from The Lancet Publishing Group.
RESEARCH LETTERS
mutation (0·8, 0·2–2·8) in this group. Universal screening
might, however, identify women who would benefit
from treatment with anticoagulants. The development of
an alternative selective screening strategy for vascular
complications in pregnancy would be problematic, because
of the subjective nature of the assessment of family history
for both VTE or pregnancy-related hypertension, and the
small risk associated with the FVL mutation. Addition of
other risk factors to refine the screening strategy might also
be difficult. Smoking, for example, is a strong risk factor
for growth restriction, but also protects against pre-
eclampsia.4
Contributors
P Clark codirected the project, collated data, and did the statistical
analysis; S Twaddle and L Scott did the economic analysis; and
I D Walker and I A Greer conceived and codirected the project.
All authors participated in the writing and preparation of the report.
Conflict of interest statement
None declared.
Acknowledgments
The research was supported by a grant form the Scottish Home and
Health Department (K/OPR/2/2/D29). The sponsors of the study had
no role in study design, data collection, data analysis, data
interpretation, or writing of the report.
1 Clark P, Greer IA, Walker ID. Interaction of the protein C/protein
S anticoagulant system, the endothelium and pregnancy. Blood Rev
1999; 13: 127–46.
2 Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of
aspirin and aspirin plus heparin in pregnant women with recurrent
miscarriage associated with phospholipid antibodies (or
antiphospholipid antibodies). BMJ 1997; 314: 253–57.
3 Greer IA. Thrombosis in pregnancy: maternal and fetal issues.
Lancet 1999; 353: 1258–65.
4 Clark P, Sattar N, Walker ID, Greer IA. The Glasgow Outcome,
APCR and Lipid (GOAL) Pregnancy Study: significance of
pregnancy-associated activated protein C resistance. Thromb
Haemost 2001; 85: 30–35.
Department of Haematology (I D Walker MD), and University
Department of Obstetrics and Gynaecology (S Twaddle PhD,
I A Greer MD), Royal Infirmary; Research and Development
Department, Stobhill Hospital, Glasgow (L Scott BA); and
Department of Transfusion Medicine, Ninewells Hospital and
Medical School, Dundee DD1 9SY, UK (P Clark MD)
Correspondence to: Dr Peter Clark
(e-mail: peter.clark@snbts.csa.scot.nhs.uk)
have included: the cost of management of complications in
those not identified as having the FVL mutation, plus the
cost of screening and prophylaxis and the cost of
management for individuals with the FVL mutation with
complications (assuming therapy would result in a 50%
reduction of the occurrence of these complications, table 2).
In the universal strategy, the cost of screening 967
women would have been £11 543, and 30 women with the
FVL mutation would have been identified. Universal
screening would have identified six people with the FVL
mutation who had a complication linked to the mutation
(four with intrauterine growth restriction, one with pre-
eclampsia, and one neonatal death). In this strategy, the
total cost of management would have included: the cost of
complications in those without a mutation, plus the cost of
screening and the cost of management of individuals with a
mutation and associated complications (table 2).
Our results suggest that universal screening for the
FVL mutation is not cost effective, even if prophylaxis
were to result in a 100% reduction in complications and
their associated costs (see incremental cost, table 2). Our
findings can be extrapolated to other thrombophilic
defects, such as prothrombin 20210A, which have a lower
population prevalence than vascular defects. There
are, however, several limitations in the interpretation of
our results. Our study implies that identification of a
mutation would result in a reduction in the frequency
of all complications by 50%. A comparable efficacy of
prophylactic low molecular weight heparin anticoagulation
in individuals with the FVL mutation to that seen with
unfractionated heparin in the management of recurrent
fetal loss and antiphospholipid antibodies2
has yet to be
assessed in a prospective study. Furthermore, we did not
account for the cost of adverse events related to treatment
with low molecular weight heparin, although this figure is
thought to be low. Finally, we did not assess the possible
benefits or costs to women of knowing that they had the
FVL mutation.
Although screening for a mutation was not cost
effective in this cohort, there was a relation between
carriage of the FVL mutation and vascular complications
(Mantel and Haenszel odds ratio 2·6, 95% CI 1·0–6·7).
The failure of selective screening could be explained
by the lack of a relation between a past family history or a
past medical history of VTE and either pregnancy
complications (0·6, 0·3–1·4) or carriage of the FVL
1920 THE LANCET • Vol 359 • June 1, 2002 • www.thelancet.com
Screening strategy
None Selective Universal
(n=967) (n=113) (n=967)
Total cost of screening strategies (UK£)
Women identified with FVL mutation (number) 0 3 30
FVL mutation with vascular complications 0 1 6
Events prevented by screening 0 0.5 3
(assumes 50% reduction with prophylaxis)
Total cost of screening for mutation 0 1305·31 11 543·29
Total cost of prophylactic postpartum low molecular weight heparin 0 595·48 5959·80
Total cost of prophylactic low molecular weight heparin 0 2774·94 27 787·20
(from 12–40 weeks’ gestation)
Averted costs of treating vascular events 0 908·13 5448·81
(assumes 50% reduction with prophylaxis)
Total cost of management strategy 158 015·49 161 781·09 197 854·97
Incremental analysis
Incremental cost per additional event prevented by screening ·· 7535·20 13 281·16
Incremental cost per additional event prevented by screening ·· 4418·04 8248·24
(assuming 75% reduction with prophylaxis)
Incremental cost per additional event prevented by screening ·· 2859·47 5732·44
(assuming 100% reduction with prophylaxis)
Table 2: Economic evaluation of screening strategies for identification of factor V Leiden (FVL) mutation in pregnant women