Articles

www.thelancet.com Vol 376 July 24, 2010 259

Lancet 2010; 376: 25966
Published Online
June 26, 2010
DOI:10.1016/S0140-
6736(10)60630-7
See Comment page 214
*Members listed at end of paper
Regional Centre for
Endocrinology and Diabetes,
Royal Victoria Hospital, Belfast,
UK (Prof D R McCance FRCP);
Nursing and Midwifery
Research Unit, School of
Nursing and Midwifery
(V A Holmes PhD) and Centre
for Public Health, School of
Medicine, Dentistry and
Biomedical Sciences
(C C Patterson PhD,
Prof I S Young FRCPath), Queens
University Belfast, Belfast, UK;
Department of Obstetrics and
Gynaecology, St Marys
Hospital for Women and
Children, Manchester, UK
(M J A Maresh FRCOG);
Department of Diabetes,
St Johns Hospital at Howden,
Livingston, UK (J D Walker MD);
and Department of Diabetes,
Aberdeen Royal Inrmary,
Aberdeen, UK
(D W M Pearson FRCPE)
Correspondence to:
Prof David R McCance, Regional
Centre for Endocrinology and
Diabetes, Royal Victoria Hospital,
Belfast BT12 6BA, UK
david.mccance@belfasttrust.
hscni.net
Vitamins C and E for prevention of pre-eclampsia in women
with type 1 diabetes (DAPIT): a randomised
placebo-controlled trial
David R McCance, Valerie A Holmes, Michael J A Maresh, Christopher C Patterson, James D Walker, Donald W M Pearson, Ian S Young,
for the Diabetes and Pre-eclampsia Intervention Trial (DAPIT) Study Group*
Summary
Background Results of several trials of antioxidant use during pregnancy have not shown a reduction in pre-eclampsia,
but the eect in women with diabetes is unknown. We aimed to assess whether supplementation with vitamins C and
E reduced incidence of pre-eclampsia in women with type 1 diabetes.
Methods We enrolled women from 25 UK antenatal metabolic clinics in a multicentre randomised placebo-controlled
trial. Eligibility criteria were type 1 diabetes preceding pregnancy, presentation between 8 weeks and 22 weeks
gestation, singleton pregnancy, and age 16 years or older. Women were randomly allocated in a 1:1 ratio to receive
1000 mg vitamin C and 400 IU vitamin E (-tocopherol) or matched placebo daily until delivery. The randomisation
sequence was stratied by centre with balanced blocks of eight patients. All trial personnel and participants were
masked to treatment allocation. The primary endpoint was pre-eclampsia, which we dened as gestational
hypertension with proteinuria. Analysis was by modied intention to treat. This study is registered,
ISRCTN27214045.
Findings Between April, 2003, and June, 2008, 762 women were randomly allocated to treatment groups (379 vitamin
supplementation, 383 placebo). The primary endpoint was assessed for 375 women allocated to receive vitamins, and
374 allocated to placebo. Rates of pre-eclampsia did not dier between vitamin (15%, n=57) and placebo (19%, 70)
groups (risk ratio 081, 95% CI 059112). No adverse maternal or neonatal outcomes were reported.
Interpretation Supplementation with vitamins C and E did not reduce risk of pre-eclampsia in women with type 1
diabetes. However, the possibility that vitamin supplementation might be benecial in women with a low antioxidant
status at baseline needs further testing.
Funding The Wellcome Trust.
Introduction
Pre-eclampsia is a multisystem disorder of pregnancy
that is characterised by pregnancy-induced or gestational
hypertension and new-onset proteinuria during the
second half of pregnancy.
1
Recognised risk factors are
nulliparity, age younger than 20 years or older than
40 years, obesity, history of pre-eclampsia, multiple
pregnancy, and pre-existing disorders such as chronic
hypertension, renal disease, autoimmune disease,
antiphospholipid syndrome, and diabetes mellitus.
2
Pre-
eclampsia results in serious maternal complications
such as eclampsia and HELLP (haemolysis, elevated
liver enzymes and low platelets) syndrome, and is a
foremost cause of maternal death.
3
Moreover, since
delivery is the only cure, up to 15% of preterm births are
associated with pre-eclampsia, with a consequent
increase in infant mortality and morbidity.
4
The global
prevalence is around 4%,
3
but the rate is raised two to
four times in women with type 1 diabetes, and increases
with complexity of diabetes.
57
The hypothesis that oxidative stress plays a key part in
pathogenesis of pre-eclampsia was proposed in the late
1980s,
8
and has since been the focus of much research.
9,10
Diabetes mellitus, specically type 1 diabetes, is associated
with increased oxidative stress and antioxidant
depletion,
11,12
which is partly related to prevailing blood
glucose concentrations.
13
Increased oxidative stress in
pregnant women with diabetes
14,15
might account for rates
of pre-eclampsia that are two to four times higher in this
group, especially in those with diabetes-related
complications,
57
and lends support to the postulated role
of oxidative stress in pathophysiology of the disorder in
diabetes-associated pregnancy.
16
In a small randomised placebo-controlled trial,
17

supplementation with vitamins C and E was associated
with a reduction in rate of pre-eclampsia from 17% to 8%
(adjusted odds ratio 039, 95% CI 017090) in
283 women at high risk of developing the disorder. These
results added to existing evidence for a role of oxidative
stress in pathogenesis of pre-eclampsia, and led to several
large trials of antioxidant treatment for prevention of pre-
eclampsia.
1824
The results of these trials have shown no
benet of vitamin C and E supplementation during
pregnancy;
18,19,2124
however, only three included women
with diabetes, and in each instance these groups were
small and poorly characterised.
18,19,23
Since pre-eclampsia
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260 www.thelancet.com Vol 376 July 24, 2010
is likely to be a heterogeneous disease,
9
pathogenesis
could vary between women with dierent risk factors.
Furthermore, in view of the increase in oxidative stress
and antioxidant depletion that occur in diabetes, a
benecial eect of antioxidant supplementation is
plausible in this group of patients.
We designed the Diabetes and Pre-eclampsia Inter-
vention Trial (DAPIT) to assess whether supplement ation
with vitamins C and E reduced incidence of pre-eclampsia
in women with type 1 diabetes.
20
Methods
Study design and patients
DAPIT was a multicentre, randomised, placebo-
controlled, parallel-group trial. Women were recruited
from 25 antenatal metabolic clinics across Northern
Ireland, Scotland, and northwest England between April,
2003, and June, 2008. The last baby was delivered in
December, 2008. Eligibility criteria were type 1 diabetes
preceding pregnancy, presentation between 8 weeks and
22 weeks gestation, singleton pregnancy, and age 16 years
or older. Women were excluded if they did not give
consent, were enrolled in another research study, were
being treated with warfarin, or were known to misuse
drugs. Women taking vitamin supplements were
excluded only if these contained 500 mg or more vitamin
C or 200 IU or more vitamin E daily. Women with chronic
hypertension were included in the trial. The West
Midlands multicentre research ethics committee provided
ethics approval (MREC 02/7/016). Participants gave
written informed consent and had at least 48 h to review
the patient information sheet.
Randomisation and masking
Participants were randomly allocated in a 1:1 ratio to receive
1000 mg vitamin C and 400 IU vitamin E or matched
placebo daily from between 8 and 22 weeks gestation until
delivery. Vitamin C and identical placebo (calcium
carbonate, microcrystalline cellulose, maltrodextrin, and
stearic acid) tablets were manufactured by Thompson &
Capper (Astmoor, Runcorn, Cheshire, UK). Natural-source
vitamin E (-tocopherol) and identical placebo (olive oil)
capsules were manufactured by Eurocaps Limited
(Dukestown, Tredegar, Gwent, UK). Victoria
Pharmaceuticals (The Royal Hospitals, Belfast, UK)
packaged tablets and capsules, 120 per bottle, according to
a randomisation sequence generated in advance by Victoria
Pharma ceuticals using PRISYM ID software (version
1.0009). The randomisation sequence was stratied by
centre with balanced blocks of eight patients, and was held
by Victoria Pharmaceuticals. Individual sealed envelopes
containing treatment allocations were given to trial
pharmacists in every centre, allowing treatment group to
be revealed in a clinical emergency. Treatment allocation
was masked from all trial personnel and participants until
trial completion.
Procedures
Eligible women who gave consent were assigned the next
available number at that centre by research midwives,
and given their rst supply of trial drugsbottles of
vitamin C tablets and vitamin E capsules (vitamin group)
or bottles of placebos (placebo group)along with a 7-day
pill dispenser to aid adherence. Participants were
instructed to take one tablet and one capsule daily until
delivery, and to leave unused pills in the bottles.
Participants attended trial visits at 26 (within 2) weeks
and 34 (within 2) weeks gestation, at which times tablets
and capsules were counted and the next supply dispensed.
Unused tablets and capsules were collected during
delivery admission or at the 6-week postnatal trial visit,
or were returned in postage prepaid envelopes.
Blood pressure at randomisation was measured with a
British Hypertension Society validated automated
instrument, (Omron M5-I, Omron Healthcare, West
Sussex, UK). After the participant had been seated for
5 min, the average of two measurements taken 3 min apart
was recorded. Biological samples obtained at baseline,
26 weeks, and 34 weeks gestation were batch analysed at
the end of the study at the central laboratory (Queens
University, Belfast) for plasminogen activator inhibitor
type 1 (PAI-1) and type 2 (PAI-2), plasma ascorbate
concentrations, serum concentrations of -tocopherol

(expressed per mmol of serum cholesterol), serum total
cholesterol, HbA
1c
, and urine microalbumin and creatinine.
Laboratory analyses are detailed in the webappendix.
When possible, follow-up data were obtained for study
participants at routine clinic visits 6 weeks after delivery
and for infants at 8 week postnatal checks with their
paediatrician, family doctor, or health visitor. These data
Figure 1: Trial prole
379 allocated to vitamin C and vitamin E 383 allocated to placebo
762 randomised
0 lost to follow-up 1 lost to follow-up
(withdrew consent)
1621 women assessed for eligibility
859 excluded
137 did not meet inclusion criteria
187 had a miscarriage during assessment timeframe
450 refused to participate
85 other
379 women completed the trial 382 women completed the trial
4 pregnancies 20 weeks
gestation
8 pregnancies 20 weeks
gestation
375 women analysed for pre-eclampsia 374 women analysed for pre-eclampsia
See Online for webappendix
Articles
www.thelancet.com Vol 376 July 24, 2010 261
were measurement of weight, length, and head
circumference and assessment of xation, following,
smiling, head control, tone, tendon reexes, heart
murmurs, and congenital abnormalities.
The primary outcome was pre-eclampsia, which we
dened as gestational hypertension with proteinuria in
accordance with the International Society for the Study of
Hypertension in Pregnancy guidelines.
1
Gestational
hypertension was dened as two diastolic blood pressure
readings of 90 mm Hg or more at least 4 h apart, or one
reading of at least 110 mm Hg, occurring after 20 weeks
gestation or up to 48 h postnatally and excluding labour.
Proteinuria was dened as a result of at least 1+ for dipstick
analysis of a midstream specimen on two or more
occasions or more than 300 mg urinary protein per 24 h.
For women with diastolic blood pressure greater than
90 mm Hg at the rst antenatal visit, superimposed pre-
eclampsia was dened as the development of proteinuria
and a rise of at least 10 mm Hg from the rst recorded
antenatal diastolic blood pressure on two occasions at least
4 h apart or one reading of at least 110 mm Hg, occurring
from 20 weeks gestation until 48 h postnatally and
excluding labour. For women with pre-existing proteinuria,
diagnosis was made by a doubling of proteinuria on the
basis of dipstick or quantitative measurements or on
clinical or biochemical grounds by identication of one
additional feature of pre-eclampsia (eg, HELLP syndrome,
eclampsia). Sta in the trial centre reviewed all participants
with hypertension. Additionally, diagnosis was
independently conrmed by three senior clinicians, who
were unaware of treatment allocation.
Secondary outcomes were placental and endothelial
function as established by PAI-1 to PAI-2 ratio, gestational
hypertension, and birthweight centile as calculated from
customised birthweight charts.
25
We prespecied several
additional maternal and neonatal outcomes, including
miscarriage, maternal death, obstetric complications and
other adverse outcomes, fetal malformation, gestational
age at delivery, and admission to a neonatal care unit. We
expressed growth measures (weight, length, head
circumference) at birth and postnatal follow-up
(612 weeks of age) as SD scores using the 1990 British
Growth Standard.
26
Statistical analysis
On the assumption of a 20% rate of pre-eclampsia, a study
size of 756 women had greater than 80% power to detect
a 40% reduction (from 20% to 12%) as signicant (p<005;
two-tailed). We did seven interim analyses for the primary
endpoint using the Haybittle-Peto method
27
and presented
results to the independent data monitoring committee.
Analysis of the primary endpoint was by modied
intention to treat, for all pregnancies of more than
20 weeks gestation. We undertook 11 predened subgroup
analyses for the primary endpoint: baseline control of
diabetes; HbA
1c
less than 7%, 78%, and more than 8%;
baseline antioxidant status (vitamin E <3 mol/mmol
cholesterol, 35 mol/mmol cholesterol, and >5 mol/
mmol cholesterol; vitamin C <10 mol/L, 1030 mol/L,
and >30 mol/L); and current smoking (yes or no).
Treatment group comparisons were summarised as
dierences in means or risk ratios (with 95% CIs) and
independent samples t tests and or Fishers exact tests
were applied. To allow for multiple comparisons, we used
a strict signicance level (p<001) for secondary
outcomes. Log transformations were applied in an
attempt to normalise the distribution of PAI-1 to PAI-2
ratio, but comparisons were done with the Mann-Whitney
U test. SPSS (version 17) was used for all analyses.
This study is registered, ISRCTN27214045.
Role of the funding source
The funder had no role in study design, data collection,
data analysis, data interpretation, or writing of the report.
The corresponding author had full access to all the data
in the study and had nal responsibility for the decision
to submit for publication.
Vitamins C and E (N=379) Placebo (N=383)
Age (years) 295 (56) 296 (57)
Gestation (weeks) 143 (36) 142 (34)
Body-mass index (kg/m2) 276 (54) 274 (46)
Ethnic origin
White 364 (96%) 371 (97%)
Black 3 (1%) 4 (1%)
Asian 6 (2%) 5 (1%)
Other/not known 6 (2%) 3 (1%)
12 years or fewer in full-time education 140 (37%) 159 (42%)
Primigravida 190 (50%) 188 (49%)
Blood pressure (mm Hg)
Systolic 1192 (122) 1184 (116)
Diastolic 746 (87) 745 (84)
Antihypertensive treatment before this pregnancy 21 (6%) 40 (10%)
History of hypertension before pregnancy 46 (12%) 66 (17%)
History of pre-eclampsia in previous pregnancy 6 (2%) 20 (5%)
Diabetes
Duration (years) 140 (83) 150 (80)
HbA
1c
at randomisation (%) 72 (09) 72 (10)
Total daily insulin dose at randomisation (units) 58 (4473) 56 (4372)
Renal status before this pregnancy
Normal 355 (94%) 338 (88%)
Microalbuminuria 13 (3%) 23 (6%)
Macroalbuminuria 1 (<1%) 3 (1%)
24-h urinary protein more than 3 g per 24 h 0 4 (1%)
Not known 10 (3%) 15 (4%)
Albumin-to-creatinine ratio at randomisation (mg/mmol) 071 (038128) 073 (041195)
Current smoker 75 (20%) 74 (19%)
Taking aspirin at randomisation 28 (7%) 31 (8%)
Taking multivitamin supplements at randomisation 38 (10%) 35 (9%)
Data are mean (SD), number (%), or median (IQR).
Table 1: Baseline maternal characteristics
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262 www.thelancet.com Vol 376 July 24, 2010
Results
Figure 1 shows the trial prole. Of the 762 women
enrolled, 379 were randomly allocated to receive vitamins
C and E and 383 to placebo. Outcome data were available
for 761 women (379 vitamin, 382 placebo), and 749 women
were assessed for pre-eclampsia, by original assigned
group (375 vitamin, 374 placebo). There were 12 deviations
from the inclusion and exclusion criteriaeight women
were enrolled outside the 22-week cuto for gestation (all
were within 4 days of this threshold) and four patients
were later reclassied as having type 2 diabetes. All
12 women were included in the analysis.
Although most maternal baseline characteristics did
not dier between groups, history of pre-eclampsia,
hypertension, antihypertensive treatment, and micro-
albuminuria were more common in the placebo group
than in the vitamin group (table 1). On the basis of counts
of returned pills after delivery (or at the 34-week visit if
no count was available after delivery, n=45) from
618 women, 524 (85%) took at least 50% of their tablets,
434 (70%) took 80% or more, and 237 (38%) took all their
tablets; 17 (3%) did not take any. Estimated percentage
adherence did not dier between groups (vitamin C,
median 95% [IQR 75100] vs placebo, 96% [74100];
vitamin E, 93% [78100] vs placebo, 93% [74100]).
Overall, 127 (17%) women developed pre-eclampsia.
Risk of pre-eclampsia did not dier between vitamin and
placebo groups (table 2). There were no signicant
dierences between groups in risk of gestational
hypertension or birthweight lower than the tenth centile
for gestational age (table 2). PAI-1 to PAI-2 ratios did not
dier between groups at baseline (p=040), 26 weeks
(p=032), and 34 weeks (p=078) (gure 2).
We noted no signicant dierences between vitamin and
placebo groups for any maternal outcome, including
delivery after a hypertension-related admission before 34 or
37 weeks, but fewer babies were born preterm (<37 weeks
gestation) in the vitamin group than in the placebo group
(table 3). There were no signicant dierences between
vitamin and placebo groups for any clinical neonatal
outcome including fetal malformation, fetal loss, infant
death, or miscarriage. Rates of admission to neonatal care,
including intensive care, were similar in both groups, as
were rates of respiratory diagnoses and other complications
(table 3). Table 4 shows mean birthweights for both vitamin
and placebo groups; risk of birthweights of 2500 g or less
(RR 082, 95% CI 056120) and 4000 g or more (125,
095164) did not dier between groups. No signicant
dierences were found in SD scores for weight, length, or
head circumference between infants from each group at
birth or follow-up (table 4). We noted no adverse events or
side eects attributable to supplementation with vitamin C
or E in mothers or infants.
Mean plasma ascorbate concentrations (vitamin, 444
[SD 260] mol/L vs placebo, 442 [260] mol/L) and
cholesterol-corrected serum -tocopherol concentrations
(615 [124] mol/mmol vs 619 [120] mol/mmol) were
similar at baseline in both groups (gure 3). Blood
Vitamins C and E (N=379) Placebo (N=382) Risk ratio (95% CI) p value
Primary outcome
Pre-eclampsia* 57/375 (15%) 70/374 (19%) 081 (059112) 020
Secondary outcomes
Gestational hypertension* 42/375 (11%) 41/374 (11%) 102 (068153) 092
Birthweight lower than the tenth centile for gestational age
25
23/373 (6%) 36/372 (10%) 064 (039105) 008
Data are n/N (%) or risk ratio (95% CI). *Analysis included all pregnancies greater than 20 weeks gestational age.
Table 2: Primary and secondary clinical outcomes
Figure 2: PAI-1 to PAI-2 ratio by weeks gestation
PAI-1 to PAI-2 ratio in vitamin and placebo groups at baseline, 26 weeks, and 34 weeks gestation (within 2 weeks).
Boxes show IQRs, and medians are shown by horizontal lines. Vertical lines extend to the highest and lowest values,
but outliers (results exceeding the upper quartile by more than 15 times the IQR) are identied as individual symbols.
Values greater than 5 are shown by arrows at the top of the gure. PAI=plasminogen activator inhibitor.
P
A
I
-
1

t
o

P
A
I
-
2

r
a
t
i
o
4
2
1
05
025
Vitamins Placebo
Treatment group
Gestation (weeks)
Baseline
2428
3236
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Vitamins C and E (N=379) Placebo (N=382) Risk ratio (95% CI) p value
Maternal
Miscarriage 4/379 (1%) 4/382 (1%) 101 (025400) 100
Elective termination 1/379 (<1%) 5/382 (1%) 020 (002172) 022
Maternal death 0/379 1/382 (<1%) NA 100
Delivery following a hypertension-related admission
<34 weeks gestation 13/375 (3%) 12/374 (3%) 108 (050234) 084
<37 weeks gestation 43/375 (11%) 48/374 (13%) 089 (061131) 057
Obstetric complications
Eclampsia 1/375 (<1%) 2/374 (1%) 050 (005548) 062
HELLP syndrome 3/375 (1%) 2/374 (1%) 150 (025890) 100
Pulmonary oedema 1/375 (<1%) 2/374 (1%) 050 (005548) 062
Placental abruption 5/375 (1%) 7/374 (2%) 071 (023222) 056
PPROM (<37 weeks) 23/375 (6%) 31/374 (8%) 074 (044124) 025
Other adverse outcomes
DBP >110 mm Hg 13/374 (3%) 15/375 (4%) 087 (042180) 071
>5 g proteinuria per day 9/375 (2%) 9/373 (2%) 099 (040248) 099
Platelets <100 000 per mL 4/368 (1%) 4/366 (1%) 099 (025395) 100
Abnormal concentrations of alanine and aspartate aminotransferases 23/368 (6%) 33/371 (9%) 070 (042117) 017
Polyhydramnios 30/374 (8%) 26/373 (7%) 115 (069191) 059
Neonatal
Fetal loss or infant death
Late fetal loss 1/379 (<1%) 0/382 NA 100
Antepartum stillbirth 9/379 (2%) 8/382 (2%) 113 (044291) 079
Neonatal death 2/364 (1%) 3/366 (1%) 067 (011399) 100
Birthweight for gestational age
<5th centile 15/373 (4%) 24/372 (6%) 062 (033117) 014
>90th centile 199/373 (53%) 186/372 (50%) 107 (093123) 036
Gestational age at delivery
<28 weeks 5/375 (1%) 2/374 (1%) 249 (049128) 045
<34 weeks 35/375 (9%) 36/374 (10%) 097 (062151) 089
<37 weeks 126/375 (34%) 152/374 (41%) 083 (069100) 0046
Major fetal malformation 12/378 (3%) 17/382 (4%) 071 (035147) 036
Admission to neonatal intensive care unit
Overall 197/363 (54%) 205/365 (56%) 097 (085110) 061
Level 1 (intensive care) 28/363 (8%) 39/365 (11%) 072 (045115) 017
Level 2 (high dependency care) 42/363 (12%) 54/365 (15%) 078 (054114) 020
Level 3 (special care in NICU) 192/363 (53%) 197/365 (54%) 098 (086112) 077
Special care provided on postnatal ward 243/363 (67%) 225/365 (62%) 109 (097121) 014
Assisted ventilation (endotracheal tube) 20/364 (5%) 25/364 (7%) 080 (045141) 044
Phototherapy 68/362 (19%) 87/363 (24%) 078 (059104) 009
Respiratory distress syndrome 26/363 (7%) 32/364 (9%) 081 (050134) 042
Complications
Necrotising enterocolitis 0/362 3/365 (1%) NA 025
Seizures necessitating use of anticonvulsant drugs 3/362 (1%) 2/364 (1%) 151 (025897) 069
Retinopathy of prematurity 1/361 (<1%) 2/365 (1%) 051 (005555) 100
Bacteraemia (proven) 6/363 (2%) 14/364 (4%) 043 (017111) 007
Chronic lung disease* 2/363 (1%) 5/363 (1%) 040 (008205) 045
Data are n/N (%) or risk ratio (95% CI). HELLP=haemolysis, elevated liver enzymes, low platelets. PPROM=preterm premature rupture of membranes. DBP=diastolic blood
pressure. NICU=neonatal intensive care unit. *Chronic lung disease was dened as a need for oxygen at 36 weeks corrected age, for infants born at less than 32 weeks
gestation, or the need for oxygen after day 28 for infants born at 32 weeks gestation or more.
Table 3: Maternal and neonatal outcomes
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264 www.thelancet.com Vol 376 July 24, 2010
samples were available for plasma ascorbate analysis in
590 (77%) patients at 26 weeks (299 vitamin, 291 placebo)
and 511 (67%) at 34 weeks (263 vitamin, 248 placebo), and
for serum -tocopherol analysis in 614 (81%) patients at
26 weeks (309 vitamin, 305 placebo) and 536 (70%) at
34 weeks (267 vitamin, 269 placebo). Concentrations of
both vitamins were signicantly higher in the vitamin
group than in the placebo group at 26 weeks and
34 weeks gestation (p<00001) (gure 3).
Table 5 compares rates of pre-eclampsia in predened
subgroup analyses. Rates of pre-eclampsia did not vary
with baseline control of diabetes or baseline smoking
status. However, fewer women with baseline plasma
ascorbate concentrations lower than 10 mol/L
developed pre-eclampsia in the vitamin group than in
the placebo group. Furthermore, fewer women with
baseline serum -tocopherol of 35 mol/mmol
cholesterol developed pre-eclampsia in the vitamin
group compared with placebo.
Discussion
In this multicentre, randomised, placebo-controlled trial,
daily supplementation with vitamins C and E from early to
mid pregnancy did not reduce risk of pre-eclampsia,
gestational hypertension, or low birthweight infants in
women with type 1 diabetes, nor did it reduce the PAI-1 to
PAI-2 ratio, which is a measure of endothelial activation.
However, in two of 11 prespecied subgroup analyses, risk
of pre-eclampsia was signicantly reduced in women with
low antioxidant status at baseline who were randomly
allocated to the vitamin group compared with women of
similar antioxidant status assigned to placebo, although
the numbers were small and neither analysis was
signicant with the more stringent interaction test that is
recommended by CONSORT.
28
We noted no evidence that
antioxidant supplementation was associated with any harm
to mother or baby; indeed, almost all of the trends were in
the direction of benet to the supplemented group.
Several large trials of antioxidant supplementation for
prevention of pre-eclampsia in women at both low
22,23,24

and high risk have already been completed.
18,19,21,23
All used
similar doses of vitamins C and E, with women randomly
allocated to treatment groups in the late rst or second
Vitamins C and E Placebo Mean dierence (95% CI) p value
N Mean (SD) N Mean (SD)
Birthweight (g) 373 3435 (802) 372 3355 (800) 80 (35 to 195) 017
Birthweight SD score 372 137 (144) 371 128 (151) 009 (012 to 030) 039
Birth length SD score 231 130 (175) 222 139 (151) 008 (038 to 022) 060
Birth head circumference SD score 349 090 (125) 338 074 (128) 016 (003 to 035) 010
Follow-up weight SD score 292 072 (113) 289 061 (112) 011 (007 to 030) 023
Follow-up length SD score 264 071 (115) 261 051 (119) 021 (001 to 041) 004
Follow-up head circumference SD score 270 062 (110) 263 046 (129) 016 (004 to 037) 012
Data are number, mean (SD), or mean dierence (95% CI).
Table 4: Growth measures at birth and at postnatal follow-up (612 weeks of age)
Figure 3: Plasma ascorbate and serum -tocopherol concentrations, by
weeks gestation
Mean plasma ascorbate (A) and serum -tocopherol (B) concentrations in
vitamin and placebo groups at baseline, 26 weeks, and 34 weeks gestation
(within 2 weeks). Error bars show 95% CIs.
P
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8
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6
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Baseline 3236 2428
Gestation (weeks)
9
12
10
B
A
Vitamin
Placebo
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www.thelancet.com Vol 376 July 24, 2010 265
trimester. The ndings have been uniformly negative for
pre-eclampsia reported as a primary
18,19,21,22
or secondary
outcome.
23,24
Increased rates of low birthweight,
18

gestational hypertension,
23,24
fetal loss,
23
stillbirth
18
or
premature rupture of membranes
21,23
were reported by
investigators in some trials, but were not conrmed across
all studies, and thus their signicance remains uncertain.
A further di culty with some of these trials is the
heterogeneous nature of the population under study.
18,19,21,23

DAPIT diers from previous trials because it focused on
the role of antioxidants in a homogeneous group of
carefully characterised women with type 1 diabetes.
In agreement with the WHO trial,
19
and by contrast with
other trials,
18,2124
we noted no evidence of harm attributable
to antioxidant supplementation either in mothers or
infants. A Cochrane review of vitamin C supplementation
in pregnancy raised concerns about a possible increased
risk of preterm birth in women supplemented with
vitamin C alone or combined with other supplements.
29

In our trial, women assigned to the vitamin group were
less likely to deliver preterm (<37 weeks gestation) than
were women taking placebo. The VIP trial raised concerns
about the eect of antioxidant supplementation on growth
restriction in a subgroup of women with diabetes.
18
Our
trial, in a much larger diabetic population than the VIP
trial subgroup, did not conrm this nding. By contrast,
women in DAPIT assigned to receive vitamins tended to
have a reduced risk of having a baby with birthweight
lower than the tenth centile for gestational age.
Additionally, the small subgroup with diabetes in the VIP
trial contained women with either type 1 or type 2 diabetes,
whereas DAPIT recruited only women with type 1 diabetes.
Although the pathways involved in pathogenesis of pre-
eclampsia could dier between women with type 1 and
type 2 diabetes, the VIP result was more likely to have
been a chance nding, since the diabetes group in this
trial was one of nine subgroups analysed.
Women in our study with a low antioxidant status at
baseline (plasma ascorbate <10 mol/L or serum
-tocopherol 5 mol/mmol cholesterol) who were
assigned to receive vitamins had a reduced risk of pre-
eclampsia compared with similar women assigned to
receive placebo. Though small, these subgroups were
almost mutually exclusive. No analysis of this type has
been reported for previous trials. Previous negative studies
are likely to have been done in women with adequate
baseline antioxidant status.
18
The exception might have
been the WHO trial,
19
in which the study population was
from developing countries and which did not show any
benecial eect of antioxidant supplementation. However,
no measurements of ascorbate or -tocopherol were
available, and women were only presumed to have low
antioxidant status on the basis of data from previous studies
in the participating clinics. Recruitment of a su cient
cohort of women with low baseline antioxidant status to a
randomised trial to conrm our nding would be di cult.
However, further characterisation of these patients in an
eort to identify women potentially at risk of antioxidant
depletion in the clinical setting will be of interest.
Finally, how should these ndings be interpreted? The
initial report of a benecial eect of antioxidant vitamins
17

could have been a chance nding. Subsequent trials
recruited women with various risk factors for pre-eclampsia,
and the presence of disparate disease processes and thus
pathophysiology might have reduced likelihood of
identication of a treatment eect. Our study in a
homogeneous population of women with type 1 diabetes
oers additional insight into disease mechanisms. In
principle, the notion that oxidative stress is implicated in
pathogenesis of pre-eclampsia remains plausible, but the
benet of vitamin supplementation might be limited to
women with vitamin depletion; however, this idea needs
conrmation. Dietary intervention rich in various
antioxidants might have benets that cannot be replicated
by individual supplements. Alternatively, prescription of
antioxidant vitamins at 822 weeks gestation might be too
late to aect the pathological process for most patients with
diabetes. Antioxidant vitamins reduce rates of fetal
malformation in rats with experimentally induced diabetes;
30

however, testing of such a hypothesis in patients would
necessitate the introduction of supplementation before or
around conception in a much larger number of women.
Contributors
DRM, ISY, MJAM, DWMP, and JDW designed and promoted the study.
ISY sought ethics approval. VAH coordinated all aspects of the trial,
managed the data, and wrote the rst draft of the nal report.
CCP provided statistical advice and analysed the data. All authors helped to
prepare the nal report.
The DAPIT Study Group
Site research midwives or coordinators and principal investigators (number of
patients recruited shown in parentheses): Scotland L McErlean (research
midwife, Aberdeen), D W M Pearson (Aberdeen Maternity Hospital; 71),
E A Cameron, M H Crombie (research midwives, Dundee), G Leese
Vitamins C and E Placebo Risk ratio (95% CI) p value*
Baseline control of diabetes
HbA
1c
<7% 18/162 (11%) 25/156 (16%) 069 (039122) 020
HbA
1c
78% 16/115 (14%) 23/101 (23%) 061 (034109) 009
HbA
1c
>8% 11/49 (22%) 15/64 (23%) 096 (048190) 090
Baseline vitamin C status*
<10 mol/L 1/15 (7%) 6/13 (46%) 014 (002076) 003
1030 mol/L 9/76 (12%) 12/89 (13%) 088 (039197) 075
>30 mol/L 36/232 (16%) 44/221 (20%) 078 (052116) 022
Baseline vitamin E status
<3 mol/mmol cholesterol 0/3 0/2
35 mol/mmol cholesterol 4/48 (8%) 10/42 (24%) 035 (012097) 004
>5 mol/mmol cholesterol 41/281 (15%) 55/291 (19%) 077 (053112) 017
Smoker at baseline
Yes 8/74 (11%) 10/73 (14%) 079 (033189) 059
No 49/301 (16%) 60/301 (20%) 082 (058115) 024
Data are n/N (%) or risk ratio (95% CI). *Plasma ascorbate concentration. Serum -tocopherol concentration adjusted
for cholesterol.
Table 5: Rates of pre-eclampsia in 11 predened subgroups
Articles
266 www.thelancet.com Vol 376 July 24, 2010
(Ninewells Hospital; 16), B A Hamilton (research coordinator, Central
Scotland), A MacLeod, J D Walker (St Johns Hospital at Howden,
Livingston; 34), C Alexander, A W Patrick (Royal Inrmary of Edinburgh,
Edinburgh; 39), C Love, M W J Strachan (Western General Hospital,
Edinburgh; 16), R Lindsay, C B Lunan, F Mackenzie, K Paterson (Princess
Royal Maternity Hospital, Glasgow; 55), A D Cameron, M Small
(The Queen Mothers Maternity Hospital, Glasgow; 28), A P Gallagher,
J Gibson, S Pringle (Southern General Hospital, Glasgow; 31), D McLellan,
K McKenna (Wishaw General Hospital, Wishaw; 37); H D MacPherson,
P Holmes, L Buchanan, C Kelly (Stirling Royal Inrmary & Falkirk and
District Royal Inrmary; 17), P Allcoat (research nurse, Fife), R Urquhart
(Forth Park Maternity Hospital; 7); Northwest England S Hooper (research
midwife, Birmingham), F Dunne, H Gee (Birmingham Womens
Hospital; 32), A Basu (City Hospital), J Milles (Good Hope Hospital; 12),
C Balachandar (Walsall Hospital; 18), H Longworth (research midwife,
Liverpool), S Walkinshaw (Liverpool Womens Hospital; 40), I Casson
(University Hospital Aintree; 17), J Marshall (research midwife,
Manchester), M J A Maresh (St Marys Hospital for Women and Children;
52), R Young (Hope Hospital, Salford; 1); Northern Ireland C Corry,
U G Donnelly, O M King, A T Langan, S Loughridge (research midwives),
K Moles (Altnagelvin Area Hospital; 41), A Kennedy (Antrim Area
Hospital; 9), K Ritchie (Craigavon Area Hospital; 31), D R McCance,
S Tharma, A I Traub (Royal-Jubilee Maternity Service, Belfast; 135),
R Harper (Ulster Hospital, Dundonald; 23).
Collaborators: M Clark, A Szczepura (economic analysis), C C Patterson
(statistical analysis), A Hill (dietician), H Halliday (neonatologist),
M McFarland (trial pharmacist).
Clinical coordinating centre: V A Holmes, O M King, S Loughridge,
D R McCance, I S Young.
Central laboratory: H Krueger, C Mercer, L McGonigle, G C McKeeman,
C McMaster, J V Woodside, I S Young, A McGinty, K Pogue, P Johnston,
S E Gilchrist.
Trial steering committee: I Allen (chair), V A Holmes, M J A Maresh,
D R McCance, D W M Pearson, J D Walker, I S Young.
Independent data monitoring committee: D Elbourne (chair), R B Fraser,
E Hey.
Conicts of interest
We declare that we have no conicts of interest.
Acknowledgments
This study is funded by grants 067028/Z/02/Z and 083145/Z/07/Z from
The Wellcome Trust (registered charity number 210183). We thank the
Clinical Research Support Centre, The Royal Hospitals, Belfast, UK, and
the Centre for Public Health, Queens University Belfast, UK for their
assistance with data entry; Victoria Pharmaceuticals, The Royal Hospitals,
Belfast, UK for packaging and distribution of trial drugs; LifeScan Inc for
the supply of blood-glucose meters to trial participants; and Action on
Pre-eclampsia (registered charity number 1013557) for publicity.
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