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Culture Documents
DOI: 10.1111/j.1471-0528.2009.02150.x
www.blackwellpublishing.com/bjog
vitamin E.
Please cite this paper as: Klemmensen A, Tabor A, sterdal M, Knudsen V, Halldorsson T, Mikkelsen T, Olsen S. Intake of vitamin C and E in pregnancy
and risk of pre-eclampsia: prospective study among 57 346 women. BJOG 2009;116:964974.
Introduction
Pre-eclampsia is one of the most important causes of
maternal and perinatal morbidity and mortality.1 Preeclampsia is a syndrome that belongs to the group of
hypertensive disorders of pregnancy, which is defined as
hypertension in pregnancy appearing after the 20th gesta-
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Klemmensen et al.
covariate since Primiparity is a risk factor for the development of pre-eclampsia.21,22 Smoking which is known to
protect against pre-eclampsia23 was included as a categorical variable (nonsmokers according to both interviews,
occasional smokers (either not smoking every day or quit
smoking from the first to the second interview), daily
smokers (<15 cigarettes per day), daily smokers (15 cigarettes per day reported in both interviews). If smoking
data was only available from the first interview, smoking
status was based on this information only. Maternal age
(years) at conception was included as a categorical variable
(20, 2139, 40).24 Maternal height (cm) has been shown
to influence the risk of pre-eclampsia25 and was divided
into quartiles (<165, 165168, 169172, 173). Heights
<140 cm were excluded. Body Mass Index (BMI) was
grouped as suggested by the National Board of Health,26
with reference to the World Health Organization recommendations.27 Socio-economic position was defined
according to the classification used by Statistics Denmark
called DISCO-88, a Danish version of the international
ISCO-88,28 which divides individuals into ten groups
according to their job description. Some of the groups
were collapsed, leaving a total of six groups, and those still
in education were placed between the group of skilled
workers and the group of unskilled workers rather than
below the group of unemployed. The womans social
status was coded as the maximum of her own and her
partners status (if the latter was available) and included
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Statistical methods
Initially, total vitamin intake (diet plus supplements) was
divided into five intervals with approximately the same
number of women in each interval. The lower intake group
was furthermore separated into two groups, according to
whether the intake was above or below the Nordic Recommended Dietary Allowance (NRDA) for pregnant women
(70 mg/day for vitamin C and 7 mg/day for vitamin E
(Nordic nutrient recommendations 1996,30), giving a total
Results
Mean intakes of vitamin C and E from the diet (energyadjusted) were estimated to be 131.3 mg (SD 74) and
6.87 mg (SD 1.54) (Table 1). The mean intakes from supplements of all types were estimated as 85.6 mg (SD 116.2)
and 10.8 (SD 21.0) for vitamin C and E respectively
Vitamin C
Mean
SD
Median
131.3
74.0
113.2
85.6
116.2
70.0
217.3
139.2
188.9
mg
mg
mg
n
<70
)130
)170
)210
)275
>275
Vitamin E
Mean
SD
Median
mg
mg
mg
mg
mg
mg
9292
25 512
10 243
5160
4275
2864
mg
mg
mg
mg
mg
mg
mg
mg
mg
16.2
44.5
17.7
9
7.5
5
20 761
21 969
3131
1645
569
1298
42
44.5
6.3
3.3
1.2
2.6
1297
7388
10 929
10 068
9985
9706
2.6
15
22.1
20.4
20.2
19.7
6.87
1.54
6.72
n
<7
)10.5
)13.5
)15.5
)18
>18
33 451
22 696
993
125
38
43
10.8
21.0
7.0
%
58.3
39.6
1.7
0.2
0.1
0.1
17.7
21.1
14.4
11 706
30 574
265
317
502
6009
23.7
61.9
0.5
0.6
1
12.2
4759
4165
10 350
10 700
10 083
9316
9.6
8.4
21
21.7
20.4
19
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Klemmensen et al.
Table 2. Crude associations between covariates and pre-eclampsia and covariates and vitamin intake
Pre-eclampsia
Severe pre-eclampsia/
eclampsia/ HELLP
Mean
Cases
OR (95% CI)
Cases
OR (95% CI)
Dietary
vitamin C
intake (mg)*
Dietary
vitamin E
intake (mg)*
21
1442
24
0.95 (0.62,1.48)
1 (ref.)
1.73 (1.15,2.62)
7
327
3
1.41 (0.66,2.98)
1 (ref.)
0.94 (0.30,2.93)
124.1
131.3
140.3
6.31
6.87
7.51
33
802
363
196
57
36
0.67 (0.47,0.96)
1 (ref.)
1.60 (1.41,1.81)
2.90 (2.47,3.41)
3.09 (2.34,4.08)
5.49 (3.86,7.80)
9
209
68
37
10
4
0.71 (0.36,1.38)
1 (ref.)
1.14 (0.86,1.50)
2.04 (1.43,2.89)
2.01 (1.06,3.80)
2.16 (0.80,5.82)
128.0
133.2
129.0
123.4
119.2
113.6
7.22
6.94
6.67
6.61
6.58
6.67
1187
178
102
20
1 (ref.)
0.90 (0.77,1.06)
0.66 (0.54,0.81)
0.72 (0.46,1.12)
288
26
20
3
1 (ref.)
0.54 (0.36,0.81)
0.54 (0.34,0.85)
0.45 (0.14,1.39)
134.1
130.8
115.6
98.8
6.88
6.91
6.80
6.70
387
387
373
340
1 (ref.)
0.92 (0.80,1.06)
0.90 (0.78,1.04)
0.76 (0.66,0.89)
105
78
85
69
1 (ref.)
0.68 (0.51,0.92)
0.76 (0.57,1.01)
0.57 (0.42,0.78)
129.3
130.5
132.2
132.8
6.83
6.86
6.89
6.90
1074
413
2.74 (2.44,3.07)
1 (ref.)
263
74
3.68 (2.83,4.77)
1 (ref.)
141.5
121.4
6.82
6.92
1 (ref.)
(1.07,1.43)
(1.09,1.47)
(0.91,1.52)
(1.27,1.84)
(0.65,1.69)
67
108
95
19
44
4
1.23
1.27
1.30
1.57
0.93
1 (ref.)
(0.90,1.66)
(0.93,1.73)
(0.79,2.16)
(1.07,2.29)
(0.34,2.56)
139.9
133.2
125.6
132.6
120.5
123.1
7.06
6.90
6.74
6.82
6.71
6.87
1060
420
7
1 (ref.)
1.05 (0.94,1.18)
1.01 (0.48,2.14)
240
95
2
1 (ref.)
1.05 (0.82,1.33)
1.28 (0.32,5.16)
130.0
134.4
136.9
6.88
6.84
6.83
1462
25
1 (ref.)
0.98 (0.66,1.47)
333
4
1 (ref.)
0.69 (0.26,1.85)
131.3
131.1
6.87
6.94
1 (ref.)
(0.80,1.30)
(1.01,1.42)
(0.86,1.20)
(0.79,1.18)
(0.74,1.39)
(0.90,1.95)
200
10
35
37
24
18
13
0.62
1.17
1.01
0.95
2.02
2.88
1 (ref.)
(0.33,1.18)
(0.82,1.68)
(0.71,1.43)
(0.62,1.45)
(1.25,3.29)
(1.64,5.07)
125.7
137.3
136.7
139.6
143.5
148.2
151.2
6.83
6.88
6.86
6.94
7.01
6.97
7.18
298
483
421
76
189
20
904
74
161
169
111
41
27
1.24
1.27
1.18
1.53
1.05
1.02
1.20
1.02
0.97
1.01
1.32
For pre-eclampsia associations, generalised estimating equations with independent working correlation were used. n = 57 346.
*Energy adjusted with the residual method.
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Table 3. Associations between risk of pre-eclampsia and intake levels of vitamin C and E
Pre-eclampsia
Cases n
OR (95% CI)
crude
OR (95% CI)
adjusted*
255
626
253
128
129
96
1.11 (0.93,1.33)
0.99 (0.86,1.15)
1 (ref.)
1.00 (0.81,1.25)
1.23 (0.99,1.52)
1.37 (1.08,1.73)
1.17 (0.98,1.41)
1.03 (0.89,1.20)
1 (ref.)
0.97 (0.78,1.20)
1.14 (0.92,1.42)
1.18 (0.93,1.51)
P = 0.91
P = 0.03/P = 0.05
P = 0.06/P = 0.09
P = 0.80/P = 0.56
872
593
20
2
1.30 (0.83,2.04)
1.31 (0.83,2.05)
1 (ref.)
0.48 (0.11,2.06)
32
193
276
261
253
279
126
111
270
287
236
264
Cases n
OR (95% CI)
crude
OR (95% CI)
adjusted*
58
150
62
31
21
15
1.03 (0.72,1.48)
0.97 (0.72,1.31)
1 (ref.)
0.99 (0.64,1.53)
0.81 (0.49,1.33)
0.86 (0.49,1.52)
1.21 (0.83,1.75)
1.08 (0.80,1.45)
1 (ref.)
0.92 (0.60,1.42)
0.72 (0.44,1.19)
0.70 (0.40,1.23)
P = 0.01
P = 0.71/P = 0.58
P = 0.04/P = 0.04
P = 0.01/P = 0.004
1.20 (0.77,1.88)
1.34 (0.85,2.11)
1 (ref.)
0.45 (0.10,1.96)
P = 0.33
P = 0.29/P = 0.71
P = 0.44/P = 0.74
P = 0.53/P = 0.40
181
149
6
1
0.89 (0.40,1.02)
1.09 (0.48,2.47)
1 (ref.)
0.80 (0.10,6.70)
0.78 (0.34,1.77)
1.07 (0.47,2.43)
1 (ref.)
0.70 (0.08,5.76)
P = 0.01
P = 0.51/P = 0.52
P = 0.23/P = 0.23
P = 0.05/P = 0.08
0.98 (0.67,1.43)
1.04 (0.86,1.25)
1 (ref.)
1.03 (0.87,1.22)
1.00 (0.84,1.19)
1.14 (0.97,1.35)
0.98 (0.64,1.49)
1.05 (0.86,1.28)
1 (ref.)
1.01 (0.85,1.20)
0.95 (0.80,1.13)
1.01 (0.85,1.21)
P = 0.75
P = 0.83/P = 0.34
P = 0.94/P = 0.53
P = 0.90/P = 0.86
9
48
65
66
53
60
1.17 (0.58,2.35)
1.09 (0.75,1.59)
1 (ref.)
1.10 (0.78,1.55)
0.89 (0.62,1.28)
1.04 (0.73,1.48)
1.27 (0.58,2.79)
1.14 (0.76,1.70)
1 (ref.)
1.06 (0.75,1.49)
0.80 (0.56,1.15)
0.85 (0.59,1.21)
P = 0.08
P = 0.05/P = 0.16
P = 0.11/P = 0.13
P = 0.64/P = 0.20
1.02 (0.82,1.26)
1.02 (0.81,1.28)
1 (ref.)
1.03 (0.87,1.22)
0.89 (0.75,1.07)
1.09 (0.92,1.29)
1.15 (0.90,1.48)
1.28 (1.01,1.63)
1 (ref.)
1.09 (0.92,1.29)
1.00 (0.84,1.20)
1.19 (1.00,1.42)
P = 0.86
P = 0.12/P = 0.71
P = 0.09/P = 0.87
P = 0.14/P = 0.90
30
29
56
69
53
64
1.17 (0.75,1.82)
1.29 (0.82,2.02)
1 (ref.)
1.19 (0.84,1.70)
0.97 (0.67,1.42)
1.27 (0.89,1.82)
1.26 (0.76,2.10)
1.53 (0.95,2.47)
1 (ref.)
1.27 (0.89,1.82)
1.10 (0.75,1.61)
1.46 (1.02,2.09)
P = 0.53
P = 0.45/P = 0.65
P = 0.60/P = 0.35
P = 0.27/P = 0.20
Vitamin intake is measured either as intake from diet alone (n = 57 346) or as total intake (diet plus supplements, n = 49 373). Generalised estimating equations with independent working correlation were used.
*Adjusted for maternal age, pre-pregnancy BMI, smoking, height, parity, socio-economic position, ownership of residence, marital status, physical
activity and intake level of either vitamin C or vitamin E.
**Intake levels coded 0,1,2,3,4,5 (vitamin C) or coded 0,1,2,3 (vitamin E).
***Spline model (restricted, cubic splines, knots at 5, 35, 65, 95 percentiles) versus linear model. Original scale/log scale.
****Spline model versus model including confounders only. Original scale/log scale.
*****Linear model versus model including confounders only. Original scale/log scale.
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Klemmensen et al.
Table 4. Associations between risk of pre-eclampsia and intake levels of fruit and selenium
Pre-eclampsia (all subgroups)
Cases n
OR (95% CI)
adjusted*
OR (95% CI)
adjusted**
1.19
0.95
1.07
1.15
1.07
1.06
0.93
1.11
0.96
0.86
0.87
0.99
Cases n
(0.99,1.42)
(0.79,1.14)
(0.89,1.28)
(0.97,1.36)
1 (ref.)
(0.90,1.27)
(0.89,1.26)
(0.78,1.10)
(0.94,1.31)
1 (ref.)
(0.81,1.13)
(0.73,1.02)
(0.74,1.03)
(0.84,1.16)
1 (ref.)
OR (95% CI)
adjusted*
OR (95% CI)
fruit adjusted**
1.28
0.96
1.12
1.41
(0.86,1.90)
(0.64,1.44)
(0.75,1.65)
(1.00,2.00)
1 (ref.)
1.02
1.06
0.82
1.09
(0.71,1.46)
(0.75,1.50)
(0.56,1.18)
(0.79,1.52)
1 (ref.)
0.85
0.98
0.79
0.91
(0.61,1.19)
(0.71,1.36)
(0.56,1.12)
(0.65,1.26)
1 (ref.)
1 (ref.)
1 (ref.)
1 (ref.)
n = 57 346. Generalised estimating equations with independent working correlation were used.
*Adjusted for maternal age, pre-pregnancy BMI, smoking, height, parity, socio-economic position, ownership of residence, marital status, physical
activity.
**Adjusted for maternal age, pre-pregnancy BMI, smoking, height, parity, socio-economic position, ownership of residence, marital status, physical activity and dietary intake of vitamin C and E.
(Table 1). When nutrient contributions from diet and supplements were aggregated, 2.6% (1297) and 9.6% (4759) of
the women had an intake of vitamin C and E below the
NRDA, respectively (Table 1). Only 0.52% of the women
had an intake of vitamin C at or above 1000 mg and only
two women had a vitamin E intake above 600mg, which
were the amounts given in recent trials.1012 Mean energy
intake was 10 269 kJ/day (SD 2431) (2454 kcal/day (SD
581)).
Dietary vitamin intake was clearly associated with age,
pre-pregnancy BMI, smoking, parity and socio-economic
status, whereas associations with mothers height, ownership of residence and marital status were weaker or nonexistent (Table 2). In univariate analyses, several of these
factors were associated with an increased incidence of preeclampsia and severe pre-eclampsia/eclampsia/HELLP. This
applied particularly to primiparity, non-smoking, low
height and pre-pregnant overweight or obesity (Table 2).
In the main study population of 57 346 women, there were
1487 (2.6%) cases of pre-eclampsia and 337 (0.6%) cases
of severe pre-eclampsia/eclampsia/HELLP.
When all types of pre-eclampsia were included as the
outcome variable, there was no evidence of an elevated risk
with decreasing levels of vitamin C intake. For severe
970
pre-eclampsia/eclampsia/ HELLP, there was a trend indicating a protective effect of dietary intake of vitamin C
(OR ranging from 1.21(0.83,1.75) to 0.70(0.40,1.23), trend
test P = 0.01) (Table 3). This trend became less clear,
when intake of vitamin C from supplements was included
(OR ranging from 1.27(0.58,2.79) to 0.85(0.59,1.21), trend
test P = 0.08) (Table 3). For total vitamin E intake, high
levels (>18 mg/day) were associated with a significantly
increased incidence of all types of pre-eclampsia (OR 1.19
(1.00, 1.42)) and an increased incidence of severe
pre-eclampsia/eclampsia/HELLP (OR 1.46 (1.02, 2.09))
(Table 3).
The trend in risk of severe pre-eclampsia/eclampsia/
HELLP versus intake levels of vitamin C from diet did not
depend on parity (interaction test P = 0.38) or BMI (interaction test with BMI dichotomised at 25.0 yielded a
P-value of 0.90). Potential interaction between vitamin C
and E was also explored; when total intake of vitamin C
and E were dichotomised at 275 mg and 18 mg respectively, there was no significant interaction between the two
vitamins, either for pre-eclampsia as a whole (P = 0.69) or
severe pre-eclampsia/eclampsia/HELLP (P = 0.90). When
dietary intake of vitamin C and E were dichotomised at
275 mg and 10.5 mg respectively, there was also no signifi-
2009 The Authors Journal compilation RCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology
Discussion
Our data could not confirm that a simultaneous, high
intake of both vitamin C and E reduces the risk of preeclampsia and this finding agrees with Poston et al.s recent
trial and Rumbold et al.s trial.11,12 Conversely, our data
suggest that, within the intake range of Danish women, the
risk of severe pre-eclampsia/eclampsia/HELLP may decrease
with increasing intake of vitamin C.
Strengths of our study include its size, its prospective
design and the general quality of data. The DNBC is so far
the largest birth cohort where dietary intake has been
assessed in pregnancy and the assessment was performed
prior to the typical onset of pre-eclampsia.
We have previously found good validity of estimated
intakes of some other vitamins (folate and retinol).32 The
FFQ was evaluated with a 7-day-weighed food diary and
the correlation ranged from 0.20 for retinol intake to 0.57
for folic acid intake. Moreover, the erythrocyte folate correlated significantly with the estimated total intake from
the FFQ (r = 0.55, P < 0.0001). This suggests that our estimations of vitamin C and E intake also have acceptable
validity.
Selection bias is always a potential problem in a study
such as this and may arise at recruitment or follow up.
During the recruitment period, approximately 35% of all
pregnant women in Denmark were enrolled into the
DNBC.13 Women who were enrolled were likely to have a
higher educational level and socio-economic status and
therefore perhaps a lower risk adverse pregnancy outcomes
such as pre-eclampsia. Such selection bias is likely to have
resulted in narrower exposure distributions and consequently lower statistical power. The prospective design of
this study should reduce this selection bias, however, as it
does not seem plausible that the likelihood of a woman
enrolling in the study in her first trimester is simultaneously associated with her vitamin intake in midpregnancy
and her risk of developing pre-eclampsia in the latter half
of pregnancy.
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Klemmensen et al.
972
Conclusions
Among 57 346 women from The Danish National Birth
Cohort, we had information on relevant confounders and
data on womens vitamin C and E intake over a 4-weekperiod in midpregnancy. Although overall there was no
correlation of vitamin C intake with the incidence of
pre-eclampsia, when the severe complications associated
with pre-eclampsia were considered, there was a trend
towards an increased incidence in these conditions in
women with low dietary vitamin C intake. We saw no such
trend for vitamin E; on the contrary, the incidence of severe
pre-eclampsia, HELLP or eclampsia was unexpectedly
increased in women consuming high amounts of vitamin E.
Disclosure of interests
There are no conflicts of interest (financial, personal, political, intellectual or religious interests).
Contribution to authorship
Ase K Klemmensen: Main author, contributed with validation of pre-eclampsia data from patient files and the general maintenance of data, contributed with main parts of
the text and revising the final paper.
Marie Louise sterdal: Main statistical management and
the general maintenance of data, contributed with parts of
the text and revising the final paper.
Ann Tabor: Contributed with parts of the text and revising the final paper.
Vibeke Kildegaard Knudsen: Contributed nutritional
expertise and wrote specific parts of the text.
Thorhallur Ingi Halldorsson: Statistical support and
management of the data sets.
Tina Broby Mikkelsen: Contributed nutritional
expertise.
Sjurdur Frodi Olsen: Contributed nutritional and epidemiological expertise and wrote parts of the text and
contributed with revising the final paper. Initiated the
study. Guarantor of study.
Funding
The study was supported by grants from the Danish Hospital Foundation for Medical Research in the Region of
2009 The Authors Journal compilation RCOG 2009 BJOG An International Journal of Obstetrics and Gynaecology
Acknowledgements
The study was supported by grants from The Danish Hospital Foundation for Medical Research in the Region of
Copenhagen, The Faeroe Islands and Greenland, the
Copenhagen Medical Society and by a grant from The
University of Copenhagen. In addition the Maternal Nutrition Group of the Danish National Birth Cohort has been
supported by the March of Dimes Birth Defects Foundation (6-FY-96-0240, 6-FY97-0553, 6-FY97-0521, 6-FY00407), EU (QLK1-CT-2000-00083), Danish National Research Foundation, Danish Medical Research Council
(9601842 and 22-03-0536), Danish Health Foundation (11/
263-96) and Danish Heart Foundation (96-2-4-83-22450).
Financial support for DNBC was also obtained from the
Danish National Research Foundation, Pharmacy Foundation, Egmont Foundation and Augustinus Foundation. The
Managerial Team of The Danish National Birth Cohort
consists of Jrn Olsen (Chair), Mads Melbye, Anne Marie
Nybo Andersen, Sjurdur F Olsen, Thorkild I.A. Srensen
and Peter Aabye.
Supporting information
The following supplementary materials are available for this
article:
Table S1. Sensitivity analysis. Women with chronic
hypertension and diabetes mellitus excluded. Associations
between risk of preeclampsia and intake levels of vitamin C
and E. Vitamin intake is measured either as intake from
diet alone (n = 56 448) or as total intake (diet plus supplements, n = 48 604). Generalised esimating equations with
independent working correlation were used.
Tables S2. Associations between risk of preeclampsia and
intake levels of vitamin C. Vitamin intake is measured either
as intake from diet alone (n = 57 346) or as total intake
(diet plus supplements, n = 49 373). Generalised esimating
equations with independent working correlation were used.
Additional Supporting Information may be found in the
online version of this article.
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