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Dietary intake of vitamin C and vitamin E and the development of hypertensive disorders of pregnancy
European Journal of Obstetrics & Gynecology and Reproductive Biology 119 (2005) 67–71 www.elsevier.com/locate/ejogrb
Dietary intake of vitamin C and vitamin E and the development of hypertensive disorders of pregnancy Alice R. Rumbolda,*, Frederike H.E. Maatsb, Caroline A. Crowthera a
Department of Obstetrics and Gynaecology, Maternal and Perinatal Clinical Trials Unit, The University of Adelaide, South Australia, Australia b Erasmus University, Rotterdam, The Netherlands Accepted 29 June 2004
Abstract Objectives: To explore the relationship, if any, between dietary intake of the antioxidant vitamins C and E, and the development of preeclampsia and gestational hypertension. Study design: A prospective cohort study of pregnant women attending the antenatal clinic of the Women’s and Children’s Hospital in Adelaide, Australia, was carried out between April and July 2001. Women completed a semi-quantitative 116-item food frequency questionnaire (FFQ). Women’s medical records were viewed after birth to collect data on pregnancy outcomes. Relationships were explored through cross-tabulations, chi-square analysis, and adjustments were made for potential confounders using binary logistic regression. Results: A total of 299 women completed the FFQ. Median intake of vitamin C was 188 mg and for vitamin E was 6.74 mg. There was no relationship between the intake of vitamin C and hypertensive disorders of pregnancy. For vitamin E, being in the lowest quartile of intake, was associated with an increased risk of hypertensive disorders (RR 1.75, 95% CI 1.11–2.75, P = 0.02). This relationship was confirmed after adjusting for the confounding factors of maternal age and parity. Conclusions: Little support was found for a relationship between dietary intake of vitamin C and the development of hypertensive disorders of pregnancy. Low vitamin E intake was associated with a significant increase in the risk of hypertensive disorders of pregnancy, even after adjustments were made for confounding factors. Further research is required to investigate whether supplementation above dietary intake of antioxidant vitamins influences the risk of hypertensive disorders of pregnancy. # 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Antioxidants; Pre-eclampsia; Dietary intake; Vitamin C; Vitamin E
1. Introduction Hypertensive disorders of pregnancy are a leading cause of maternal and perinatal morbidity and mortality worldwide [1,2]. Hypertensive disorders of pregnancy include gestational hypertension, high blood pressure that arises after 20 weeks gestation, and pre-eclampsia, where high blood pressure is complicated with proteinuria [3]. Preeclampsia can involve multiple organ systems, where the * Corresponding author. Present address: Department of Obstetrics and Gynaecology, Women’s and Children’s Hospital, 72 King William Rd., North Adelaide, SA 5006, Australia. Tel.: +61 8 8161 7768; fax: +61 8 8161 7652. E-mail address: [email protected] (A.R. Rumbold).
liver, kidneys, brain and blood clotting system may be compromised. Women with severe pre-eclampsia may also experience life-threatening complications such as eclampsia and the HELLP syndrome (haemolysis, elevated liver enzymes and low platelet count). For the infant, preeclampsia is associated with pre-term birth and intrauterine growth restriction, which confer significant short- and longterm health consequences. Much focus has been placed on strategies aimed at preventing hypertensive disorders of pregnancy, with clinical trials evaluating calcium [4], antiplatelet agents [5] and fish oil [6]; however to date, no clear and effective strategy for prophylaxis has emerged. The cause of pre-eclampsia is unclear, although the aetiology is likely to be multi-factorial. A critical factor involved in the pathogenesis of pre-eclampsia is abnormal
0301-2115/$ – see front matter # 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2004.06.027
68
A.R. Rumbold et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 119 (2005) 67–71
implantation, resulting from inadequate cytotrophoblast invasion of the maternal spiral arteries [7]. Abnormal placental development may then occur along with a reduction in blood flow through the placenta and placental under perfusion. This under perfusion is likely to cause the release of particular ‘pre-eclamptic factors’ that target endothelial cells and act systemically to result in the maternal clinical syndrome [8]. Likely factors include inflammatory factors such as cytokines, as well as harmful reactive oxygen species, which contribute to a state of oxidative stress [7]. Oxidative stress has been implicated in the pathogenesis of pre-eclampsia, and refers to an imbalance in the concentrations of harmful oxidants, such as free radicals and the antioxidants available to counteract these harmful molecules. In oxidative stress, the pro-oxidant state is favoured. A pathogenic role for oxidative stress in preeclampsia is supported by the findings that women with established pre-eclampsia have decreased plasma and placental concentrations of both antioxidant enzymes such as superoxide dismutase and glutathione reductase [9], as well as the free radical scavenging antioxidants such as vitamin C and vitamin E [10,11]. Vitamin C has been proposed as the first antioxidant defence mechanism damaged in women with pre-eclampsia [12,10]. As vitamin C and vitamin E are unable to be produced endogenously by humans, the only source of these vitamins is through dietary intake. While decreased concentrations of antioxidants seen in women with pre-eclampsia are likely to be due to increased metabolism due to the demands of oxidative stress, little is known about whether dietary intake may influence the risk of oxidative stress and pre-eclampsia. One clinical trial evaluating vitamin C and vitamin E supplementation in women at high risk of developing preeclampsia has shown a promising reduction in the risk of pre-eclampsia [13], although the benefit for women at low risk is yet to be established. This study aimed to look at dietary intake of vitamin C and vitamin E during pregnancy in a prospective cohort of women. The aim was to explore the relationship, if any, between dietary intake of the antioxidant vitamins C and E, and the development of preeclampsia and gestational hypertension.
116-item food frequency questionnaire (FFQ) developed by Willet et al. [14,15]. This questionnaire asks about the average frequency of intake of over 100 foods, as well as information about type, dose and duration of use of vitamin and mineral supplements. This FFQ has been shown to accurately assess vitamin C and E intakes in the general population [14,16] and during pregnancy [17]. The FFQ was administered to determine frequency of food use for the preceding four weeks, to reduce the effect of variations in diet that have been observed during pregnancy [18]. The FFQ was self-administered, but the researcher was present during the assessment to answer any questions. If women were unable to fill the FFQ out themselves, the researcher would administer the FFQ. Immediately after completion of the FFQ, it was reviewed for missing responses. If any questions were unanswered, women were asked to complete the missing items. When approached in clinic, women were unaware that dietary information would be collected, and were therefore unlikely to alter their diet in anticipation. 2.1. Determination of outcomes Women’s medical records were reviewed after birth to collect pregnancy outcome data. Hypertensive disease was categorised according to criteria from the Australian Society for the Study of Hypertension in Pregnancy [3]. Gestational hypertension was considered to be hypertension arising after 20 weeks in pregnancy, namely a systolic blood pressure of 140 mm Hg and/or diastolic blood pressure of 90 mm Hg on two occasions more than 4 h apart. Pre-eclampsia was considered to be gestational hypertension associated with one or more of the following: proteinuria (300 mg protein in a 24-h urine collection or a spot protein/creatinine ratio of 30 mg/mmol), renal insufficiency (serum/plasma creatinine 0.09 mmol/L or oliguria), liver disease (raised serum transaminases and or severe epigastric pain), neurological problems (convulsions, hyperreflexia with clonus, severe headaches with hyperreflexia, persistent visual disturbances), haematological disturbances (thrombocytopenia, disseminated intravascular coagulation, haemolysis) or fetal growth restriction (birthweight <10th centile).
2. Methods
2.2. Statistical analysis
A total of 336 women attending the antenatal clinic between April and July 2001 at the Women’s and Children’s Hospital in Adelaide, Australia, were invited to participate in this study. Women were attending the antenatal clinic for routine antenatal care. Any English-speaking woman at any stage of her pregnancy was eligible to participate. This study was approved by the Research and Ethics Committee of the Women’s and Children’s Hospital, Adelaide. Women were interviewed after giving informed written consent. The interview initially involved collection of demographic data and then an assessment of diet using a
Women’s demographic characteristics were first explored using chi-square analysis for categorical variables and Student’s t-test for continuous variables. Intakes of vitamin C and vitamin E were categorised into quartiles of intake and relationships between quartile of intake and the development of hypertensive disease were explored using cross-tabulations and chi-square analysis. For vitamin E, intake was categorised into a binary outcome where quartile 1 of intake was compared with quartiles 2–4 combined. Using cross-tabulations, potential confounding factors were explored, where a confounder was defined as being
A.R. Rumbold et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 119 (2005) 67–71
associated with both vitamin C or E intake and the development of hypertensive disease. Factors investigated for confounding were: maternal age, parity, body mass index (BMI), pre-eclampsia in a previous pregnancy, preterm delivery in a previous pregnancy, family history of preeclampsia, smoking status, maternal race, maternal education status, postcode, first trimester nausea and first trimester bleeding. Where confounders were identified, adjustments were made using binary logistic regression. All analyses were performed using Statistical Packages for Social Sciences [19].
3. Results 301 of the 336 women eligible consented to participate in the study and completed the dietary assessment. Thirty-five women declined participation in the study. Pregnancy outcome data was available for 299 (99%) women. Of the 299 women, 38 women (12%) developed either gestational hypertension (20 women, 7%) or pre-eclampsia (17 women, 5%). Ten women had a history of chronic hypertension. Women’s demographic characteristics according to their hypertensive disease status are presented in Table 1. Women were between 15 and 44 years of age with a mean age of 28 years, mainly Caucasian (91%), married (89%) and nonsmokers (83%). There were six twin pregnancies, and no difference in the number of twins according to hypertensive disease status (P = 0.35). Women with hypertensive disease were more likely to have a higher BMI (P < 0.001), have previously had pre-eclampsia (P = 0.002) and for pregnancy outcomes, have their labour induced (P < 0.001) and give birth at an earlier gestational age (1 week) (P = 0.03). The mean gestation at completion of the FFQ was 30 weeks, and women with and without hypertensive disease completed the questionnaire at a similar gestational age (30.5 versus 31.7 weeks, P = 0.39). Use of dietary supplements was common with 199 women (66.5%) taking a dietary supplement during pregnancy, most often a range of multi-vitamins, or iron and/ or folic acid supplements. Women who developed hypertensive disease were less likely to report taking a dietary supplement in pregnancy (47% versus 69%, P = 0.007). The median intake and range of vitamin C was 188 mg (22–1340 mg). Excluding intake of vitamin C contributed from vitamin supplements, the median intake was 177 mg. The percentages of women with hypertensive disorders in each quartile of vitamin C intake are presented in Table 2, where quartile 1 represents the lowest intake and quartile four represents the highest intake. Using cross-tabulation and chi-square analysis, no relationship was found between intake of vitamin C and the development of hypertensive disorders of pregnancy (x2 =3.02, P = 0.4). After exploring for potential confounders, calorie intake was the only factor associated with vitamin C intake, which would be expected. However, as there was no association identified between calorie intake and hypertensive disease,
69
Table 1 Demographic characteristics of women with and without hypertensive disorders of pregnancy
Maternal age (yrs)* Primiparous Race Caucasian Other Smoker Use of dietary supplements BMI <20 20–24 25–29 30 Previous PEy PE family history Gestation at delivery (wks)* Pre-term birth (<37 wks) Onset of delivery Spontaneous Induced No labour Mode of delivery Normal vaginal Forceps/ventouse LSCS Postpartum haemorrhage Postpartum pyrexia Maternal hospital stay >7 days Placental abruption Birth weightz Apgar <4 at 5 min Meconium-stained liquor SGA
No hypertensive disease
Hypertensive disease
n = 261
n = 38
%
P-value
%
28 127
5 49
28 21
5 55
ns ns
237 24 45 181
91 9 17 69
35 3 5 18
92 8 13 47
ns
9 93 50 32 9 13 39 6
5 50 27 17 7 5 1 2
0 6 10 16 6 2 38 1
0 19 31 50 35 5 1 2
<0.001
174 60 27
67 23 5
13 23 2
34 60 10
<0.001
162 34 71 23 6 4
61 13 26 9 2 2
19 10 9 6 0 0
50 26 24 16 0 0
ns
ns ns ns
1 3503 1 55 13
<1 482 <1 21 5
1 3585 0 7 2
2 598 0 18 5
ns ns ns ns ns
ns 0.007
0.002 ns 0.03 ns
Figures are n, % or *mean, S.D. yn = 151, zn = 305. ns = not statistically significant; PE = pre-eclampsia; LSCS = lower segment caesarean section; SGA = small-for-gestational-age.
no adjustments were made for calorie intake. Binary logistic regression including quartile of vitamin C intake and hypertensive disorders of pregnancy failed to support any relationship (P = 0.42). The median intake and range for vitamin E was 6.74 mg (2–408 mg). The median intake of vitamin E excluding Table 2 Incidence of hypertensive disorders of pregnancy according quartile of vitamin C intake Vitamin C intake
Quartile Quartile Quartile Quartile
1 2 3 4
No hypertensive disorder
Hypertensive disorders of pregnancy
Total (n = 299)
n = 261
%
n = 38
%
64 62 69 66
86 83 92 88
10 13 6 9
14 17 8 12
74 75 75 75
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A.R. Rumbold et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 119 (2005) 67–71
Table 3 Incidence of hypertensive disorders of pregnancy according to quartile of vitamin E intake Vitamin E intake
Quartile Quartile Quartile Quartile
1 2 3 4
No hypertensive disorder
Hypertensive disorders of pregnancy
n = 261
%
n = 38
%
59 68 68 66
80 91 91 88
15 7 7 9
20 9 9 12
Total (n = 299)
74 75 75 75
supplement use was 6.15 mg. Percentages of women with hypertensive disease in each quartile of vitamin E intake are presented in Table 3. Using cross-tabulations, low intake of vitamin E was associated with the development of hypertensive disease. After categorising intake into quartile 1 and combining quartiles 2–4, being in the lowest quartile was associated with a significantly increased risk of hypertensive disease (RR 1.75, 95% CI 1.11–2.75, P = 0.02). Using cross-tabulations, factors that were associated with vitamin E intake included parity, where nulliparity was associated with having a low intake; maternal age, where low maternal age was associated with low intake; and calorie intake, where as calorie intake increased, so did vitamin E intake. Factors that were associated with hypertensive disease include BMI, pre-eclampsia in a previous pregnancy, gestational age at delivery and onset of delivery. None of these factors were associated with vitamin E intake; however, because nulliparity and maternal age are known risk factors for hypertensive disease, these factors were considered to be confounders and adjusted for in the logistic regression. After completing these adjustments for parity and maternal age, the results did not change where being in the lowest quartile of vitamin E intake was associated with an increased risk of hypertensive disease (OR 2.23, 95% CI 1.08–4.58, P = 0.03).
4. Discussion These data suggest that having a very low intake of vitamin E in mid to late pregnancy is associated with an increased risk of pre-eclampsia and gestational hypertension. No relationship was demonstrated between intake of vitamin C and the risk of hypertensive disorders of pregnancy. To date there is conflicting evidence on the relationship with dietary intake of antioxidants such as vitamins C and E, and hypertensive disorders of pregnancy. Dietary intakes measured in the Calcium for Pre-eclampsia Prevention (CPEP) trial of 4313 women in the United States [20] found no significant association between hypertensive disorders of pregnancy and intake of any of the 23 nutrients measured, including vitamin C and vitamin E, when measured at entry into the CPEP trial (between 13 and 21 weeks gestation). In this trial, nulliparous women were
supplemented with 2 g calcium or placebo from early in pregnancy, and calcium was found to have no favourable effect on the risk of hypertensive diseases in pregnancy. As a result, the calcium supplements were not included in the overall nutrient totals and in the logistic regression analysis. In contrast, intake of vitamin C that is below recommended dietary intakes has been shown to be associated with a doubling in the risk of pre-eclampsia [21]. For other birth outcomes, Mathews et al. [22] demonstrated an independent association between vitamin C intake in early pregnancy and birth weight as well as an association between placental weight and intake of vitamin C, vitamin E and folate. One explanation for these conflicting findings may be in the methodology used to assess dietary intake, where some studies have used 24-h recall compared with a food frequency questionnaire, or it may be due to differences in the gestational age at the time of the dietary assessment. One potential limitation of the current study is error in women’s recall about their diet, however the researchers were present with the women during completion of the questionnaire and so were able to help prompt the women and further explain the questions. Similarly, due to the small numbers of women with hypertensive disease who were further divided into groups of intake, this study lacked statistical power to show small differences in vitamin intake. In this study, being in lowest quartile only of vitamin E intake was associated with hypertensive disease, which suggests a threshold effect of vitamin E intake and risk of hypertensive complications. However given the relatively small numbers of women with hypertensive disease in this study, a more linear increase in risk may be seen with larger numbers of women. The role of vitamin E in the development of pre-eclampsia remains controversial with conflicting findings to date. Zhang et al. [23] found a linear increase in risk of pre-eclampsia with increasing plasma concentrations of alpha-tocopherol (OR of the highest quartile 3.13, 95% CI 1.06–9.23, P = 0.04). Similarly, Schiff et al. [24] reported higher plasma vitamin E concentrations in women with pre-eclampsia and found no evidence that low vitamin E consumption was related to the development of pre-eclampsia. Higher plasma concentrations of vitamin E were speculated to represent a response to oxidative stress. While the role of vitamin E in the development of preeclampsia is not yet fully understood, this study will help to contribute evidence supporting the role of oxidative stress in pre-eclampsia. In general women in this study had a low intake of vitamin E, with the median intake of vitamin E being just below the recommended dietary intake for Australian women of 7 mg per day [25]. Intake of vitamin E was not greatly affected by the influence of dietary supplements, despite the relatively large use of dietary supplements in this cohort, with significantly more women who did not develop hypertensive disease taking a dietary supplement. This suggests that increasing consumption of foods rich in vitamin E may be an important public health campaign.
A.R. Rumbold et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 119 (2005) 67–71
This study contributes to the current literature in support of oxidative stress having a pathogenic role in the development of pre-eclampsia. We await further studies assessing the role of antioxidant supplementation in pregnancy in influencing the risk of hypertensive complications of pregnancy.
[11] [12]
[13]
Acknowledgements [14]
We gratefully acknowledge Kristyn Willson for advice on statistical analysis and all the staff at the Antenatal Clinic of the Women’s & Children’s Hospital, Adelaide.
[15]
References
[16]
[1] HMSO. Report on confidential enquiries into maternal deaths in the United Kingdom 1994–96. Department of Health Welsh Office, Scottish Office Home and Health Department, Department of Health and Social Security Northern Ireland. London: HMSO; 1998. [2] NHMRC. Report on maternal Deaths in Australia 1991–1993. Maternal Mortality Working Party, NHMRC; 1998. [3] Brown MA, Hague WM, Higgins J, Lowe S, McCowan L, Oats J, et al. The detection, investigation and management of hypertension in pregnancy: full consensus statement. Aust N Z J Obstet Gynaecol 2000;40(2):139–55. [4] Atallah AN, Hofmeyr GJ, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems (Cochrane Review), in: The cochrane library, no. 4. Oxford: Update Software; 2003. [5] Knight M, Duley L, Henderson-Smart DJ, King JF. Antiplatelet agents for preventing and treating pre-eclampsia (Cochrane review), in: The cochrane library, no. 4. Oxford: Update Software; 2003. [6] Olsen S, Secher NJ, Tabor A, Weber T, Walder JJ, Gluud C. Randomised clinical trials of fish oil supplementation in high risk pregnancies. Br J Obstet Gynaecol 2000;107:382–95. [7] Roberts JM, Cooper DW. Pathogenesis and genetics of pre-eclampsia. Lancet 2001;357:53–6. [8] Roberts JM, Lain KY. Recent insights into the pathogenesis of preeclampsia. Placenta 2002;23(5):359–72. [9] Wang Y, Walsh SW. Antioxidant activities and mRNA expression of superoxide dismutase, catalase, and glutathione peroxidase in normal and preeclamptic placentas. J Soc Gynecol Invest 1995;3:179–84. [10] Hubel CA, Kagan VE, Kisin ER, McLaughlin MK, Roberts JM. Increased ascorbate radical formation and ascorbate depletion in
[17]
[18]
[19] [20]
[21]
[22]
[23]
[24]
[25]
71
plasma from women with preeclampsia: implications for oxidative stress. Free Rad Biol Med 1997;23:597–609. Kharb S, Gulati N, Singh V, Singh GP. Lipid peroxidation and vitamin E levels in preeclampsia. Gynecol Obstet Invest 1998;46:238–40. Mikhail MS, Anyaegbunam A, Garfinkel D, Palan PR, Basu J, Romney SL. Preeclampsia and antioxidant nutrients: Decreased plasma levels of reduced ascorbic acid, a-tocopherol, and beta-carotene in women with preeclampsia. Am J Obstet Gynecol 1994; 171:150–7. Chappell LC, Seed PT, Briley AL, et al. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. Lancet 1999;354(9181):810–6. Willet WC, Sampson L, Stamper MJ, et al. Reproducibility and validity of a semiquantitive food frequency questionnaire. Am J Epidemiol 1985;122(1):51–65. Willet WC, Sampson L, Browne MJ, et al. The use of a selfadministered questionnaire to assess diet four years in the past. Am J Epidemiol 1988;127(1):188–99. Jacques PF, Sulsky SI, Sadowski JA, Philips JC, Rush D, Willett WC. Comparison of micronutrient intake measured by a dietary questionnaire and biochemical indicators of micronutrient status. Am J Clin Nutr 1993;57(2):182–9. Brown JE, Buzzard IM, Jacobs DR, et al. A food frequency questionnaire can detect pregnancy-related changes in diet. J Am Diet Assoc 1996;96(3):262–6. Launer LJ, Kardjati S, Kusin JA, Reed GF. Patterns of variability in the nutrient intake of nutritionally vulnerable pregnant women. Eur J Clin Nutr 1991 Mar;45(3):131–8. SPSS for Windows Release 9.0 SPSS, Inc. Morris CD, Jacobson S, Anand R, Ewell MG, Hauth JC, Curet LB, et al. Nutrient intake and hypertensive disorders of pregnancy: evidence from a large prospective cohort. Am J Obstet Gynecol 2001;184: 643–51. Zhang C, Williams MA, King IB, Dashow EE, Sorensen TK, Frederick IO, et al. Vitamin C and the risk of preeclampsia – results from dietary questionnaire and plasma assay. Epidemiology 2002;13(4):382–3. Mathews F, Yudkin P, Neil A. Influence of maternal nutrition on outcome of pregnancy: prospective cohort study. BMJ 1999;319: 338–43. Zhang C, Williams MA, Sanchez SE, King IB, Ware-Jauregui S, Larrabure G, et al. Plasma concentrations of carotenoids, retinol, and tocopherols in preeclamptic and normotensive pregnant women. Am J Epidemiol 2001;153(6):572–80. Schiff E, Friedman SA, Stampfer M, Kao L, Barrett PH, Sibai BM. Dietary consumption and plasma concentrations of vitamin E in pregnancies complicated by preeclampsia. Am J Obstet Gynecol 1996;175:1024–8. NHMRC. Recommended dietary intakes for use in Australia, vol. 42. Food Australia: 1989; p. 839–41.
Dietary intake of vitamin C and vitamin E and the development of hypertensive disorders of pregnancy Alice R. Rumbolda,*, Frederike H.E. Maatsb, Caroline A. Crowthera a
Department of Obstetrics and Gynaecology, Maternal and Perinatal Clinical Trials Unit, The University of Adelaide, South Australia, Australia b Erasmus University, Rotterdam, The Netherlands Accepted 29 June 2004
Abstract Objectives: To explore the relationship, if any, between dietary intake of the antioxidant vitamins C and E, and the development of preeclampsia and gestational hypertension. Study design: A prospective cohort study of pregnant women attending the antenatal clinic of the Women’s and Children’s Hospital in Adelaide, Australia, was carried out between April and July 2001. Women completed a semi-quantitative 116-item food frequency questionnaire (FFQ). Women’s medical records were viewed after birth to collect data on pregnancy outcomes. Relationships were explored through cross-tabulations, chi-square analysis, and adjustments were made for potential confounders using binary logistic regression. Results: A total of 299 women completed the FFQ. Median intake of vitamin C was 188 mg and for vitamin E was 6.74 mg. There was no relationship between the intake of vitamin C and hypertensive disorders of pregnancy. For vitamin E, being in the lowest quartile of intake, was associated with an increased risk of hypertensive disorders (RR 1.75, 95% CI 1.11–2.75, P = 0.02). This relationship was confirmed after adjusting for the confounding factors of maternal age and parity. Conclusions: Little support was found for a relationship between dietary intake of vitamin C and the development of hypertensive disorders of pregnancy. Low vitamin E intake was associated with a significant increase in the risk of hypertensive disorders of pregnancy, even after adjustments were made for confounding factors. Further research is required to investigate whether supplementation above dietary intake of antioxidant vitamins influences the risk of hypertensive disorders of pregnancy. # 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Antioxidants; Pre-eclampsia; Dietary intake; Vitamin C; Vitamin E
1. Introduction Hypertensive disorders of pregnancy are a leading cause of maternal and perinatal morbidity and mortality worldwide [1,2]. Hypertensive disorders of pregnancy include gestational hypertension, high blood pressure that arises after 20 weeks gestation, and pre-eclampsia, where high blood pressure is complicated with proteinuria [3]. Preeclampsia can involve multiple organ systems, where the * Corresponding author. Present address: Department of Obstetrics and Gynaecology, Women’s and Children’s Hospital, 72 King William Rd., North Adelaide, SA 5006, Australia. Tel.: +61 8 8161 7768; fax: +61 8 8161 7652. E-mail address: [email protected] (A.R. Rumbold).
liver, kidneys, brain and blood clotting system may be compromised. Women with severe pre-eclampsia may also experience life-threatening complications such as eclampsia and the HELLP syndrome (haemolysis, elevated liver enzymes and low platelet count). For the infant, preeclampsia is associated with pre-term birth and intrauterine growth restriction, which confer significant short- and longterm health consequences. Much focus has been placed on strategies aimed at preventing hypertensive disorders of pregnancy, with clinical trials evaluating calcium [4], antiplatelet agents [5] and fish oil [6]; however to date, no clear and effective strategy for prophylaxis has emerged. The cause of pre-eclampsia is unclear, although the aetiology is likely to be multi-factorial. A critical factor involved in the pathogenesis of pre-eclampsia is abnormal
0301-2115/$ – see front matter # 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2004.06.027
68
A.R. Rumbold et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 119 (2005) 67–71
implantation, resulting from inadequate cytotrophoblast invasion of the maternal spiral arteries [7]. Abnormal placental development may then occur along with a reduction in blood flow through the placenta and placental under perfusion. This under perfusion is likely to cause the release of particular ‘pre-eclamptic factors’ that target endothelial cells and act systemically to result in the maternal clinical syndrome [8]. Likely factors include inflammatory factors such as cytokines, as well as harmful reactive oxygen species, which contribute to a state of oxidative stress [7]. Oxidative stress has been implicated in the pathogenesis of pre-eclampsia, and refers to an imbalance in the concentrations of harmful oxidants, such as free radicals and the antioxidants available to counteract these harmful molecules. In oxidative stress, the pro-oxidant state is favoured. A pathogenic role for oxidative stress in preeclampsia is supported by the findings that women with established pre-eclampsia have decreased plasma and placental concentrations of both antioxidant enzymes such as superoxide dismutase and glutathione reductase [9], as well as the free radical scavenging antioxidants such as vitamin C and vitamin E [10,11]. Vitamin C has been proposed as the first antioxidant defence mechanism damaged in women with pre-eclampsia [12,10]. As vitamin C and vitamin E are unable to be produced endogenously by humans, the only source of these vitamins is through dietary intake. While decreased concentrations of antioxidants seen in women with pre-eclampsia are likely to be due to increased metabolism due to the demands of oxidative stress, little is known about whether dietary intake may influence the risk of oxidative stress and pre-eclampsia. One clinical trial evaluating vitamin C and vitamin E supplementation in women at high risk of developing preeclampsia has shown a promising reduction in the risk of pre-eclampsia [13], although the benefit for women at low risk is yet to be established. This study aimed to look at dietary intake of vitamin C and vitamin E during pregnancy in a prospective cohort of women. The aim was to explore the relationship, if any, between dietary intake of the antioxidant vitamins C and E, and the development of preeclampsia and gestational hypertension.
116-item food frequency questionnaire (FFQ) developed by Willet et al. [14,15]. This questionnaire asks about the average frequency of intake of over 100 foods, as well as information about type, dose and duration of use of vitamin and mineral supplements. This FFQ has been shown to accurately assess vitamin C and E intakes in the general population [14,16] and during pregnancy [17]. The FFQ was administered to determine frequency of food use for the preceding four weeks, to reduce the effect of variations in diet that have been observed during pregnancy [18]. The FFQ was self-administered, but the researcher was present during the assessment to answer any questions. If women were unable to fill the FFQ out themselves, the researcher would administer the FFQ. Immediately after completion of the FFQ, it was reviewed for missing responses. If any questions were unanswered, women were asked to complete the missing items. When approached in clinic, women were unaware that dietary information would be collected, and were therefore unlikely to alter their diet in anticipation. 2.1. Determination of outcomes Women’s medical records were reviewed after birth to collect pregnancy outcome data. Hypertensive disease was categorised according to criteria from the Australian Society for the Study of Hypertension in Pregnancy [3]. Gestational hypertension was considered to be hypertension arising after 20 weeks in pregnancy, namely a systolic blood pressure of 140 mm Hg and/or diastolic blood pressure of 90 mm Hg on two occasions more than 4 h apart. Pre-eclampsia was considered to be gestational hypertension associated with one or more of the following: proteinuria (300 mg protein in a 24-h urine collection or a spot protein/creatinine ratio of 30 mg/mmol), renal insufficiency (serum/plasma creatinine 0.09 mmol/L or oliguria), liver disease (raised serum transaminases and or severe epigastric pain), neurological problems (convulsions, hyperreflexia with clonus, severe headaches with hyperreflexia, persistent visual disturbances), haematological disturbances (thrombocytopenia, disseminated intravascular coagulation, haemolysis) or fetal growth restriction (birthweight <10th centile).
2. Methods
2.2. Statistical analysis
A total of 336 women attending the antenatal clinic between April and July 2001 at the Women’s and Children’s Hospital in Adelaide, Australia, were invited to participate in this study. Women were attending the antenatal clinic for routine antenatal care. Any English-speaking woman at any stage of her pregnancy was eligible to participate. This study was approved by the Research and Ethics Committee of the Women’s and Children’s Hospital, Adelaide. Women were interviewed after giving informed written consent. The interview initially involved collection of demographic data and then an assessment of diet using a
Women’s demographic characteristics were first explored using chi-square analysis for categorical variables and Student’s t-test for continuous variables. Intakes of vitamin C and vitamin E were categorised into quartiles of intake and relationships between quartile of intake and the development of hypertensive disease were explored using cross-tabulations and chi-square analysis. For vitamin E, intake was categorised into a binary outcome where quartile 1 of intake was compared with quartiles 2–4 combined. Using cross-tabulations, potential confounding factors were explored, where a confounder was defined as being
A.R. Rumbold et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 119 (2005) 67–71
associated with both vitamin C or E intake and the development of hypertensive disease. Factors investigated for confounding were: maternal age, parity, body mass index (BMI), pre-eclampsia in a previous pregnancy, preterm delivery in a previous pregnancy, family history of preeclampsia, smoking status, maternal race, maternal education status, postcode, first trimester nausea and first trimester bleeding. Where confounders were identified, adjustments were made using binary logistic regression. All analyses were performed using Statistical Packages for Social Sciences [19].
3. Results 301 of the 336 women eligible consented to participate in the study and completed the dietary assessment. Thirty-five women declined participation in the study. Pregnancy outcome data was available for 299 (99%) women. Of the 299 women, 38 women (12%) developed either gestational hypertension (20 women, 7%) or pre-eclampsia (17 women, 5%). Ten women had a history of chronic hypertension. Women’s demographic characteristics according to their hypertensive disease status are presented in Table 1. Women were between 15 and 44 years of age with a mean age of 28 years, mainly Caucasian (91%), married (89%) and nonsmokers (83%). There were six twin pregnancies, and no difference in the number of twins according to hypertensive disease status (P = 0.35). Women with hypertensive disease were more likely to have a higher BMI (P < 0.001), have previously had pre-eclampsia (P = 0.002) and for pregnancy outcomes, have their labour induced (P < 0.001) and give birth at an earlier gestational age (1 week) (P = 0.03). The mean gestation at completion of the FFQ was 30 weeks, and women with and without hypertensive disease completed the questionnaire at a similar gestational age (30.5 versus 31.7 weeks, P = 0.39). Use of dietary supplements was common with 199 women (66.5%) taking a dietary supplement during pregnancy, most often a range of multi-vitamins, or iron and/ or folic acid supplements. Women who developed hypertensive disease were less likely to report taking a dietary supplement in pregnancy (47% versus 69%, P = 0.007). The median intake and range of vitamin C was 188 mg (22–1340 mg). Excluding intake of vitamin C contributed from vitamin supplements, the median intake was 177 mg. The percentages of women with hypertensive disorders in each quartile of vitamin C intake are presented in Table 2, where quartile 1 represents the lowest intake and quartile four represents the highest intake. Using cross-tabulation and chi-square analysis, no relationship was found between intake of vitamin C and the development of hypertensive disorders of pregnancy (x2 =3.02, P = 0.4). After exploring for potential confounders, calorie intake was the only factor associated with vitamin C intake, which would be expected. However, as there was no association identified between calorie intake and hypertensive disease,
69
Table 1 Demographic characteristics of women with and without hypertensive disorders of pregnancy
Maternal age (yrs)* Primiparous Race Caucasian Other Smoker Use of dietary supplements BMI <20 20–24 25–29 30 Previous PEy PE family history Gestation at delivery (wks)* Pre-term birth (<37 wks) Onset of delivery Spontaneous Induced No labour Mode of delivery Normal vaginal Forceps/ventouse LSCS Postpartum haemorrhage Postpartum pyrexia Maternal hospital stay >7 days Placental abruption Birth weightz Apgar <4 at 5 min Meconium-stained liquor SGA
No hypertensive disease
Hypertensive disease
n = 261
n = 38
%
P-value
%
28 127
5 49
28 21
5 55
ns ns
237 24 45 181
91 9 17 69
35 3 5 18
92 8 13 47
ns
9 93 50 32 9 13 39 6
5 50 27 17 7 5 1 2
0 6 10 16 6 2 38 1
0 19 31 50 35 5 1 2
<0.001
174 60 27
67 23 5
13 23 2
34 60 10
<0.001
162 34 71 23 6 4
61 13 26 9 2 2
19 10 9 6 0 0
50 26 24 16 0 0
ns
ns ns ns
1 3503 1 55 13
<1 482 <1 21 5
1 3585 0 7 2
2 598 0 18 5
ns ns ns ns ns
ns 0.007
0.002 ns 0.03 ns
Figures are n, % or *mean, S.D. yn = 151, zn = 305. ns = not statistically significant; PE = pre-eclampsia; LSCS = lower segment caesarean section; SGA = small-for-gestational-age.
no adjustments were made for calorie intake. Binary logistic regression including quartile of vitamin C intake and hypertensive disorders of pregnancy failed to support any relationship (P = 0.42). The median intake and range for vitamin E was 6.74 mg (2–408 mg). The median intake of vitamin E excluding Table 2 Incidence of hypertensive disorders of pregnancy according quartile of vitamin C intake Vitamin C intake
Quartile Quartile Quartile Quartile
1 2 3 4
No hypertensive disorder
Hypertensive disorders of pregnancy
Total (n = 299)
n = 261
%
n = 38
%
64 62 69 66
86 83 92 88
10 13 6 9
14 17 8 12
74 75 75 75
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A.R. Rumbold et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 119 (2005) 67–71
Table 3 Incidence of hypertensive disorders of pregnancy according to quartile of vitamin E intake Vitamin E intake
Quartile Quartile Quartile Quartile
1 2 3 4
No hypertensive disorder
Hypertensive disorders of pregnancy
n = 261
%
n = 38
%
59 68 68 66
80 91 91 88
15 7 7 9
20 9 9 12
Total (n = 299)
74 75 75 75
supplement use was 6.15 mg. Percentages of women with hypertensive disease in each quartile of vitamin E intake are presented in Table 3. Using cross-tabulations, low intake of vitamin E was associated with the development of hypertensive disease. After categorising intake into quartile 1 and combining quartiles 2–4, being in the lowest quartile was associated with a significantly increased risk of hypertensive disease (RR 1.75, 95% CI 1.11–2.75, P = 0.02). Using cross-tabulations, factors that were associated with vitamin E intake included parity, where nulliparity was associated with having a low intake; maternal age, where low maternal age was associated with low intake; and calorie intake, where as calorie intake increased, so did vitamin E intake. Factors that were associated with hypertensive disease include BMI, pre-eclampsia in a previous pregnancy, gestational age at delivery and onset of delivery. None of these factors were associated with vitamin E intake; however, because nulliparity and maternal age are known risk factors for hypertensive disease, these factors were considered to be confounders and adjusted for in the logistic regression. After completing these adjustments for parity and maternal age, the results did not change where being in the lowest quartile of vitamin E intake was associated with an increased risk of hypertensive disease (OR 2.23, 95% CI 1.08–4.58, P = 0.03).
4. Discussion These data suggest that having a very low intake of vitamin E in mid to late pregnancy is associated with an increased risk of pre-eclampsia and gestational hypertension. No relationship was demonstrated between intake of vitamin C and the risk of hypertensive disorders of pregnancy. To date there is conflicting evidence on the relationship with dietary intake of antioxidants such as vitamins C and E, and hypertensive disorders of pregnancy. Dietary intakes measured in the Calcium for Pre-eclampsia Prevention (CPEP) trial of 4313 women in the United States [20] found no significant association between hypertensive disorders of pregnancy and intake of any of the 23 nutrients measured, including vitamin C and vitamin E, when measured at entry into the CPEP trial (between 13 and 21 weeks gestation). In this trial, nulliparous women were
supplemented with 2 g calcium or placebo from early in pregnancy, and calcium was found to have no favourable effect on the risk of hypertensive diseases in pregnancy. As a result, the calcium supplements were not included in the overall nutrient totals and in the logistic regression analysis. In contrast, intake of vitamin C that is below recommended dietary intakes has been shown to be associated with a doubling in the risk of pre-eclampsia [21]. For other birth outcomes, Mathews et al. [22] demonstrated an independent association between vitamin C intake in early pregnancy and birth weight as well as an association between placental weight and intake of vitamin C, vitamin E and folate. One explanation for these conflicting findings may be in the methodology used to assess dietary intake, where some studies have used 24-h recall compared with a food frequency questionnaire, or it may be due to differences in the gestational age at the time of the dietary assessment. One potential limitation of the current study is error in women’s recall about their diet, however the researchers were present with the women during completion of the questionnaire and so were able to help prompt the women and further explain the questions. Similarly, due to the small numbers of women with hypertensive disease who were further divided into groups of intake, this study lacked statistical power to show small differences in vitamin intake. In this study, being in lowest quartile only of vitamin E intake was associated with hypertensive disease, which suggests a threshold effect of vitamin E intake and risk of hypertensive complications. However given the relatively small numbers of women with hypertensive disease in this study, a more linear increase in risk may be seen with larger numbers of women. The role of vitamin E in the development of pre-eclampsia remains controversial with conflicting findings to date. Zhang et al. [23] found a linear increase in risk of pre-eclampsia with increasing plasma concentrations of alpha-tocopherol (OR of the highest quartile 3.13, 95% CI 1.06–9.23, P = 0.04). Similarly, Schiff et al. [24] reported higher plasma vitamin E concentrations in women with pre-eclampsia and found no evidence that low vitamin E consumption was related to the development of pre-eclampsia. Higher plasma concentrations of vitamin E were speculated to represent a response to oxidative stress. While the role of vitamin E in the development of preeclampsia is not yet fully understood, this study will help to contribute evidence supporting the role of oxidative stress in pre-eclampsia. In general women in this study had a low intake of vitamin E, with the median intake of vitamin E being just below the recommended dietary intake for Australian women of 7 mg per day [25]. Intake of vitamin E was not greatly affected by the influence of dietary supplements, despite the relatively large use of dietary supplements in this cohort, with significantly more women who did not develop hypertensive disease taking a dietary supplement. This suggests that increasing consumption of foods rich in vitamin E may be an important public health campaign.
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This study contributes to the current literature in support of oxidative stress having a pathogenic role in the development of pre-eclampsia. We await further studies assessing the role of antioxidant supplementation in pregnancy in influencing the risk of hypertensive complications of pregnancy.
[11] [12]
[13]
Acknowledgements [14]
We gratefully acknowledge Kristyn Willson for advice on statistical analysis and all the staff at the Antenatal Clinic of the Women’s & Children’s Hospital, Adelaide.
[15]
References
[16]
[1] HMSO. Report on confidential enquiries into maternal deaths in the United Kingdom 1994–96. Department of Health Welsh Office, Scottish Office Home and Health Department, Department of Health and Social Security Northern Ireland. London: HMSO; 1998. [2] NHMRC. Report on maternal Deaths in Australia 1991–1993. Maternal Mortality Working Party, NHMRC; 1998. [3] Brown MA, Hague WM, Higgins J, Lowe S, McCowan L, Oats J, et al. The detection, investigation and management of hypertension in pregnancy: full consensus statement. Aust N Z J Obstet Gynaecol 2000;40(2):139–55. [4] Atallah AN, Hofmeyr GJ, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems (Cochrane Review), in: The cochrane library, no. 4. Oxford: Update Software; 2003. [5] Knight M, Duley L, Henderson-Smart DJ, King JF. Antiplatelet agents for preventing and treating pre-eclampsia (Cochrane review), in: The cochrane library, no. 4. Oxford: Update Software; 2003. [6] Olsen S, Secher NJ, Tabor A, Weber T, Walder JJ, Gluud C. Randomised clinical trials of fish oil supplementation in high risk pregnancies. Br J Obstet Gynaecol 2000;107:382–95. [7] Roberts JM, Cooper DW. Pathogenesis and genetics of pre-eclampsia. Lancet 2001;357:53–6. [8] Roberts JM, Lain KY. Recent insights into the pathogenesis of preeclampsia. Placenta 2002;23(5):359–72. [9] Wang Y, Walsh SW. Antioxidant activities and mRNA expression of superoxide dismutase, catalase, and glutathione peroxidase in normal and preeclamptic placentas. J Soc Gynecol Invest 1995;3:179–84. [10] Hubel CA, Kagan VE, Kisin ER, McLaughlin MK, Roberts JM. Increased ascorbate radical formation and ascorbate depletion in
[17]
[18]
[19] [20]
[21]
[22]
[23]
[24]
[25]
71
plasma from women with preeclampsia: implications for oxidative stress. Free Rad Biol Med 1997;23:597–609. Kharb S, Gulati N, Singh V, Singh GP. Lipid peroxidation and vitamin E levels in preeclampsia. Gynecol Obstet Invest 1998;46:238–40. Mikhail MS, Anyaegbunam A, Garfinkel D, Palan PR, Basu J, Romney SL. Preeclampsia and antioxidant nutrients: Decreased plasma levels of reduced ascorbic acid, a-tocopherol, and beta-carotene in women with preeclampsia. Am J Obstet Gynecol 1994; 171:150–7. Chappell LC, Seed PT, Briley AL, et al. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. Lancet 1999;354(9181):810–6. Willet WC, Sampson L, Stamper MJ, et al. Reproducibility and validity of a semiquantitive food frequency questionnaire. Am J Epidemiol 1985;122(1):51–65. Willet WC, Sampson L, Browne MJ, et al. The use of a selfadministered questionnaire to assess diet four years in the past. Am J Epidemiol 1988;127(1):188–99. Jacques PF, Sulsky SI, Sadowski JA, Philips JC, Rush D, Willett WC. Comparison of micronutrient intake measured by a dietary questionnaire and biochemical indicators of micronutrient status. Am J Clin Nutr 1993;57(2):182–9. Brown JE, Buzzard IM, Jacobs DR, et al. A food frequency questionnaire can detect pregnancy-related changes in diet. J Am Diet Assoc 1996;96(3):262–6. Launer LJ, Kardjati S, Kusin JA, Reed GF. Patterns of variability in the nutrient intake of nutritionally vulnerable pregnant women. Eur J Clin Nutr 1991 Mar;45(3):131–8. SPSS for Windows Release 9.0 SPSS, Inc. Morris CD, Jacobson S, Anand R, Ewell MG, Hauth JC, Curet LB, et al. Nutrient intake and hypertensive disorders of pregnancy: evidence from a large prospective cohort. Am J Obstet Gynecol 2001;184: 643–51. Zhang C, Williams MA, King IB, Dashow EE, Sorensen TK, Frederick IO, et al. Vitamin C and the risk of preeclampsia – results from dietary questionnaire and plasma assay. Epidemiology 2002;13(4):382–3. Mathews F, Yudkin P, Neil A. Influence of maternal nutrition on outcome of pregnancy: prospective cohort study. BMJ 1999;319: 338–43. Zhang C, Williams MA, Sanchez SE, King IB, Ware-Jauregui S, Larrabure G, et al. Plasma concentrations of carotenoids, retinol, and tocopherols in preeclamptic and normotensive pregnant women. Am J Epidemiol 2001;153(6):572–80. Schiff E, Friedman SA, Stampfer M, Kao L, Barrett PH, Sibai BM. Dietary consumption and plasma concentrations of vitamin E in pregnancies complicated by preeclampsia. Am J Obstet Gynecol 1996;175:1024–8. NHMRC. Recommended dietary intakes for use in Australia, vol. 42. Food Australia: 1989; p. 839–41.