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Plasma Concentrations of Carotenoids, Retinol and Tocopherols in Preeclamptic and Normotensive Pregnant Women. Cuilin Zhang Department of Epidemiology University of Washington, Seattle, USA. BACKGROUND (1). Preeclampsia - pregnancy induced hypertension and proteinuria

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slide1

Plasma Concentrations of Carotenoids, Retinol and Tocopherols in Preeclamptic and Normotensive Pregnant Women

Cuilin Zhang

Department of Epidemiology

University of Washington, Seattle, USA

background 1
BACKGROUND (1)
  • Preeclampsia - pregnancy induced hypertension and proteinuria
    • One of the common medical complications in pregnancy;
    • One of the leading causes of maternal mortality in pregnancy;
    • An important cause of premature delivery, fetal growth retardation, perinatal mortality.
  • Etiology & Pathogenesis
    • Unsolved mysteries;
    • Endothelial cell dysfunction appears to be the final common pathway in the pathogenesis of preeclampsia.
slide3

BACKGROUND (2)

Figure 1: Framework of the Biological Background of the Study

Free Radicals

Scavenge

Inhibit

Promote

Evoke

  • Antioxidants
  • Carotenoids
  • Retinol
  • Tocopherols

Endothelial

Cell

Dysfunction

Preeclampsia

Reactive

Oxygen

Species

slide4

BACKGROUND (3)

Results from Previous Studies:

  • Imbalances between lipid peroxidation and antioxidant defenses in preeclampsia;
  • lower plasma -carotene, -carotene and retinol levels in preeclamptic women;
  • -tocopherol in preeclampia: parodoxical;
  • Reports concerning other lipid-soluble antioxidants in pregnancies complicated with preeclampsia are scarce;
hypothesis of this study
HYPOTHESIS OF THIS STUDY

Plasma concentrations of fat-soluble vitamins or their precursors and related antioxidants are decreased in women with preeclampsia.

objectives
OBJECTIVES

Examine the relation of plasma concentrations of carotenoids, tocopherols and retinol with the risk of preeclampsia while the effects of potential confounding factors were evaluated.

materials and methods 1
MATERIALS AND METHODS (1)
  • Case-control study
  • Conducted at the Maternal and Perinatal Hospital of Lima and the Dos de Mayo Hospital in Lima, Peru, June 1997 - January 1998.
  • Approved by the Ethical Committee of the Dos de Mayo Hospital, the Maternal Perinatal Hospital of Lima, and the Human Subjects Committee of the University of Washington Medical Center.
  • Potential study subjects - all new admissions to antepartum wards, emergency room wards, and labor and delivery wards of the study hospitals. Recruited during their hospital stay.
materials and methods 2
MATERIALS AND METHODS (2)
  • Definition of Cases
  • Cases- women with a diagnosis of preeclampsia.
  • Preeclampsia was defined as:
    • persistent (i.e. lasting more than 6 hours) 15 mm Hg diastolic rise or a 30 mm Hg rise in systolic blood pressure, or
    • persistent blood pressures of at least 140/90 mm Hg.
    • and urine protein concentration ( 30 mg/dl or more (or 1+ on a urine dipstick) in at least two random specimens collected at least 4 hours apart.
  • 193 (97% of 199 eligible cases approached) cases agreed to participate the study.
materials and methods 3
MATERIALS AND METHODS (3)

Definition of Controls

  • Controls- pregnant women uncomplicated by pregnancy-induced hypertension or proteinuria.
  • Controls were frequency matched to cases for gestational age of admission (within 2 weeks) and on maternal age (within 5 years).
  • 196 (96% of 204 eligible controls approached) controls agreed to participate the study.
materials and methods 4
MATERIALS AND METHODS (4)

Exclusion Criteria

Subjects with chronic hypertension prior to pregnancy;

Subjects whose blood samples were drawn during the intrapartum period or after delivery;

  • Overall, 125 preeclampsia cases and 179 normotensive controls comprised our study population .
materials and methods 5
MATERIALS AND METHODS (5)

Data Collection

Details regarding data collection methods have been previously described.

1. Sanchez SE, Zhang C, Williams MA, et al. J Repro Immu 2000;47: 49-63.

2. Sanchez SE, Zhang C, Malinow MR, et al. Am J Epidemiol (in press, 2000)

3. Ware-Jauregui S, Sanchez SE, Zhang C, et al. Int J Gynecol Obstet. 1999;67:147-55.

materials and methods 6
MATERIALS AND METHODS (6)
  • Standardized structured questionnaire, in-person interviews
  • Maternal and infant records were reviewed
  • Maternal anthropometric measures (height, weight and mid-arm circumference) were taken during participants' hospital stay
  • Gestational age-LMP, confirmed by ultrasound
  • Blood samples were stored at the Blood Bank Laboratory of Dos de Mayo Hospital after collection with standard method and then shipped to the United States for biochemical analyses
materials and methods 7
MATERIALS AND METHODS (7)

Laboratory Analyses

  • PHS Core Laboratory, Fred Hutchinson Cancer Research Center.
  • Antioxidant nutrients- high performance liquid chromatography (HPLC).
  • Plasma total cholesterol concentrations-enzymatically, standardized by the Lipid Standardization Program of the Centers for Disease Control and Prevention, Atlanta, GA.
  • All laboratory analyses were performed without knowledge of pregnancy outcome.
materials and methods 8
MATERIALS AND METHODS (8)

Statistical Analyses

  • Standard analysis of continuous data (i.e. means, SEM, Student's t test) was performed.
  • Comparisons of categorical variables were made between case and control subjects using Chi-squared or Fisher's exact tests.
  • Spearman's correlation coefficient was calculated to estimate the correlation between maternal plasma concentrations of antioxidant and cholesterol.
materials and methods 9
MATERIALS AND METHODS (9)
  • Statistical Analyses
  • Categorizing each subject according to quartiles determined by the distribution of antioxidant concentrations in controls. Using the lowest category as the referent group, odds ratios (i.e, estimates of relative risk) and their 95% CI were calculated.
  • Logistic regression procedures were used to calculate odds ratios adjusted by multiple confounding.
slide17

Table 1. Distribution of Preeclampsia Cases and Normotensive Control Subjects According to Selected Characteristics, Lima, Peru 1997-1998

Cases (N = 125) Controls(N = 179)

Characteristic n % n %

Maternal Age < 19 21 16.8 26 14.6

(years) 19-34 84 57.2 125 69.8

 35 20 16.0 28 16.1

Maternal Age (years)† 26.6  0.6 26.3  0.5

Maternal Race/Ethnicity

European Ancestry 10 8.0 17 9.5

African Ancestry 6 4.8 0 0.0

Inca Indian Ancestry 109 87.2 162 90.5

Unmarried 85 68.0 120 67.0

No Family Support 7 5.6 13 7.3

< 12 years Education 20 16.0 28 15.6

Nulliparous 59 47.2 57 31.8

No Prenatal Vitamins 53 42.4 69 38.5

Smoked During Pregnancy 1 0.8 4 2.2

Unplanned Pregnancy 39 31.2 42 23.5

Pre-pregnancy BMI*† 24.1  0.4 23.4  0.2

Gestational Age (weeks)† 36.0  0.3 37.3  0.3

Total Cholesterol (mmol/l)† 6.5  0.2 6.1  0.1

  • p-values < 0.05 for comparisons between preeclampsia cases versus controls.
  • *Pre-pregnancy body mass index = BMI = weight (kg)/height (m2).
  • †Mean  SEM
slide18
Table 2. Plasma Concentrations (mol/l) of Antioxidant Nutrients

among Preeclamptic and Normotensive Pregnant Women, Lima, Peru, 1997-1998

Antioxidan Cases Controls

Nutrients N=125 N=179

(mol/l) Mean ± SEM (Median) Mean ± SEM (Median) P-value

-carotene 0.122 ± 0.006 (0.110) 0.122 ± 0.005 (0.110) 0.977

-carotene 0.261 ± 0.014 (0.212) 0.258 ± 0.014 (0.220) 0.870

Lycopene 0.184 ± 0.012 (0.141) 0.193 ± 0.009 (0.160) 0.504

-cryptoxanthin 0.347 ± 0.023 (0.282) 0.428 ± 0.030 (0.271) 0.345*

Lutein 0.362 ± 0.014 (0.336) 0.347 ± 0.011 (0.329) 0.390

Zeaxanthin 0.073 ± 0.003 (0.067) 0.073 ± 0.002 (0.069) 0.990

Retinol 0.774 ± 0.038 (0.681) 0.871 ± 0.024 (0.855) <0.001

 -tocopherol 3.274 ± 0.144 (3.005) 2.976 ± 0.089 (2.753) 0.080

-tocopherol 25.448 ± 0.702 (24.526) 22.856 ± 0.464 (22.480) 0.002

-tocopherol ( µmol/l ) / cholesterol ( mmol/l )

3.961 ± 0.060 (3.890) 3.740 ± 0.043 (3.671) 0.033

P-values from Student’s t test.

* P-values from Mann-Whitney U test

slide19

Table 4. Odds Ratios (OR) and 95% Confidence Intervals (CI) of Preeclampsia According to Quartile of Maternal Plasma

Antioxidant Concentrations, Lima, Peru, 1997-1998

Antioxidants

Concentrations Cases Controls

(mol) n n OR (95% CI) OR (95% CI) † P-value*

-tocopherol

<18.337 22 46 1.00 referent 1.00 referent

18.337-22.480 26 44 1.24 (0.61, 2.52) 1.71 (0.75, 3.93)

22.481-26.013 27 45 1.26 (0.62, 2.54) 1.83 (0.70, 4.75)

>26.013 50 44 2.38 (1.23, 4.60) 4.98 (1.77,13.98) 0.003

*Adjusted P-value of test of linear trend.

†Adjusted for maternal age, nulliparity, pre-pregnancy body mass index (BMI) (quartile), use of prenatal vitamins, gestational age at blood collection, education, planned pregnancy, and total cholesterol concentration.

‡Adjusted for maternal age, nulliparity, pre-pregnancy BMI (quartile), use of prenatal vitamins, gestational age at blood collection, education, and planned pregnancy

slide20

Table 3. Odds Ratios (OR) and 95% Confidence Intervals (CI) of Preeclampsia According to Quartile of Maternal Plasma

Antioxidant Concentrations, Lima, Peru, 1997-1998

Antioxidants

Concentrations Cases Controls

(mol) n n OR (95% CI) OR (95% CI) † P-value*

Retinol

<0.642 57 47 1.00 referent 1.00 referent

0.642-0.855 25 44 0.44 (0.23, 0.82) 0.48 (0.24, 0.95)

0.856-1.082 20 45 0.36 (0.18, 0.70) 0.31 (0.14, 0.66)

>1.082 23 43 0.40 (0.21, 0.75) 0.32 (0.15, 0.69) 0.001

*Adjusted P-value of test of linear trend.

†Adjusted for maternal age, nulliparity, pre-pregnancy body mass index (BMI) (quartile), use of prenatal vitamins, gestational age at blood collection, education, planned pregnancy, and total cholesterol concentration.

‡Adjusted for maternal age, nulliparity, pre-pregnancy BMI (quartile), use of prenatal vitamins, gestational age at blood collection, education, and planned pregnancy

slide21

Table 5. Odds Ratios (OR) and 95% Confidence Intervals (CI) of Preeclampsia According to Quartile of Maternal Plasma

Antioxidant Concentrations, Lima, Peru, 1997-1998

Antioxidants

Concentrations Cases Controls

(mol) n n OR (95% CI) OR (95% CI) † P-value*

Ratio of -tocopherol (mol/l)/ total cholesterol (mmol/l)

<3.31 18 44 1.00 referent 1.00 referent‡

3.31-3.71 30 46 1.69 (0.82, 3.48) 1.73 (0.76, 3.92)

3.72-4.10 26 45 1.44 (0.68, 3.02) 1.85 (0.81, 4.24)

>4.10 50 44 2.88 (1.44, 5.76) 3.47 (1.60, 7.57) 0.002

*Adjusted P-value of test of linear trend.

†Adjusted for maternal age, nulliparity, pre-pregnancy body mass index (BMI) (quartile), use of prenatal vitamins, gestational age at blood collection, education, planned pregnancy, and total cholesterol concentration.

‡Adjusted for maternal age, nulliparity, pre-pregnancy BMI (quartile), use of prenatal vitamins, gestational age at blood collection, education, and planned pregnancy

results 2
RESULTS (2)
  • Summary of results
    • Plasma concentrations of retinol and (-tocopherol are associated with the risk of preeclampsia.
  • Retinol:
    • A negative relationship between plasma concentrations of retinol with risk of preeclampsia: mean value lower in cases; ORs decreased across increasing quartiles of plasma retinol concentrations.
results 3
RESULTS (3)
  • -tocopherol, ratio of -tocopherol to total plasma cholesterol concentrations :
    • A strong positive relationship between plasma concentrations of  -tocopherol with risk of preeclampsia: mean values- higher in cases; ORs of preeclampsia- increased with successively higher quartiles
  • No clear patterns of preeclampsia risk associated with plasma concentrations of -carotene, -carotene, -cryptoxanthin, lutein, lycopene, zeaxanthin, and -tocopherol, respectively.
discussion 1
DISCUSSION (1)
  • Potential Limitations & Strengths
  • Limitations
    • Cannot determine cause- effect sequence;
    • Lack of information pertaining to maternal dietary habits, limited our ability to assess maternal dietary intake of these antioxidants and risk of preeclampsia;
    • Unable to measure the co-antioxidants (-tocopherol- ascorbic acid), and antioxidant enzymes (i.e. superoxide dismutase and glutathione peroxidase).
discussion 2
DISCUSSION (2)
  • Strengths
    • Relatively large sample size
    • Adjusting for potential confounders, esp. gestational age at sample collection and plasma lipid level
    • Differential misclassification of maternal plasma antioxidant concentrations - unlikely
discussion 3
DISCUSSION ( 3 )

Explainations for possible pathophysiologic mechanisms for the observed puzzling association between -tocopherol and risk of preeclampsia

-- Compensatory increase in response to the elevated oxidative stress of preeclampsia

-- -tocopherol: antioxidant, prooxidant?

-- Altered placental physiology in preeclampsia

Preeclampsia-related placental abnormalities the transfer of maternal nutrients to the fetus

slide27

-tocopherol

(in vitro)

-- Mild oxidative condition

Prooxidant

Antioxidant

-- Strong oxidative condition or

-- Mild oxidative condition + high concentration of co- antioxidant (ascorbic acid,..)

TocH (-tocopherol) + R (free radical) RH + Toc  ( -tocopheroxyl radical)

Toc + R Non-radical products

Toc + AscH (Ascorbic acid) TocH + Asc 

Toc + LH (Lipid) TocH + L 

Anatol Kontush, etc. J. Lipid Research. 1996; 37: 1436-1448.

Bowry, V. W., etal. J. Am. Chem. Soc. 1993; 115:6029-6044.

Bowry, V. W., etal. Biochem. J. 1992; 288:341-344.

Bowry, V.W., etal. J. Biol. Chem. 1995; 270: 5756-5763.

Bisby, R. H., etal. Arch. Biochem. Biophys. 1995; 317: 170-178.

slide28

-tocopherol: antioxidant, prooxidant?

  • It is possible that under the physiological oxidative stress (if it is mild), commonly identified in preeclampsia, after -tocopherol co-antioxidants such as ascorbate acid are consumed, -tocopherol may act as a prooxidant rather than an antioxidant.
conclusion future studies
CONCLUSION & FUTURE STUDIES
  • Preeclampsia may not be a state of global antioxidant deficiency in maternal peripheral circulation.
  • Future prospective longitudinal studies involving measurements of concentrations of antioxidant nutrients and enzymes in blood and placental tissue and oxidative condition are needed to confirm and expand upon our findings.
acknowledgements 1
ACKNOWLEDGEMENTS (1)
  • This research was supported by awards from the National Institutes of Health (T37-TW00049 and HD/HL R01-32562).
  • Michelle A. Williams ScD. Department of Epidemiology, University of Washington, Seattle, WA, USA;
  • Irena B. King Ph.D. PHS Core Laboratory, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Wendy M. Leisenring, ScD. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Suzie Ware-Jauregui. School of Medicine, University of Washington, Seattle, WA, USA.
  • Sixto E. Sanchez MD, MPH. Dos de Mayo Hospital, Lima Peru.
  • Gloria Larrabure MD, Victor Bazul, MD. Materno-Perinatal Institute, Lima Peru.
  • The authors thank Mirtha Grande, Elena Sanchez,Nelly Toledo, Hong Tang, Mohammed Adem, and June Hu for their skillful technical assistance.