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Effects of a Combination of Evening Primrose Oil (Gamma Linolenic Acid) and Fish Oil (Eicosapentaenoic + Docahexaenoic Acid) versus Magnesium, and versus Placebo in Preventing PreEclampsia a
a
Arminda D'Almeida MPH , James P. Carter MD, DrPH , A. Anatol a
MD & Claude Prost MD
a
a
Nutrition Program, School of Public Health and Tropical Medicine, Tulane University Published online: 26 Oct 2008.
To cite this article: Arminda D'Almeida MPH , James P. Carter MD, DrPH , A. Anatol MD & Claude Prost MD (1992) Effects of a Combination of Evening Primrose Oil (Gamma Linolenic Acid) and Fish Oil (Eicosapentaenoic + Docahexaenoic Acid) versus Magnesium, and versus Placebo in Preventing PreEclampsia, Women & Health, 19:2-3, 117-131, DOI: 10.1300/J013v19n02_07 To link to this article: http://dx.doi.org/10.1300/J013v19n02_07
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Effects of a Combination of Evening Primrose Oil (Gamma Linolenic Acid) and Fish Oil (Eicosapentaenoic + Docahexaenoic Acid) versus Magnesium, and versus Placebo in Preventing Pre-Eclampsia Arminda D'Almeida, MPH James P. Carter, MD, DrPH A. Anatol, MD Claude Prost, MD
ABSTRACT. In a placebo controlled, partially double-blinded, clinical trial, a combination of evening primrose oil and fish oil was compared to Magnesium Oxide, and t o a Placebo in preventing PreArminda D' Almeida, lames P. Carter, A. Anatol, and Claude Pmst are affiliated with the Nutrition Program, School of Public Health and Tropical Medicine, Tulanc University, New Orleans, LA USA and with the M.O.H. Govcmment of the Republic of Angola, Luanda, Angola, Southern Africa. The authors would especially like to thank Dr. David Hombin, who is C.E.O. and Research Director of Efamol, LTD for his technical assistance, h a n cia1 support and for the provision of supplies by his Company. The logistical support of Mr. Chitlow on his staff was valuable especially during the civil war in Angola. We would also like to express our appreciation to Dr. Sylvio D'Almeida, MD, Dean of the Angola Medical School, and to Dr. Margaret Moore, the former for his encouragement and support, the latter for her valuable assistance with the dietary analyses. Finally, we would like to express our thanks to the many other students, health professionals and researchers who helped us in any way to complete this research under circumstances so difficult that others would not have dared to try. Women & Health, Vol. 19(2/3) 1992 0 1992 by The Haworth Press, Inc. All rights reserved.
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Eclampsia of Pregnancy. All were given as nutritional supplements for six months to a group of primiparous and multiparous pregnant women. Some of these women had personal or family histories of hypertension (21 96). Only those patients who received prenatal care at the Central Maternity Hospital for Luanda were included in the study. Compared to the Placebo group (29%), the group receiving the mixture of evening primrose oil and fish oil containing Gammalinolenic acid (GLA), Eicosapentaenoic acid (EPA), and Docosahexaenoic acid (DHA) had a significantly lower incidence of edema (1346, p = 0.004). The group receiving Magnesium Oxide had statistically significant fewer subjects who developed hypertension of pregnancy. There were 3 cases of eclampsia, all in the Placebo group.
INTRODUCTION AND REVIEW OF LITERATURE Despite increasing understanding of its pathophysiology, preeclampsia remains a common and potentially dangerous complication of pregnancy. Aside from general promotion by most obstetricians of a "balanced" but Standard American Diet Wrewer alone recommends a High Protein Diet), little has been done to influence its incidence. Toxemia, as it is sometimes called, or pre-eclampsia is defined as the simultaneous occurrence of the clinical triad of hypertension, edema and proteinuria, at any time during the course of the pregnancy. A great deal of research has focused on the idea that prostaglandins and thromboxane are involved in the development and clinical expression of pre-eclampsia. These prostaglandins are intense modulators of vascular smooth muscle tone and platelet aggregability. The mechanism by which this occurs is proposed to be through an imbalance between thromboxane A, and prostacyclin. 'OJ" Pre-eclampsia is characterized by increased vasoconstriction, Frequently associated with increased platelet aggregation, reduced uteroplacental blood flow, and premature delivery. Thromboxane A, and prostacyclin are both synthesized from arachidonic acid. However, they possess opposite physiological properties. Many studies suggest that the maintenence of normal vascular integrity is
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D Xbneida er al.
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dependent upon a balance between thromboxane A, and prostacyclin. Studies looking at patients with inhibition andlor deficiencies in crucial enzymes to the formation of either thromboxane or prostaglandins have given support to this idea. Thus, it appears that the manifestations of pre-eclampsia, platelet aggregation, and the occurrence of proteinuria may be coupled to an imbalance between these substances. Because there is evidence that prostacyclin deficiency is a specific feature in pre-eclampsia lo and because lower levels of this potent vasodilator and inhibitor of platelet activity could explain three of the most significant clinical consequences of toxemia: hypertension, platelet consumption, and reduced uteroplacental blood flow,9 it has been suggested by some investigators that increasing the levels of PGE,, which would be expected to produce similar effects to prostacyclin, l2 would offset the effects of prostacyclin deficiency, and correct the clinical manifestations of the syndrome. The fact that serum arachidonic acid levels are significantly lower in maternal phospholipids and cholesterol esters in normal pregnancy than in pre-eclampsia,'' suggests that a diet low in arachidonic acid might be protective against pre-eclampsia. Although linoleic acid from vegetable oils can be converted to arachidonic acid, it first must be converted in the body to gamma-linolenic acid (GLA). The enzyme deltaddesaturase @6D) is essential for this conversion. If this step is sluggish or defective, this reaction does not work. Many factors are known to block D6D, such as saturated fats, processed vegetable oils in which the fatty acids have been converted to the trans configuration, diabetes, obesity, and cigarette smoking. Furthermore, changes in $e renin-aldosterone system which occur in pre-eclampsia are now thought to be secondary to changes in prostaglandin production, based on the work of Pedersen et a l . I 8 Also, increased thromboxane A, production and normal prostacyclin production have been demonstrated in the placentae of hypertensive pregnancies. " Minus et al. have also demonstrated reduced excretion of vasodilator prostaglandins in pre-eclampsia. l3 Prostaglandin El (PGE,) is a vasodilator of the uterine artery. This has been demonstrated in a number of studies on dogs and rats, and has been summarized quite recently in a paper by Clifford et al.'
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PGE, as a vasodilator acts on the uterine arteries and the systemic circulation. It counteracts the pressor effects of norepinephrine1' and it also decreases platelet aggregation. An increased production of PGE, might, therefore, improve placental perfusion, reduce thrombotic complications, and thereby prevent or ameliorate many of the characteristic features and complications of pre-eclampsia. A controlled clinical trial of evening primrose oil (GLA) supplementation showed a significant reduction in blood pressure after six weeks.' Diets rich in linoleic acid also tend to reduce blood pressure.6 Pre-treatment with evening primrose oil (GLA) has been shown to reduce vascular response to both renin and angiotensin in rats.p Horrobin reports47 that evening primrose oil (GLA) supplementation appears to produce this benefit in the majority of patients with Raynaud's Syndrome, a vasospastic disorder which can be treated with intravenous PGE,.3 GLA supplementation also produces gradual effects which build up over several weeks, as tissue levels of dihomogammalinolenic acid @GLA) rise.s It, therefore, surely can be exploited as a preventive nutritional measure. Studies conducted by one of us, J.P.C.,at The Farm, a community of spiritually-gathered young people living in Summertown, TN, have shown that it is possible to sustain a perfectly normal pregnancy on a vegan diet, and that vegetable protein d o e not seem to affect birthweight differently than animal protein, if vegans are health conscious, receive continuous prenatal care, and supplement their diets with prenatal vitamins, calcium and iron. Since pre-eclampsia may be caused by a relative deficiency in prostacyclin levels, in the face of,excess thromboxane A, production, a strict vegan diet (low in arachidonic acid) might protect against this condition, especially if the conversion of linoleic acid to gammalinolenic acid is inhibited by a low activity of delta 6 dehydrogenase @6D), and the conversion of dihomogammalinolenic to arachidonic acid is inhibited by low activity of the enzyme delta 5 dehydrogenase @SD). When maternity care records of 775 strict vegan mothers, from The Farm, were analyzed for pre-eclampsia symptoms, only one met the clinical criteria'for the diagnosis of pre-eclampsia. This is an extremely low incidence, 0.13%,in comparison with any other hospital-based or population-based surveys taken anywhere in the U.S.
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MATERIALS AND METHODS This study was conducted at Maternidade Central de Luanda, Angola, during the time period from December, 1986 to March, 1987. One hundred and fifty pregnant volunteers were selected from a population of similar ethnic background and socio-economic status. The volunteers were randomized into three groups: (1) one group was a placebo (control) group; (2) the second group was an experimental group which received a mixture of evening primrose oil (GLA). plus fish oil (EPA & DHA); and (3) the third group received Magnesium Oxide. The patients were primiparous and multiparous, and also had to be in the first four months of pregnancy to be eligible to enroll in the program. A questionnaire was completed, an anthropometric nutritional assessment done, and informed consent was obtained on each potential participant. The study was a partially double-blinded one. The Magnesium Oxide tablets had a different appearance than the oil-containing capsules. The Center selected one hundred and fifty pregnant mothers for the study. Each pregnant mother was randomly assigned to Group I, 11, III, using a random numbers table. See Table I. The mixture of GLA, EPA, & DHA, and the Placebo capsules were packed in separate containers labeled from 1-100. The Magnesium Oxide was packed in separate containers labeled from 101150. The capsules of the combination of GLA, EPA, and DHA, and the capsules of Placebos were prepared by the Efamol Research Institute and Efamol, Ltd. in Nova Scotia and London, England, respectively. The patients in Groups I and II received, at the beginning of the supplementation period, 240 capsules (8 per day) and those in Group 111 received 60 Magnesium tablets a month (2 tablets per day of 500mg). The combination capsules contained 37mg GLA., 18mg EPA and lOmg DHA. The placebo capsules contained olive oil, without vitamin E. Patients were asked to remain on their "normal" diets during the trial, and to make no attempt to alter their lifestyles. The code of the capsules was not made known by the manufacturer, until the end of the treatment period.
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TABLE l Comparison of Nutrient Intakes by Group Using 24 Hour Dietary Recall
Means
GL4.EPA. Variable
'Kcal
1102.02
*Kcal
*Total Protein
41.424
*Total Protein
*Total Protein
13.574
Animal Protein
35.534
Animal Protein
Animal
9.212
Vegetable Protein
Vegetable Protein
Vegetable Protein
.
+ OHAbroup II
Placebo-Grou~I Variable
5.886
Means
MG-Group Ill Variable
Means
638.060
.Kcal
4.368
.Total Fat
61.370
'Total Fat
'Total Fat
Animal Fat
4.448
Animal Fat
Animal Fat
Fish Fat
6.680
Fish Fat
Fish Fat
0.946
Vegetable Fat
Vegetable Fat
28.240
Vegetable Fat
47.554
34 4.032
Hydr Fat
2.686
Hydr Fat
Hydr Fat
1.790
Palmitic
6.588
Palmitic
.Palmitic
3.674
Oleic
9.766
'Oleic
'Oleic
6.314
Linoleic
7.124
Linoleic
Linoleic
6.874
Linolenic
0.794
Liolenic
Linolenic
0.764
Arachidonic
2.214
Arachidonic
Arachidonic
0.308
Tot. Cholesterol
Tot. Cholesterol 72.906
Fiber
Fiber
3233.140
Vitamin A
Vitamin A
Vitamin 0,
0.000
Vitamin 8,
Vitamin 8,
0.000
Vitamin 8,
0.000
Vitamin 0,
Vitamin B,
0.000
Vitamin C
0.003
Vitamin C
Vitamin C
0.000
Tot. Cholesterol Fiber Vitamin A
101.540 8.308
4.050 1808.880
D Xlmeida er al. TABLE I CONTINUED Comparison of Nutrient Intakes by Group Using 24 Hour Dietary Recall
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PlaceboGroup I Variable
Means
GlA.EPA, Variable
+ DHA-Group I1 Means
MGGroup Ill Variable
Means
NUTRITIONAL ASSESSMENT
Before administering the supplements to the patients, they underwent an anthropometric nutritional assessment which included weight, triceps skinfold, and mid-arm circumference. Hemoglobin was also recorded. Theresa Oseiboma of the Charles Drew Medical School, based on a data set from pregnant women in Bangladesh, has suggested an appropriate cut-off point for the value of Mid-Arm Circumferences, in cm, for risk category of malnutrition, to be < 22. Viegas, Cole, and Wharton in 1987 published additional data on the value of measuring the Triceps Skinfold during the second ~ stated that if a pregnant mother does trimester of p r e g n a n ~ y .They not increase her triceps skinfold by > 20 micromillimeters per week during the 2nd trimester, she is considered nutritionally at risk of having a small baby.
Defined as the simultaneous occurrence of the clinical triad of hypertension, edema, and proteinuria at any time during the course of pregnancy.
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A. Hypertension. A rise in systolic BP greater than 30mm Hg andlor a rise in diastolic BP greater than 15mm Hg; either one or both, during the course of the pregnancy, consitutes pregnancy associated hyperten~ion.~ B. Proteinwia. Protein greater than one determined by test tape. C. Edema. Visible fluid accumulation in the ankles and feet; indentation produced by pressure applied by the thumb over the anterior surface of the tibia.
RESULTS Demographic Data: There were 150 subjects. Their ages ranged from 14-40 years. Fifty-four percent were married; forty-six percent were single. Sixty-nine percent were employed; ninety-four percent of their husbands were employed. Clinical Data: Sixty-seven percent of the subjects gave a recent history of malaria or a fever of unknown origin. Thirty-four percent gave a personal andlor family history of sicklecell trait or disease. Twenty-seven percent gave a history of anemia. Four percent had a history of previous premature labor and delivery, and twenty-one percent had a history of pregnancy-associated hypertension or other hypertensive disorder.
Side-Effectsof Nutritional Supplementation Group II, or the fatty acid supplemented group, had a significantly greater incidence of vomiting @ = .04625). More subjects in Group III, the Magnesium Oxide group, complained of diarrhea during the pregnancy @ = .0005)
Mothers' general condition was rated as Good, Fair, or Poor, based on the obstetrician's (A.A.) overall objective impression of nutritional status, mental alertness, stamina and presence or absence of infection, etc. Thirty-six percent were rated as Good. Sixty-one percent rated as Fair; and three percent rated as Poor.
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Comparing the overall effects of supplementation taken during six months of pregnancy, there were greater qualitative improvements in the condition of the mothers in Group II and 111, the fatty acid supplemented and the Magnesium supplemented groups, respectively, than in Group I, the Placebo group. There was a significant difference in weight gain between the 1st and 3rd trimesters. Subjects in the Magnesium supplemented group 111 gained less weight than subjects in either the fatty acid supplemented or the placebo groups (p = 0.00665). The average weight gains for groups I, 11, and 111 respectively, were 10.8, 8.5 and 5.8 Kg. According to guidelines from Oseiboma, Viegas et al., it can be shown that based on mid-arm circumference and triceps skinfold measurements there are individuals at high risk in all of the study groups. Group I, or the placebo group, however, has more malnourished subjects than Groups I1 and III (p = 0.220NS).
Pre-Edampsia, Eclampsia, and Pregnancy Outcome A rise in systolic BP greater than 30mm Hg andlor a rise in diastolic BP greater than 15mm Hg; either one or both, during the course of the pregnancy, constitutes pregnancy associated hypertension." A comparison of before and after BP, between the 1st and 3rd trimesters, by treatment group, reveals the number of cases in each group which meet one or both of the above criteria. See Table II below. There are more cases of pregnancy associated hypertension in the Placebo group or Group I. Group III, the Magnesium supplemented group, had the fewest number of cases of hypertension. The numbers of cases with edema in each group can be seen in Table III. The Placebo group had 29 cases of edema; the fatty acid supplemented group had 13 cases; the Magnesium group had 12 cases (p = .ooo45). Proteinuria occurred in 16.7% of the cases, and was evenly distributed across all three groups. Of those cases with the complete pre-eclampsia triad of edema, proteinuria, and hypertension, 5 cases occurred in Group I; 2 cases in Group 11; and 2 cases in Group III. Groups II and 111 both differ from Group I, therefore. Subjects who delivered with signs and
WOMEN & HEALTU TABLE II Comparison of differences between groups during the 1st and 3rd trimesters for participants who experienced a rise of SBP' > 3 0 and/or DBP' > 15.
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Group #
# of patients
% Total Group
Group Size
I
' SBP = Systolic Blood Pressure
' DBP = Diastolic Blood Pressure TABLE Ill
Distribution of edema by study group. Group # Edema
I
II
Ill
% Total
Present
29
13
12
36
Absent
21
37
38
54
Tofal
50
50
50
symptoms of pre-eclampsia were greater in the groups who received Placebo than in those who received fatty acid an Magnesium supplementation, @ = .0005)See Table IV. Severe eclampsia, with one or two convulsions, occurred only in Group I, the placebo group. There were three cases and all three women survived. See Table V. The babies' condition, after 24 hours, was evaluated on the basis of skin color, heart rate, respiratory effort and muscle tone and 86.7% were rated as Good; 11.3% were rated as Fair; 2% were rated as Poor. m e r e was no significant difference between groups.
D ;4lmeido et al. TABLE IV Those with signs and symptoms of Pre-Eclampsia and Eclampsia 'Pre-Eclampsia triad with edema. proteinuria. and hypertension.
I
Group #
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Severity of disease
I
II
111
% Total Population
Total
Mild
3
1
1
5
3
Moderate
1
0
1
2
1.3
Severe
1
1
o
2
1.3
TABLE V Eclampsia with one or t w o convulsion episodes and rise of SBP' > 3 0 andlor OBP' > 15
Mild
0
0
0
0.0
Moderate
0
0
0
0.0
Severe
3
0
0
2.1
' SBP = Systolic Blood Pressure
' DBP = Diastolic Blood Pressure I
In regard to birth weights, Groups I1 and III had more babies whose weights were > 3000gms than did Group I, the Placebo group. No data available on average fetal weights. See Table VI. DISCUSSION
The data from this study show that there is an increase of > 20 micromillimeters per week in triceps skinfold thickness during the second and third trimester in all three Groups, with Group I showing the greatest increase.
i . i
i
WOMEN
& HEALTH TABLE VI
Distribution of babies by weight and by group 2 4 hours after birth 1% total population in parenthesesl.
Group #
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Wtlgms
I
II
111
< 2000
513.31
2(1.31
7c4.7)
> 3000
1171
6141
6141
50
50
50
Number of babies
A comparison of nutrient intakes by Group, using 24 hr recall, is given in Table I. All three Groups had intakes of calories, protein, vitamins, and minerals much below the RDA's for pregnancy. If anything, Group I, the placebo group, had consistently higher intakes of most of the nutrients measured than either Group 11 or Group III. This study suggests that a mixture of the fatty acids GLA, EPA, & DHA, together with elemental Magnesium, might prevent pre-eclampsia of pregnancy. Previous observations made by Carter et al.' suggested that a Vegan diet which is low in arachidonic acid, might protect against pre-eclampsia, especially if the conversions of linoleic acid to GLA 'and of dihomogammalinolenic acid to arachidonic acid are inhibited by decreased activities of the enzymes deltaddehydrogenase and delta-Sdehydrogenase, respectively .lo Speculation about our results suggests that there is no significant difference in the incidence of pre-eclampsia between our subjects and pregnant populations surveyed in'communities in the West and other developing countries. An incidence of 8% as seen in our study is high, however, when compared to that seen among vegan mothers studied in Tennessee; but it is significantly lower than that seen in many other hospital based studies." Perhaps we should regard pre-eclampsia as a dietary-induced lifestyle disorder. Other lifestyle behaviors that could influence its
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occurrence include cigarette smoking and stress. We did not obtain smoking histories from these women. We also have no information about stressful life events. They were living in War Time. Their lifestyle was an active one, judging from the kinds of chores that the women undertook. Such a lifestyle would therefore be expected to contribute to a reduction in blood pressure, rather than to hypertension and pre-eclampsia. Three quarters of the fat in their diets came from vegetable sources. Twenty to thirty percent of the total was saturated and coming from palm oil, margarine, and a tiny amount of animal fat (not including fish sources). Perhaps this was enough to cause a relative excess of thromboxane A,, in the face of a relative deficiency of prostacyclin. However, every women in these studies consumed a relatively high quantity of fresh fish and fresh green leaves in their diets. There is some EPA and DHA in the fish, but there is very little arachidonic acid in plant products, with the exception of certain types of sea vegetation. This should have helped to offset the above postulated imbalance. The hypotensive effects of GLA and elemental Magnesium are consistent with previous reports that evening primrose oil can reduce vascular reactivity to pressor agentsI8 and can lower blood pressure in man.' They are also consistent with the clinical observation that Magnesium can lower blood pressure in the treatment of Eclampsia. The results of this study, while significant, are preliminary and indicate the need for further research, with modifications in location, design, and possibly duration. Since the risk of pre-eclampsia varies with parity and age, it would be beneficial to stratify the groups. A larger sample size, observed over a longer period of time would be helpful. Nevertheless, serious consideration should be given to adding GLA, EPA, DHA, and elemental Magnesium to either the diet, as natural foods, or to routine prenatal vitamin and mineral supplementation programs used by most obstetricians. This would be a more natural and physiological approach to correcting the imbalance in prostaglandins in pre-eclampsia, rather than prescribing aspirin from the 14th week of gestation, as is currently being recommended, with its inherent potential for side-effects.
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REFERENCES 1. Bansal, YP,PreeclampsialEclampsia: A profile from Pumwani, Maternity Hospital, Nairobi, Kenya. East Afr Med J 1965 Oct:62(10):691-8. 2. Carter, JP, MD, DrPH and Hutcheson RH, MD, MPH: Preeclampsia and Reproductive Performance in a Community of Vegans, Southern Medical Journal, June 1986. 3. Clifford PC, Martin, MFR, Sheddon, EJ, Kirby JD, Baird RN, Dicppe PA: Treatment of Vasospastic Disease with Prostaglandin E l , British Medical Journal 281: 1031, 1980. 4. Douglas, HC. Charmers, JG, et al: A Placebo-Contmlled Trail of Evening Primrose Oil in the Treatment of Human Obesity. In: Horrobiin DF ed. Clinical Uses of Essential Patty Acids. Montreal: Eden Ress, 1983, 63-71. 5. Garcia, CM. Carter, J. and Chou, A. Gamma linolenic acid causes weight loss and lower blood pressure in overweight patients, with family history of obesity. Swed. J. Biol. Med., April, 1986. 6. Horrobiin DF and Huang YS: The Role of linolcic acid and its metabolites in the lowering of plasma cholesterol and the prevention of cardiovascular disease. 1987, International Journal of Cardiology, 17: 241. 7. Hormbin DF. A new concept of lifestyle-related cardiovascular disease. The importance of interactions bemeen cholesterol, essential fatty acids, prostaglandin E,, and lhromboxanc A,. Med Hypotheses 6: 687-709, 1980. 8. Horrobin DF. Loss of delta 6 desaturase as a key factor in nutrition intervention. Mcd Hypotheses 7: 1219-28. 1987. 9. Kase, NG. Reyniak, JV:Endocrinology of pregnancy, Mount Sinai J Med 52: 11-34, 1985. 10. Makila UM. Vinikka L. Ylidorkala 0 : Evidence that Prostacyclin Deficiency is a Specific Feature in PKeclampsia. American Journal of Obstet-Gynecol 148:772-774, 1984. 11. Makila UM, V i L, Ylidorkala 0: Increased thromboxane A, Production but Normal Prostacyclin production by the Placenta in Hypertensive Pregnancies, Prostaglandins 1984 (27), 84-95. 12. McCarty MF: Nutritional Prevention of Preeclampsia-A Special Role for 1 Series Prostaglandin Precursors? Medical Hypotheses 9: 283-291, 1982. 13. Minuz, P., Covi, G., Corsato, M., Pmgitzer, P.. Spiazzi, L., Paluani, F., Degan, M., Lechi. C., and Lechi, A. Reduced Excretion of Vasodilator Prostaglandins in Preeclampsia, Agents Actions (Suppl) 1987 22: 175-81. 14. Moncada, Sand Vane, J.R. Pharmacology and endogenous roles of prostaglandin enoperoxides, thromboxane A,, and prostacyclin. Pharmacol Rev 30:293332, 1979. 15. O'Brien WF; Saba, HI; Knuppel RA, Sceho JC; Cohen GR. Alterations in platelet concentration and aggregation in normal pregnancy and preeclampsia. Am J Obstet Gynecol 1986 Sep; 155(3): 48690. 16. Oian, P, Kjeldsen SE, Eide I, Maltau JM. Increased arterial catecholamines in preeclampsia. Acta Obstet Gynecol Scand 1986; 65(1):11-3.
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17. Osbum, PL. Jr., Wfiams, PP, Johnsbn, SB: Serum Arachidonic Acid Levels in Normal and Preeclamptic Pregnancies. American Journal Obstet Gynecol 148: 5-9. 1984. 18. Pedersen, EB. Christensen, NJ. Christensen, P. et a].: Prostaglandins, renin, aldosterone, and catecholamines in p-larnpsia. Acta Med Scand 677 (suppl): 40-43, 1983. 19. Rosing U, Olund A. Serum Arachidonic acid levels (letter) Am J Obstet Gynecol 1985 Nov 15; 153(6): 713-4. 20. Report of a WHO Study Gmup, The hypertensive disorders of pregnancy, World Health Organization Technical Report Series, 758, 1987. 21. Schokens BA, Gehring D, Scholotte V et al.: Evening Primrose Oil, a Dietary Prostaglandin h u r s o r , Diminishes Vascular Reactivity in Rats. Prostaglandins Medical Joumal, 1982; 8:273-276. 22. Viegas, OAC, Cole, T.J.,and Whatton, BA: Impaired Fat Deposition in Pregnancy: An Indicator for Nutritional Intervention. American Journal of Clinical Nutrition 1987; 45: 23-28. 23. Walsh. SW: Precclampsia: an imbalance in placental pmstacyolin and thromboxane production, Am J. Obstet Gynecol 151:335-340, 1985
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Effects of a Combination of Evening Primrose Oil (Gamma Linolenic Acid) and Fish Oil (Eicosapentaenoic + Docahexaenoic Acid) versus Magnesium, and versus Placebo in Preventing PreEclampsia a
a
Arminda D'Almeida MPH , James P. Carter MD, DrPH , A. Anatol a
MD & Claude Prost MD
a
a
Nutrition Program, School of Public Health and Tropical Medicine, Tulane University Published online: 26 Oct 2008.
To cite this article: Arminda D'Almeida MPH , James P. Carter MD, DrPH , A. Anatol MD & Claude Prost MD (1992) Effects of a Combination of Evening Primrose Oil (Gamma Linolenic Acid) and Fish Oil (Eicosapentaenoic + Docahexaenoic Acid) versus Magnesium, and versus Placebo in Preventing PreEclampsia, Women & Health, 19:2-3, 117-131, DOI: 10.1300/J013v19n02_07 To link to this article: http://dx.doi.org/10.1300/J013v19n02_07
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Effects of a Combination of Evening Primrose Oil (Gamma Linolenic Acid) and Fish Oil (Eicosapentaenoic + Docahexaenoic Acid) versus Magnesium, and versus Placebo in Preventing Pre-Eclampsia Arminda D'Almeida, MPH James P. Carter, MD, DrPH A. Anatol, MD Claude Prost, MD
ABSTRACT. In a placebo controlled, partially double-blinded, clinical trial, a combination of evening primrose oil and fish oil was compared to Magnesium Oxide, and t o a Placebo in preventing PreArminda D' Almeida, lames P. Carter, A. Anatol, and Claude Pmst are affiliated with the Nutrition Program, School of Public Health and Tropical Medicine, Tulanc University, New Orleans, LA USA and with the M.O.H. Govcmment of the Republic of Angola, Luanda, Angola, Southern Africa. The authors would especially like to thank Dr. David Hombin, who is C.E.O. and Research Director of Efamol, LTD for his technical assistance, h a n cia1 support and for the provision of supplies by his Company. The logistical support of Mr. Chitlow on his staff was valuable especially during the civil war in Angola. We would also like to express our appreciation to Dr. Sylvio D'Almeida, MD, Dean of the Angola Medical School, and to Dr. Margaret Moore, the former for his encouragement and support, the latter for her valuable assistance with the dietary analyses. Finally, we would like to express our thanks to the many other students, health professionals and researchers who helped us in any way to complete this research under circumstances so difficult that others would not have dared to try. Women & Health, Vol. 19(2/3) 1992 0 1992 by The Haworth Press, Inc. All rights reserved.
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Eclampsia of Pregnancy. All were given as nutritional supplements for six months to a group of primiparous and multiparous pregnant women. Some of these women had personal or family histories of hypertension (21 96). Only those patients who received prenatal care at the Central Maternity Hospital for Luanda were included in the study. Compared to the Placebo group (29%), the group receiving the mixture of evening primrose oil and fish oil containing Gammalinolenic acid (GLA), Eicosapentaenoic acid (EPA), and Docosahexaenoic acid (DHA) had a significantly lower incidence of edema (1346, p = 0.004). The group receiving Magnesium Oxide had statistically significant fewer subjects who developed hypertension of pregnancy. There were 3 cases of eclampsia, all in the Placebo group.
INTRODUCTION AND REVIEW OF LITERATURE Despite increasing understanding of its pathophysiology, preeclampsia remains a common and potentially dangerous complication of pregnancy. Aside from general promotion by most obstetricians of a "balanced" but Standard American Diet Wrewer alone recommends a High Protein Diet), little has been done to influence its incidence. Toxemia, as it is sometimes called, or pre-eclampsia is defined as the simultaneous occurrence of the clinical triad of hypertension, edema and proteinuria, at any time during the course of the pregnancy. A great deal of research has focused on the idea that prostaglandins and thromboxane are involved in the development and clinical expression of pre-eclampsia. These prostaglandins are intense modulators of vascular smooth muscle tone and platelet aggregability. The mechanism by which this occurs is proposed to be through an imbalance between thromboxane A, and prostacyclin. 'OJ" Pre-eclampsia is characterized by increased vasoconstriction, Frequently associated with increased platelet aggregation, reduced uteroplacental blood flow, and premature delivery. Thromboxane A, and prostacyclin are both synthesized from arachidonic acid. However, they possess opposite physiological properties. Many studies suggest that the maintenence of normal vascular integrity is
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dependent upon a balance between thromboxane A, and prostacyclin. Studies looking at patients with inhibition andlor deficiencies in crucial enzymes to the formation of either thromboxane or prostaglandins have given support to this idea. Thus, it appears that the manifestations of pre-eclampsia, platelet aggregation, and the occurrence of proteinuria may be coupled to an imbalance between these substances. Because there is evidence that prostacyclin deficiency is a specific feature in pre-eclampsia lo and because lower levels of this potent vasodilator and inhibitor of platelet activity could explain three of the most significant clinical consequences of toxemia: hypertension, platelet consumption, and reduced uteroplacental blood flow,9 it has been suggested by some investigators that increasing the levels of PGE,, which would be expected to produce similar effects to prostacyclin, l2 would offset the effects of prostacyclin deficiency, and correct the clinical manifestations of the syndrome. The fact that serum arachidonic acid levels are significantly lower in maternal phospholipids and cholesterol esters in normal pregnancy than in pre-eclampsia,'' suggests that a diet low in arachidonic acid might be protective against pre-eclampsia. Although linoleic acid from vegetable oils can be converted to arachidonic acid, it first must be converted in the body to gamma-linolenic acid (GLA). The enzyme deltaddesaturase @6D) is essential for this conversion. If this step is sluggish or defective, this reaction does not work. Many factors are known to block D6D, such as saturated fats, processed vegetable oils in which the fatty acids have been converted to the trans configuration, diabetes, obesity, and cigarette smoking. Furthermore, changes in $e renin-aldosterone system which occur in pre-eclampsia are now thought to be secondary to changes in prostaglandin production, based on the work of Pedersen et a l . I 8 Also, increased thromboxane A, production and normal prostacyclin production have been demonstrated in the placentae of hypertensive pregnancies. " Minus et al. have also demonstrated reduced excretion of vasodilator prostaglandins in pre-eclampsia. l3 Prostaglandin El (PGE,) is a vasodilator of the uterine artery. This has been demonstrated in a number of studies on dogs and rats, and has been summarized quite recently in a paper by Clifford et al.'
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PGE, as a vasodilator acts on the uterine arteries and the systemic circulation. It counteracts the pressor effects of norepinephrine1' and it also decreases platelet aggregation. An increased production of PGE, might, therefore, improve placental perfusion, reduce thrombotic complications, and thereby prevent or ameliorate many of the characteristic features and complications of pre-eclampsia. A controlled clinical trial of evening primrose oil (GLA) supplementation showed a significant reduction in blood pressure after six weeks.' Diets rich in linoleic acid also tend to reduce blood pressure.6 Pre-treatment with evening primrose oil (GLA) has been shown to reduce vascular response to both renin and angiotensin in rats.p Horrobin reports47 that evening primrose oil (GLA) supplementation appears to produce this benefit in the majority of patients with Raynaud's Syndrome, a vasospastic disorder which can be treated with intravenous PGE,.3 GLA supplementation also produces gradual effects which build up over several weeks, as tissue levels of dihomogammalinolenic acid @GLA) rise.s It, therefore, surely can be exploited as a preventive nutritional measure. Studies conducted by one of us, J.P.C.,at The Farm, a community of spiritually-gathered young people living in Summertown, TN, have shown that it is possible to sustain a perfectly normal pregnancy on a vegan diet, and that vegetable protein d o e not seem to affect birthweight differently than animal protein, if vegans are health conscious, receive continuous prenatal care, and supplement their diets with prenatal vitamins, calcium and iron. Since pre-eclampsia may be caused by a relative deficiency in prostacyclin levels, in the face of,excess thromboxane A, production, a strict vegan diet (low in arachidonic acid) might protect against this condition, especially if the conversion of linoleic acid to gammalinolenic acid is inhibited by a low activity of delta 6 dehydrogenase @6D), and the conversion of dihomogammalinolenic to arachidonic acid is inhibited by low activity of the enzyme delta 5 dehydrogenase @SD). When maternity care records of 775 strict vegan mothers, from The Farm, were analyzed for pre-eclampsia symptoms, only one met the clinical criteria'for the diagnosis of pre-eclampsia. This is an extremely low incidence, 0.13%,in comparison with any other hospital-based or population-based surveys taken anywhere in the U.S.
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MATERIALS AND METHODS This study was conducted at Maternidade Central de Luanda, Angola, during the time period from December, 1986 to March, 1987. One hundred and fifty pregnant volunteers were selected from a population of similar ethnic background and socio-economic status. The volunteers were randomized into three groups: (1) one group was a placebo (control) group; (2) the second group was an experimental group which received a mixture of evening primrose oil (GLA). plus fish oil (EPA & DHA); and (3) the third group received Magnesium Oxide. The patients were primiparous and multiparous, and also had to be in the first four months of pregnancy to be eligible to enroll in the program. A questionnaire was completed, an anthropometric nutritional assessment done, and informed consent was obtained on each potential participant. The study was a partially double-blinded one. The Magnesium Oxide tablets had a different appearance than the oil-containing capsules. The Center selected one hundred and fifty pregnant mothers for the study. Each pregnant mother was randomly assigned to Group I, 11, III, using a random numbers table. See Table I. The mixture of GLA, EPA, & DHA, and the Placebo capsules were packed in separate containers labeled from 1-100. The Magnesium Oxide was packed in separate containers labeled from 101150. The capsules of the combination of GLA, EPA, and DHA, and the capsules of Placebos were prepared by the Efamol Research Institute and Efamol, Ltd. in Nova Scotia and London, England, respectively. The patients in Groups I and II received, at the beginning of the supplementation period, 240 capsules (8 per day) and those in Group 111 received 60 Magnesium tablets a month (2 tablets per day of 500mg). The combination capsules contained 37mg GLA., 18mg EPA and lOmg DHA. The placebo capsules contained olive oil, without vitamin E. Patients were asked to remain on their "normal" diets during the trial, and to make no attempt to alter their lifestyles. The code of the capsules was not made known by the manufacturer, until the end of the treatment period.
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TABLE l Comparison of Nutrient Intakes by Group Using 24 Hour Dietary Recall
Means
GL4.EPA. Variable
'Kcal
1102.02
*Kcal
*Total Protein
41.424
*Total Protein
*Total Protein
13.574
Animal Protein
35.534
Animal Protein
Animal
9.212
Vegetable Protein
Vegetable Protein
Vegetable Protein
.
+ OHAbroup II
Placebo-Grou~I Variable
5.886
Means
MG-Group Ill Variable
Means
638.060
.Kcal
4.368
.Total Fat
61.370
'Total Fat
'Total Fat
Animal Fat
4.448
Animal Fat
Animal Fat
Fish Fat
6.680
Fish Fat
Fish Fat
0.946
Vegetable Fat
Vegetable Fat
28.240
Vegetable Fat
47.554
34 4.032
Hydr Fat
2.686
Hydr Fat
Hydr Fat
1.790
Palmitic
6.588
Palmitic
.Palmitic
3.674
Oleic
9.766
'Oleic
'Oleic
6.314
Linoleic
7.124
Linoleic
Linoleic
6.874
Linolenic
0.794
Liolenic
Linolenic
0.764
Arachidonic
2.214
Arachidonic
Arachidonic
0.308
Tot. Cholesterol
Tot. Cholesterol 72.906
Fiber
Fiber
3233.140
Vitamin A
Vitamin A
Vitamin 0,
0.000
Vitamin 8,
Vitamin 8,
0.000
Vitamin 8,
0.000
Vitamin 0,
Vitamin B,
0.000
Vitamin C
0.003
Vitamin C
Vitamin C
0.000
Tot. Cholesterol Fiber Vitamin A
101.540 8.308
4.050 1808.880
D Xlmeida er al. TABLE I CONTINUED Comparison of Nutrient Intakes by Group Using 24 Hour Dietary Recall
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PlaceboGroup I Variable
Means
GlA.EPA, Variable
+ DHA-Group I1 Means
MGGroup Ill Variable
Means
NUTRITIONAL ASSESSMENT
Before administering the supplements to the patients, they underwent an anthropometric nutritional assessment which included weight, triceps skinfold, and mid-arm circumference. Hemoglobin was also recorded. Theresa Oseiboma of the Charles Drew Medical School, based on a data set from pregnant women in Bangladesh, has suggested an appropriate cut-off point for the value of Mid-Arm Circumferences, in cm, for risk category of malnutrition, to be < 22. Viegas, Cole, and Wharton in 1987 published additional data on the value of measuring the Triceps Skinfold during the second ~ stated that if a pregnant mother does trimester of p r e g n a n ~ y .They not increase her triceps skinfold by > 20 micromillimeters per week during the 2nd trimester, she is considered nutritionally at risk of having a small baby.
Defined as the simultaneous occurrence of the clinical triad of hypertension, edema, and proteinuria at any time during the course of pregnancy.
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A. Hypertension. A rise in systolic BP greater than 30mm Hg andlor a rise in diastolic BP greater than 15mm Hg; either one or both, during the course of the pregnancy, consitutes pregnancy associated hyperten~ion.~ B. Proteinwia. Protein greater than one determined by test tape. C. Edema. Visible fluid accumulation in the ankles and feet; indentation produced by pressure applied by the thumb over the anterior surface of the tibia.
RESULTS Demographic Data: There were 150 subjects. Their ages ranged from 14-40 years. Fifty-four percent were married; forty-six percent were single. Sixty-nine percent were employed; ninety-four percent of their husbands were employed. Clinical Data: Sixty-seven percent of the subjects gave a recent history of malaria or a fever of unknown origin. Thirty-four percent gave a personal andlor family history of sicklecell trait or disease. Twenty-seven percent gave a history of anemia. Four percent had a history of previous premature labor and delivery, and twenty-one percent had a history of pregnancy-associated hypertension or other hypertensive disorder.
Side-Effectsof Nutritional Supplementation Group II, or the fatty acid supplemented group, had a significantly greater incidence of vomiting @ = .04625). More subjects in Group III, the Magnesium Oxide group, complained of diarrhea during the pregnancy @ = .0005)
Mothers' general condition was rated as Good, Fair, or Poor, based on the obstetrician's (A.A.) overall objective impression of nutritional status, mental alertness, stamina and presence or absence of infection, etc. Thirty-six percent were rated as Good. Sixty-one percent rated as Fair; and three percent rated as Poor.
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Comparing the overall effects of supplementation taken during six months of pregnancy, there were greater qualitative improvements in the condition of the mothers in Group II and 111, the fatty acid supplemented and the Magnesium supplemented groups, respectively, than in Group I, the Placebo group. There was a significant difference in weight gain between the 1st and 3rd trimesters. Subjects in the Magnesium supplemented group 111 gained less weight than subjects in either the fatty acid supplemented or the placebo groups (p = 0.00665). The average weight gains for groups I, 11, and 111 respectively, were 10.8, 8.5 and 5.8 Kg. According to guidelines from Oseiboma, Viegas et al., it can be shown that based on mid-arm circumference and triceps skinfold measurements there are individuals at high risk in all of the study groups. Group I, or the placebo group, however, has more malnourished subjects than Groups I1 and III (p = 0.220NS).
Pre-Edampsia, Eclampsia, and Pregnancy Outcome A rise in systolic BP greater than 30mm Hg andlor a rise in diastolic BP greater than 15mm Hg; either one or both, during the course of the pregnancy, constitutes pregnancy associated hypertension." A comparison of before and after BP, between the 1st and 3rd trimesters, by treatment group, reveals the number of cases in each group which meet one or both of the above criteria. See Table II below. There are more cases of pregnancy associated hypertension in the Placebo group or Group I. Group III, the Magnesium supplemented group, had the fewest number of cases of hypertension. The numbers of cases with edema in each group can be seen in Table III. The Placebo group had 29 cases of edema; the fatty acid supplemented group had 13 cases; the Magnesium group had 12 cases (p = .ooo45). Proteinuria occurred in 16.7% of the cases, and was evenly distributed across all three groups. Of those cases with the complete pre-eclampsia triad of edema, proteinuria, and hypertension, 5 cases occurred in Group I; 2 cases in Group 11; and 2 cases in Group III. Groups II and 111 both differ from Group I, therefore. Subjects who delivered with signs and
WOMEN & HEALTU TABLE II Comparison of differences between groups during the 1st and 3rd trimesters for participants who experienced a rise of SBP' > 3 0 and/or DBP' > 15.
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Group #
# of patients
% Total Group
Group Size
I
' SBP = Systolic Blood Pressure
' DBP = Diastolic Blood Pressure TABLE Ill
Distribution of edema by study group. Group # Edema
I
II
Ill
% Total
Present
29
13
12
36
Absent
21
37
38
54
Tofal
50
50
50
symptoms of pre-eclampsia were greater in the groups who received Placebo than in those who received fatty acid an Magnesium supplementation, @ = .0005)See Table IV. Severe eclampsia, with one or two convulsions, occurred only in Group I, the placebo group. There were three cases and all three women survived. See Table V. The babies' condition, after 24 hours, was evaluated on the basis of skin color, heart rate, respiratory effort and muscle tone and 86.7% were rated as Good; 11.3% were rated as Fair; 2% were rated as Poor. m e r e was no significant difference between groups.
D ;4lmeido et al. TABLE IV Those with signs and symptoms of Pre-Eclampsia and Eclampsia 'Pre-Eclampsia triad with edema. proteinuria. and hypertension.
I
Group #
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Severity of disease
I
II
111
% Total Population
Total
Mild
3
1
1
5
3
Moderate
1
0
1
2
1.3
Severe
1
1
o
2
1.3
TABLE V Eclampsia with one or t w o convulsion episodes and rise of SBP' > 3 0 andlor OBP' > 15
Mild
0
0
0
0.0
Moderate
0
0
0
0.0
Severe
3
0
0
2.1
' SBP = Systolic Blood Pressure
' DBP = Diastolic Blood Pressure I
In regard to birth weights, Groups I1 and III had more babies whose weights were > 3000gms than did Group I, the Placebo group. No data available on average fetal weights. See Table VI. DISCUSSION
The data from this study show that there is an increase of > 20 micromillimeters per week in triceps skinfold thickness during the second and third trimester in all three Groups, with Group I showing the greatest increase.
i . i
i
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& HEALTH TABLE VI
Distribution of babies by weight and by group 2 4 hours after birth 1% total population in parenthesesl.
Group #
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Wtlgms
I
II
111
< 2000
513.31
2(1.31
7c4.7)
> 3000
1171
6141
6141
50
50
50
Number of babies
A comparison of nutrient intakes by Group, using 24 hr recall, is given in Table I. All three Groups had intakes of calories, protein, vitamins, and minerals much below the RDA's for pregnancy. If anything, Group I, the placebo group, had consistently higher intakes of most of the nutrients measured than either Group 11 or Group III. This study suggests that a mixture of the fatty acids GLA, EPA, & DHA, together with elemental Magnesium, might prevent pre-eclampsia of pregnancy. Previous observations made by Carter et al.' suggested that a Vegan diet which is low in arachidonic acid, might protect against pre-eclampsia, especially if the conversions of linoleic acid to GLA 'and of dihomogammalinolenic acid to arachidonic acid are inhibited by decreased activities of the enzymes deltaddehydrogenase and delta-Sdehydrogenase, respectively .lo Speculation about our results suggests that there is no significant difference in the incidence of pre-eclampsia between our subjects and pregnant populations surveyed in'communities in the West and other developing countries. An incidence of 8% as seen in our study is high, however, when compared to that seen among vegan mothers studied in Tennessee; but it is significantly lower than that seen in many other hospital based studies." Perhaps we should regard pre-eclampsia as a dietary-induced lifestyle disorder. Other lifestyle behaviors that could influence its
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occurrence include cigarette smoking and stress. We did not obtain smoking histories from these women. We also have no information about stressful life events. They were living in War Time. Their lifestyle was an active one, judging from the kinds of chores that the women undertook. Such a lifestyle would therefore be expected to contribute to a reduction in blood pressure, rather than to hypertension and pre-eclampsia. Three quarters of the fat in their diets came from vegetable sources. Twenty to thirty percent of the total was saturated and coming from palm oil, margarine, and a tiny amount of animal fat (not including fish sources). Perhaps this was enough to cause a relative excess of thromboxane A,, in the face of a relative deficiency of prostacyclin. However, every women in these studies consumed a relatively high quantity of fresh fish and fresh green leaves in their diets. There is some EPA and DHA in the fish, but there is very little arachidonic acid in plant products, with the exception of certain types of sea vegetation. This should have helped to offset the above postulated imbalance. The hypotensive effects of GLA and elemental Magnesium are consistent with previous reports that evening primrose oil can reduce vascular reactivity to pressor agentsI8 and can lower blood pressure in man.' They are also consistent with the clinical observation that Magnesium can lower blood pressure in the treatment of Eclampsia. The results of this study, while significant, are preliminary and indicate the need for further research, with modifications in location, design, and possibly duration. Since the risk of pre-eclampsia varies with parity and age, it would be beneficial to stratify the groups. A larger sample size, observed over a longer period of time would be helpful. Nevertheless, serious consideration should be given to adding GLA, EPA, DHA, and elemental Magnesium to either the diet, as natural foods, or to routine prenatal vitamin and mineral supplementation programs used by most obstetricians. This would be a more natural and physiological approach to correcting the imbalance in prostaglandins in pre-eclampsia, rather than prescribing aspirin from the 14th week of gestation, as is currently being recommended, with its inherent potential for side-effects.
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REFERENCES 1. Bansal, YP,PreeclampsialEclampsia: A profile from Pumwani, Maternity Hospital, Nairobi, Kenya. East Afr Med J 1965 Oct:62(10):691-8. 2. Carter, JP, MD, DrPH and Hutcheson RH, MD, MPH: Preeclampsia and Reproductive Performance in a Community of Vegans, Southern Medical Journal, June 1986. 3. Clifford PC, Martin, MFR, Sheddon, EJ, Kirby JD, Baird RN, Dicppe PA: Treatment of Vasospastic Disease with Prostaglandin E l , British Medical Journal 281: 1031, 1980. 4. Douglas, HC. Charmers, JG, et al: A Placebo-Contmlled Trail of Evening Primrose Oil in the Treatment of Human Obesity. In: Horrobiin DF ed. Clinical Uses of Essential Patty Acids. Montreal: Eden Ress, 1983, 63-71. 5. Garcia, CM. Carter, J. and Chou, A. Gamma linolenic acid causes weight loss and lower blood pressure in overweight patients, with family history of obesity. Swed. J. Biol. Med., April, 1986. 6. Horrobiin DF and Huang YS: The Role of linolcic acid and its metabolites in the lowering of plasma cholesterol and the prevention of cardiovascular disease. 1987, International Journal of Cardiology, 17: 241. 7. Hormbin DF. A new concept of lifestyle-related cardiovascular disease. The importance of interactions bemeen cholesterol, essential fatty acids, prostaglandin E,, and lhromboxanc A,. Med Hypotheses 6: 687-709, 1980. 8. Horrobin DF. Loss of delta 6 desaturase as a key factor in nutrition intervention. Mcd Hypotheses 7: 1219-28. 1987. 9. Kase, NG. Reyniak, JV:Endocrinology of pregnancy, Mount Sinai J Med 52: 11-34, 1985. 10. Makila UM. Vinikka L. Ylidorkala 0 : Evidence that Prostacyclin Deficiency is a Specific Feature in PKeclampsia. American Journal of Obstet-Gynecol 148:772-774, 1984. 11. Makila UM, V i L, Ylidorkala 0: Increased thromboxane A, Production but Normal Prostacyclin production by the Placenta in Hypertensive Pregnancies, Prostaglandins 1984 (27), 84-95. 12. McCarty MF: Nutritional Prevention of Preeclampsia-A Special Role for 1 Series Prostaglandin Precursors? Medical Hypotheses 9: 283-291, 1982. 13. Minuz, P., Covi, G., Corsato, M., Pmgitzer, P.. Spiazzi, L., Paluani, F., Degan, M., Lechi. C., and Lechi, A. Reduced Excretion of Vasodilator Prostaglandins in Preeclampsia, Agents Actions (Suppl) 1987 22: 175-81. 14. Moncada, Sand Vane, J.R. Pharmacology and endogenous roles of prostaglandin enoperoxides, thromboxane A,, and prostacyclin. Pharmacol Rev 30:293332, 1979. 15. O'Brien WF; Saba, HI; Knuppel RA, Sceho JC; Cohen GR. Alterations in platelet concentration and aggregation in normal pregnancy and preeclampsia. Am J Obstet Gynecol 1986 Sep; 155(3): 48690. 16. Oian, P, Kjeldsen SE, Eide I, Maltau JM. Increased arterial catecholamines in preeclampsia. Acta Obstet Gynecol Scand 1986; 65(1):11-3.
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17. Osbum, PL. Jr., Wfiams, PP, Johnsbn, SB: Serum Arachidonic Acid Levels in Normal and Preeclamptic Pregnancies. American Journal Obstet Gynecol 148: 5-9. 1984. 18. Pedersen, EB. Christensen, NJ. Christensen, P. et a].: Prostaglandins, renin, aldosterone, and catecholamines in p-larnpsia. Acta Med Scand 677 (suppl): 40-43, 1983. 19. Rosing U, Olund A. Serum Arachidonic acid levels (letter) Am J Obstet Gynecol 1985 Nov 15; 153(6): 713-4. 20. Report of a WHO Study Gmup, The hypertensive disorders of pregnancy, World Health Organization Technical Report Series, 758, 1987. 21. Schokens BA, Gehring D, Scholotte V et al.: Evening Primrose Oil, a Dietary Prostaglandin h u r s o r , Diminishes Vascular Reactivity in Rats. Prostaglandins Medical Joumal, 1982; 8:273-276. 22. Viegas, OAC, Cole, T.J.,and Whatton, BA: Impaired Fat Deposition in Pregnancy: An Indicator for Nutritional Intervention. American Journal of Clinical Nutrition 1987; 45: 23-28. 23. Walsh. SW: Precclampsia: an imbalance in placental pmstacyolin and thromboxane production, Am J. Obstet Gynecol 151:335-340, 1985
