Project
In such a context I find it useful to present our research
project. Our hope is that other researchers will be in a position
to conduct similar studies among other populations with low
standards of living, particularly on the African or Asian continents.
We are in the process of designing a randomised controlled trial
of food supplementation at the Alexander Fleming hospital, in
a poor district of Rio de Janeiro, Brazil. In that hospital,
where the number of births a year is around 6 000, eclampsia
is still common. The objective is to evaluate the effects on
the incidence of eclampsia of giving canned sardines to a certain
number of women, as early as possible in pregnancy. The choice
of canned sardines is based on theoretical considerations that
we have previously presented in several occasions.(4,5) We’ll
just summarize the main points of the hypothesis our study is
supposed to test.
Why canned sardines? Testing a hypothesis
There is a widespread belief that reduced uteroplacental perfusion
is the central pathophysiological process in preeclampsia. Several
puzzling aspects of the disease challenge this belief. For example,
a study looking at 97,270 births in 35 hospitals in Alberta,
Canada, revealed that there is a significant association between
preeclampsia and large-for-gestational-age infants, in addition
to the well-known association with small-for-gestational age
infants.6 Such findings are more easily interpreted if this
multifactorial syndrome is presented as an expression of a maternal/fetal
conflict. From this perspective, it is plausible that a large
fetus's high demand for nutrients can be the root of conflict.
Faulty placentation, inadequate maternal nutrition, and certain
combinations of maternal and fetal genotypes are other factors
that can independently increase the probability of conflict.
Since mother and fetus do not carry identical gene sets, maternal
and fetal interests are not always in harmony. The nature and
the expression of such conflicts differ according to the species
of mammals being considered.
For example, veterinarians use the term eclampsia to refer to
a life-threatening disease that occurs in various mammals, including
dogs. In this species, the so-called eclampsia is in fact related
to hypocalcemia (it is a "puerperal tetany"). Of course,
where dogs are concerned, the priority at the end of pregnancy
and at the beginning of lactation is development of the bones
of the offspring, which are much more developed at birth than
the bones of other mammalian species.
Interspecies comparisons encourage us to raise new questions
concerning the potential for conflict among humans. The spectacular
brain growth spurt during the second half of fetal life is a
specifically human trait. A conflict between the demands expressed
by the fetus and which of those demands the mother can fulfill
without depleting her body leads us to consider first the needs
of the developing brain.
It is well known that the developing brain has special needs
for long-chain polyunsaturates from the n-6 and n-3 families,
particularly arachidonic acid (AA = 20:4 n-6) and docosahexaenoic
acid (DHA = 22:6 n-3). At least 50% of the molecules of fatty
acids that incorporate into the brain are represented by DHA.
One can therefore assume that the most likely reason for a conflict
is when the mother cannot keep up with the increased demands
for DHA. A disease will be the price the mother's body has to
pay to meet the needs of the developing brain.
The concept of maternal-fetal conflicts directs us to establish
a new classification of the numerous well-documented biological
imbalances associated with preeclampsia among humans. The first
step should be to look at the status of maternal fatty acids
at the end of normal pregnancy and in preeclampsia. We should
look particularly at the group of long-chain n-3 polyunsaturates,
which includes DHA and eicosapentaenoic acid (EPA = 20:5 n-3).
It seems that the central imbalance in human preeclampsia is
the enormous discrepancy between the maternal plasma levels
of DHA and EPA. In preeclampsia, the level of DHA is not significantly
decreased, whereas the level of the parent molecule EPA is about
10 times lower than in normal pregnancy.(7) These are exactly
the data we are expecting when assuming that brain development
is a priority among humans. Such data are confirmed by the "Curacao
study,"(8) which looked at the fatty acid compositions
of maternal and umbilical cord platelets from preeclamptic women.
Whatever the circumstances, the levels of DHA remain stable.
This fact is noticeable when keeping in mind the low delta 4
-desaturase activity among humans.(9) The price of a stable
DHA is an imbalance inside the family of n-3 fatty acids that
is at the root of a long chain of further imbalances.
This is how one can understand the onset of a vicious circle
when the demand in long-chain fatty acids is at its greatest:
at that stage, if the amount of n-3 polyunsaturates available
is low, the priority is to keep the level of DHA as stable as
possible.
The use of biochemical markers of dietary intakes of lipids
has demonstrated that a diet poor in n-3 fatty acids is a risk
factor for preeclampsia. Studies of the erythrocyte fatty acids
profile found that women with the lowest levels of n-3 fatty
acids were 7.6 times more likely to have had their pregnancies
complicated by preeclampsia as compared with those women with
the highest levels of n-3.(10) A 15% increase in the ratio of
n-3 to n-6 was associated with a 46% reduction in the risk of
preeclampsia. Evaluating the fatty acid compositions of maternal
platelets is another way to use biological markers of dietary
fat intake. According to the Curacao study,8 the ratio of AA
to EPA is significantly higher in maternal platelets of preeclamptic
women (109.13 vs 78.13; P < .05).
These concordant and significant data suggest that when the
amount of n-3 available is low, the first compensatory effect
-- in order to maintain an adequate supply of DHA available
-- is the collapse of the level of the parent molecule EPA:
this precipitating factor explains the well-known imbalances
in the system of prostaglandins and particularly the decreased
ratio of prostacyclin to thromboxane-2. When the level of EPA
has collapsed, there is no production of the physiologically
inactive thromboxane-3. This leads to an overproduction of the
physiologically active thromboxane-2, through a mechanism of
enzymatic competition. Moreover, when the level of EPA is low,
there is no production of the physiologically active prostacyclin-3.
In normal pregnancy, the ratio of prostacyclin to thromboxane-2
in maternal blood progressively favors prostacyclin.
Our theory of preeclampsia is in a position to address the many
intriguing aspects of the disease. One of them is that preeclampsia
is principally a disease of first pregnancies. We must recall
that the metabolism of n-3 fatty acids is influenced by parity.(11,12)
The DHA content of cord blood phospholipids depends on birth
order; in other words, the capacity to provide preformed DHA
is depleted with repeated pregnancies. It is as if brain development
is a higher priority in the case of a first baby.
Our perspective can also establish links between different approaches
that have been used in the effort to prevent preeclampsia. Effective
preventive action at the very beginning of the chain of events
-- at the stage of faulty placental implantation -- cannot be
considered.(13) The fact that a previous miscarriage, a previous
blood transfusion,(14) or a long sexual cohabitation before
conception(15) reduces the risk of preeclampsia confirms the
probable importance of the immune response during that phase.
It seems more realistic, on the other hand, to try to moderate
the effects of the precipitating factors during the second half
of pregnancy.
Theoretically, the most direct way to prevent preeclampsia would
be to consume sea fish that is rich in n-3 polyunsaturates and
also in minerals that are essential nutrients for the brain
(eg, iodine, selenium, and zinc). This conforms with the geographical
variations in the rates of preeclampsia and with the results
of our encouragement of pregnant women to eat sea fish.(16)
Until now, all studies have been conducted in wealthy countries
with very low rates of preeclampsia, such as Scandinavian countries.
These studies usually involved controlled trials of fish oil
supplementation that began during the second half of pregnancy.
Based on the results of several studies, preeclampsia has not
been dissociated from the framework of pregnancy-induced hypertension.
For many reasons, it is therefore not surprising that meta-analyses(17)
and systemic reviews (18, 19) have found insufficient evidence
of the effects of fish oil on the risk of preeclampsia. In fact,
most studies were too small to even address the issue of preeclampsia.
We can make such comments about our own study, conducted during
the years 1991-1992 in a London hospital.(16) We randomly selected
499 pregnant women and encouraged them to increase their intake
of oily sea fish and to reduce their intake of food rich in
trans fatty acids. A hospital- and parity-matched control group
included 500 pregnant women. Because of the study's size and
the fact that the study population had a low rate of preeclampsia,
we did not find it relevant to mention in the abstract or in
the conclusion that there were no cases of eclampsia or severe
preeclampsia in the study group vs 1 case of eclampsia with
convulsions and 2 cases of severe preeclampsia in the control
group.
It is remarkable that the only study that demonstrated highly
significant effects of fish oil supplementation on the risk
of “toxemia” was conducted in London by the People's
League of Health during 1938-9, at a time when the rates of
severe "toxemia" were in the region of 6%. This controlled
trial was saved from oblivion by S.F. Olsen and N.J. Secher.(20)
The authors randomized 5644 pregnant women to receive or not
receive a dietary supplement containing vitamins, minerals,
and halibut liver oil from about week 20 of pregnancy. A significant
effect of treatment was seen in primiparae, with a 31.1% reduction
in the incidence of “toxemia” (95% CI 5-50%, P =
.021). Interestingly, no significant effect of treatment was
seen with regard to the incidence of hypertension in the absence
of edema and proteinuria.
Our understanding of preeclampsia also suggests that catalysts
for the metabolism of unsaturated fatty acids should be preventive
agents. Let us recall that only the precursor in the n-3 family
(18:3 n-3) is abundantly provided by the land food chain. Magnesium,(21)
calcium,(22) and zinc(23) are such catalysts and have been explored
as preventive agents.
It also makes sense that, in order to prevent preeclampsia,
the level of blocking agents of the metabolic pathways must
be reduced as much as possible. Alcohol, pure sugar, and trans
fatty acids are such blocking agents. A correlation has been
established between the intake of trans fatty acids and the
risk of preeclampsia.(24) Hormones such as cortisol are also
known blocking agents. This can explain how the emotional state
of the pregnant woman influences the risk of preeclampsia.(25)
It is also theoretically important to avoid a fast destruction
(via peroxidation reactions) of the available long chain fatty
acids. The preventive effects of antioxidants are well documented.(26)
Food from the land and food from the sea
In theory, it is easier to meet the specific needs of the developing
human brain when the diet includes some food from the sea, because
the sea food chain provides preformed and abundant molecules
of very long-chain fatty acids. The sea food chain has other
characteristics. Any food from the sea is rich in iodine, a
major component of thyroid hormones, which are involved in brain
development. Imbalances of thyroid hormones (high ratio of thyroxine
[T4] to triidothyronine [T3]) are associated with preeclampsia
and should not be overlooked. Finally, it appears that pregnant
women (and probably Homo sapiens in general) ideally need a
certain balance between food from the land and food from the
sea. Studies of preeclampsia in the framework of evolutionary
medicine are needed.(27) In conclusion, preeclampsia may be
understood as the price some human beings must pay for having
a large brain when they are more or less separated from the
sea food chain.
Those who understand that brain development is a priority among
humans, those who are interested in eclampsia as the “disease
of theories”, and those who are aware of the high rates
of maternal deaths related to eclampsia in low-income populations
should be easily convinced that a new generation of research
is urgently needed.
References
- 1 – Duley L. Maternal mortality associated with hypertensive
disorders of pregnancy in Africa, Asia, Latin America and the
Caribbean. Br J Obstet Gynaecol 1992; 99: 547-553.
- 2 – Begum MR, Begum A, Quadir E, et al. Eclampsia: still
a problem in Bangladesh. http://www.medscape.com/viewarticle/488386_1.
- 3 – Villar J, Say L, Shennan A, et al. Methodological
and technical issues related to the diagnosis, screening, prevention,
and treatment of pre-eclampsia and eclampsia {review}. Int J
Gynaecol Obstet. 2004; 85 (Suppl 1):S28-41.
- 4 - Odent M. Pre-eclampsia as a maternal - fetal conflict.
The link with fetal brain development. International Society
for the Study of Fatty Acids and Lipids (ISSFAL) News. 2000;7:7-10.
- 5 – Odent M. Hypothesis: Preeclampsia as a Maternal-Fetal
Conflict. MedGenMed September 5, 2001. © 2001 Medscape,
Inc.
- 6 - Xiong X, Demianczuk NN, Buekens P, Saunders LD. Association
of preeclampsia with high birth weight for age. Am J Obstet
Gynecol. 2000;183:148-155.
- 7 -Wang Y, Kay HH, Killam AP. Decreased levels of polyunsaturated
fatty acids in pre-eclampsia. Am J Obstet Gynecol. 1991;164:812-818.
- 8 -Velzing-Aarts FV, van der Klis FR, van der Dijs FP, Muskiet
FA. Umbilical vessels of preeclamptic women have low contents
of both n-3 and n-6 long-chain polyunsaturated fatty acids.
Am J Clin Nutr. 1999;69:293-298.
- 9 - Sanders TAB, Younger KM. The effect of dietary supplements
of n-3 polyunsaturated fatty acids on the fatty acid composition
of platelets and plasma choline phosphoglycerides. Br J Nutr.
1981;45:613-616.
- 10 -Williams MA, Zingheim RW, King IB, Zebelman AM. Omega-3
fatty acids in maternal erythrocytes and risk of pre-eclampsia.
Epidemiology. 1995;6:232-237.
- 11 - Carlson E, Salem N. Essentiality of omega-3 fatty acids
in growth and development in infants. In: Simopoulos AP, Kifer
RR, Martin RE, Barlow SM, eds. Effects of Polyunsaturated Fatty
Acids in Seafoods. World Rev Nutr Diet; Basel, Karger; 1991;
66: 74-86.
- 12 - Al MD, Van Houwelingen AC, Hornstra G. Relation between
birth order and the maternal and neonatal docosahexaenoic acid
status. Eur J Clin Nutr. 1997;51:548-553.
- 13 - De Groot CJM, O'Brien TJ, Taylor RN. Biochemical evidence
of impaired trophoblastic invasion of decidual stroma in women
destined to have pre-eclampsia. Am J Obstet Gynecol. 1996;175:24-29.
- 14 - Feeney JC, Tovey LAD, Scott JS. Influence of previous
blood transfusion on incidence of pre-eclampsia. Lancet. 1977;ii:874-875.
- 15 - Robillard PY, Husley TC, Perianiu J, et al. Association
of pregnancy-induced hypertension with duration of sexual cohabitation
before conception. Lancet. 1994;344:973-975.
- 16 - Odent M, McMillan L, Kimmel T. Prenatal care and sea
fish. Eur J Obstet Gynecol. 1996;68:49-51.
- 17 - Appel LJ, Miller ER, Seidler AJ et al. Does supplementation
of diet with 'fish oil' reduce blood pressure? A meta-analysis
of controlled trials. Arch Intern Med. 1993;153:1429-1438.
- 18 - Makrides M, Gibson RA. Long-chain polyunsaturated fatty
acids requirements during pregnancy and lactation. Am J Clin
Nutr. 2000;71(suppl 1):307S-311S.
- 19 - Duley L. Prophylactic fish oil in pregnancy. In: Pregnancy
and Childbirth Module "Cochrane Database Systemic Reviews."
Review No. 05941. Published through "Cochrane Updates on
Disk"; 1994.
- 20 - Olsen SF, Secher NJ. A possible preventive effect of
low-dose fish oil on early delivery and pre-eclampsia: indications
from a 50-year-old controlled trial. Br J Nutr. 1990;64:599-609.
- 21 - Eclampsia Trial Collaborative Group. Which anticonvulsant
for women with eclampsia? Lancet. 1995;345:1455-1463.
- 22 - Bucher HC, Guyatt CH, Cook RJ, et al. Effect of calcium
supplementation on pregnancy-induced hypertension and pre-eclampsia.
JAMA. 1996;275:1113-1117.
- 23 - Kiilhoma P, Pakarinen P, Gronroos M. Copper and zinc
in pre-eclampsia. Acta Obstet Gynecol Scand. 1984;63:629-631.
- 24 - Williams MA. Risk of pre-eclampsia in relation to elaidic
acid (trans fatty acid) in maternal erythrocytes. SPO abstracts.
In: Am J Obstet Gynecol. 1995;436:380.
- 25 - Kurki T, Hiilesmaa V, Raitasalo R, et al. Depression
and anxiety linked to pre-eclampsia. Obstet Gynecol. 2000;95:487-490.
- 26 - 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;354:810-816.
27 - Odent M. The primary human disease. An evolutionary perspective.
ReVision. 1995;18:19-21.
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