Author: giada pozzi
Date: 07/02/2010



Preeclampsia is defined as gestational blood pressure elevation with proteinuria that develops after 20 weeks' gestation.
In women with preexisting chronic hypertension and proteinuria before 20 weeks' gestation, the preeclampsia can be diagnosed when the blood pressure (BP) is exacerbated BP (systolic >160 mmHg or diastolic >110 mmHg) during the last half of pregnancy or when proteinuria significantly increases.
Preeclampsia is one of four major hypertensive disorders of pregnancy. The other three conditions that comprise these hypertensive complications of pregnancy include gestational hypertension, chronic hypertension, and chronic hypertension with superimposed preeclampsia.

Wikipedia, Diseases Database, OMIM


A World Health Organization (WHO) analysis reveals that hypertensive disorders complicate 15% of pregnancies, and are the leading cause of maternal death in Latin America and the Caribbean (25.7%), as well as a major contributor to maternal death in Africa (9.1%) and Asia (9.1%). Although the exact prevalence is unknown, approximately 2-4% of pregnancies (4 million women) are estimated to be complicated by preeclampsia annually; 2% of these women develop eclampsia.

Among nulliparous women, the incidence of preeclampsia is reported to be 5-7%. In the United Kingdom, 15% of maternal deaths are related to preeclampsia-eclampsia syndrome.
Approximately 80% of the world's cases preeclampsia are late onset.
Preterm birth is more common among pregnancies complicated by preeclampsia, which accounts for as many as 15% of preterm deliveries.
High rates of neonatal mortality are reported in the remaining pregnancies complicated by early-onset preeclampsia (11.5%) and eclampsia (30%).

Symptoms and Signs

Pre-eclampsia is often asymptomatic, hence its detection depends on signs or investigations. Nonetheless, one symptom is crucially important because it is so often misinterpreted. The epigastric pain, which reflects hepatic involvement and is typical of the HELLP syndrome, may easily be confused with heartburn, a very common problem of pregnancy. However, it is not burning in quality, does not spread upwards towards the throat, is associated with hepatic tenderness, may radiate through to the back, and is not relieved by giving antacids. It is often very severe, described by sufferers as the worst pain that they have ever experienced. Affected women are not uncommonly referred to general surgeons as suffering from an acute abdomen, for example acute cholecystitis.

In general, none of the signs of pre-eclampsia is specific; even convulsions in pregnancy are more likely to have causes other than eclampsia in modern practice. Diagnosis, therefore, depends on finding a coincidence of several pre-eclamptic features, the final proof being their regression after delivery.

For more about clinical


Pre-eclampsia is diagnosed when a pregnant woman develops high blood pressure (two separate readings taken at least 4 hours apart of 140/90 or more) and 300 mg of protein in a 24-hour urine sample (proteinuria). A rise in baseline BP of 30 systolic or 15 diastolic, while not meeting the absolute criteria of 140/90 is still considered important to note but no longer diagnostic. Swelling, or edema, (especially in the hands and face) was originally considered an important sign for a diagnosis of pre-eclampsia, but in current medical practice only hypertension and proteinuria are necessary for a diagnosis. However, pitting edema (unusual swelling, particularly of the hands, feet, or face, notable by leaving an indentation when pressed on) can be significant, and should be reported to a health care provider.

"Severe preeclampsia" involves a BP over 160/110, and additional symptoms.

Pre-eclampsia may progress to eclampsia, characterized by the appearance of tonic-clonic seizures. This happens only very rarely, but eclampsia is potentially fatal.

Risk Factors

  • Age
    Maternal age of younger 20 years and older than 35-40 years are among the clinical risk factors for the development of preeclampsia. The increased incidence of preeclampsia noted among patients older than 35 years probably reflects undiagnosed chronic hypertension with superimposed PIH.
  • First time pregnancy
    Some research suggests that one's risk of preeclampsia is increased with a first pregnancy with a new partner/husband, however recent research suggests that the key factor in that increased risk is not the new husband, but in fact increased maternal age.
  • History
    Previous history of preeclampsia, particularly if onset is before the third trimester;
    History of chronic high blood pressure, diabetes or kidney disorder;
    Family history of the disorder (i.e., a mother, sister, grandmother or aunt who had the disorder).
  • BMI
    Women with greater than 30% Body mass Index (BMI).
  • Mother disease
    Polycystic ovarian syndrome;
    Lupus or other autoimmune disorders such as rheumatoid arthritis, sarcoidosis or MS.
  • Multiple gestation


Several complications can occur during the course of Preeclampsia, including:

  • Maternal morbidity
  • Fetal and infant mortality and morbidity
  • Risk of later cardiovascular disease
  • Intergenerational effects.

For more about complication


Current concepts regarding the pathophysiology of preeclampsia recognize that preeclampsia is a multisystem disorder characterized by vasoconstriction, metabolic changes, endothelial dysfunction, and activation of the coagulation cascade in conjunction with an inflammatory response. A 2-stage model of preeclampsia has been proposed in which failure of placental vascular remodeling results in reduced placental perfusion and initiates a cascade of events that result in serious maternal illness with the potential for significant perinatal morbidity and death.


There are a number of theories trying to explain the origin of preeclampsia, ranging from too much blood flow to too little, from genetics to nutritional problems. Some current theories include:

Preexisting maternal conditions: Mother has undiagnosed high blood pressure or other preexisting problems such as diabetes, lupus, sickle cell disorder, hyperthyroidism, kidney disorder, etc.

Nutritional Problems/Poor Diet: Insufficient protein, excessive protein, not enough fresh fruit and vegetables (antioxidants), among others theories.

High Body Fat: High body fat may actually be the symptom of the tendency to develop this disorder linked to the genetic tendency towards high blood pressure, diabetes and insulin resistance.

Uterine ischemia/ underperfusion: Insufficient blood flow to the uterus.

Hemodynamic vascular injury: Injury to the blood vessels due to too much blood flow.

Endothelial activation and dysfunction: Damage to the lining of the blood vessels that regulates the diameter of the blood vessels keeping fluid and protein inside the blood vessels and keeps blood from clotting.

Immunological Activation: The immune system believes that damage has occurred to the blood vessel and in trying to fix the "injury" actually makes the problem worse (like scar tissue) and augments the process.

Oxidative stress: Candidate placental mediators for maternal endothelial dysfunction in preeclampsia, include products of oxidative stress, released into the maternal circulation, for example Xanthine oxidase.

Insufficient Magnesium Oxide and B6: involved mostly in pathogenesis of eclampsia, magnesium stabilizes vascular smooth muscles and helps regulate vascular tone

Magnesium for seizure prophylaxis in patients with mild preeclampsia.

Magnesium sulphate for the management of preeclampsia

Prostacyclin/thromboxane imbalance (ASA): Disruption of the balance of the hormones that maintain the diameter of the blood vessels.

Prostacyclin/thromboxane early changes in pregnancies that are complicated by preeclampsia

Acetylsalicylic acid for the prevention of preeclampsia and intra-uterine growth restriction in women with abnormal uterine artery Doppler: a systematic review and meta-analysis

Calcium deficiency: Calcium helps maintain vasodilation, so a deficiency would impair the function of vasodilation (see above).

Serum calcium, magnesium and uric acid in preeclampsia and normal pregnancy

We can focus our attention on some particular topics, that we find as the subject of various recent studies:

- GENETIC ASPECTS: there are studies of candidate genes that, thus far, have very much reflected the pathophysiological research interests of the investigators. The multifaceted nature of PE and the difficulties of accurate phenotyping require the accumulation of a large, very carefully phenotyped, database.

What is the place of genetics in the pathogenesis of pre-eclampsia?

One of the studied genes is the AGTR gene, the one who codes for the Angiotensin II receptor.

Angiotensin II (AII) acts as a growth factor in local systems, mediating diverse effects such as cellular proliferation and apoptosis. These effects are controlled through two main receptor subtypes: AGTR1 and AGTR2.

The study doesn’t evidence a significant difference in haplotype frequency between preeclamptic and normotensive women, but identifies two novel polymorphisms in AGTR2: there was evidence for a significant increase in the frequency of one haplotype in women with preeclampsia.

Haplotypes of the angiotensin II receptor genes AGTR1 and AGTR2 in women with normotensive pregnancy and women with preeclampsia

Another important American study concerns the Soluble fms-like tyrosine kinase 1: it reports that mRNA expression of placental sFlt1 in patients with preeclampsia is higher than in normotensive term pregnancies, and, in fact, the average serum level of sFlt1 was almost five times higher in patients with severe preeclampsia than in normotensive pregnant women.
Excess (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia through his various interactions:

  • sFlt1 is known to antagonize the proangiogenic molecules VEGF and PlGF by binding to them and preventing their interaction with their cell-surface receptors, Flt1 and KDR, so in preeclampsia excess sFlt1 causes widespread endothelial dysfunction, decreasing levels of unbound VEGF and PlGF;
  • endogenous sFlt1 gives also antiangiogenic properties to the serum of preeclamptic patients, for the reduction of VEGF and PlGF.
  • it significantly reduces VEGF- and PlGF-induced vasodilation in patients with severe preeclampsia, so it might oppose physiologic vasorelaxation, thus contributing to hypertension.
  • sFlt1 induces glomerular endotheliosis: glomerular enlargement with occlusion of the capillary loops by swelling and hypertrophy of endocapillary cells; in this way it contributes to proteinuria.

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia

Maternal serum placental growth factor and soluble fms-like tyrosine kinase 1 as early predictors of preeclampsia

Serum sFlt1 concentration during preeclampsia and mid trimester blood pressure in healthy nulliparous women

Placental growth factor and soluble FMS-like tyrosine kinase-1 in early-onset and late-onset preeclampsia

- IRON STATUS: In preeclamptic women, serum iron concentration, ferritin, and percent saturation of transferrin are higher than in control subjects, whereas unsaturated iron-binding capacity and apotransferrin levels are significantly lower.
Released iron species in preeclampsia may contribute to the etiology of the disease, because it exacerbates lipid peroxidation and endothelial cell injury; iron free radicals are released from ischaemic placenta, so this connection between mother and fetus may contribute to pre eclampsia etiology.
Routine investigation of serum iron status of pregnant women, as part of antenatal checkup, may help in the establishment of diagnosis of pre eclampsia before appearance of its clinical manifestation.

Abnormal iron parameters in the pregnancy syndrome preeclampsia

Alteration in iron status in pre eclampsia

Iron status and body iron are sometimes decreased in physiological pregnancies, and have to be monitored because women may need an iron supplementation.
Anyway, there is no increased frequency of preeclampsia in women taking iron supplements.
An expedient seems to be the schedule of somministration: daily supplementation with ferrous sulphate results in greater lipid peroxidation than weekly supplementation.

Iron and pregnancy—a delicate balance

Comparison of effect of daily versus weekly iron supplementation during pregnancy on lipid peroxidation





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Pozzi Giada, Schirò Matteo

2012-07-11T23:06:52 - Elisa Mistretta

Preeclampsia and chocolate


Preeclampsia is one of the complications that can occur during pregnancy.
We can define PREECLAMPSIA as a condition in which blood pressure (BP) results, in two separate readings taken at least six hours apart, 140 or more in systolic blood pressure and/or 90 or more in distolic blood pressure and 300mg of proteins in a 24 hours urine sample after 20 weeks' gestation.
So, it is generally characterized by cardiovascular manifestations as well as proteinuria (significant amount of proteins in urine).
"Severe preeclampsia" occurs when blood pressure is over 160/110 with additional symptoms.


Causes are not well defined. It is likely that there are substances from the placenta that can cause endothelial dysfunction in maternal blood vessels, as well as in the kindney or liver. We can also find vasoconstrictive factors releasing in association with original damages.

Preeclampsia is now considerated as a "2 stages disease process" in which 1st and 3rd trimester are "critical windows" for exposure and hypotetical interventions.
In the first trimester, placental oxydative stress and inflammation is hypothesized to trigger the release of pro-inflammatory syncytiotrophoblast derived factors which lead to maternal systemic vascular endothelial disruption and eventual clinical manifestation of preeclampsia in the 3rd trimester of pregnancy.



What we interested on is if chocolate intake during pregnancy can reduce the risk of preeclampsia and gestational hypertension.
Chocolate contains alkaloids such as theobromine, which have some physiological effects in humans, but the presence of theobromine renders it toxic to some animals, such as dogs and cats. Dark chocolate has been promoted for unproven health benefits, as it seems to possess substantial amount of antioxidants that reduce the formation of free radicals.

Chocolate conteins flavonoids, magnesium and theobromine.

FLAVONOIDS are potent antioxidants that can induce nitric oxide-dependent vasodilatation, as well as they can have antiplatelet and anti-inflammatory effects.

MAGNESIUM deficit have been linked with hypertension and other cardiovascular diseases.

THEOBROMINE is a dimethylxantine very represented in dark chocolate whom primary effects include diuresis, myocardial stimulation, vasodilatation and smooth muscle relaxation.


500-1000mg/die of MAGNESIUM are required to reduce hypertension.
It has been demonstrated that magnesium consumption and blood pressure are inversely related. In fact, magnesium:
- competes with sodium to the binding sites in the smooth muscle
-acts as a calcium antagonist
-increases prostaglandin E (PGE)
- cooperates with the potassium to induce the reduction of blood pressure.


THEOBROMINE is the primary alkaloid found in cocoa and chocolate.
In modern medicine, theobromine is used as a vasodilator (a blood vessel widener), a diuretic (urination aid), and heart stimulant, so it has been used to treat high blood pressure. The American Journal of Clinical Nutrition notes that historic use of theobromine as a treatment for other circulatory problems including arteriosclerosis, certain vascular diseases, angina pectoris, and hypertension should be considered in future studies.

Even without dietary intake, theobromine may occur in the body as it is a product of the human metabolism of caffeine.

Like other methylated xanthine derivatives, is both a
1. competitive nonselective phosphodiesterase inhibitor,which:
- raises intracellular cAMP
- activates PKA, that stimulates myocardial contraction through phospholamban phosphorylation and inhibits smooth muscle contraction (↑cAMP → ↑PKA activity → phosphorylation of MLCK → ↓MLCK activity → dephosphorylation of MLC)
- inhibits TNF-alpha and leukotriene synthesis
- reduces inflammation and innate immunity
2. nonselective adenosine receptor antagonist.

As a phosphodiesterase inhibitor, theobromine helps prevent the phosphodiesterase enzymes from converting the active cAMP to an inactive form. cAMP works as a second messenger in many hormone- and neurotransmitter-controlled metabolic systems, such as the breakdown of glycogen. When the inactivation of cAMP is inhibited by a compound such as theobromine, the effects of the neurotransmitter or hormone that stimulated the production of cAMP are much longer-lived. In general, the net result is a stimulatory effect.

During pregnancy, theobromine can induce a better placental circulation and inhibit xantine oxidase that can lead to the production of ROS and free radicals.

xantina + H2O + O2 =uric acid + H2O2

Since preeclampsia shows many cardiovascular symptoms, as endothelial dysfunction, oxydative stress and hypertension, chocolate consumption could be associated with preeclampsia prevention.

Some studies analyze prospective cohort study to determine if regular chocolate intake during pregnancy is associated with reduced risk of preeclampsia.
Many pregnant women were recruited, whome chocolate consumption was misured by self report in the first and third trimester.
In these studies there are some limitations. For example, self-reported exposure data may have led to an uncorrect classification because it's very difficult quantify serving size of different products. In addiction, women BMI is a possibly confounder, as well as smoking.

1) Epidemiology. 2008 May; 19(3): 459–464.

PubMed Consumption in Pregnancy and Reduced Likelihood of Preeclampsia"

Elizabeth W. Triche,a Laura M. Grosso,a Kathleen Belanger,a Amy S. Darefsky,b Neal L. Benowitz,c and Michael B. Brackena

In the Triche et al. study, it results that cord serum theobromine concentration were negatively associated with preeclampsia.

OR=0,31 (IC 95%: 0,11-0,87)

Compared with women consuming under 1 serving of chocolate weekly, women consuming 5+ servings per week had decreased risk.

2 )Ann Epidemiol. 2010 August; 20(8): 584–591.

PubMed Does Chocolate Intake During Pregnancy Reduce the Risks of Preeclampsia and Gestational Hypertension?

Audrey F. Saftlas, Ph.D., MPH,1 Elizabeth W. Triche, Ph.D.,2 Hind Beydoun, Ph.D., MPH,1 and Michael B. Bracken, Ph.D.2

In the Saftlas et al. study, it results that chocolate intake was more frequent among normotensive women (80,7%) than preeclamptics (62,5%) or GH women (75,8%) and associated with reduced ODDS.

Preeclampsia odds:

First trimester: OR=0,55 (IC 95%: 0,32-0,95)
Third trimester: OR=0,56 (IC 95%: 0,32-0,97)

No differences were found between chocolate foods or chocolate drinks.


Both studies provide evidences of the benefit of chocolate in preventing preeclampsia during pregnancy even if causality may also contribute to these findings.

2010-10-20T16:39:35 - Gianpiero Pescarmona

Stress and the brain: from adaptation to disease 2005

Reprod Sci. 2010 Sep;17(9):833-43. Epub 2010 Jul 8.
Hypoxia and preeclampsia: increased expression of urocortin 2 and urocortin 3.

Imperatore A, Rolfo A, Petraglia F, Challis JR, Caniggia I.

Department of Physiology, Obstetrics and Gynecology and Medicine, University of Toronto, Toronto, Canada.

OBJECTIVE: Urocortin 2 (Ucn2) and urocortin 3 (Ucn3) are new members of the corticotrophin-releasing hormone (CRH) family of peptides expressed and localized in human placenta. In the current study, we aimed to asses whether hypoxia affects placental Ucn2/Ucn3 messenger RNA (mRNA) expression and protein localization in physiological or pathological hypoxia and to evaluate whether the effect is modulated by the hypoxia-inducible factor 1alpha (HIF-1alpha).

METHODS: Early first-trimester placental specimens from elective termination of pregnancy were used for villous explants and term placental tissue were used for primary cell cultures. The samples were incubated under different oxygen conditions; parallel sets exposed to hypoxia re-oxygenation (HR). Dimethyloxalylglycine (DMOG), an HIF-1alpha stabilizer, was used to mimic the effects of hypoxia in villous explants. Real-time polymerase chain reaction (PCR) and immunohystochemistry were performed on early pregnancy and preeclamptic (PE) placentae. mRNA levels were measured on villous explants and cell cultures incubated under different oxygen and reagent conditions.

RESULTS: Both Ucn2 and Ucn3 mRNA expression was significantly higher at 6 to 9 weeks of gestation than 10 to 12 wks and in primary trophoblast cell cultures and explants exposed to low O(2) tension (3%) compared to 20% O(2). Strong Ucn2/Ucn3 immunoreactivity was present in trophoblast villi from 6 weeks placentae. Ucn2 immunostaining was stronger in early PE (E-PE) samples relative to controls whereas Ucn3 showed stronger immunoreactivity in late-PE (L-PE) placentae. Only Ucn2 transcript levels increased in HR explants. Ucn2 and Ucn3 expression by first-trimester explants was significantly greater in the presence of DMOG. All PE placentae expressed significantly higher Ucn2 and Ucn3 mRNA compared to controls.

DISCUSSION: Placental Ucn2 and Ucn3 expression is sensitive to O(2) tensions and mediated by HIF-1alpha. During early pregnancy, Ucn2/Ucn3 may influence trophoblast proliferation and establishment of pregnancy. In PE placentae, the increased expression of both peptides may reflect a response to the oxidative stress.

AA percentage UCN1 UCN2 UCN3

2010-02-24T15:20:06 - alessandro fiumefreddo


A lot of studies on preeclamptic women showed an increase in oxidative stress, and high magnitude suppression/decrease in antioxidant enzymes activities in erythrocytes. This indicates that an increase in the risk of preeclampsia with maternal age could be due to an increase in oxidative very important the role of oxidative stress in preeclampsia.

Erythrocyte markers of oxidative stress in higher age-group preeclamptic and normal pregnant mothers

Oxidative stress and changes in antioxidative defense system in erythrocytes of preeclampsia in women

Selenium, acting through the selenoprotein glutathione peroxidases, has critical roles in regulating antioxidant status. Recent reports implicate poor maternal selenium status as a nutritional factor predisposing the mother to preeclampsia. Measurement of selenium concentrations, expression, and activity levels of glutathione peroxidase and markers of oxidative stress were performed on maternal and umbilical venous blood samples or the placenta.

The results of this studies revealed highly significant reductions in serum selenium concentrations and plasma glutathione peroxidase activity in pregnancy per se compared to nonpregnant controls. Moreover, these levels were further decreased in the preeclamptic mothers and babies compared to normal pregnancies. Umbilical venous selenium was particularly low (42.1+/-11.8 and 29.0+/-9.9 microg/L; mean+/-SD; P<0.05). Both mother and baby had significantly increased levels of markers for oxidative stress in the preeclamptic group. The placental glutathione peroxidase activity and immunohistochemical staining were also reduced in the preeclampsia placentae.

Oxidative stress associated with preeclampsia may be a consequence of reduced antioxidant defense pathways specifically involving glutathione peroxidases, perhaps linked to reduced selenium availability. Reduced glutathione peroxidases could be associated with increased generation of toxic lipid peroxides contributing to the endothelial dysfunction and hypertension of preeclampsia.

Reduced selenium concentrations and glutathione peroxidase activity in preeclamptic pregnancies




Alessandro Fiumefreddo

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