THE CORRELATION BETWEEN CAFFEINE INTAKE AND SMOKING IN PREGNANT WOMEN AGAINST THE OUTCOMES FETAL GROWTH RESTRICTION

BY : MIRA SHARASWATI 030.05.148

THE FACULTY OF MEDICINE TRISAKTI UNIVERSITY JAKARTA, 2008

CONTENTS
ABSTRACT INTRODUCTION CHAPTER I DEFINITION PHARMACOLOGY EFFECT WHEN TAKE IN MODERATION OVERUSE CAFFEINE INTOXICATION CAFFEUNE INTAKE DURING PREGNANCY CHAPTER II SMOKING CHAPTER III DEFINITION CAUSES PATOPHYSIOLOGY DIAGNOSIS AND SURVEILLANCE

CONCLUSION REFERENCES

ABSTRACT
Epidemiologic studies have been unable to conclusively evaluate whether caffeine intake during pregnancy is associated with reduced birth weight and/or fetal growth restriction. Of 953 women recruited in early pregnancy in Uppsala County, Sweden, from 1996 to 1998, 873 women delivering liveborn singleton infants were included in the analysis. Caffeine exposures were ascertained from in-person interviews at 612 and 3234 completed gestational weeks, and maternal plasma was analyzed for cotinine levels as an indicator of smoking. Analysis of variance was used to estimate the effect of caffeine on birth weight, gestational age at delivery, and birth weight ratio after accounting for the effects of other covariates, such as maternal sociodemographic characteristics, plasma cotinine, and pregnancy symptoms. 6) Nowadays, many teenage girls and young women have the habit of smoking .They get access to the smoking habit because of peer pressure or from their elders .Women continue their smoking habit during their pregnancy also .This creates lot of hazards to their health and result in complication.5) Key words : Caffeine; Smoking; Pregnant women; Fetal Growth Retardation

INTRODUCTION
Caffeine is the most widely consumed xenobiotic in pregnancy, with the potential to adversely affect the developing fetoplacental unit. Maternal caffeine intake has been reported to be associated with a reduction in birth weight, but the precise level of intake above which the risk is increased remains unknown. Caffeine intake of 300 mg/day has been associated with fetal growth restriction. More controversially, others have shown that maternal caffeine concentration has an inverse association with birth weight when confounders such as smoking were taken into account. In 2001 the Committee on Toxicity of Chemicals in Food, UK, after a thorough review of the literature, concluded that, although caffeine intake >300 mg/day might be associated with low birth weight and spontaneous miscarriage, the evidence was inconclusive. Possible reasons for these inconsistent outcomes include inaccurate estimation of caffeine consumption, including an assumption that tea and coffee are the only sources of caffeine, retrospective assessment of caffeine intake, assessment of association based on consumption in individual trimesters rather than throughout pregnancy, failure to allow for individual variations in caffeine metabolism, inadequate control for confounding factors such as smoking and alcohol consumption, and non-uniformity in defining the primary outcome measures. Variations in caffeine metabolic activity have been found to be more closely associated with fetal growth restriction than have blood caffeine concentration. Therefore, any comprehensive study of the effects of caffeine on fetal growth must include an assessment of caffeine metabolism.

CHAPTER I
CAFFEINE 2) DEFINITION Caffeine is a bitter white crystalline xanthine that acts as a psychoactive stimulant drug and a mild diuretic (speeds up urine production) in humans and other animals. Caffeine is also called guaranine when found in guarana, mateine when found in mate, and theine when found in tea; all of these names are synonyms for the same chemical compound. In humans, caffeine is a central nervous system (CNS) stimulant, having the effect of temporarily warding off drowsiness and restoring alertness. Beverages containing caffeine, such as coffee, tea, soft drinks and energy drinks enjoy great popularity. Caffeine is the world's most widely consumed psychoactive substance, but unlike most others, it is legal and unregulated in nearly all jurisdictions. In North America, 90% of adults consume caffeine daily. The U.S. Food and Drug Administration lists caffeine as a "Multiple Purpose Generally Recognized as Safe Food Substance". One 2008 study suggested that women consuming 200 milligrams or more of caffeine per day had about twice the miscarriage risk as women who had none, while another 2008 study found no link between miscarriage and caffeine consumption. Tea is another common source of caffeine. Although tea contains more caffeine than coffee, a typical serving contains much less, as tea is normally brewed much weaker. Besides strength of the brew, growing conditions, processing techniques and other variables also affect caffeine content. Certain types of tea may contain somewhat more caffeine than other teas. Tea contains small amounts of theobromine and slightly higher levels of theophylline

than coffee. Preparation and many other factors have a significant impact on tea, and color is a very poor indicator of caffeine content. Caffeine is also a common ingredient of soft drinks such as cola, originally prepared from kola nuts. Soft drinks typically contain about 10 to 50 milligrams of caffeine per serving. Chocolate derived from cocoa contains a small amount of caffeine. The weak stimulant effect of chocolate may be due to a combination of theobromine and theophylline as well as caffeine. Various manufacturers market caffeine tablets, claiming that using caffeine of pharmaceutical quality improves mental alertness. These effects have been borne out by research that shows that caffeine use (whether in tablet form or not), results in decreased fatigue and increased attentiveness. These tablets are used by students studying for their exams and by people who work or drive for long hours. PHARMACOLOGY Caffeine is a central nervous system and metabolic stimulant, and is used both recreationally and medically to reduce physical fatigue and restore mental alertness when unusual weakness or drowsiness occurs. Caffeine stimulates the central nervous system first at the higher levels, resulting in increased alertness and wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination, and later at the spinal cord level at higher doses. Once inside the body, it has a complex chemistry, and acts through several mechanisms as described below. Caffeine is completely absorbed by the stomach and small intestine within 45 minutes of ingestion. After ingestion it is distributed throughout all tissues of the body and is eliminated by first-order kinetics. Caffeine can also be ingested rectally, evidenced by the

formulation of suppositories of ergotamine tartrate and caffeine (for the relief of migraine) and chlorobutanol and caffeine (for the treatment of hyperemesis). The half-life of caffeinethe time required for the body to eliminate one-half of the total amount of caffeine consumed at a given timevaries widely among individuals according to such factors as age, liver function, pregnancy, some concurrent medications, and the level of enzymes in the liver needed for caffeine metabolism. In healthy adults, caffeine's half-life is approximately 34 hours. In women taking oral contraceptives this is increased to 510 hours, and in pregnant women the half-life is roughly 911 hours. Other factors such as smoking can shorten caffeine's half-life. Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system (specifically, the 1A2 isozyme) into three metabolic dimethylxanthines, which each have their own effects on the body:

Paraxanthine (84%): Has the effect of increasing lipolysis, leading to elevated glycerol and free fatty acid levels in the blood plasma.

Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in cocoa, and therefore chocolate.

Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma. The therapeutic dose of theophylline, however, is many times greater than the levels attained from caffeine metabolism.

Like alcohol and nicotine, caffeine readily crosses the bloodbrain barrier that separates the bloodstream from the interior of the brain. Once in the brain, the principal mode of action is as an antagonist of adenosine receptors. The caffeine molecule is structurally similar to adenosine, and binds to adenosine receptors on the surface of cells without activating them (an "antagonist" mechanism of action). Therefore, caffeine acts as a competitive inhibitor.

Adenosine is found in every part of the body, because it plays a role in the fundamental ATP-related energy-metabolizing system, but it has special functions in the brain. There is a great deal of evidence that brain adenosine concentrations are increased by various types of metabolic stress (including anoxia and ischemia), and act to protect the brain by suppressing neural activity, and by increasing blood flow. Thus caffeine, by counteracting adenosine, has a generally disinhibitory effect on brain activity. Exactly how these effects translate into
EFFECT WHEN TAKE IN MODERATION

The precise amount of caffeine necessary to produce effects varies from person to person depending on body size and degree of tolerance to caffeine. It takes less than an hour for caffeine to begin affecting the body and a mild dose wears off in three to four hours. Consumption of caffeine does not eliminate the need for sleep, it only temporarily reduces the sensation of being tired. With these effects, Caffeine citrate has proven to be of short and long term benefit in treating the breathing disorders of apnea of prematurity and bronchopulmonary displasia in premature infants. The only short term risk associated with caffeine citrate treatment is a temporary reduction in weight gain during the therapy, and longer term studies (18 to 21 months) have shown lasting benefits of treatment of premature infants with caffeine. Because adenosine, in part, serves to regulate blood pressure by causing vasodilation, the increased effects of adenosine due to caffeine withdrawal cause the blood vessels of the head to dilate, leading to an excess of blood in the head and causing a headache and nausea. Reduced catecholamine activity may cause feelings of fatigue and drowsiness. A reduction in serotonin levels when caffeine use is stopped can cause anxiety, irritability, inability to

concentrate and diminished motivation to initiate or to complete daily tasks; in extreme cases it may cause mild depression. Together, these effects have come to be known as a "crash".
OVERUSE

In large amounts, and especially over extended periods of time, caffeine can lead to a condition known as caffeinism. Caffeinism usually combines caffeine dependency with a wide range of unpleasant physical and mental conditions including nervousness, irritability, anxiety, tremulousness, muscle twitching (hyperreflexia), insomnia, headaches, respiratory alkalosis, and heart palpitations. Furthermore, because caffeine increases the production of stomach acid, high usage over time can lead to peptic ulcers, erosive esophagitis, and gastroesophageal reflux disease. CAFFEINE INTOXICATION An acute overdose of caffeine, usually in excess of about 300 milligrams, dependent on body weight and level of caffeine tolerance, can result in a state of central nervous system over-stimulation called caffeine intoxication, colloquially "caffeine jitters". The symptoms of caffeine intoxication are not unlike overdoses of other stimulants. It may include restlessness, nervousness, excitement, insomnia, flushing of the face, increased urination, gastrointestinal disturbance, muscle twitching, a rambling flow of thought and speech, irritability, irregular or rapid heart beat, and psychomotor agitation. In cases of much larger overdoses mania, depression, lapses in judgment, disorientation, disinhibition, delusions, hallucinations, rhabdomyolysis, or psychosis may occur.

CAFFEINE INTAKE DURING PREGNANCY

The Food Standards Agency has recommended that pregnant women should limit their caffeine intake to less than 300 mg of caffeine a day the equivalent of four cups of coffee a day. A higher intake may be associated with miscarriage. Dr De-Kun Li of Kaiser Permanente Division of Research, which appears in the American Journal of Obstetrics and Gynecology, concludes that an intake of 200 milligrams or more per day, representing two or more cups, "significantly increases the risk of miscarriage". However, Dr. David Savitz, a professor in community and preventive medicine at New York's Mount Sinai School of Medicine and lead author of the other new study on the subject published in the January issue of Epidemiology, found no link between miscarriage and caffeine consumption.

CHAPTER II
SMOKING 4)

BACKGROUND ` Cigarette smoking is a major preventable cause of disease worldwide, and it is the

major cause of premature death in North America. In 1912, Adler first suggested that inhalation of cigarette smoke might be a cause of lung cancer. Since then, knowledge about the adverse health effects of smoking has accumulated. The important causes of mortality are atherosclerotic vascular disease, cancer, and chronic obstructive pulmonary disease (COPD). Smoking also can contribute to other diseases, eg, histiocytosis X, respiratory bronchiolitis, obstructive sleep apnea, idiopathic pneumothorax, low birth weight, and perinatal mortality. Research investigating why people smoke has shown that smoking behavior is multifaceted. Factors influencing smoking initiation differ from those of smoking behavior maintenance. Nicotine dependence, genetic factors, and psychosocial factors influence maintenance of smoking behavior. Nicotine meets the criteria of a highly addictive drug. Nicotine is a potent psychoactive drug that induces euphoria, serves as a reinforcer of its use, and leads to nicotine withdrawal syndrome when it is absent. As an addictive drug, nicotine has 2 very potent issues: it is a stimulant and it is also a depressant. It can make affects mood and performance and is the source of addiction to tobacco.
PATHOPHYSIOLOGY

Nicotine releases hormone noted in the following paragraphs that act on various receptors in the brain. Nicotine use results in more efficient processing of information and reduction of fatigue. In addition, nicotine has a sedative action, reduces anxiety, and induces euphoria. Nicotine effects are related to absolute blood levels and to the rate of increase in drug concentration at receptors.

Nicotine stimulates the hypothalamic-pituitary axis; this, in turn, stimulates the endocrine system. Continually increasing dose levels of nicotine are necessary to maintain the stimulating effects. With regards to dependence, some experts rank nicotine ahead of alcohol, cocaine, and heroin. A teenager who smokes as few as 4 cigarettes might develop a lifelong addiction to nicotine. Small rapid doses of nicotine produce alertness and arousal, as opposed to long drawn-out doses, which induce relaxation and sedation. Nicotine has a pronounced effect on the major stress hormones. Nicotine stimulates hypothalamic corticotropin-releasing factor (CRF), and it increases levels of endorphins, adrenocorticotropic hormone (ACTH), and arginine vasopressin in a dose-related manner. Corticosteroids also are released in proportion to plasma nicotine concentration. Nicotine alters the bioavailability of dopamine and serotonin and causes a sharp increase in heart rate and blood pressure. Nicotine acts on brain reward mechanisms, indirectly through endogenous opioid activity and directly through dopamine pathways.
EPIDEMIOLOGY

United States In 1965, 52% of men and 34% of women were cigarette smokers. Presently, the incidence of cigarette smoking has decreased to 28% and 24%, respectively. The incidence of smoking is highest in blacks, blue-collar workers, less-educated persons, and persons in the lower socioeconomic strata.

The trend is decreasing in more educated persons. Forty percent of men with less than 12 years of education, 35.9% of high school graduates, and 17.4% of college

graduates smoke. Of women, 30.7% with less than 12 years of education, 29.6% of high school graduates, and 15.1% of college graduates smoke.

Economic status also is related to smoking behavior. Of men with an income of $10,000-20,000 per year, 36.3% smoke, as opposed to 23.2% of men who make $50,000 or more per year. Of women who had a family income of $20,000 or less per year, 29.8% smoke, as opposed to 19.5% who make $50,000 or more per year.

In 1983, a comparison was made between white-collar workers, of whom 27.9% smoked, and blue-collar workers, of whom 42.7% smoked.

Twenty-five percent of pregnant women who smoke quit during pregnancy; yet 80% resume smoking after childbirth.

Recent surveys show that 20% of teenage girls smoke, and 15% of teenage boys smoke.

International Worldwide, approximately 1.1 billion people smoke. In China, more than 70% of men older than 25 years smoke. Smoking is more prevalent in developing countries and is continuing to increase. Prevalence of smoking in North America is decreasing, currently approximately 25% of North Americans smoke.
Mortality/Morbidity

The health consequences of this addiction are enormous. Tobacco smoking is responsible for 1 of every 5 deaths and is the most common cause of cancer-related deaths in the United States. Children smoke 1.1 billion packs of cigarettes yearly. This accounts for more than $200 billion in future health care costs.

Tobacco accounts for more than 85% of all deaths due to lung cancer. Approximately 10 million people in the United States have died from causes attributed to smoking since the Surgeon General's first report in 1964; 2 million of these were from lung cancer alone. Furthermore, tobacco also has been identified as the leading cause of emphysema, COPD, bronchitis, and heart disease. CLINICAL
History

Nicotine addiction is classified as nicotine use disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IVTR). The criteria for this diagnosis include any 3 of the following within a 1-year time span:
o

Tolerance to nicotine with decreased effect and increasing dose to obtain same effect

o o o o o o

Withdrawal symptoms after cessation Smoking more than usual Persistent desire to smoke despite efforts to decrease intake Extensive time spent smoking or purchasing tobacco Postponing work, social, or recreational events in order to smoke Continuing to smoke despite health hazards

Nicotine withdrawal is classified as a nicotine-induced disorder according to the DSM-IV-TR. Symptoms include difficulty concentrating, nervousness, headaches, weight gain due to increased appetite, decreased heart rate, insomnia, irritability, and depression. These symptoms peak in the first few days but eventually disappear within a month.

Symptoms of nicotine toxicity, otherwise known as acute nicotine poisoning, include nausea, vomiting, salivation, pallor, abdominal pain, diarrhea, and cold sweat.

A previous history of depression, use of antidepressants in the past, and onset of depression during previous quit attempts should be obtained.

Physical

Physical effects of nicotine use include increased heart rate, accelerated blood pressure, and weight loss.

Physical effects of nicotine withdrawal and smoking cessation include weight gain due to increase in appetite, decreased heart rate, and improvement in the senses of taste and smell.

CHAPTER 3
IUGR 3) DEFINITION

Intrauterine growth restriction (IUGR) refers to a condition in which a fetus is unable to achieve its genetically determined potential size. This functional definition seeks to identify a population of fetuses at risk for modifiable but otherwise poor outcomes. This definition intentionally excludes of fetuses that are small for gestational age (SGA) but are not pathologically small. SGA is defined as growth at the 10th or less percentile for weight of all fetuses at that gestational age. Not all fetuses that are SGA are pathologically growth restricted and, in fact, may be constitutionally small. Similarly, not all fetuses that have not met their genetic growth potential are in less than the 10th percentile for estimated fetal weight (EFW). CAUSES Maternal causes of IUGR (adapted from Severi et al, 2000)1 include the following:

Chronic hypertension Pregnancy-associated hypertension Cyanotic heart disease Class F or higher diabetes Hemoglobinopathies Autoimmune disease Protein-calorie malnutrition Smoking Substance abuse Uterine malformations Thrombophilias Prolonged high-altitude exposure

Placental or umbilical cord causes of IUGR include the following:

Twin-to-twin transfusion syndrome Placental abnormalities Chronic abruption Placenta previa Abnormal cord insertion Cord anomalies Multiple gestations

PATOPHYSIOLOGY

IUGR occurs when gas exchange and nutrient delivery to the fetus are not sufficient to allow it to thrive in utero. This process can occur primarily because of maternal disease causing decreased oxygen-carrying capacity (eg, cyanotic heart disease, smoking,

hemoglobinopathy), a dysfunctional oxygen delivery system secondary to maternal vascular disease (eg, diabetes with vascular disease, hypertension, autoimmune disease affecting the vessels leading to the placenta), or placental damage resulting from maternal disease (eg, smoking, thrombophilia, various autoimmune diseases). Evaluation of causative factors for intrinsic disorders leading to poor growth may include a fetal karyotype, maternal serology for infectious processes, and an environmental exposure history. DIAGNOSIS AND SURVEILLANCE Criteria for diagnosis of IUGR For most purposes, an EFW at or below the 10th percentile is used to identify fetuses at risk. Importantly, however, understand that this is not a definitive cutoff for uteroplacental insufficiency. A certain number of fetuses at or below the 10th percentile may be

constitutionally small. In these cases, short maternal or paternal height, the neonate's ability to maintain growth along a standardized curve, and a lack of other signs of uteroplacental insufficiency (eg, oligohydramnios, abnormal Doppler findings) can be reassuring to the clinician and parents. Importantly, review the dating criteria before offering intervention to treat growth restriction in a fetus. If dates are uncertain or unknown, obtaining a second growth assessment over a 2to 4-week interval is important unless strong supportive data or risk factors warrant an immediate change in management plans. Screening the fetus for growth restriction Although no single biometric or Doppler measurement is completely accurate for helping make or exclude the diagnosis of growth restriction, screening for IUGR is important to identify at-risk fetuses. Dependent upon the maternal condition associated with IUGR (see Maternal causes of IUGR) patients may undergo serial sonography during their pregnancies. An initial scan may be obtained in the middle of the second trimester (at 18-20 wk) to confirm dates, evaluate for anomalies, and identify multiple gestations. A repeat scan may be scheduled at 28-32 weeks' gestation to assess fetal growth, evidence of asymmetry, and stigmata of brain-sparing physiology (eg, oligohydramnios, abnormal Doppler findings). Screening for IUGR in the general population relies on symphysisfundal height measurements. This is a routine portion of prenatal care from 20 weeks' until term. Although recent studies have questioned the accuracy of fundal height measurements, particularly in obese patients, a discrepancy of greater than 3 cm between observed and expected measurements may prompt a growth evaluation using ultrasound (Jelks et al).9 The clinician should be aware that the sensitivity of fundal height measurement is limited, and he or she

should maintain a heightened awareness for potential growth-restricted fetuses. In an unselected hospital population, only 26% of fetuses that were SGA were suggested to be SGA based on clinical examination findings. Biometry and amniotic fluid volumes Most ultrasonographic machines report aggregate gestational age measurements and individual parameters. Assessing individual values is important to identify a fetus that is growing asymmetrically. In the presence of normal head and femur measurements, abdominal circumference (AC) measurements of less than 2 standard deviations below the mean appear to be a reasonable cutoff to consider a fetus asymmetric. Baschat and Weiner showed that a low AC percentile had the highest sensitivity (98.1%) for diagnosing IUGR (birth weight <10th percentile). The sensitivity of EFW (birth weight below the 10th percentile) is 85.7%; however, an AC below the 2.5 percentile had the lowest positive predictive value (36.3%), while a low EFW had a 50% positive predictive value.11 Uterine artery Doppler measurement Both arterial Doppler and venous Doppler have been used in recent literature to support expectant management or delivery of IUGR fetuses and to identify fetuses at risk. Doppler velocimetry has been shown to contribute to the identification of fetuses at risk of IUGR. To follow is an overview of the various Doppler techniques and their clinical applications. Although these measurements appear promising, the sensitivity and specificity of uterine artery Doppler measurements is relatively low, and, because no proven interventions are available to prevent IUGR, uterine artery blood flow measurements are not included in routine surveillance protocols.

Umbilical artery Doppler measurement In normal pregnancies, umbilical artery (UA) resistance shows a continuous decline; however, this does not occur in fetuses with uteroplacental insufficiency. The most commonly used measure of gestational agespecific UA resistance is the systolic-to-diastolic ratio of flow, which changes from a baseline value to an elevated value with worsening disease. As the insufficiency progresses, end-diastolic velocity is lost and, finally, reversed. UA Doppler measurements may help the clinician decide whether a small fetus is truly growth restricted. Baschat and Weiner looked at UA resistance to determine if it can help improve the accuracy of diagnosing IUGR and help identify a small fetus at risk of chronic hypoxemia. Middle cerebral artery Doppler Fong and colleagues identified 297 singleton pregnancies in which EFW was below the 10th percentile in anatomically normal fetuses. These investigators studied middle cerebral artery (MCA), renal artery, and UA Doppler findings. They addressed outcomes, including cesarean delivery for fetal distress, cord pH less than or equal to 7.10, and Apgar score less than or equal to 7 at 5 minutes. They concluded that a normal MCA Doppler finding may be useful to help identify small fetuses that are not likely to have a major adverse outcome with a reported negative predictive value of 86%.18 Venous Doppler waveforms Venous Doppler has been measured at the ductus venosus (DV), umbilical vein (UV), inferior vena cava (IVC), and 7 other sites. This provides information about fetal cardiovascular and respiratory responses to its intrauterine environment. These measurements

have been reported to become consistently abnormal when a fetus is severely compromised, thus providing evidence in support of an expedited delivery. While the optimal vessel for use for venous Doppler evaluations has not been identified, the knowledge gained from these measurements provides additional information for the timing of delivery, especially in extremely premature (<32 wk) gestations. Three-dimensional ultrasonography With the introduction and use of obstetrical 3-dimensional ultrasonography, many new applications for this technology are constantly explored. The use of these techniques in the evaluation of the growth-restricted fetus has been evaluated as well. As fetal femur dysplasia is associated with IUGR, Chang et al used 3-dimensional ultrasonography to measure fetal femur volume as a predictor of IUGR. They found a 10th percentile femur volume threshold, which differentiates growth-restricted fetuses from normal fetuses. Using this technique, they obtained a sensitivity of 71.4%, specificity of 94.1%, positive predictive value of 62.5%, negative predictive value of 96.0%, and accuracy of 91.3% in prediction of growth restriction. As a single biometric measurement, fetal femur volume is better in prediction of growth restriction than fetal AC and biparietal diameter.22

CONCLUSION

REFERENCES
1)

http://aje.oxfordjournals.org/cgi/content/full/155/5/429? maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=(corre

lation+AND+between+AND+maternal+AND+caffeine+AND+intake+A ND+and+AND+fetal+AND+growth)&searchid=1&FIRSTINDEX=0&re sourcetype=HWCIT

2)

http://en.wikipedia.org/wiki/Caffeine http://www.emedicine.com/med/topic3247.

3)

4) http://www.emedicine.com/med/topic1642.htm 5) http://aje.oxfordjournals.org/cgi/content/abstract/127/2/274 6) http://www.scielo.br/pdf/csp/v14n3/0089.