Teratogens: a public health issue – a Brazilian overview

Abstract Congenital anomalies are already the second cause of infant mortality in Brazil, as in many other middle-income countries in Latin America. Birth defects are a result of both genetic and environmental factors, but a multifactorial etiology has been more frequently observed. Here, we address the environmental causes of birth defects – or teratogens – as a public health issue and present their mechanisms of action, categories and their respective maternal-fetal deleterious effects. We also present a survey from 2008 to 2013 of Brazilian cases involving congenital anomalies (annual average of 20,205), fetal deaths (annual average of 1,530), infant hospitalizations (annual average of 82,452), number of deaths of hospitalized infants (annual average of 2,175), and the average cost of hospitalizations (annual cost of $7,758). Moreover, we report on Brazilian cases of teratogenesis due to the recent Zika virus infection, and to the use of misoprostol, thalidomide, alcohol and illicit drugs. Special attention has been given to the Zika virus infection, now proven to be responsible for the microcephaly outbreak in Brazil, with 8,039 cases under investigation (from October 2015 to June 2016). From those cases, 1,616 were confirmed and 324 deaths occurred due to microcephaly complications or alterations on the central nervous system. Congenital anomalies impact life quality and raise costs in specialized care, justifying the classification of teratogens as a public health issue.


Deficiency in intrauterine
growth and postnatal growth, cognitive abnormalities, leading to a set of characteristics called fetal alcohol syndrome (FAS), characterized by: alterations in facial appearance (small palpebral fissures, large epicanthal folds, small head, small upper jaw, smooth philtrum, thin upper lip), decreased muscle tone, poor coordination, heart defects (ventricular and atrial septal defects), late reasoning, speech, movement and social skills development. FAS is the main cause of intellectual disability. (Rostand et al., 1990;Sampson et al., 1997) Tobacco Nicotine is a vasoconstrictor interfering in intrauterine growth due to decreased perfusion fetal tissues, which may lead to placental abruption. Carbon monoxide present in the smoke of the cigarette also crosses the placenta, producing an increase in carboxyhemoglobin in blood.
Oral clefts, low birth weight, intrauterine growth retardation, spontaneous abortion, premature birth. (Werler 1997;Nicoletti et al., 2014) Marijuana It is extracted from the cannabis sativa plant. Liposoluble active compound 8, 9tetrahydrocannabinol crosses the placenta easily, reaching the fetus. This compound binds to cannabinoid receptors, acting on the analgesia route, as well as the anxiolytic route and immunological system. Intrauterine growth restriction, cognitive and neurobehavioral imbalance, respiratory and hormonal disorders. (Kuczkowski 2004) Categories Teratogen Characteristic Effects Reference LSD LSD (lysergic acid diethylamide) produces a series of distortions in the functioning of the brain, changing the psychic, circulatory and thermal functions.
Brain damage, abnormalities in the lower jaw, modification of facial contours, defects in the limbs and eyes, joint problems and miscarriage.
( McGlothlin et al., 1970) Cocaine Cocaine has vasoconstrictor activity, which may result in an interruption of blood flow to the fetus.
Stimulation of integrin subunit B3 genes transcription, which are responsible for stimulation of angiogenesis in the developing limb buds, which promotes the growth from the root

Influenza
Caused by influenza A, B and C, typically occurring during the winter, associated with periods of fever and secondary bacterial infections of the respiratory system. The influenza virus infection appears to have no significant effects in the fetal development.
The effects observed are postnatal periods which include fever and respiratory problems. (Acs et al., 2005) Cytomegalovirus Caused by viruses of the family Herpesviridae, reaching the fetus in phases of acute viremia in the different embryonic stages.

Phenylketonuria
Characterized by decreased activity of the enzyme phenylalanine hydroxylase, which is responsible for transforming phenylalanine to tyrosine, which leads to accumulation of phenylalanine in the fetus Intrauterine growth retardation, microcephaly, cardiovascular defects, intellectual disabilities. (Levy and Ghavami 1996;Matalon et al., 2003) Hypoglycemia Stages of hypoglycemia during pregnancy stop the power supply to the fetus, as well as induced hypoxia.
Spontaneous abortion, intrauterine growth retardation. (Zamudio et al., 2010) Hyperthermia Maternal body temperature above 39 ° C can lead to cell death or delay of the proliferation of neuroblasts. It can also lead to fetal vascular disruption.
Anencephaly, microphthalmia, arthrogryposis, abdominal wall defects, abnormalities of the distal limbs, midface hypoplasia and intellectual disabilities. (Isaacs and Gericke 1990;Graham et al., 1998;Edwards 2006) *Zika virus was confirmed to cause an outbreak of microcephaly in newborns of women that contracted the virus during pregnancy (Rasmussen et al., 2016). Here we present this virus as a new teratogenic agent. Shepard's criteria have already been contemplated (Rasmussen et al., 2016), more epidemiological studies are being performed to establish the teratogenic potential and spectrum of malformations.