BIRTH DEFECT IS CAUSED BY ENVIRONMENT

By: E.Suryadi Department of Anatomy, Embryology and Anthropology Faculty of Medicine GMU

EPIDEMIOLOGY
Annually, approximately 3-5% of live births are born with birth defects. Defects may be anatomical or physiological. Medications are uncommon causes, accounting for 1-3% of birth defects.

 Birth defects are found about 1 in 33 babies born in US Birth defect are leading cause 20% of infant mortality in US Birth defects are the fifth leading causes of years of potential life lost and contribute substantially to childhood illness and long term disability The cause of about 50-60% of all birth defect is unknown Evaluation of environment, genetic, dietary and personal risk factor are important

conception cleavage Gametogenesis

Ovum/ spermatozoo Zygot

Implantation

Meiosis

adult

Blastula puberty Reproductive cycle child fetus infant neomate

mitosis partus/ delivery organogenesis

Embryo

Critical period
pregnancy

critic al period

KOMPONEN ORGANOGENESIS
MITOSIS (proliferating) inter-phase: G1SG2 mitotic phase: pro- meta- ana- telophase-diakinesis RESTRICTION AND DETERMINATION activation & inhibition a certain gene DIFFERENTIATION morphological and functional expression of the cells MORFOGENESIS cells + extra-cellular matrix apoptosis, migration- aggregation-foldingfusion

inductioninteraction- growth factor

Dysmorphogenic Mechanisms
General mechanisms involving the fetomaternal unit Genetic mechanisms response & susceptibility Mechanisms which interfere with cell proliferation and which concern cell kinetic study Mechanisms acting on the basic physiological activities of the cells

GATHERING INFORMATION to DIAGNOSE

Family history: is an essential aspect of such evaluation. (e.g. a similar type of problem) Early history: the onset and vigor of fetal activity, gestational timing, indication of uterus constraint, mode of delivery, size at birth, neonatal adaptation, problem post natal growth/development The physical examination should be complete

INTERPRET THE PATIENTS ANOMALIES

The defect in morphogenesis ! Single problem, type of patterns of structural defect: malformation sequel, deformation sequel, and disruptive sequel Malformation syndromes? Etiology?

ETIOLOGY
Genetic: gene mutation (7-8%), chromosome aberration (6-7%) Environment (7-10%) chemise: drug biology: virus physic: radiation mechanic: be tied umbilical string Multifactor: interaction between genetic and environment (20-25%) Unknown (50-60%)

 All drugs can affect the health of both mother and fetus; therefore, medications should be dispensed with care during pregnancy. Some drugs are safe for mother but dangerous for embryo The teratogenic effect of medications varies temporally. That is, the fetus' susceptibility varies depending on the fetus' apposite critical periods of development. Different organs have different critical periods, although the interim from gestation day 15 to day 60 is critical for many organs.

For Example
The heart is most sensitive during the third and fourth weeks of gestation, while the external genitalia are most sensitive during the eighth and ninth weeks. The brain and skeleton are always sensitive, from the beginning of the third week to the end of pregnancy and the neonatal period

 Genetic defects and medications can cause similar abnormalities.

Axial malformations in mice can result from mutations in certain HOX genes or exposure to retinoids.

Pesticide Use
A herbicides applied in the spring may be a factor in the birth defects and A fungicides can be a significant factor in the determination of sex of the children of the families. Thus, two distinct classes of pesticides seem to have adverse effects on different reproductive outcomes.

Effect of teratogen
The teratogenic effect of medications varies temporally. That is, the fetus' susceptibility varies depending on the fetus' apposite critical periods of development. Different organs have different critical periods, although the interim from gestation day 15 to day 60 is critical for many organs. The heart is most sensitive during the third and fourth weeks of gestation, while the external genitalia are most sensitive during the eighth and ninth weeks. The brain and skeleton are always sensitive, from the beginning of the third week to the end of pregnancy and the neonatal period.
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TERATOGEN

Abnormality form Varying degrees of masculinization of female fetus ; most have labial fusion and clitoral hypertrophy Wide range of skeletal defect and malformations of the CNS Stunted growth, skeletal abnormalities corneal opacities, cleft palate hypoplasia of various organ Multiple malformation, especially skeletal

Androgenic Agents Ethisterone Nonethisterone

Antitumor Agents Aminopterin

Busolfan (Myleran) G mercaptopurine

Methotrexate

Thalidomide

Meromelie and other limb malformations, external ear, cardiac and gastrointestinal malformations 16

Thalidomide effect

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Infectious Agents

MALFORMATIONS

Cytomegaloviruse

Microcephaly, hydrocephaly microphthalmia, microgyria and mental retardation

Cataract, chorioretinitis, deafness microphtalmia and congenital heart defects

Rubella virus

Toxoplasma gondii

Microcephaly, microphthalmia, hydrocephaly and chorioretinitis Microcephaly and skeletal Malformation

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Therapeutic Radiations

Three components of typical teratogen exposure leading to BD

Hereditary predisposition to a malformation Hereditary predisposition to the effects of a given teratogen ( genetic susceptibility) Administration of the teratogen at a vulnerable period embryogenesis.

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Cellular Sites of Action of Various Dysmorphogenic Drug

Teratogenic drugs
ACE inhibitor Azathioprine Bleomycin Busulfan Cisplatin Chlorambucil Cyclophosphamide Flurazepam (X) Mechlorethamine Lithium - D Methimazole - D Methylene blue - C Temazepam (X) Triazolam (X) Tamoxifen - D Tetracycline - D Thalidomide - X Valproic acid - D Warfarin X ect

ACE inhibitor (captopril) are antihypertension medications. They appear to be teratogenic when used in the second and third trimesters. Reported complications in pregnancy include oligohydramnios, intrauterine growth restriction (IUGR), premature labor, and fetal and neonatal renal failure. Reported birth defects include bony malformations, limb contractures, persistent patent ductus arteriosus, pulmonary hypoplasia, respiratory distress syndrome, prolonged hypotension, neonatal death, fetal calvarial hypoplasia or aplasia, oligohydramnios, and renal anomalies.

Infectious agents to cause BD

Cytomegalovirus: microcephaly, hydrocephaly, microgyria and mental retardation. Rubella virus: cataract, chorioretinitis, deafness, microphthalmia and congenital heart disease Toxoplasma gondii: microcephaly, microphthalmia, hydrocephaly and chorioretinitis. Herpes simplex virus: chorioretinitis, hepatomegaly, thrombocytopenia, hydraencephaly.

Cellular Sites of Action of Various Dysmorphogenic Drug

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Origin of the malformation Point mutation

Normal development
Genetic information

Abnormal development
Dominant or recessive defect Syndrome of chromosomal aberration Important defects Metabolic anomalies genital system nervous system

Chromosomal aberration
Placenta of mother

Exogenous and multifactorial actions

Embryo Organogenesis

Fetus

Malformations

Normal neonate

Malformed neonate/ birth defect

FACTUAL
Newborns of obese mothers are at an increased risk for birth defect The association between tea consumption and spina bifida Folic acid and primary prevention of congenital malformation Gene environment interaction in pathogenesis of birth defect Associations between major malformations and mild errors of morphogenesis

 The Risk of Major Birth Defects After Intracytoplasmic Sperm Injection and In Vitro Fertilization. Infants conceived with use of intracytoplasmic sperm injection (ICSI) or in vitro fertilization have twice as high a risk of a major birth defect as naturally conceived infants.

 The close association between cystic hygroma, cytogenetic anomalies and adverse pregnancy outcome
An increase risk of fetal malformation in pregnancy of diabetic mother An increased risk of fetal death due to congenital anomalies among twin birth compared to singletons.

Prenatal diagnostic
USG examination
Amniocentesis Villi-chorion biopsy

Prevention
Marriage counseling Prenatal counseling and diagnostic Education Consume folic acid Eat a healthy diet Exercise regularly Avoid smoking Avoid alcohol Avoid illicit drugs