Birth defects

Dr .Eman khammas al-sadi Embryology lecturer

Birth defect

congenital malformation,

and congenital anomaly

are synonymous terms used to describe structural, behavioral, functional, and metabolic disorders present at birth. . major structural anomalies occur in 2% to 3% of live born infants, an additional 2% to 3% are recognized in children by age 5 years, total 4% to 6% . birth defects are the leading cause of infant mortality, accounting for approximately 21% of infant deaths.

Causes:-

1-unknown cause. 40% to 60%, 2- Genetic factors, 15%; 3-environmental factors 10%; 4-a combination of genetic and environmental influences (multifactorial inheritance) 20% to 25%; 5-twinning causes 0.5% to 1%.

Minor anomalies occur in approximately 15% of newborns.

These structural abnormalities,
such as

microtia (small ears), pigmented spots, short palpebral fissures,

in some cases, are associated with major defects. For example, infants with

one minor anomaly have a 3% chance of having a major malformation; two minor anomalies have a 10% chance; three or more minor anomalies have a 20% chance.
Therefore, minor anomalies serve as clues for diagnosing more serious underlying defects


A.
B. C. D.

Types of Abnormalities

E.

Malformations Disruptions Deformations A syndrome Association

1-Malformations:
occur during formation of structures, for example, during organogenesis.
They may result in 1- complete or partial absence of a structure 2-or in alterations of its normal configuration. caused by environmental and/or genetic factors. Occur during the third to eighth weeks of gestation

2-Disruptions
result in morphological alterations of already formed structures and are caused by destructive processes. 1- Vascular accidents leading to bowel Artesia 2-defects produced by amniotic bands are examples of destructive factors that produce disruptions 1

3-Deformations :
result from mechanical forces that mold a part of the fetus over a prolonged period. Clubfeet,

4-A syndrome
is a group of anomalies occurring together that have a specific common cause. This term indicates that a diagnosis has been made and that the risk of recurrence is known.

5-

association:

is the non random apperance of two or more anomalies that occur together more frequently than by chance alone. But the cause has not been determind.like VACTERL association A. Vertebral, B. anal C. cardiac D. tracheoesophageal E. renal F. limb anomalies.

Environmental Factors
German measles affecting a mother during early pregnancy caused abnormalities in the embryo,.

linked limb defects to the sedative thalidomide Since that time, many agents have been identified as teratogens (factors that cause birth defects)

Principles of Teratology
They include the following: 1. Susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which this genetic composition interacts with the environment.
The maternal genome is also important with respect to drug metabolism, resistance to infection, and other biochemical and molecular processes that affect the conceptus.

2. Susceptibility to teratogens varies with the developmental stage at the time of exposure. The most sensitive period for inducing birth defects is the third to eighth weeks of gestation. the

For example, cleft palate can be induced at the 1- blastocyst stage (day 6), 2-during gastrulation (day 14), 3- at the early limb bud stage (fifth week), 4- or when the palatal shelves are forming (seventh week). Furthermore, no stage of development is completely safe

3. Manifestations of abnormal development:depend on dose and duration of exposure to a teratogen. 4. Teratogens act in specific ways (mechanisms) & pathogenesis Mechanisms on developing cells& tissue.Like inhibition of a specific biochemical or molecular process;pathogenesis may involve A. cell death, B. decreased cell proliferation, C. or other cellular phenomena. 5. Manifestations of abnormal development are 1. death, 2. malformation, 3. growth retardation, 4. and functional disorders

Infectious Agents
include a number of viruses. 1- Rubella used to be a major problem. Today, approximately 85% of women are immune. 2-CMV (Cytomegalovirus) is a serious threat. 3-Herpes simplex virus, 4-varicella virus, 5-human immunodeficiency virus (HIV) can cause

Other Viral Infections and Hyperthermia

Malformations following maternal infection with 1. measles, 2. mumps, 3. hepatitis, 4. poliomyelitis, 5. echovirus, 6. Coxsackie virus, 7. and influenza virus have been described.

Prospective studies indicate that the malformation rate after exposure to these agents is low if not non existent. A complicating factor introduced by these and other infectious agents is that most are pyrogenic, and elevated body temperature (hyperthermia) is teratogenic.

Defects produced by exposure to elevated temperatures include

1- anencephaly, 2-spina bifida, 3- mental retardation, 4- microphthalmia, 5- cleft lip and palate, 6- limb deficiencies, 7- omphalocele, 8- and cardiac abnormalities. In addition to febrile illnesses, use of hot tubs and saunas can produce sufficient temperature elevations to cause birth defects

Toxoplasmosis and syphilis

:cause

birth defects. 1. Poorly cooked meat; 2. domestic animals, especially cats; 3. and feces in contaminated soil can carry the protozoan parasite Toxoplasmosis gondii. A characteristic feature of fetal toxoplasmosis infection is cerebral calcifications

 Ionizing radiation 1. kills rapidly proliferating cells, 2. it is a potent teratogen 3. , producing any type of birth defect depending upon the dose and stage of development of the conceptus at the time of exposure. 4. Radiation from nuclear explosions is a mutagenic agent and can lead to genetic alterations of germ cells and subsequent malformations

Radiation:

Chemical Agents
1- Only 20% of pregnant women used no drugs during their pregnancy. 2- few drugs used during pregnancy have been positively identified as being teratogenic. One example is thalidomide,. The causal relation between thalidomide and meromelia was discovered only because the drug produced such an unusual abnormality.

Other drugs with teratogenic potential include

1- the anticonvulsants
1-(phenytoin), 2- valproic acid, 3-trimethadione, which are used by epileptic women. fetal hydantoin syndromes. Facial clefts are particularly common in these syndromes. Valproic acid also causes craniofacial abnormalities but has a particular propensity for producing( neural tube defects.)

2-Antipsychotic and antianxiety agents (major and

minor tranquilizers, respectively) are suspected producers of congenital malformations. The antipsychotics 1- phenothiazine 2-lithium have been implicated as teratogens.

3- antianxiety agents
meprobamate, chlordiazepoxide, and diazepam (Valium.

4-The anticoagulant
warfarin is teratogenic, whereas heparin does not appear to be.

5- Antihypertensive agents
that inhibit (ACE inhibitors) produce growth retardation, renal dysfunction, fetal death, and oligohydramnios

Harmfull drugs 1-propylthiouracil and potassium iodide (goiter and mental retardation), 2-streptomycin (deafness), 3-sulfonamides (kernicterus), 4-imipramine (limb deformities), 5- tetracyclines (bone and tooth anomalies), 6- amphetamines (oral clefts and cardiovascular abnormalities), 7- quinine (deafness). 8-aspirin (salicylates), the most commonly ingested drug during pregnancy, may harm the developing offspring when used in large doses 9- marijuana, alcohol, and cocaine , 10-Cigarette smoking has not been linked to major birth defects

Hormones
Androgenic Agents In the past, synthetic progestins were frequently used during pregnancy to prevent abortion. They have considerable androgenic activity, and many cases of masculinization of the genitalia in female embryos have been reported. The abnormalities consist of an enlarged clitoris associated with varying degrees of fusion of the labioscrotal folds

Endocrine

Disrupters

are exogenous agents that interfere with the normal regulatory actions of hormones controlling developmental processes
Mostly interfere with the action of estrogen through its receptor to cause developmental abnormalities of the central nervous system and reproductive tract.

Oral Contraceptives Birth control pills, containing estrogens and progestogens appear to have a low teratogenic potential

Maternal Diseases
1-Diabetes
Disturbances in carbohydrate metabolism during pregnancy in diabetic mothers cause 1. a high incidence of stillbirths, 2. neonatal deaths, 3. abnormally large infants, 4. and congenital malformations

2-Phenylketonuria
. Women with PKU who maintain their lowphenylalanine diet prior to conception and throughout pregnancy reduce the risk to their infants to that observed in the general population.

3-Nutritional Deficiencies
Although many nutritional deficiencies, particularly vitamin deficiencies, have been proven to be teratogenic in laboratory animals, the evidence in humans is sparse

4-Obesity
is associated with a 2-3 fold increased risk for having a child with a neural tube defect,a heart defect, omphalocele, multiple anomalies, and obesity.

5- Heavy Metals
1- organic mercury
2-Lead

Male-Mediated Teratogenesis
1- exposures to chemicals and other agents, can cause mutations in male germ cells. 2-Advanced paternal age is a factor for an increased risk of
1. 2. 3.

limb and neural tube defects, Down syndrome, and new autosomal dominant mutations.

3- men with birth defects themselves have a greater than twofold risk of having an affected child.

Clinical Correlates

Prevention of Birth Defects 1-supplementation of salt or water supplied with iodine eliminates mental retardation and bone deformities resulting from cretinism.
2-Placing women with diabetes or PKU under strict metabolic control prior to conception. 3-Folate supplementation lowers the incidence of neural tube defects, such as spina bifida and anencephaly, 4-reduces the risk for hyperthermia-induced abnormalities. 5-Avoidance of alcohol and other drugs during pregnancy

6- initiate interventions prior to conception. Such

PRENATAL DIAGNOSIS
approaches for assessing growth and development of the fetus in utero, Including 1-ultrasound 2- maternal serum screening 3-amniocentesis 4-and chorionic villus sampling. .

these techniques are designed to detect

malformations, genetic abnormalities, overall fetal growth, and complications of pregnancy, such as placental or uterine abnormalities. The use and development of in utero therapies have heralded a new concept in which the fetus is now a patient.

Maternal Serum Screening

A search for biochemical markers of fetal status led to development of maternal serum screening tests. A--serum alpha_-fetoprotein (AFP)

concentrations
In cases of neural tube defects and several other abnormalities AFP levels increase in amniotic fluid and maternal serum in: 1-omphalocele. 2- gastroschisis. 3-bladder exstrophy. 4-amniotic band syndrome. 5-sacrococcygeal teratoma. 6- intestinal atresia. 7-neural tube defects

AFP concentrations decrease, as, for

example, 1) in Down syndrome 2) trisomy 18, 3) sex chromosome abnormalities, 4) and triploidy.

(are also associated with lower serum concentrations of)human chorionic

gonadotropin (hCG) and unconjugated estriol.
Therefore, maternal serum screening provides a relatively noninvasive technique for an initial assessment of fetal well-being.

Amniocentesis
During amniocentesis, a needle is inserted transabdominally into the amniotic cavity (and approximately 20 to 30 mL of fluid is withdrawn . not usually performed before 14 weeks' gestation The risk of fetal loss as a result of the procedure is 1%, The fluid itself is analyzed for biochemical factors, such as 1-AFP and 2-acetylcholinesterase. 3-karyotyping and other genetic analyses . This culture period requires 8 to 14 days , making a diagnosis is delayed

Chorionic Villus Sampling

Chorionic villus sampling (CVS) involves inserting a needle transabdominally or transvaginally into the placental mass and aspirating approximately 5 to 30 mg of villus tissue. , the time for genetic characterization of the fetus is reduced compared with amniocentesis. The risk of fetal loss from chorionic villus sampling is approximately twofold greater than with amniocentesis, the procedure carries an increased risk for limb defects. . Indications for using the tests include the following: 1-Advanced maternal age (35 years and older); 2-Previous family history of a genetic problem, such as the parents having had a child with

FETAL THERAPY
1-Fetal Transfusion 2-Fetal Medical Treatment 3-Fetal Surgery 4-Stem Cell Transplantation 5-Gene Therapy

FETAL THERAPY
1-Fetal Transfusion In cases of fetal anemia produced by maternal antibodies or other causes, blood transfusions for the fetus can be performed. Ultrasound is used to guide insertion of a needle into the umbilical cord vein, and blood is transfused directly into the fetus. 2-Fetal Medical Treatment
Treatment for infections, fetal cardiac arrhythmias, compromised thyroid function, and other medical problems is usually provided to the mother and reaches the fetal compartment after crossing the placenta. In some cases, however, agents may be administered to the fetus directly by intramuscular injection into the gluteal region or via the umbilical

Fetal Surgery
including placing shunts to remove fluid from organs and cavities. For example, 1- in obstructive urinary disease of the urethra, a pigtail shunt may be inserted into the fetal bladder. One problem is diagnosing the condition early enough to prevent renal damage. Ex utero surgery, in which the uterus is opened and the fetus is operated on directly, has been used for repairing 2-congenital diaphragmatic hernias, 3- removing cystic (adenomatoid) lesions in the lung,

Stem Cell Transplantation and Gene Therapy

Because the fetus does not develop any immunocompetence before 18 weeks' gestation, it may be possible to transplant tissues or cells before this time without rejection. Research in this field is focusing on hematopoietic stem cells for treatment of immunodeficiency and hematologic disorders.

Gene therapy for inherited metabolic diseases, such as

Tay-Sachs and cystic fibrosis, is also being investigated

Thank you