Birth Defects and Prenatal Diagnosis PDF

Embryology L6 BIRTH DEFECTS AND PRENATAL DIAGNOSIS  Birth defects: Birth defect, congenital malformation, and congenital anomaly are synonymous terms used to describe structural, behavioral, functional, and metabolic disorders present at birth. terms used to describe the study of...

Embryology L6 BIRTH DEFECTS AND PRENATAL DIAGNOSIS  Birth defects: Birth defect, congenital malformation, and congenital anomaly are synonymous terms used to describe structural, behavioral, functional, and metabolic disorders present at birth. terms used to describe the study of these disorder are teratology and dysmorphology. Dysmorphologists are usually within a department of clinical genetics. Major structural anomalies occur in 2% to 3% of liveborn infants, and an additional 2% to 3% are recognized in children by age 5 years, for a total of 4% to 6%. birth defects are the leading cause of infant mortality, accounting for approximately 21% of infant deaths. They are the fifth leading cause of years of potential life lost prior to age 65 and a major contributor to disabilities.  Birth defects: In 40% to 60% of persons with birth defects, the cause is unknown. Genetic factors, such as chromosome abnormalities and mutant genes, account for approximately 15%; environmental factors produce approximately 10%; a combination of genetic and environmental influences produces 20% to 25% and twinning causes 0.5% to 1%. Minor anomalies occur in approximately 15% of newborns. These structural abnormalities, such as microtia (small ears ), pigmented spots, and short palpebral fissures, are not themselves detrimental to health but, in some cases, are associated with major defects. For example, infants with one minor anomaly have a 3% chance of having a major malformation; those with two minor anomalies have a 10% chance; and those with three or more minor anomalies have a 20% chance. Therefore, minor anomalies serve as clues for diagnosing more serious underlying defects. In particular, ear anomalies are easily recognizable indicators of other defects and are observed in virtually all children with syndromic malformations.  Types of abnormalities: Malformation: occur during formation of structures, for example, during organogenesis. Malformations are caused by environmental and/ or genetic factors. Most malformation have their origin during the third to eighth weeks of gestation. Deformations: result from mechanical forces that mold a part of the fetus over a prolonged period. Clubfeet, for example, are caused by compression in the amniotic cavity. Deformation often involve the musculoskeletal system and may be reversible postnatally. Disruptions: result in morphological alteration of already formed structures and are caused by destructive processes. Vascular accidents leading to bowel atresias and defects produced by amniotic bands are examples of destructive factors that produce disruptions.  Types of abnormalities: 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 of recurrence is known. In contrast, association is the nonrandom appearance of two or more anomalies that occur together more frequently than by chance alone, but the cause has not been determined. An example is the VACTERL association (vertebral, anal, cardiac, tracheoesophageal, renal, and limb anomalies). Although they do not constitute a diagnosis, association are important because recognition of one or more of the components promotes the search for other in the group.  Principles of teratology: Factors determining the capacity of an agent to produce birth defect have been defined and set forth as the principle of teratology. They include the following 1- Susceptibility to teratogensis 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 period of embryogenesis. 3- Manifestations of abnormal development depend on dose and duration of exposure to a teratogen. 4- Teratogens act in specific ways (mechanisms) on developing cells and tissues to initiate abnormal embryogenesis (pathogenesis). Mechanisms may involve inhibition of a specific biochemical or molecular process; pathogenesis may involve cell death, decreased cell proliferation, or other cellular phenomena. 5- Manifestations of abnormal development are death, malformation, growth retardation, and functional disorders.  Infectious agents Infectious agents that cause birth defects include a number of viruses. Rubella used to be a major problem, but the ability to detect serum antibody titers and development of a vaccine have significantly lowered the incidence of birth defects from this cause. Today, approximately 85% of women are immune. Cytomegalovirus is a serious threat. Often, the mother has no symptoms, but the effects on the fetus can be devastating. The infection is often fatal, and if it is not, meningoencephalitis caused by the virus produces mental retardation. Herpes simplex virus, varicella virus, and human immunodeficiency virus (HIV) can cause birth defects.  Other viral infections and hyperthermia Malformations following maternal infection with measles, mumps, hepatitis, poliomyelitis, echovirus, coxsackie virus, and influenza virus have been described. Prospective studies indicate that the malformation rate after exposure to these agents is low if not nonexistent. Toxoplasmosis and syphilis cause birth defects. Poorly cooked meat; domestic animals, especially cats; and feces in contaminated soil can carry the protozoan parasite Toxoplasmosis gondii. A characteristic feature of fetal toxoplasmosis infection is calcifications.  Radiation Ionizing radiation kills rapidly proliferating cells, so it is a potent teratogen, producing virtually any type of birth defect depending upon the dose and stage of development of the conceptus at the time of exposure. Radiation from nuclear explosion is also teratogenic. Among women survivors pregnant at the time of the atomic bomb explosions over Hiroshima and Nagasaki, 28% aborted, 25% gave birth to children who died in their first year of life, and 25%gave birth to children who had severe birth defects involving the central nervous system. Radiation is also a mutagenic agent and can lead to genetic alteration of germ cells and subsequent malformations.  Chemical agents The role of chemical agents and pharmaceutical drugs in the production of abnormalities in humans is difficult to assess for two reasons: (1) most studies are retrospective, relying on the mothers memory for a history of exposure, and (2) pregnant women take a large number of pharmaceutical drugs. Even with this widespread use of chemical agents, relatively few of the many drugs used during pregnancy have been positively identified as being teratogenic. One example is thalidomide, an antinauseant and sleeping pill. In 1961, it was noted in West Germany that the frequency of amelia and meromelia (total or partial absence of the extremities), a rare hereditary abnormality, had suddenly increased. This observation led to examination of the prenatal histories of affected children and to the discovery that many mothers had taken thalidomide early in pregnancy. The causal relation between thalidomide and meromelia was discovered only because the drug produced such an unusual abnormality. If the defect had been a more common type, such as cleft lip or heart malformation, the association with the drug might easily have been overlooked.  Chemical agents The anticoagulant warfarin is teratogenic, whereas heparin does not appear to be. Antihypertensive agents that inhibit angiotensinconverting enzyme (ACE inhibitors) produce growth retardation, renal dysfunction, fetal death, and oligohydramnios. Caution has also been expressed regarding a number of other compounds that may damage the embryo or fetus. The most prominent among these are propylthiouracil and potassium iodide(goiter and mental retardation), streptomycin (deafness), sulfonamides (kernicterus), the antidepressant imipramine (limb deformities), tetracyclines (bone and tooth anomalies), amphetamines (oral clefts and cardiovascular abnormalities), and quinine (deafness). Finally, there is increasing evidence that aspirin (salicylates), the most commonly ingested drug during pregnancy, may harm the developing offspring when used in large doses. One of the increasing problems in todays society is the effect of social drugs, such as marijuana, alcohol, and cocaine. Cocaine has been reported to cause a number of birth defects, possibly because of its action as a vasoconstrictor that causes hypoxia. There is a well- documented association between maternal alcohol ingestion and congenital abnormalities, because alcohol may induce a broad spectrum of defects, ranging from mental retardation to structural abnormalities, the term fetal alcohol spectrum disorder (FASD) is used to refer to any alcohol-related defects. Fetal alcohol syndrome (FAS) represents the severe end of the spectrum and includes structural defects, growth deficiency, and mental retardation. alcohol is the leading cause of mental retardation. Cigarette smoking has not been linked to major birth defects, but it does contribute to intrauterine growth retardation and premature delivery. There is also evidence that it causes behavioral disturbances.  Hormones Androgenic agents: In the past, synthetic progestins were frequently used during pregnancy to prevent abortion. The progestins ethisterone and norethisterone 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. Oral contraceptives: Birth control pills, containing estrogens and progestogens, appear to have a low teratogenic potential. Because other hormones such as diethylstilbestrol produce abnormalities, however, use of oral contraceptives should be discontinued if pregnancy is suspected. Cortisone: Experimental work has repeatedly shown that cortisone injected into mice and rabbits at certain stages of pregnancy causes a high percentage of cleft palates in the offspring. It has been impossible, however, to implicate cortisone as an environmental factor causing cleft palate in humans.  Maternal disease Diabetes: Disturbances in carbohydrate metabolism during pregnancy in diabetic mothers cause a high incidence of stillbirths, neonatal deaths, abnormally large infants, and congenital malformations. The risk of congenital anomalies in children of insulin-dependent diabetic mothers is three to four times that for the offspring of nondiabetic mothers and has been reported to be as high as 80% in the offspring of diabetic with long-standing disease. Various observed malformation include caudal dysgenesis (sirenomelia). In the case of noninsulin-depended and gestational diabetes, there is a slightly increased risk of having a malformed infant, perhaps because of altered maternal glucose metabolism. Also, oral hypoglycemic agents that might be taken by these individuals, such as the biguanides and sulfonylureas, may act as teratogens.  Nutritional deficiencies Although many nutritional deficiencies, particularly vitamin deficiencies, have been proven to be teratogenic in laboratory animals, the evidence in humans is sparse. Thus, with the exception of endomic cretinism, which is related to iodine deficiency, no analogies to animal experiments have been discovered. The evidence suggests, however, that poor maternal nutrition prior to and during pregnancy contributes to low birth weight and birth defects.  Obesity Obesity has reached epidemic proportions in the united states and has nearly doubled in the past 15 years. Prepregnancy obesity, defined as having a body mass index (BMI) >30 kg/m2 , is associated with a two to threefold increased risk for having a child with a neural tube defect. Causation has not been determined but may relate to maternal metabolic disturbances affecting glucose, insulin, or other factors. Prepregnancy obesity also increases the risk for having a baby with a heart defect, omphalocele, multiple anomalies, and obesity.  Hypoxia Hypoxia induces congenital malformation in a great variety of experimental animals. Whether the same is valid for humans remains to be seen. Although children born at relatively high altitudes are usually lighter in weight and smaller than those born near or at sea level, no increase in the incidence of congenital malformations has been noted. In addition, women with cyanotic cardiovascular disease often give birth to small infants but usually without gross congenital malformation.  Heavy metals In the United States, noted were made when seed corn sprayed with a mercury- containing fungicide was fed to hogs and the meat was subsequently eaten by pregnant women. Likewise, in Iraq, several thousand babies were affected after mothers ate grain treated with mercury-containing fungicides. Lead has been associated with increased abortions, growth retardation, and neurological disorders.  Male-mediated teratogenesis A number of studies have indicated that exposures to chemicals and other agents, such as ethylnitrosourea and radiation. Can cause mutations in male germ cells. Epidemiological investigations have linked paternal occupational and environmental exposures to mercury, lead, solvents, alcohol, cigarette smoking, and other compounds to spontaneous abortion, low birth weight, and birth defects. Advanced paternal age is a factor for an increased risk of limb and neural tube defects, down syndrome, and new autosomal dominant mutations. Interestingly, men younger than 20 also have a relatively high risk of fathering a child with a birth defect. Even transmission of paternally mediated toxicity is possible through seminal fluid and from household contamination from chemicals brought home on work clothes by the father. Studies also show that men with birth defects themselves have a greater than twofold risk of having an affected child.  Prenatal diagnosis The perinatologist has several approaches for assessing growth and development of the fetus in utero, including ultrasound, maternal serum screening, amniocentesis, and chorionic villus sampling, in combination, these techniques are designed to detect malformation, genetic abnormalities, overall fetal growth, and complications of pregnancy, such as placenta or uterine abnormalities. The use and development of in utero therapies have heralded a new concept in which the fetus is now a patient.  Ultrasonography Ultrasonography is a relatively noninvasive technique that uses high frequency sound waves reflected from tissues to create images. The approach may be transabdominal or transvaginal, with the latter producing image with higher resolution. The technique is safe and commonly used, with approximately 80% of pregnant women in the united stated receiving at least one scan. Important parameters revealed by ultrasound include characteristics of fetal age and growth; presence or absence of congenital anomalies; status of the uterine environment, including the amount of amniotic fluid; placental position and umbilical blood flow; and whether multiple gestations are present. All of these factors are then used to determine proper approaches for management of the pregnancy. Congenital malformation that can be determined by ultrasound include the neural tube defects anencephaly and spine bifida. abdominal wall defects, such as omphalocele and gastroschisis; and heart and facial defects, including cleft lip and palate.  Maternal serum screening A search for biochemical markers of fetal stratus led to development of maternal serum screening. One of the first of these tests assessed serum α-fetoprotein (AFP) concentrations. AFP is produced normally by the fetal liver, peaks at approximately 14 weeks, and leaks into the maternal circulation via the placenta. Thus, AFP concentrations increase in maternal serum during the second trimester and then begin a steady decline after 30 weeks of gestation. In cases of neural tube defects and several other abnormalities, including omphalocele, gastroschisis, bladder exstrophy, amniotic band syndrome, sacrococcygeal teratoma, and intestinal atresia, AFP levels increase in amniotic fluid and maternal serum. In other instances, AFP concentrations decrease, as, for example, in Down syndrome, trisomy 18, sex chromosome abnormalities, and triploidy. These conditions are also associated with lower serum concentrations of human chorionic gonadotropin (hCG) and unconjugated estriol. Therefore, maternal serum screening provide 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. because of the amount of fluid required, the procedure is not usually performed before 14 weeks gestation, when sufficient quantities are available without endangering the fetus. The risk of fetal loss as a result of the procedure is 1% but it is less in centers skilled in the technique. The fluid itself is analyzed for biochemical factors, such as AFP and acetylcholinesterase. In addition, fetal cells, sloughed into the amniotic fluid, can be recovered and used for metaphase karyotyping and other genetic analyses.  Chorionic villus sampling Chorionic villus sampling (CVS) involves inserting a needle transabdominally or transvaginally into the placental mass and aspiration approximately 5 to 30 mg of villus tissue. Cells may be analyzed immediately, but accuracy of results is problematic because of the high frequency of chromosomal errors in the normal placenta. Therefore, cells from the mesenchymal core are isolated by trypsinization of the external trophoblast and cultured. Because of the large number of cells obtained, only 2 to 3 days in culture are necessary to permit genetic analysis. Thus, 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, however, and there have been indications that the procedure carries an increased risk for limb reduction defects.  Generally, these prenatal diagnostic test are not used on a routine basis (although ultrasonography is approaching routine use), being reserved instead for high- risk pregnancies, 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 down syndrome or a neural tube defect 3- The presence of maternal disease, such as diabetes 4- An abnormal ultrasound or serum screening test.  Fetal therapy 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. Fetal medical treatment: Treatment for infection, 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 vein.  Fetal therapy Fetal surgery: Because of advances in ultrasound and surgical procedures, operating on fetuses has become possible. Because of risks to the mother, infant, and subsequent pregnancies, however, procedures are only performed in centers with well-trained teams and only when there are no reasonable alternatives. Several types of surgeries may be performed, including placing shunts to remove fluid from organs and cavities. For example, 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 congenital diaphragmatic hernia, removing cystic (adenomatoid) lesions in the lung, and repairing spina bifida defects. Repairs of hernias and lung lesions have good outcomes if proper selection criteria for cases are employed, and one of these is the fetal that, without surgery, fetal demise is almost certain. Surgery for neural tube defects is more controversial because the abnormalities are not life- threatening. Also, the evidence is not conclusive that repair of the lesion improves neurological function, although it does alleviate the accompanying hydrocephalus by freeing the tethered spinal cord and preventing herniation of the cerebellum into the foramen magnum.  Fetal therapy 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 disease, such as Tay-Sachs and cystic fibrosis, is also being investigated. SUMMARY THANK YOU！