Prenatal Diagnosis and Ultrasound Examination

Birth Defects

• Birth defect, congenital malformation, and congenital anomaly are synonymous terms for structural, behavioral, functional, and metabolic disorders present at birth.
• Teratology and dysmorphology are terms used to describe the study of birth defects. Dysmorphologists frequently work in clinical genetics departments.
• Major structural anomalies occur in 2% to 3% of liveborn infants; an additional 2% to 3% are identified by age 5. This totals 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 before age 65, and a significant contributor to disabilities.
• In 40% to 60% of cases with birth defects, the cause is unknown. Contributing factors include genetics (chromosome abnormalities and mutant genes, approximately 15%), environmental factors (approximately 10%), a combination of genetic and environmental factors (20% to 25%), and multiple births (0.5% to 1%).

Types of Abnormalities

• Malformation: Occurring during the formation of structures (e.g., organogenesis) during the third to eighth weeks of gestation; caused by environmental and/or genetic factors.
• Deformation: Resulting from prolonged mechanical forces molding a part of the fetus (e.g., clubfoot); caused by compression in the amniotic cavity; often involves the musculoskeletal system and may be reversible postnatally.
• Disruption: Resulting in morphological alteration of already formed structures due to destructive processes (e.g., vascular accidents leading to bowel atresia, amniotic bands).

Risk of Birth Defects During Gestation

• A graph displays an increasing risk of birth defects occurring during the embryonic and fetal periods of gestation.

Syndromes and Associations

• Syndrome: A group of anomalies occurring together with a specific common cause. This indicates a diagnosis is made, and recurrence is known.
• Association: The nonrandom appearance of two or more anomalies occurring more frequently than by chance, but with an unknown cause. (E.g., VACTERL association: vertebral, anal, cardiac, tracheoesophageal, renal, and limb anomalies).

Principles of Teratology

• Susceptibility: Depends on the genotype of the conceptus and the interaction with the environment. Maternal genome impacts drug metabolism, infection resistance, and biochemical/molecular processes in the conceptus.
• Susceptibility Variations: Varies with the developmental stage at the time of exposure, with the third to eighth week of gestation being most sensitive.
• Manifestations: Depend on the dose and duration of exposure to the teratogen.
• Mechanism: Involves ways teratogens affect cells and tissues, initiating abnormal embryogenesis (pathogenesis); may inhibit biochemical/molecular processes, cause cell death, decreased cell proliferation, or other cellular phenomena.
• Manifestations: Include death, malformation, growth retardation, and functional disorders.

Infectious Agents

• Rubella, a serious concern historically, now has a significantly low incidence due to vaccines (approx 85% immunity).
• Cytomegalovirus (CMV) is a serious threat; can be devastating for the fetus, frequently resulting in death or severe mental retardation. Maternal infections often exhibit no symptoms.
• Herpes simplex virus (HSV), varicella virus, and HIV can also cause birth defects.

Other Viral Infections and Hyperthermia

• Malformations can also occur after maternal exposure to measles, mumps, hepatitis, poliomyelitis, echovirus, coxsackie virus, or influenza virus. Prospective studies suggest the rates after exposure are usually low.
• Toxoplasmosis and syphilis can cause birth defects. Poorly cooked meat, domestic animals (especially cats), and feces in contaminated soil can transmit the parasite. A characteristic feature in fetal toxoplasmosis infection is calcification.

Radiation

• Ionizing radiation kills rapidly proliferating cells and is a potent teratogen, producing various birth defects depending on the dose and gestational stage at the time of exposure. Exposure to nuclear explosions carries a high risk for congenital defects.

Chemical Agents

• Pharmaceutical drugs' contribution to birth defects is difficult to assess; there are many drugs taken during pregnancy and most studies are retrospective.
• Thalidomide, an antinauseant and sleeping pill, was found to be teratogenic in 1961, causing widespread limb abnormalities.
• Other chemical agents include anticoagulants (warfarin), antihypertensives (ACE inhibitors), propylthiouracial, potassium iodide, streptomycin, sulfonamides, antidepressants (imipramine), tetracyclines, amphetamines, quinine, and aspirin (salicylates).

Hormones

• Androgenic agents: Synthetic progestins used to prevent abortion could lead to masculinization of female embryos, resulting in clitoris enlargement and labioscrotal fusion.
• Oral contraceptives: Low teratogenic potential, but use should be discontinued if pregnancy is suspected due to other hormones producing abnormalities.
• Cortisone: Studies indicate it is a teratogenic agent when injected into mice and rabbits during pregnancy, causing a high incidence of cleft palates; there is not enough evidence to link it to birth defects in humans.

Maternal Disease

• Diabetes: Disturbances in carbohydrate metabolism in diabetic mothers can cause stillbirths, neonatal deaths, large infants, and congenital malformations; risk is 3-4 times higher for offspring.
• Risk for malformations is also seen in non-insulin-dependent and gestational diabetes because of possible alteration in maternal glucose metabolism. Oral hypoglycemics, like biguanides and sulfonylureas, may also be teratogenic.

Nutritional Deficiencies

• Many nutritional deficiencies (particularly vitamin deficiencies), shown to be teratogenic in animals, have sparse evidence in humans. Endemic cretinism from iodine deficiency is an exception. Insufficient maternal nutrition leads to low birth weights and potential defects.

Obesity

• Prepregnancy obesity (>30 kg/m2 BMI) is associated with a two-to-threefold increased risk of neural tube defects, and possible birth defects. Maternal metabolic disturbances affecting glucose and insulin levels may be causative factors. Other outcomes are heart defects, omphalocele, and multiple anomalies.

Hypoxia

• Hypoxia can lead to congenital malformations in various animals. However, there's limited evidence regarding humans and altitude.

Heavy Metals

• Mercury-contaminated seed corn and fungicides have been linked to birth defects and increased abortions, and lead to growth retardation and neurological disorders.

Male-mediated Teratogenesis

• Exposure to chemicals (ethylnitrosourea, radiation), solvents, alcohol, cigarette smoking, and other environmental factors can cause mutations in male germ cells leading to spontaneous abortion, low birth weight, and birth defects in offspring.
• Advanced paternal age is a risk factor for defects.

Prenatal Diagnosis

• Approaches include ultrasound, maternal serum screening, amniocentesis, and chorionic villus sampling to assess fetal growth, development and detect malformations, genetic abnormalities, and complications of pregnancy.

Ultrasonography

• A non-invasive technique using high-frequency sound waves to produce images of the fetus. It's a safe technique, used frequently in modern pregnancies to assess fetal age, growth, congenital anomalies, amniotic fluid, placental position, and blood flow, and multiple pregnancies.
• Ultrasound can detect neural tube defects, abdominal wall defects, heart and facial defects, including cleft lip and cleft palate.

Maternal Serum Screening

• Biochemical markers, such as alpha-fetoprotein (AFP), are assessed to identify fetal abnormalities such as neural tube defects, omphalocele, gastroschisis, bladder exstrophy, amniotic band syndrome, sacrococcygeal teratoma, and intestinal atresia, or conditions such as Down syndrome, trisomy 18, sex chromosome abnormalities and triploidy.

Amniocentesis

• A needle is inserted into the amniotic cavity for fluid withdrawal and analysis for biochemical factors (AFP, acetylcholinesterase), and fetal cells for chromosomal analysis. It is less risky in expert centers.

Chorionic Villus Sampling

• A needle is inserted to obtain placental tissue for immediate or cultured analysis to assess fetal abnormalities and chromosome abnormalities. It carries a twofold greater risk of fetal loss than amniocentesis.

Fetal Therapy

• Includes fetal transfusion for anemia, medical treatments for infections, cardiac arrhythmias, thyroid dysfunction, direct fetal injection into the gluteal region or via the umbilical vein. Surgical procedures, including fetal shunts, removing fluid from organs (for example: in obstructive urinary disease of the urethra-- placing a pigtail shunt into the fetal bladder). Repairing congenital diaphragmatic hernia, removing cystic lesions, and repairing spina bifida defects.

• Stem cell transplantation and gene therapy are researched for the potential treatment of immunodeficiencies and inherited metabolic disorders such as Tay-Sachs and cystic fibrosis.