Prenatal Diagnosis and Fetal Therapy

Christiana P. Calagui, M.D., FPSMSOB-GYN

Prenatal Diagnosis

2 to 3 % incidence of major abnormalities at birth

Etiology of Birth Defects

1) Malformation - an intrinsic abnormality "programmed" in development, regardless of whether a precise genetic etiology is knownEx. - spina bifida

2) Deformation - caused when a genetically normal fetus develops abnormally because of mechanical forces imposed by the uterine environmentEx. - an otherwise normal limb that develops

contractures because of prolonged oligohydramnios

3) Disruption - more severe change in form or function that occurs when genetically normal tissue is modified as the result of a specific insultEx. - damage from an amnionic band causing a

cephalocele or limb-reduction abnormality

Prenatal Diagnosis of Neural-Tube Defects

Neural-Tube Defects (NTDs)

open neural-tube defects Anencephaly

Spina bifida Cephalocele

rare spinal fusion (schisis) abnormalities

Risk Factors for Neural-Tube Defects

Genetic cause• Family history—multifactorial inheritance

• MTHFR mutation—677CT

• Syndromes with autosomal recessive inheritance– Meckel-Gruber – Roberts – Joubert – Jarcho-Levin – HARDE - hydrocephalus–agyria–retinal

dysplasia–encephalocele

• Aneuploidy – Trisomy 13 – Trisomy 18 – Triploidy

Exposure to certain environmental agents• Diabetes—hyperglycemia

• Hyperthermia – Hot tub or sauna – Fever (controversial)

• Medications – Valproic acid – Carbamazepine – Coumadin – Aminopterin– Thalidomide – Efavirenz

Geographical region—ethnicity, diet, other factor• United Kingdom

• India

• China

• Egypt

• Mexico

• Southern Appalachian

• United States

Alpha-Fetoprotein (AFP)

glycoprotein

synthesized early in gestation by the fetal yolk sac and later by the fetal gastrointestinal tract and liver

major serum protein in the embryo-fetus

analogous to albumin

AFP screening in all women during the second-trimester (ACOG)

between 15 and 20 weeks

Some Conditions Associated with Abnormal Maternal Serum Alpha-Fetoprotein Concentrations

• Elevated Levels– Underestimated gestational age– Multifetal gestation– Fetal death– Neural-tube defects– Gastroschisis– Omphalocele– Low maternal weight– Pilonidal cysts– Esophageal or intestinal

obstruction– Liver necrosis– Cystic hygroma– Sacrococcygeal teratoma

– Urinary obstruction– Renal anomalies—polycystic

kidneys, renal agenesis– Congenital nephrosis– Osteogenesis imperfecta– Congenital skin defects– Cloacal exstrophy– Chorioangioma of placenta– Placental abruption– Oligohydramnios– Preeclampsia– Low birthweight– Maternal hepatoma or

teratoma

• Low Levels– Obesity– Diabetes– Chromosomal trisomies– Gestational trophoblastic

disease– Fetal death– Overestimated

gestational age

Women with abnormally elevated serum AFP levels should be referred for genetic counseling and offered a diagnostic test

specialized sonographic evaluation

amniocentesis

Specialized Sonography

lemon sign- frontal bone scalloping or inward bowing of frontal bone

banana sign - bowing of the cerebellum with effacement of the cisterna magna

Management of the Fetus with a Neural-Tube Defect

Controversial - cesarean versus vaginal delivery

Prenatal Diagnosis of Down Syndrome and Other Aneuploidies

Aneuploidy Screening Protocols

risk of fetal trisomy increases considerably with maternal age and rises most rapidly beginning at age 35

Screening to all women who present for prenatal care before 20 weeks

Second-Trimester Screening - 15 to 20 weeksDown syndrome pregnancies "triple test“

AFP = 0.7 MoMhuman chorionic gonadotropin (hCG) =2.0 MoMunconjugated estriol concentration = 0.8 MoM

Trisomy 18 all three serum markers are decreased

First-Trimester Screening - between 11 and 14 weeks

serum hCG and pregnancy-associated plasma protein-A (PAPP-A)

sonographic nuchal translucency

Sonographic Screening for Aneuploidy

Major Structural Defects

2 to 3 percent of infants

Second-Trimester Markers or "Soft Signs" Associated with Some Down Syndrome Fetuses

• Nuchal fold thickening• Nasal bone absence or

hypoplasia• Shortened frontal lobe or

brachycephaly• Short ear length• Echogenic intracardiac

focus• Echogenic bowel• Mild renal pelvis dilation

• Widened iliac angle• Widened gap between

first and second toes—"sandal gap"

• Clinodactyly, hypoplastic mid-phalanx of fifth digit

• Single transverse palmar crease

• Short femur• Short humerus

Fetuses at Increased Risk for Genetic Disorders

Fetal Aneuploidy

50 % of first-trimester abortions

5 to 7 % of all stillbirths and neonatal deaths

Women with Increased Risk of Fetal Aneuploidy

• Singleton pregnancy and maternal age older than 35 at deliverya

• Dizygotic twin pregnancy and maternal age older than 31 at delivery

• Previous autosomal trisomy birth

• Previous 47,XXX or 47,XXY birth

• Patient or partner is carrier of chromosome translocation

• Patient or partner is carrier of chromosomal inversion

• History of triploidy

• Some cases of repetitive early pregnancy losses

• Patient or partner has aneuploidy

• Major fetal structural defect by sonography

Familial Genetic Disease

Genetic counseling

should be offered to couples with a personal or family history of a heritable genetic disorder

Ethnic Groups at High Risk

Diagnostic Techniques

Second-Trimester Amniocentesis

performed between 15 and 20 weeks

20 mL of fluid is then collected for fetal karyotyping

used to diagnose fetal aneuploidy and other genetic disorders

Complications infrequent

transient vaginal spotting or amnionic fluid leakage in 1 to 2 percent

chorioamnionitis in less than 0.1 percent

Early Amniocentesis

performed between 11 and 14 weeks

1 mL for each week of gestation

Chorionic Villus Sampling (CVS)

performed at 10 to 13 weeks

contraindications vaginal bleeding or spotting active genital tract infectionextreme uterine ante- or retroflexion body habitus precluding easy uterine access or

clear sonographic visualization

indications for CVS are essentially the same as for amniocentesis

primary advantage of villous biopsy results are available earlier in pregnancy, which

lessens parental anxiety when results are normal

allows earlier and safer methods of pregnancy termination when results are abnormal

Complicationsamnionic fluid leakage or infection is less than 0.5

percent

limb-reduction defects

Fetal Blood Sampling

Aka percutaneous umbilical blood sampling (PUBS) or cordocentesis

performed primarily for assessment and treatment of confirmed red cell or platelet alloimmunization and in the evaluation of nonimmune hydrops

used to obtain cells for genetic analysis when CVS or amniocentesis results are confusing or when rapid diagnosis is necessary

Complicationscord vessel bleeding—50%cord hematoma—17%fetal-maternal hemorrhage—66% with an anterior

placenta and 17% with a posterior placentafetal bradycardia—3 to 12%

Fetal Tissue Biopsy

used for muscle biopsy to diagnose muscular dystrophy or mitochondrial myopathy

Preimplantation Genetic Diagnosis

use of assisted reproductive technologies

zygotes affected with a severe genetic disorder can be identified so that they are not used for in vitro fertilization

only unaffected embryos are selected for implantation

Fetal Therapy

Fetal Transfusion

Fetal Anemiacauses

Alloimmunization

infection

genetic diseases such as thalassemia

fetal-to-maternal hemorrhage

Identification of fetal anemiafetal blood sampling

Doppler evaluation of the fetal middle cerebral artery peak systolic velocity

Fetal Medical Therapy

ThyrotoxicosisFetal thyroid status can be assessed by

cordocentesis for thyroid hormones

If hyperthyroidism is confirmed, propylthiouracil administered to the mother is carried transplacentally to suppress the fetal thyroid

Congenital Adrenal Hyperplasiacharacterized by impaired synthesis of cortisol

from cholesterol by the adrenal cortex

Treatment to prevent virilization must begin early, ideally prior to 9 weeks

dexamethasone, given orally to the mother at a dosage of 20 g/kg/d in three divided doses

ArrhythmiasMaternal administration of antiarrhythmic drugs

that cross the placenta is used to convert to a normal rhythm or to lower the baseline heart rate and thereby forestall failure

most commonly used medicationsdigoxin, sotalol, flecainide and procainamide

Congenital InfectionsA number of infectious agents cross the placenta

and cause fetal infection with serious consequences

Prompt maternal treatment—and thus fetal treatment—may prevent or mitigate associated fetal morbidity

Metabolic DisordersFetal methylmalonic acidemia - treated with maternal

oral and intramuscular vitamin B12

Smith-Lemli-Opitz syndrome - Fetal umbilical vein and intraperitoneal transfusions of fresh-frozen plasma

fetal 3-phosphoglycerate-dehydrogenase deficiency - maternal oral L-serine supplementation

Fetal Stem Cell Transplantation

could be used to treat a variety of hematological, metabolic, and immunological diseases

could serve as a delivery vehicle for gene transfer to treat other genetic conditions

most successful in the treatment of immunodeficiency syndromes

Fetal Gene Therapy

attempted only in animal models

Fetal Surgery

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