Download - Prenatal Diagnosis and Fetal Therapy
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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