Prenatal diagnosis

• Prenatal diagnosis

  The science of identifying congenital abnormalities and genetic conditions in the fetus

  
• Prenatal diagnosis encompasses the diagnosis of structural malformations with specialized ultrasound, screening tests for aneuploidy, carrier screening for genetic diseases, and diagnostic tests performed on chorionic villi and amniotic fluid
• 4 per 1000 pregnancies have a chromosomal abnormality based on population-based registry data
• If chromosomal microarray analysis (CMA) is performed, an additional 4 per 1000 are found to have a pathogenic copy number variant
• It is important for all pregnant women to be offered both screening and diagnostic tests
• The goal of prenatal diagnosis

  To provide accurate information about short- and long-term prognosis, recurrence risk, and potential therapy
• Nondirective counseling

  Provision of unbiased knowledge
• Management of an affected pregnancy

  1. Diagnostic testing

  2. Discussion of potential fetal therapy options and postnatal care

  3. Decisions related to expectant management or pregnancy termination
• Fetal imaging of congenital anomalies is discussed in Chapter 15, fetal therapy in Chapter 19, and pregnancy termination in Chapter 11

  
• Brock observed that pregnancies complicated by neural-tube defects had higher levels of alpha-fetoprotein (AFP) in maternal serum and amniotic fluid

  Nearly 50 years ago
• Widespread serum screening began in 1977 after a collaborative trial from the UK established the association between elevated maternal serum AFP levels (MSAFP) and fetal open neural-tube defects
• Screening at 16 to 18 weeks' gestation detected 90 percent of fetuses with anencephaly and 80 percent of those with open spina bifida, similar to current screening performance

  
• Level I ultrasound

  Screening examination that demonstrated one third of pregnancies with MSAFP elevation had incorrect gestational age, multifetal gestation, or fetal demise as the etiology
• Level II ultrasound

  Examination performed if the amniotic fluid AFP concentration was elevated, to detect and characterize a fetal abnormality

  
• An elevated amniotic fluid AFP level prompted a concurrent assay for amniotic fluid acetylcholinesterase, as it leaks from the exposed neural tissue into the amniotic fluid
• Other fetal abnormalities are associated with elevated amniotic fluid AFP and positive assay results for acetylcholinesterase, including ventral wall defects, esophageal atresia, fetal teratoma, cloacal exstrophy, and skin abnormalities
• Most neural-tube defects are now detected with a standard ultrasound examination, and the detailed ultrasound examination is the preferred diagnostic test
• The designation "advanced maternal age" (AMA) became popular as MSAFP screening was being adopted
• A 1979 NIH Consensus Development Conference recommended advising pregnant women who were 35 years and older about the possibility of amniocentesis for fetal karyotyping
• In 1984, Merkatz and colleagues reported that midtrimester MSAFP levels were lower in pregnancies with trisomies 21 and 18 than in unaffected pregnancies
• The MSAFP screen detected approximately 25 percent of cases of fetal trisomy 21 when the threshold ratio for a positive result was set at 1:270
• Aneuploidy

  The presence of one or more extra chromosomes, usually resulting in trisomy, or loss of a chromosome—monosomy
• Of recognized pregnancies with chromosomal abnormalities, trisomy 21 accounts for approximately half of cases; trisomy 18 accounts for 15 percent; trisomy 13 for 5 percent; and the sex chromosomal abnormalities for approximately 12 percent
• The risk for fetal trisomy increases with maternal age, particularly after age 35
• Women aged 35 years and older account for 18 percent of deliveries in the US, and the majority of Down syndrome births occur in this age group
• Other important aneuploidy risk factors include a numerical chromosomal abnormality or structural chromosomal rearrangement in the woman or her partner, or a prior pregnancy with autosomal trisomy or triploidy
• Cell-free DNA (cfDNA) screening

  More sensitive and specific than analyte-based screening, with a much higher positive predictive value
• The average positive predictive value was 80 percent for cfDNA but only 3 percent for first-trimester screening in a prospective screening study for trisomy 21 in 15,000 pregnancies
• Analyte-based screening has the unusual benefit that an abnormal result may indicate a genetic abnormality for which screening was not specifically performed
• No aneuploidy screening test is diagnostic, and prenatal diagnosis is strongly recommended before acting upon a result
• Aneuploidy screening is not recommended following diagnosis of a major fetal abnormality, as the fetal risk cannot be normalized with a negative aneuploidy screening result
• Analyte-based screening tests are not valid in the setting of an abnormality that affects the AFP component, such as a neural-tube defect or ventral-wall defect
• All aneuploidy screening methods are less accurate in twin gestations and are invalid in triplet gestations and higher-order multiples
• Sensitivity (detection rate)

  The proportion of fetuses with a particular aneuploidy who are detected by the screening test
• Specificity

  The proportion of unaffected pregnancies with a negative screening result
• Positive predictive value

  The proportion of screen-positive results that are true positives
• Screening evaluates whether the pregnancy is at increased risk for specific conditions and estimates the degree of risk, but does not provide information regarding all genetic abnormalities
• With a negative screening test result, the risk is decreased but not eliminated
• False-negative rate

  The proportion of affected pregnancies that are missed by the screening test
• False-positive rate

  The proportion of those without aneuploidy who nonetheless screen positive