Down syndrome occurs in approximately 1 of 800 live births. In 95% of cases, it is a result of meiotic nondisjunction of the chromosome 21 pair, usually in the mother’s gamete, resulting in a 47, +21 karyotype. The risk of a fetus with Down syndrome, as well as trisomy 13 and 18, increases with maternal age. The incidence of karyotypic abnormalities at birth including Down syndrome in relation to maternal age is shown in Table 6.8 in this book. Four percent of cases of Down syndrome result from a translocation, and approximately 1% result from mosaicism. These cases are not related to advanced maternal age.

A number of maternal serum markers have proven useful in screening for Down syndrome. Historically, a maternal age at delivery of 35 years was used as a cutoff to identify women at the highest risk for having a baby with Down syndrome. Various combinations of serum biochemical markers have been used to screen for Down syndrome since 1984, when it was found that low second-trimester maternal serum α-fetoprotein (MSAFP) levels were associated with Down syndrome. In the 1990s, it was reported that elevated human chorionic gonadotropin (hCG) levels and decreased unconjugated estriol (uE₃) levels were associated with Down syndrome. The combination of these three markers in combination with maternal age, the triple screen, or triple test yields a 69% detection rate for Down syndrome at a 5% positive screen rate. A fourth marker, inhibin A, which may be increased in the serum of women carrying a fetus with Down syndrome, further increases the detection rate for Down syndrome in the second trimester. When inhibin A is included in the second-trimester screening test, known as the quadruple or quad screen, the estimated detection rate increases to 81% with a 5% false positive rate. The triple and quadruple screens should ideally be offered between 15 and 18 weeks gestation, although they can be performed between 15 and 22 weeks. It is critical to know the precise gestational age, because the median values for the biochemical markers and the risk ratios are based on gestational age.

First-trimester screening for Down syndrome using fetal nuchal translucency, a measurement obtained by ultrasound, and maternal serum markers, pregnancy-associated plasma protein A (PAPP-A) and the free beta subunit of human chorionic gonadotropin (fβ-hCG) in conjunction with maternal age (combined screening), yields a detection rate of approximately 85% at a 5% false-positive rate. The optimal gestational age for first-trimester screening appears to be 11 weeks, as the detection rate may be the highest (87%) at this time. First-trimester screening may be performed between 10 weeks/3 days and 13 weeks/6 days. The first-trimester combined screen may also be used to screen for trisomy 18. Nuchal translucency alone is associated with detection rates of 75% rate for trisomy 18, 72% for trisomy 13, 87% for Turner syndrome, 59% for triploidy, and 55% for other significant chromosomal abnormalities.

Down syndrome screening strategies that involve a combination of first- and second-trimester markers yield the
highest detection rates. There are a variety of possible approaches to combined first- and second-trimester screening. The various Down screening tests and their detection rates are listed in Table 7.1. The integrated screen determines a Down syndrome risk assessment based on a combination of maternal age, first-trimester nuchal translucency, and PAPP-A and the second-trimester quad screen markers. The patient is provided with a single risk for Down syndrome after the quad screen has been interpreted. The integrated screen yields a 94% to 96% detection rate at a 5% positive screen rate. A potential disadvantage of the integrated screen is that the patient does not receive any information regarding Down syndrome risk until the second trimester. The serum integrated screen is similar to the integrated screen except that the patient does not have a nuchal translucency measurement in the first trimester. The serum integrated screen is an effective screening option for patients who do not have access to a center that can perform nuchal translucency measurement This yields a detection rate of 88% at a 5% positive screen rate. The stepwise sequential screen consists of the measurement of nuchal translucency, PAPP-A, and fβ-hCG in the first trimester and the quad screen in the second trimester. The results are provided to the patient after each test. An advantage of the stepwise sequential screen is that Down syndrome risk assessment is provided after the first-trimester screen, which gives the patient the option of having CVS if her initial risk is high. The stepwise sequential screen has a 95% detection rate at a 5% positive screen rate. The contingent sequential screen determines an initial Down syndrome risk based on first-trimester nuchal translucency, PAPP-A, and fβ-hCG measurements. Women with the highest risk from first-trimester screening are offered invasive testing by CVS, and women with the lowest risks are told that second-trimester testing is not necessary. Women with intermediate risks after the first-trimester screen have their risks reassessed by integrating their first-trimester results with second-trimester quad screen results.

In cases of first-trimester screening where the fetal nuchal translucency is 3.5 mm or greater, patients should be offered a targeted ultrasound examination and fetal echocardiogram. In addition to the increased risk for aneuploidies, these fetuses are at increased risk for having structural abnormalities, including heart defects as well as genetic syndromes.

Women with an increased nuchal translucency measurement or abnormal first-trimester serum markers may be at increased risk for adverse obstetric outcomes, including preeclampsia, preterm birth, low birth weight, spontaneous fetal loss before 24 weeks gestation, and fetal demise later in gestation. Currently, there are no data to indicate whether or not fetal surveillance in the later pregnancy will be helpful in the care of these patients.

In addition to nuchal translucency, other ultrasonographic markers for Down syndrome have proven to be useful adjunctive noninvasive screening tools. Absence of the fetal nasal bone in the first trimester has been observed in fetuses with Down syndrome. The assessment of absence of the fetal nasal bone, increased resistance to flow in the ductus venosus, or the presence of tricuspid regurgitation may be used to further modify first-trimester Down syndrome risk assessment.

The American College of Obstetrics and Gynecology published an updated technical bulletin on Screening for Fetal Chromosomal Abnormalities in January, 2007. The previous bulletin had recommended that screening for aneuploidy should be offered to all women younger than 35 at their estimated date of delivery and that invasive prenatal diagnostic testing should be offered to all women who will be 35 years or older at the estimated date of their delivery and to women with risk factors for having a fetus with aneuploidy including a significant family history, a positive screening test or an abnormality noted on prenatal ultrasound. The updated bulletin recommends that screening and invasive testing should be available to all women who
present for prenatal care before 20 weeks of gestation regardless of maternal age.

It is likely that new markers may be implemented in the future to improve the sensitivity and specificity of maternal serum screening. ADAM 12, a metalloprotease that binds insulin growth factor binding protein-3 (IGFBP-3), appears to be an effective early Down syndrome marker. Decreased levels of ADAM 12 may be detected in cases of trisomy 21 as early as 8 to 10 weeks gestation. Maternal serum ADAM 12 and PAPP-A levels at 8 to 9 weeks gestation in combination with maternal age yielded a 91% detection rate for Down syndrome at a 5% false-positive rate. When nuchal translucency data from approximately 12 weeks gestation was added, this increased the detection rate to 97%.

Cellfree fetal DNA was first detected in the maternal circulation over a decade ago. Fetal epigenetic markers such as DNA methylation or a placental epigenetic marker called maspin can be utilized to discriminate fetal DNA from maternal DNA. The detection of fetal DNA in the maternal circulation holds great promise for prenatal diagnosis of fetal disorders and pregnancy complications. To date, cellfree DNA has been used for fetal rhesus D blood typing and fetal gender determination for carriers of X-linked recessive disease and fetuses at risk for congenital adrenal hyperplasia.

Neural tube defects are an etiologically heterogeneous group of conditions characterized by failure of closure of the embryonic neural tube. These abnormalities of the brain and vertebral column can occur as an isolated defect or as part of a genetic syndrome. Isolated neural tube defects occur in approximately 1.4 to 2 per 1,000 pregnancies and are the second most common major congenital anomaly. They are thought to result from a combination of genetic predisposition and environmental influences. Approximately 90% to 95% of all infants with neural tube defects are born to women with no history of a child with a neural tube defect. Factors known to be associated with neural tube defects include low folic acid intake, geographic region, ethnicity, maternal valproic acid and carbamazepine exposure, high maternal core temperature, and maternal diabetes.

MSAFP screening for neural tube defects was introduced in the 1980s. MSAFP evaluation is an effective screening test for neural tube defects and should be offered to all pregnant women. This type of screening is most accurate from weeks 16 to 18, as there is the widest margin between abnormal and normal distributions at this period in gestation. Although screening for neural tube defects should optimally be performed between 16 and 18 weeks gestation, it can be done between 15 and 22 weeks.

In the United States, a screen-positive cutoff of 2.5 multiples of the median (MoM) is commonly used, yielding a screen-positive rate of approximately 5%. This results in the detection of more than 95% of anencephalic fetuses and 80% of fetuses with open spina bifida. It is important to adjust MSAFP values for diabetes, race, maternal weight, and multiple gestation. In insulin-dependent diabetics, the MSAFP level is approximately 60% of nondiabetic controls, and it is inversely correlated with the hemoglobin A_1C levels. Blacks have approximately 1.1 times the MSAFP level of whites, and Asians have an intermediate level between blacks and whites. The median twin MSAFP level from 16 to 20 weeks is approximately 2.5 multiples of the median for a singleton pregnancy. The detection rate for twins is approximately 80%.

An inaccurate gestational age determination is the most common reason for an abnormally elevated MSAFP. The false-positive rate can be lowered by performing an ultrasound examination before MSAFP screening to verify the gestational age and diagnose multiple gestations and cases of intrauterine fetal demise, which may also be associated with elevated MSAFP levels. Table 7.2 lists conditions that may be associated with an elevated MSAFP level.

Women with MSAFP levels higher than the predetermined cutoff (usually 2.0 to 2.5 MOM) and women with risk factors for carrying a fetus with a neural tube defect including a positive family history or previous affected
pregnancy, diabetes, or first-trimester valproic acid or carbamzepine use should be referred for genetic counseling and consideration of a diagnostic test. All women with a positive MSAFP screen should have a specialized ultrasound to further assess the risk of neural tube defects and rule out other fetal anomalies. According to the ACOG bulletin, genetic amniocentesis is the traditional diagnostic test offered to women with an elevated MSAFP. An elevated amniotic fluid AFP in association with the presence of acetylcholinesterase in the amniotic fluid is considered diagnostic for a fetal neural tube defect. If an amniocentesis is performed secondary to an elevated MSAFP, a sample of amniotic fluid should also be sent for cytogenetic analysis, as there are several studies that have reported an association between elevated MSAFP levels and fetal aneuploidy.

There are many centers in the United States that use ultrasound as a diagnostic tool in women with a high risk for neural tube defects. Studies have shown that in experienced centers, ultrasound can yield a 97% sensitivity and a 100% specificity in the diagnosis of neural tube defects. If the fetal anatomy is well visualized and no abnormalities are detected, the risks and benefits of both amniocentesis and specialized ultrasound examination can be discussed with the patient. Many high-risk patients decline to have amniocentesis performed after a reassuring specialized ultrasound examination. Alternatively, amniocentesis should be offered if ultrasound visualization of the fetus is suboptimal and in patients in whom a fetal defect is identified.

The most common indications for consideration of invasive prenatal diagnostic testing include an abnormal prenatal screen conferring an increased risk for fetal aneuploidy or spina bifida, a thickened nuchal translucency >3 mm, increased risk for a genetic condition based on parental carrier status, and identification of a fetal anomaly on prenatal ultrasound. Table 7.3 lists indications for consideration of invasive prenatal diagnostic testing.