1: Fetal Assessment

Prenatal diagnosis refers to those testing modalities used during pregnancy to screen and diagnose fetal aneuploidies and anomalies.

An ultrasound measurement of the amount of fluid behind the neck of the fetus, best done between 10 3/7 and 13 6/7 weeks. An increase in the NT correlates with an elevated risk for chromosomal abnormalities such as trisomy 21 or 18. In addition, those gestations with increased NT have an elevated risk of adverse pregnancy outcomes, including fetal cardiac defects and intrauterine fetal demise, even when karyotype is normal. A measurement of NT alone has a low detection rate for trisomy 18 and 21; therefore, it is not recommended as a sole screening test for aneuploidy.

Nuchal translucency combined with a measurement of the maternal serum markers, free beta human chorionic gonadotropin (free β-hCG) and pregnancy-associated plasma protein A (PAPP-A), is used to calculate the risk for trisomies 18 and 21. It is performed between 10 3/7 and 13 6/7 weeks' gestation. It is an effective screening tool, with a detection rate of 82–87% for trisomy 21 at a 5% false-positive screen rate. Free β-hCG is elevated and PAPP-A is decreased in a pregnancy affected by Down syndrome.

The quadruple screen (Quad screen) involves analyzing levels of maternal serum alpha fetoprotein (MSAFP), total hCG, unconjugated estriol, and inhibin A between 15 and 21 weeks' gestation to calculate the risk for trisomies 18 and 21. In addition, it provides a risk assessment for open neural tube defects. For patients who present after 13 6/7 weeks or choose not to undergo first-trimester screening, the Quad screen is an option. In a pregnancy affected by Down syndrome, both MSAFP and unconjugated estriol are low and hCG and inhibin A are elevated. The Quad screen has a detection rate of 81% for Down syndrome at a 5% false-positive rate. Like first-trimester screening, the Quad screen requires an invasive test to confirm the diagnosis of a chromosomal abnormality (ie, amniocentesis or chorionic villous sampling [CVS]). For those patients who chose to undergo first-trimester screening and/or CVS, neural tube defect screening in the form of a second-trimester MSAFP level should be offered. The MSAFP is elevated in the presence of an open neural tube defect. Evidence exists that focused ultrasound during the second trimester is an effective tool for detecting an open neural tube defect.

These options involve a combination of first- and second-trimester screening.

1. Integrated screen. The NT and maternal serum levels of PAPP-A are obtained in the first trimester, and the Quad screen is obtained in the second trimester. When the test does not include an NT measurement it is called serum integrated. With both full-integrated screening and serum screening the results are reported when all the tests are completed, yielding a detection rate for Down syndrome of 94% and 87%, respectively, at a 5% false-positive rate.

2. Sequential screening. NT, PAPP-A, and free β-hCG are measured in the first trimester followed by a Quad screen in the second trimester. With the independent approach, results are given after the first trimester, and women with an increased risk are offered invasive testing. If there's a low risk, a second-trimester screening is completed and interpreted independently of first-trimester results with a high false-positive rate of 11% at a detection rate of 94%. With the step-wise approach, those patients determined to be at high risk after the first-trimester screenings are offered invasive testing. Otherwise, the second-trimester portion is completed and the results are given and combined with those in the first trimester. The detection rate is 95% at a 5% false-positive rate. The contingent approach does the first-trimester portion of the sequential testing and follows with the Quad screen when an elevated risk is noted. Those at intermediate risk complete the second portion. However, those at low risk do not undergo further testing. The contingent sequential screening has an excellent detection rate and a low false-positive rate, and it is the most cost-effective screening tool for trisomy 21.

Uterine ultrasound examination is used in the following circumstances:

1. Determination of pregnancy viability. Fetal heart motion can be detected at 6 weeks' gestation by an abdominal scan and a few days earlier by transvaginal ultrasound. Once the crown-rump length (CRL) is ≥5 mm, fetal heart motion should be seen. Ultrasound is also used in the case of a suspected fetal demise later in pregnancy.

2. Calculation of gestational age. Measurement of the CRL between 6 and 14 weeks' gestation allows for the most accurate assessment of gestational age, to within 5 days. After the first trimester, a combination of biparietal diameter, head circumference, abdominal circumference, and femur length is used to estimate gestational age and fetal weight. Measurements in the second trimester are accurate to within ∼10–14 days and in the third trimester to within 14–21 days. See also Chapter 5.

3. Diagnosis of multiple pregnancy and determination of chorionicity and amnionicity. The determination of chorionicity and amnionicity is made by ultrasound examination of the fetal membranes and is best done as early as possible in the first trimester but after 6 weeks' and prior to 14 weeks' gestation.

4. Anatomic survey. A large number of congenital anomalies can be diagnosed reliably by ultrasonography, including anencephaly, hydrocephalus, congenital heart defects, gastroschisis, omphalocele, spina bifida, renal anomalies, diaphragmatic hernia, cleft lip and palate, and skeletal dysplasia. Identification of these anomalies before birth can help determine the safest method of delivery and the support personnel needed at delivery. Ultrasonography can also aid in determining fetal gender for patients in whom this determination impacts the likelihood of a known X-linked genetic disorder.

5. Visual guidance. Ultrasound is used for guidance during procedures such as amniocentesis, CVS, percutaneous umbilical blood sampling (PUBS), and some fetal surgeries (eg, placement of bladder or chest shunts).

6. Assessment of growth and fetal weight. Ultrasonography is useful to detect and monitor both intrauterine growth restriction (IUGR; defined as an estimated fetal weight <10%) and fetal macrosomia (estimated fetal weight >4500 g). Evidence is accumulating that maternal physical size and race should be considered in customizing the fetal weight for determination of IUGR. Estimation of fetal weight is also important in counseling patients regarding expectations after delivering a premature infant. Ultrasound assessment for fetal weight by an experienced sonographer is accurate within 10–20% of actual weight.

7. Assessment of amniotic fluid volume. Amniotic fluid volume may be assessed objectively with ultrasound by measuring the maximum vertical pocket (MVP) or amniotic fluid index (AFI: total of cord-free deepest vertical pockets in four quadrants) in centimeters.

   1. Oligohydramnios. Defined as an AFI of <5 cm, AFI <10% for gestational age, or MVP <2 cm. Oligohydramnios is associated with increased fetal morbidity, and mortality with spontaneous rupture of membranes as the most common cause. Other causes include placental insufficiency, chronic hypertension, postdates gestation, and fetal anomalies such as renal agenesis, bladder outlet obstruction, cardiac disease, and karyotypic abnormalities.

   2. Polyhydramnios. Defined as an AFI >25 cm, AFI >95% for gestational age, or MVP >8 cm. Causes of polyhydramnios include diabetes, multiple gestation with twin-twin transfusion syndrome, nonimmune hydrops, and fetal anomalies such as open neural tube defects, cardiac diseases, and gastrointestinal obstruction. Most cases of polyhydramnios are idiopathic; however, the risk for fetal anomalies increases with the severity of the polyhydramnios.

8. Assessment of placental location and presence of retroplacental hemorrhage. This is useful in suspected cases of placenta previa or accreta. Most cases of abruptio placentae are not diagnosed by ultrasonography because abruption is a clinical diagnosis.

9. Assessment of fetal well-being

   1. Biophysical profile. Ultrasonography is used to assess fetal movements, fetal breathing, fetal tone, and amniotic fluid volume. See biophysical profile under antepartum tests of fetal well-being (Table 1–1).

   2. Doppler studies. Doppler ultrasonography of fetal vessels, particularly the umbilical artery, is a useful adjunct in the management of high-risk pregnancies, especially those complicated by IUGR. Changes in the vascular Doppler pattern (ie, increased systolic/diastolic ratios and absent or reversed end-diastolic flow in the umbilical artery) signal elevations in placental vascular resistance. These abnormalities correlate with an increased risk for perinatal morbidity and mortality. In high-risk pregnancies, assessment of the middle cerebral artery is useful for evaluating for the presence of fetal anemia, and Doppler assessment of the uterine artery may be useful in the prediction and evaluation of preeclampsia. The overall use of Doppler ultrasonography has been associated with a 29% decrease in perinatal mortality and fewer inductions of labor and cesarean deliveries in high-risk pregnancies; however, no benefit in using this technique has been demonstrated in screening a low-risk population.

Amniotic fluid can be analyzed for prenatal diagnosis of karyotypic abnormalities, genetic disorders (for which testing is available), fetal blood type and hemoglobinopathies, fetal lung maturity, and monitoring the degree of isoimmunization by measurement of the content of bilirubin in the fluid, and for the diagnosis of chorioamnionitis. Testing for karyotypic abnormalities is usually done at 16–20 weeks' gestation. A sample of amniotic fluid is removed under ultrasound guidance. Fetal cells in the fluid can be grown in tissue culture for genetic study. With visual guidance from the ultrasound, the pregnancy loss rate related to amniocentesis is usually quoted at between 1 per 200 and 1 per 1600. Early amniocentesis (before 14 weeks) is generally not recommended because it is associated with a significantly higher rate of fetal loss and limb deformities. Indications for amniocentesis include women at an increased risk of aneuploidy, either by history or abnormal first- or second-trimester screening tests; women with prior children with a chromosomal abnormality; suspected X-linked disorder; autosomal recessive disorders when both parents are carriers of the trait in question; and evaluation of inborn errors of metabolism.

CVS is usually performed between 10 and 12 weeks' gestation. Chorionic villi are withdrawn from the placenta, either through a needle inserted through the abdomen or through a trans-cervical catheter, and the cells obtained are grown and analyzed. Indications are the same as those for amniocentesis. Pregnancy loss rates after CVS are similar to those for amniocentesis but are highly operator dependent. CVS is generally not recommended prior to 10 weeks' gestation due to the increased rate of limb anomalies reported.

Under ultrasound guidance, a needle is placed transabdominally into the fetal umbilical artery or vein. Samples of fetal blood can be obtained for karyotype, viral studies, fetal blood type, hematocrit, or platelet count. This also provides a route for in utero transfusion of red blood cells or platelets. PUBS is most often used in cases of severe hemolytic disease of the fetus with or without hydrops, such as that due to Rh or atypical antibody isoimmunization.

Antepartum testing refers to those testing modalities used during pregnancy to assess fetal health and identify fetuses at risk for poor pregnancy outcome.

The nonstress test is a simple noninvasive test used to check fetal well-being by measuring the heart rate in response to fetal movements. Fetal well-being is confirmed if the baseline heart rate is normal and there are periodic accelerations in the fetal heart rate. The following guidelines can be used, although there may be variations between institutions.

1. Reactive NST. In a 20-minute monitoring period, there are ≥2 accelerations of the fetal heart rate 15 beats/min above the baseline, each lasting at least 15 seconds. In a fetus <32 weeks' gestation, the accelerations must reach 10 beats/min above the baseline and last at least 10 seconds. The perinatal mortality within 1 week after a reactive NST is ∼1.9 per 1000.

2. Nonreactive NST. Fetal heart rate does not meet the established criteria during a prolonged period of monitoring (usually at least 1 hour). There are many causes of a nonreactive NST besides fetal compromise, including fetal sleep cycle, chronic maternal smoking, and exposure to medications such as central nervous system depressants and propranolol. Because of this low specificity (the false-positive rate is ∼75–90%), a nonreactive NST should be followed by more definitive testing such as a biophysical profile or a contraction stress test.

The biophysical profile is another test used to assess fetal well-being. It involves performing an NST to assess fetal heart rate and ultrasound over 30 minutes to assess fetal breathing movements, gross body movements, tone, and amniotic fluid index (AFI).Two points are given for each variable if present and zero if absent during the observation period (see Table 1–1). A score of 8–10 is considered normal, 6 is equivocal and warrants a repeat BPP in 24 hours, and 0–4 is abnormal with delivery usually indicated. Changes in the BPP parameters are due to fetal hypoxemia. Caution is needed since it can also be affected by other factors such as gestational age, medications, and improper technique. The BPP is widely used among institutions to monitor high-risk pregnancies. However, evidence from randomized clinical trials does not support its use to monitor complicated pregnancies. Institutional variation exists regarding gestational age for performance of BPP, starting as low as 24 weeks, even when its utility has only been studied at higher gestational ages.

Modified biophysical profile. The BPP scoring system has been modified to shorten testing time. The most common combination includes an evaluation of only an NST and AFI. In some cases, the modified BPP is used as an initial test and if abnormal, it is followed by additional testing including a full BPP. The stillbirth rate within 1 week of a normal BPP or a modified BPP is the same at 0.8 per 1000.

The CST is used to assess a fetus at risk for uteroplacental insufficiency. The fetal heart rate and uterine contractions are continuously monitored. An adequate test consists of three 40- to 60-second contractions within a period of 10 minutes. If sufficient contractions do not occur spontaneously, oxytocin or nipple stimulation may be used. If oxytocin is needed to produce contractions for the CST, it is called the oxytocin challenge test (OCT). If late decelerations occur during or after contractions, uteroplacental insufficiency may be present. The CST may be contraindicated in patients with placenta previa, those who have had a previous cesarean section with a vertical incision, and those with high-risk factors for preterm delivery (eg, premature rupture of membranes or cervical insufficiency). Test results are interpreted as follows:

1. Negative (normal) test. No late decelerations occur. This result is associated with a very low perinatal mortality rate of 0.3 per 1000 in the week following the test.

2. Positive (abnormal) test. Late decelerations occur with at least 50% of the contractions. This result is associated with an increased risk of perinatal morbidity or mortality and indicates that delivery is usually warranted.

3. Equivocal (suspicious) test. Late decelerations occur but with <50% of the contractions. Prolonged fetal monitoring is usually recommended, and the CST should be repeated in 24 hours.

See Doppler studies under prenatal diagnosis section.

Maternal perception of fetal movement has been proposed as a tool to evaluate fetal well-being. Different methods have been evaluated including “the count to 10,” which involves counting 10 fetal movements over 2 hours during maternal rest. Other approaches include counts for some period of time each day or some days per week. However, results from different studies in the literature are mixed, and the utility of maternal kick counts to predict stillbirth is controversial. Maternal reports of abnormal fetal counting warrants further evaluation.

Intrapartum testing refers to those testing modalities used during labor to identify fetuses at risk for acidosis, adverse neonatal outcome, or death.

Although EFM has become widely used, its benefits over intermittent auscultation of the fetal heart rate have been controversial. It was not until recently that EFM was associated with a decrease in early infant and neonatal mortality, a decreased risk for Apgar scores <4 at 5 minutes, and a decreased risk of neonatal seizures. EFM is associated with an increase in the rates of both cesarean sections and operative vaginal deliveries. Fetal heart rate monitoring may be internal, with an electrode attached to the fetal scalp, or external, with a monitor attached to the maternal abdomen. The nomenclature and interpretation of EFM are based on the 2008 National Institute of Child Health and Human Development (NICHD) workshop report:

1. Baseline fetal heart rate. The baseline fetal heart rate (FHR) is the rate maintained for at least 2 minutes apart from periodic variations, rounded to the nearest 5 beats/min over a 10-minute period. The normal FHR is 110–160 beats/min. Fetal tachycardia is present at >160 beats/min and fetal bradycardia at <110 beats/min. Causes of fetal tachycardia include maternal or fetal infection, fetal hypoxia, thyrotoxicosis, and maternal use of drugs such as parasympathetic blockers or β-mimetic agents. Causes of bradycardia include hypoxia, complete heart block, and maternal use of drugs such as β-blockers.

2. Variability. In the normal mature fetus there are rapid fluctuations in the baseline FHR. This variability indicates a functioning sympathetic–parasympathetic nervous system interaction and is the most sensitive indicator of fetal well-being. An amplitude range from peak to trough of 6–25 beats/min indicates moderate variability and suggests the absence of fetal hypoxia. Marked variability occurs when >25 beats/min is noted. Minimal variability is quantified as <5 beats/min; absent variability refers to an amplitude range that is undetectable. Decreased variability may be caused by severe hypoxia, anencephaly and other fetal neurologic abnormalities, complete heart block, and maternal use of drugs such as narcotics or magnesium sulfate. In addition, variability is decreased during normal fetal sleep cycles.

3. Accelerations. Accelerations are often associated with fetal movement and are an indication of fetal well-being. The presence of accelerations suggests the absence of any acidosis.

4. Decelerations. There are three types of decelerations (Figure 1–1).

   1. Early decelerations. Early decelerations result from physiologic head compression and occur secondary to an intact vagal reflex tone, which follows minor, transient fetal hypoxic episodes. These are benign and are not associated with fetal compromise. They appear as mirror images of the contraction pattern.

   2. Late decelerations. Late decelerations are a result of uteroplacental insufficiency (UPI) and indicate the presence of fetal hypoxia. Potential causes include maternal hypotension, sometimes as a result of supine positioning or regional anesthesia, as well as uterine hypertonicity. More chronic causes of UPI, such as hypertension, postdate gestation, and preeclampsia may predispose a fetus to the development of late decelerations. Although by themselves they reflect only a decreased oxygen tension for the fetus, their persistence may lead to the development of fetal acidemia and eventual compromise. The nadir occurs after the contraction peaks, with the shape demonstrating a gradual decrease and slow return to baseline.

   3. Variable decelerations. Variable decelerations result from abrupt compression of the umbilical cord. They can also be seen as a consequence of cord stretch, as in phases of rapid fetal descent, and with a cord prolapse. Variable decelerations tend to increase in the setting of oligohydramnios. The majority of these decelerations are benign and not predictive of an acidemic fetus. However, severe variable decelerations (those lasting >60 seconds), especially in the setting of decreased variability and/or tachycardia, may portend a compromised fetus. They have a V or W nonuniform shape with a rapid descent and return to baseline: time from baseline to the nadir of the deceleration is 30 seconds.

5. Interpretation of electronic fetal monitoring. FHR patterns can be classified in one of 3 categories: I (Normal), II (Indeterminate), or III (Abnormal).

   1. Category I FHR pattern. This has 4 characteristics: normal baseline rate (110–160 beats/min), moderate variability (6–25 beats/min), absence of late or variable decelerations, and absence or presence of early decelerations or accelerations. In the setting of these findings, there is a high likelihood of a normally oxygenated fetus.

   2. Category III FHR pattern. Conversely, there are 4 FHR patterns predictive of abnormal fetal acid-base status grouped in category III.

      1. Sinusoidal pattern. These include a sinusoidal heart rate, defined as a pattern of regular variability resembling a sine wave, with fixed periodicity of 3–5 cycles/min and amplitude of 5–40 beats/min. A sinusoidal pattern may indicate fetal anemia caused by fetomaternal hemorrhage or alloimmunization.

      2. Baseline FHR variability is absent. The other three abnormal FHR patterns in category III are diagnosed when baseline FHR variability is absent and any one of the following is present:

         1. Recurrent late decelerations

         2. Recurrent variable decelerations

         3. Bradycardia

   3. Category II. Comprises all FHR patterns not in category I or III. Category II tracings are not predictive of abnormal fetal acid-base status. When a category II tracing is identified, a fetal scalp stimulation test may help identify fetuses in which acid-base status is normal.

FHR had been used during labor to determine the fetal acid-base status when the FHR tracing was nonreassuring or equivocal. Many practitioners have little experience in obtaining the sample, and noninvasive methods (vibroacoustic and fetal scalp stimulation) provide similar reassurance. Therefore, it is not commonly used in clinical care.

An acceleration in FHR in response to either manual stimulation of the fetal presenting part or vibroacoustic stimulation through the maternal abdomen has been associated with a fetal pH of >7.20. These tests are often used in labor to determine fetal well-being; however, a lack of fetal response to stimulation is not predictive of acidemia.

This technique was designed as an adjunct to FHR monitoring in labor and involves the placement of a fetal pulse oximeter transcervically next to the fetal cheek. Normal fetal oxygen saturation as measured by pulse oximetry (Spo₂) is 30–70%. Due to the lack of clinical significance it is currently not recommended.

Fetal lung maturity testing is recommended when considering delivery at <39 weeks unless clinically indicated for maternal/fetal reasons. Testing at <32 weeks is not recommended since most likely it will be immature. A mature result from any fetal lung maturity test indicates a very low likelihood of neonatal respiratory distress syndrome (RDS). The positive predictive value of all of the tests is poor, ranging from 30 to 60%, implying that an immature result does not correlate well to the presence of RDS. The choice and availability of tests for fetal lung maturity are institution dependent.

Lecithin is a phospholipid that can be measured specifically in amniotic fluid. It is a principal active component of surfactant and is manufactured by type II alveolar cells. Sphingomyelin is a phospholipid found predominantly in body tissues other than the lungs. The L-S ratio compares levels of lecithin, which gradually increase after 28 weeks, to levels of sphingomyelin, which remain constant. An L-S ratio ≥2:0 is considered mature.

Some disorders are associated with delayed lung maturation including diabetes mellitus and Rh isoimmunization complicated by fetal hydrops. Acceleration of fetal lung maturity is seen in sickle cell disease, maternal narcotic addiction, prolonged rupture of membranes, chronic maternal hypertension, IUGR, and smoking. Differences may also occur in various racial groups. The L-S ratio measurement can be affected by the presence of blood or meconium. In addition, the L-S ratio is costly, difficult to perform, and time-consuming compared with other available tests.

Phosphatidylglycerol appears in amniotic fluid at ∼35 weeks, and levels increase at 37–40 weeks. This substance is a useful marker for lung maturation late in pregnancy because it is the last surfactant to appear in the fetal lung. It is reported as either present or absent, and its presence is a strong marker that RDS will not occur. PG levels are not affected by blood or meconium contamination and can also be performed on vaginal pool specimens from patients who have ruptured membranes.

This test (Abbott Laboratories, Abbott Park, IL) measures the relative concentrations of surfactant and albumin (milligrams of surfactant per gram of albumin) in amniotic fluid, which increases with increasing lung maturity. Like the L-S ratio, blood and meconium can interfere with the results. A value ≤39 mg/g is considered immature, 40–54 mg/g is indeterminate, and ≥55 mg/g is mature. TDx FLM II has several advantages over the L-S ratio: less technical expertise is required, it is performed more easily, and results are available quicker. Unfortunately, this test will no longer be available since it has been discontinued by the manufacturer.

After its secretion by type II pneumocytes, surfactant is packaged into storage granules called lamellar bodies. This test uses a standard hematologic cell counter to count these lamellar bodies. A count >50,000 per microliter suggests lung maturity. Like the TDx FLM II, this test provides quicker results and is easier to perform than the L-S ratio at an equal or better sensitivity. Both blood and meconium can affect the interpretation of this test.

Stem cells from the umbilical cord are collected after the baby is born and are stored by private or public cord blood banks. The family is given a collection kit to bring on the day of delivery. The delivering provider typically collects the blood after the baby is delivered. After the umbilical cord has been clamped, the blood is drawn with a needle that transfers the blood into a bag that is sealed after the collection is completed. The sample is then taken to the cord blood bank. Parents can opt for cord blood banking, understanding the benefits and limitations; however, it is not universally recommended. Private cord blood banking should be considered when there is a family member with a known condition that can be treated with a hematopoietic transplant. The cells can potentially be used to treat some diseases with an estimated chance of an individual using his or her own cells of 1:2700. However, some diseases including inborn errors of metabolism and genetic diseases cannot be treated in the same individual since the cells contain the mutation.