Elevated Alpha Fetoprotein

Armando Fuentes and Charlotte Henningsen

• Describe the clinical use of serum alpha fetoprotein as a screen for various fetal anomalies.

• Describe the appropriate diagnostic approach to a patient with an elevated alpha fetoprotein value.

• Identify potential pregnancy complications in the setting of an unexplained elevated alpha fetoprotein value.

• Identify the sonographic appearance of neural tube disorders commonly associated with an elevated alpha fetoprotein value.

• Identify fetal abdominal wall anomalies associated with elevated alpha fetoprotein values.

• Describe the sonographic appearance of abdominal wall defects commonly associated with an elevated alpha fetoprotein value.

• Differentiate sonographic features of limb–body wall complex and amniotic band syndrome.

CLINICAL SCENARIO

A 22-year-old woman with no significant medical history is seen for a sonogram at gestational age 18 weeks, 5 days. The pregnancy has been relatively uncomplicated until now except for one episode of first-trimester spotting; a first-trimester sonogram obtained at the time of spotting confirmed a gestational age of 6 weeks. She had a routine maternal serum alpha fetoprotein (MSAFP) test at 17 weeks’ gestation, which was reported as 7.4 multiples of the median. The information was given to her the previous day at her physician’s office, and fetal heart tones were auscultated.

Sonographic evaluation reveals the coronal views of the fetal face and spine shown in Figure 23-1. Fetal biometry of the fetal abdomen and femur confirms the established gestational age; in addition, a single umbilical artery is noted. What is the most likely diagnosis?

FIGURE 23-1 **(A),** Coronal image of the fetal face. **(B),** Coronal spine and base of the calvaria.

Maternal Serum Alpha Fetoprotein

One of the most common tests routinely offered to pregnant women is serum screening for Down syndrome and neural tube defects (NTD). MSAFP historically has been used to screen for NTDs. Since its discovery, MSAFP screening has been used to identify chromosomal abnormalities, anterior abdominal wall defects, ovarian carcinoma, and various other fetal and maternal conditions. This chapter describes various etiologies for abnormal MSAFP levels.

Alpha fetoprotein is structurally and functionally related to albumin, and genes for both proteins originate on chromosome 4. Alpha fetoprotein is a fetal-specific protein that is synthesized sequentially by the yolk sac, gastrointestinal tract, and liver. Its function is unknown, although there are various theories involving its function, such as immunoregulation during pregnancy or intravascular transport protein. The peak concentration in fetal serum is at the end of the first trimester. As pregnancy progresses, the fetal liver continues to produce a constant amount of alpha fetoprotein until 30 weeks’ gestation, which is secreted by the fetal kidneys into the amniotic fluid. Amniotic fluid contains high concentrations of alpha fetoprotein, although it decreases similarly to the fetal serum concentration after 30 weeks. In maternal serum, alpha fetoprotein increases in the second trimester, and the fetal serum alpha fetoprotein decreases. The transfer of alpha fetoprotein to the maternal circulation occurs through the placenta and amniotic fluid.

The optimal period for screening of MSAFP is between 15 and 18 weeks of gestation. MSAFP screening is intended to detect open spina bifida and anencephaly, but other disorders, such as ventral wall defects, tumors, congenital nephrosis, and aneuploidy, can also be identified. The results of MSAFP screening are reported as multiples of the median (MoM) for each gestational age. Measurements of alpha fetoprotein can be affected by laboratory technique. Also, standard deviations may be influenced by the spread of data. MoM reflect an individual patient’s value compared with the median. Each laboratory develops its own reference values. Factors that can influence MSAFP results include gestational age, maternal weight, ethnicity, diabetes mellitus, fetal viability, and multiple gestation.

Several studies have demonstrated the reliability of MSAFP screening for NTDs. Wang et al.¹ published a meta-analysis comprising 684,112 patients screened in the second trimester that showed a sensitivity of 75.1 and specificity of 97.7. Detection of anencephaly is even higher. Data from various studies indicate that major fetal anomalies are present in 30% to 58% of patients with MSAFP levels of 5.0 MoM or greater.^2,3 When a cutoff of 2.5 MoM is used, MSAFP screening detects approximately 88% of anencephalic fetuses and 79% of fetuses with open spina bifida. When no explanation can be determined for an elevated alpha fetoprotein value, despite sonographic and chromosomal investigation, 20% to 38% of pregnancies have adverse outcomes. These adverse outcomes include low birth weight, prematurity, intrauterine growth restriction, preeclampsia, and placental abruption.⁴

Sonography has become a very effective tool for detecting NTDs, and it has replaced MSAFP testing as a screening tool in some centers.⁵ Sonographic detection of NTDs is influenced by gestational age, maternal body habitus, and type of NTD. First-trimester screenings have reported greater than 90% detection rates for anencephaly and 80% detection rates for encephalocele. In the second trimester, sonographic screening has a detection rate of 92% to 95% for spina bifida.⁶

Neural Tube Defects

Failure of neural tube closure between the third and fourth week of embryologic development results in NTDs. Approximately 18 days after conception, the neural plate folds to form a central neural groove and bilateral neural folds. The neural folds fuse in the midline and begin to form the neural tube. Fusion progresses simultaneously toward the cranial and caudal ends. Closure of the anterior neuropore occurs by day 24, and closure of the posterior neuropore occurs by day 26. The cranial end of the neural tube becomes the forebrain, midbrain, and hindbrain, and failure of closure results in anencephaly. The caudal end of the neural tube becomes the spinal cord, and failure of posterior neuropore closure results in spina bifida.⁷

Several different types of NTDs can occur, which can affect the spinal cord or cranium. The spinal defects are classified as either open or closed; this classification is dependent on whether neural tissue is exposed. Because approximately 20% of spina bifida lesions are closed, not all NTDs are detected with MSAFP screening. Elevations in alpha fetoprotein occur because of communications between the nervous system and amniotic fluid. The most severe elevations are seen in the setting of anencephaly and severe open spinal defects where large areas of neural tissue are exposed.

Most NTDs are either isolated defects or multifactorial. Several factors have been implicated, including folic acid deficiency,⁸ medications (valproic acid), genetic factors (MTHFR polymorphism, Meckel-Gruber syndrome),⁹ and vitamin B₁₂ deficiency.¹⁰ Environmental factors associated with NTDs include hyperthermia, maternal diabetes mellitus, and obesity.^11,12 The incidence of NTDs in the United States is commonly quoted as 1:1000; this is highly dependent on ethnic and geographic variability. The incidence appears to be higher in Hispanic and non-Hispanic whites compared with African Americans and Asians. Higher rates of NTDs have also been seen in the eastern and southern United States compared with the western United States. Additionally, there is an increased risk of recurrence in families with a history of a prior NTD.

The introduction of screening programs and folic acid supplementation has significantly reduced the incidence of NTDs. In 2006, birth data from the United States revealed a combined incidence of anencephaly and spina bifida of 0.3:1000 live births, which is significantly lower than 1:1000 reported in the 1990s.¹³

Anencephaly

Anencephaly, which results in absence of the cranium and brain above the orbits, is the most common NTD. It can also occur as a result of destruction of brain matter exposed to amniotic fluid in fetuses with acrania. It has been identified in 1:1000 pregnancies,¹⁴ but the incidence of live births is significantly lower.

Acrania and anencephaly both have been diagnosed sonographically in the first trimester. Sonography also is highly accurate in the second trimester. Because there is complete communication with the amniotic fluid, alpha fetoprotein values are extremely elevated, which may trigger a sonographic evaluation.

Anencephaly is more common in females and monozygotic twins. Additionally, associated anomalies may be seen in fetuses affected by anencephaly, including spina bifida, cranioschisis, cleft lip/palate, talipes, omphalocele, and aneuploidy (especially when multiple anomalies are seen).

Sonographic Findings

Anencephaly is diagnosed when absence of the calvaria above the orbits and absence of the brain are noted (Fig. 23-2, A). It is best seen in the coronal plane where the orbits appear prominent revealing a “frog’s eye” appearance (Fig. 23-2, B). There may be a small, abnormal remnant of tissue seen above the orbits, known as the cerebrovasculosa. If the fetal head is difficult to visualize because of a low vertex position, an endovaginal sonogram may be necessary. Polyhydramnios is commonly identified in gestations with anencephaly secondary to a decreased swallowing reflex.

FIGURE 23-2 **(A),** Fetal profile with absent calvaria with presence of cerebrovasculosa. **(B),** Image of anencephaly shows typical froglike appearance.

Spina Bifida

Spina bifida indicates a cleft in the spinal column. The two main types of spina bifida are spina bifida aperta and spina bifida occulta. Spina bifida occulta is formed when there is failure of the dorsal portions of the vertebrae to fuse with one another, and it is covered by skin and not noticeable unless there is a small tuft of hair or a dimple. In spina bifida aperta, a disruption of the skin and subcutaneous tissues is visible over the area of the spine where the incomplete closure occurs. As a result, the meninges protrude out of the vertebral defect and are exposed to the amniotic fluid. In the absence of nervous tissue extruding into the meningeal sac, the lesion is termed a meningocele and is not related to hydrocephalus or neurologic defects. In most cases, nervous tissue is incorporated into the lesion, and it is termed a meningomyelocele; it is frequently associated with hydrocephalus.

The most common locations for spina bifida anomalies are the thoracolumbar, lumbar, and lumbosacral areas. Also, a wide variation is seen in the size of the lesions, resulting in higher MSAFP values in large defects. Additional anomalies may be seen in association with spinal defects, including microcephaly, cephaloceles, cleft lip/palate, hypotelorism, and hypertelorism.

Sonographic Findings

Complete evaluation of the spine involves viewing of spinous structures in the longitudinal and transverse aspects, from the nuchal origin to the distal sacrum. In the transverse plane, the posterior ossification centers tilt toward the midline. Spina bifida should be considered when the posterior ossification centers assume a splayed “V,” “C,” or “U” configuration when viewed in the transverse plane (Fig. 23-3, A). In addition, abnormal curvature of the spine (kyphosis, lordosis, or scoliosis) may be observed. The most superior aspect of vertebral misalignment defines the level of the lesion, which relates to outcome (Fig. 23-4); three-dimensional reconstruction may be useful in clarifying the anatomic level of the defect.¹⁵

FIGURE 23-3 **(A),** “V” shape of vertebra is consistent with spina bifida. **(B),** The fetus shows classic findings of spina bifida, including a sac protruding from the defect containing neural elements and ventriculomegaly. **(C),** This fetus with spina bifida has a lemon-shaped head with a banana-shaped cerebellum.

An intracranial anomaly known as Arnold-Chiari malformation often accompanies spina bifida aperta. Arnold-Chiari malformation is characterized by cerebral ventriculomegaly (lateral ventricle >10 mm), decreased intracranial pressure leading to frontal bone collapse (lemon sign), abnormal curvature of the cerebellum as it is impacted into the posterior fossa (banana sign), decreased cerebellar size (which may lead to failure of identification), and obliteration of the cisterna magna (see Fig. 23-3, B and C).

Cephalocele

Cephalocele or encephalocele is defined as a defect in the cranium through which intracranial tissue protrudes, including meninges with or without brain tissue. The incidence is 0.8:10,000 to 4:10,000 live births.¹⁶ Occipital encephaloceles are usually considered within the NTD group. Associated conditions with occipital encephaloceles include Meckel-Gruber syndrome, amniotic band syndrome (ABS), cerebellar dysgenesis, short limb dysplasia, and warfarin syndrome. Frontal or parietal encephaloceles are not considered a NTD and may be environmental in origin.

MSAFP may not help with the diagnosis because most of these lesions are covered with intact meninges. The outcome is poorer when encephaloceles are associated with hydrocephalus or when significant brain tissue is in the defect.

Sonographic Findings

Sonographically, a cephalocele appears as herniation of the meninges with or without brain through a defect in the calvaria (Fig. 23-5). The sac may appear cystic or solid and can vary in size. Ventriculomegaly is often seen, and traction on the intracranial contents may result in microcephaly. Cephaloceles may also vary in appearance throughout gestation.