Prenatal Diagnosis of Congenital Anomalies

Alpha-Fetoprotein

Alpha-fetoprotein (AFP) is the major protein in fetal serum and is produced by the yolk sac in early gestation and later in pregnancy by the fetal liver. AFP is found in the fetal spine, gastrointestinal tract, liver, and kidneys. This protein is transported into the amniotic fluid by fetal urination and reaches maternal circulation through the fetal membranes ( Fig. 55.1 ). AFP may be measured in the maternal serum (MSAFP) or amniotic fluid (AFAFP).

AFP levels are considered abnormal when elevated or low. Neural tube defects, such as anencephaly and open spina bifida, are common reasons for high AFP levels. In both instances, AFP leaks from the defect to enter the amniotic fluid and then diffuses into the maternal bloodstream (see Fig. 55.1 ). AFP elevations will not be found in cases where there is closed spina bifida (occulta) because there is no opening to allow leakage into the maternal bloodstream.

Monitoring of AFP is a screening test for neural tube defects and other conditions ( Box 55.1 ). Evaluation is usually based on 2.0 to 2.5 multiples of the median, but false positives do occur. MSAFP screening detects approximately 75% to 90% of open neural tube defects and may also detect up to 85% of abdominal wall defects.

MSAFP levels increase with advancing gestational age and peak from 15 to 18 weeks of gestation (the ideal sampling time). AFAFP, in contrast, decreases with fetal age. A common reason for elevations is incorrect dates. Because AFP levels vary with gestational age, if the fetus is older or younger than expected, AFP levels will be reported as increased or decreased.

Other reasons for elevations are acrania and encephalocele (which may occur in association with Meckel-Gruber syndrome), with AFP leakage from the exposed membranes and tissue. The concentration of AFP correlates with the size of the defect. AFP levels tend to be significantly higher in fetuses with anencephaly than with spina bifida because more tissue is exposed. It is important to remember that approximately 20% of spina bifida lesions are covered by skin, so AFP elevations will not be detected in serum or amniotic fluid. Sacrococcygeal teratomas are also known to be associated with high AFP levels.

Two common abdominal wall defects, omphalocele and gastroschisis, produce elevations of AFP. With an omphalocele , AFP leaks through the membrane encasing the herniated bowel or liver. In gastroschisis, AFP diffuses directly into the serum and amniotic fluid from the herniated bowel, which lacks a covering membrane; thus, AFP levels are higher in a fetus with gastroschisis than in a fetus with an omphalocele.

Other abdominal wall defects cause leakage in the same manner. Bladder or cloacal exstrophy, ectopia cordis (herniation of the heart out of the chest), limb-body wall complex, and amniotic band syndrome are examples of other anomalies that may present with an elevated AFP level.

It is expected that the AFP level in a twin pregnancy will be twice that of a singleton pregnancy because two fetuses make twice the AFP. AFP may be higher than normal in multiple gestations in which there is death of a co-twin (fetus papyraceous) or when one twin is acardiac.

Obstructions of the gastrointestinal tract may cause reduced clearance of AFP. This may explain elevations with anomalies, such as an annular pancreas, esophageal atresia, and duodenal atresia.

A fetus with a kidney lesion may produce increased AFP. In congenital nephrosis, the kidneys excrete extremely high levels of AFP. Polycystic kidneys and urinary tract obstruction may also lead to higher levels of AFP because there is abnormal clearance or filtration of AFP because of kidney maldevelopment and urinary tract leakage.

Placental lesions, such as chorioangiomas, hemangiomas, and hematomas, are responsible for AFP elevations. Placental problems, in general, may explain the prevalence of growth restriction, fetal death, and abruption in patients with unexplained AFP elevations.

In heart failure, faulty diffusion of AFP may lead to an abnormal AFP increase when hydrops, ascites, or lymphangiectasia is present. Severely sensitized fetuses with Rh isoimmunization may have heart failure because of severe anemia. In the fetus with a cystic hygroma , obstructed lymph sacs lead to AFP diffusion through the hygroma into the bloodstream and amniotic fluid.

Liver disease in the mother or fetus may cause high AFP levels. Hepatitis, maternal herpes virus, resultant fetal liver necrosis, skin lesions, hepatocellular carcinoma, and fetal liver tumors (hamartomas) are rare causes of elevated AFP.

Other causes include chromosomal abnormalities associated with fetal anomalies or placental problems that permit the abnormal passage of AFP. Fetuses with trisomy 13 or trisomy 18 may also have renal anomalies, neural tube defects, ventral wall defects, or skin lesions that cause elevated AFP levels. Fetuses with Turner syndrome often present with cystic hygromas. In triploidy, abnormal placental molar degeneration leads to increased AFP diffusion.

Cystic adenomatoid malformations cause rises in AFP because of excessive leakage from the lungs. Pilonidal cysts of the back and various skin disorders and tumors, such as epignathus and intracranial lesions, are also associated with high AFP levels. Rarely does the fetus manufacture excessive amounts of AFP as a hereditary condition.

Fetal death is a frequent cause of a high MSAFP level. Pregnancies complicated by oligohydramnios may have higher concentrations of AFP because of less amniotic fluid to diffuse the protein. Contamination of an amniotic fluid specimen by blood may also falsely increase the level of AFP.

In utero viral infections (cytomegalovirus and parvovirus) are reported to permit excessive AFP leakage because the maternal-fetal surface may be irritated and disrupted by inflammation.

Unexplained elevations in MSAFP suggest that the pregnancy is at increased risk for complications and poor outcomes, including low birth weight and stillbirth. Preeclampsia, hypertension, and abruption placentae are other third-trimester complications associated with these elevations.

Mothers with elevated MSAFP values and normal AFAFP values are potentially at risk for other fetal anomalies unrelated to neural tube defects. Hydrocephalus, without a spinal defect (increased cerebrospinal fluid allows increased diffusion), and congenital heart disease (probable altered perfusion of blood flow through placenta) are reported in conjunction with unexplained, non–neural tube defect problems.

Low AFP levels have been found with chromosomal abnormalities, such as trisomy 21, trisomy 18, and trisomy 13 ( Box 55.2 ). Other causes include incorrect patient dates (fetus younger than expected), fetal death, hydatidiform moles, spontaneous abortion, and a nonpregnant state. In some cases, the cause may remain unknown.