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Roy A. Filly, MD #{149}Peter W. Callen, MD #{149}Ruth B. Goldstein, MD
a-Fetoprotein Screening Programs:What Every Obstetric SonologistShould Know’
1
State ofthe Art
T HE compound a-fetoprotein (AFP)is a glycoprotein that is synthe-
sized predominantly in the normalfetal liver but also in the yolk sac andgut (1). It is produced only in verylow concentrations by adult livercells. This protein demonstrates anelectrophoretic motion that is similarto that of albumin and is the majorcirculatory protein of the early fetus.
AFP is found in high concentrationin fetal serum. Serum levels peak at2-3 mg/mL at approximately the 14thweek of gestation, after which thelevel progressively decreases (1). Nor-mally, small quantities of AFP enterthe amniotic fluid compartment (AF-AFP). The AF-AFP is much more di-lute (measured in micrograms permilliliter) than fetal serum concentra-tions (Table 1). The mechanism bywhich AFP passes from the fetal circu-lation into the amniotic fluid is notfully understood, although two likelypathways are fetal proteinuria and
transudation across immature epithe-
hum (normal events in early pregnan-cy). The AFP in amniotic fluid demon-strates a unimodal concentration
curve peaking early in the second hi-mester and then, as with fetal serumAFP, declining as pregnancy progresses(1). Very small but measurable quanti-
Index terms: Down syndrome, 10.184 #{149}Fetus,abnormalities, 30.1452, 856.874 #{149}Fetus, central
nervous system, 30.1452, 856.8741, 856.8746 #{149}Fetus, US, 856.1298 #{149}Pregnancy, complications
State-of-art reviews
Radiology 1993; 188:1-9
I From the Department of Radiology, Umver-sity of California, San Francisco, 505 Parnassus,Rm L-374, San Francisco, CA 94143-0628. Re-ceived December 8, 1992; accepted and revisionrequested January 22, 1993; revision receivedMarch 17. Address reprint requests to R.A.F.
0 RSNA, 1993
See also the article by Robbin et al (pp 165-169) and the editorial by Benacerraf (pp 17-18)in this issue.
ties (nanograms per milliliter) of thisprotein enter the maternal circulationfrom the amniotic fluid compartmentand acros�the placenta. Levels of ma-ternal serum AFP (MS-AFP) rise pro-gressively from the 7th week to the32nd week and then decline (1). Preg-nancies that do not produce fetal fis-sues (eg, hydatidiform mole) are char-acterized by very low levels of MS-AFP.
Measurement of AF-AFP has beensuccessfully employed for many years
to detect open neural tube defects inthe fetus (1-4). When an open neuraltube defect is present, a portion of thefetus lacks a normal integumentary
covering. For example, in anenceph-aly there is no skin covering the ab-normality. Instead, the cranial surfaceis covered by a thick angiomatousstroma (Fig 1). In memngocele, my-elomeningocele (Fig 2), and manycephaloceles (Fig 3), only a membra-nous covering, or no covering at all, ispresent. This allows abnormally largequantities of AFP to “leak” into theamniotic fluid, which is reflected as anabnormal increase in the maternalserum level (5).
Open neural tube defects are
among the most common congenitalanomalies occurring in the UnitedStates. The overall prevalence of thesemafformations has been estimated tobe 16 per 10,000 (0.16%) births (1).However, the prevalence is higher inthe eastern United States than thewestern United States and higheramong caucasians than among blacks.The prevalence is very much higherin children born to families with ahistory of open neural tube defects. Inthe United States, the risk of having asecond child with a neural tubeanomaly is 2%-3%, and of having athird abnormal child is approximately6% (1). Because the birth of a childwith an open neural tube defect maycause emotional, as well as financial,hardship, patients at risk for recur-rence of neural tube defects in a su1�-
sequent pregnancy are routinelyscreened with measurement of AF-AFP levels. However, if all womenwho had previously delivered a childwith an open neural tube defect werescreened by means of amniocentesisfor elevation of the AF-AFP, only 10%of all fetuses with an open neuraltube defect would be detected; 90%occur as first-time events (1). The risksof amniocentesis make AF-AFP deter-mination impractical as a screeningtool. MS-AFP rather than AF-AFP
must be employed for large-scalescreening studies of pregnant women.
ROUTINE MS-AFP SCREENING
MS-AFP screening was first per-formed in Great Britain (6). In GreatBritain, however, the general popula-tion risk for neural tube defect is sub-stantially greater than in the UnitedStates (7): The overall frequency ofneural tube defects is five to seven per1,000 pregnancies, compared withone to two per 1,000 pregnancies inthe United States. Nonetheless, anumber of screening programs havebeen instituted in the United Statesand demonstrate clear evidence ofbenefit despite the lower prevalence(8-li). Table 2 demonstrates the prob-ability of an abnormal fetal outcomewhen the MS-AFP level is elevated fora patient in the United States corn-pared with a patient in Great Britain,due to the lower population preva-lence (6,7).
To minimize the number of falseresults, selection of the normal range
is critical. Setting the upper limit ofnormal at a high level reduces thefalse-positive rate, but it also reducesthe number of abnormal cases de-tected. Setting a lower level for the
Abbreviations: AF-AFP = amniotic fluid AFP,AFP = a-fetoprotein, MOM = multiples of themean, MS-AFP = maternal serum AFP, UCSF =
1).
Table 1
Comparison of AFF Levels
Maternal serum 30Amniotic fluid 20,000Fetal plasma 3,000,000
LL��b.
Figure 1. Anencephaly. (a) The calvaria (ar-
rows) above the orbits (o) is absent on this US
scan. (b) Presence of angiomatous stoma (ar-
rows) should not dissuade the examiner
from the correct diagnosis of anencephaly.0 orbits.
2 #{149}Radiology July 1993
upper limit improves the detectionrate but increases the false-positiverate (Table 3) (1). The cutoff value forMS-AFP levels should be adjusted forthe mother’s weight. Other factorsknown to affect the maternal serumlevels include diabetes and ethnicity(12,13). False-negative results occurbecause the range of normal valuesoverlaps the range of abnormal val-ues.
Significant abnormalities are de-tected both on the basis of abnormallyhigh and abnormally low levels ofMS-AFP. The causes and associationsof high MS-AFP levels have beenmore widely publicized than those oflow MS-AFP levels (5,12-17). Low 1ev-els are seen in patients who are notpregnant, have a hydatidiform mole(absence of fetal tissues), have had afetal demise, have a misdated preg-nancy, have a trisomic fetus, or have anormal pregnancy (18-23). It is partic-ularly the category of trisomic fetusesthat has generated so much interest.Approximately 20% of trisomy 21 fe-tuses are found in women undergo-ing amniocentesis for a maternal agegreater than 35 years. An additional20% of trisomy 21 fetuses are found in
women whose MS-AFP level is lowafter adjustment for age (24). The riskof trisomy 21 when the MS-AFP is lowis significant enough to warrant am-
niocentesis for karyotype determina-tion. In California, 7% of pregnantwomen are older than 35 years. Con-versely, only 3% of pregnant womenscreened with MS-AFP measurementsare judged to have an abnormally lowlevel. Therefore, twice as many fe-tuses with Down syndrome will bedetected per amniocentesis per-formed because of low MS-AFP levelcompared with those performed be-cause of advanced maternal age. Thepotential of finding this additional20% of Down syndrome fetuses
through MS-AFP testing is highly at-tractive. This yield may be further
increased by also measuring humanchorionic gonadotropin levels andserum estnol levels in conjunctionwith the MS-AFP level (25). Thesethree markers (“triple markers”) refinethe risk for trisomy to a greater de-gree than MS-AFP measurementalone.
Causes of elevated MS-AFP levelsare also numerous. However, themost common are twins, fetal demise,misdated pregnancy, neural tube de-fect, other anatomic abnormalities,aberrations in the placenta, and nor-mal pregnancy (5,14-17,26). Further,there is growing evidence that in theabsence of an anatomic abnormality
ApproximateLevel
Sample Site (ng/mL)
an elevated MS-AFP level may por-
tend obstetric problems (prematurity,intrauterine growth retardation, andstillbirth) later in pregnancy (27,28).
Technical errors can occur in themeasurement of AFP levels (29-31).
To eliminate technical errors, all ab-normal tests should be checked by
repeat measurement. False results aremore commonly obtained because ofother reasons (32). Because false-posi-tive results may lead to termination ofa normal pregnancy, the reasons forfalse-positive results should be care-
fully excluded. The most common of
these is overlap of the upper end ofnormal with the lower end of the ab-normal range. Other common entities
are multiple pregnancy and errors indating. Less common causes of falseelevations are concurrent maternalliver disease and collection of MS-AFPsamples after amniocentesis (fetal-
maternal blood mixing).There are numerous benefits to
screening programs for MS-AFP ele-vation (Fig 4). These include earlyidentification of twins and fetal de-mise. Many misdated pregnancies are
reassigned a corrected gestational
age. The program allows many struc-tural and chromosomal anomalies to
be found and thereby decreases theanxiety of women carrying normalfetuses. As noted above, it allows p0-
tential future obstetric problems to beidentified and can point the way toidentification of patients who harbora hydatidiform mole or choriocarci-
noma or who are not pregnant at all.
Unfortunately, such programs alsohave significant problems, whichmust be minimized (Fig 4). One of the
most significant is the anxiety caused
by physiologically increased or de-
creased AFP levels (33,34). It is impor-
tant to note that affected fetuses willbe missed by the screening program,and the parents of these children willfeel especially “cheated.” Similarly,
affected children will be born to lateregistrants or women who do not
comply with the program. Some
mothers will lose normal fetuses due
to the complications of amniocentesis.
One must know that mothers may
elect to abort a fetus solely on the ba-
sis of an abnormal AFP level that is
falsely positive or may fall victim to a
sonographic false-positive or false-
negative diagnosis. A national pro-
gram of this nature would generate
approximately 40,000 more amniocen-
teses per year, which must, in many
instances, be followed up with high-
level sonography. Developing and
maintaining high-quality centers to
perform these tasks is difficult.MS-AFP testing has had very en-
couraging results. These results havecaused the American College of Ob-
stetrics and Gynecology to recom-
mend that pregnant women at the
appropriate gestational age be offered
this test (35). As large numbers of
women are screened, virtually all
sonologists performing obstetric diag-nostic studies will encounter patients
in whom abnormal MS-AFP levels
have been recorded. Familiarity with
guidelines for the appropriate sono-
graphic evaluation of a pregnancy inwhich an abnormal MS-AFP result
Figures 2, 3. (2) Myelomeningocele. The top of the lesion (short arrow) is estimated by counting up from the last sacral ossification center
(long arrow), assumed to be S-4 in the second trimester and S-5 in the third trimester. The age of the fetus in this US scan was 36 menstrual
weeks, and the top of the myelomeningocele was L-5. (3) Cephalocele. Acute angles with integument (straight arrows), calvarial defect (curved
arrow), and “cyst within a cyst” (c) appearance (possibly reflect the herniated fourth ventricle into the cephalocele sac) help distinguish this
from a cystic hygroma.
Table 2
Probability of an Abnormal Outcome If the MS-AFP Level Is Elevated andPopulation Statistics Are Known
Location of MS-AFP PopulationStudy Level Prevalence
ProbableAbnormal
Great Britain 2.5 MOM 4.5/1,000United States 2.5 MOM 2/1,000California program 2.5 MOM . . .
1/101/201/15
Note-MOM = multiples of the mean.
Table 3
Cutoff Values for MS-AFP, by Detection Rates for Abnormalities
Anencephaly Spina Bifida
(%) (%)
Normal
(%)
2.OMOM 91 902.5 MOM 88 79
(97) (80)
7.23.3
Note.-All numbers are percentages. Numbers in parentheses are results from California MS-AFPprogram, which used 2.5 MOM as a cutoff value.
Volume 188 #{149}Number I Radiology #{149}3
has been obtained is becoming in-
creasingly important.
THE CALIFORNIA MS-AFP
SCREENING PROGRAM
The California MS-AFP Screening
Program has already tested well over
1 million women. This report will con-
centrate on patients with elevated
MS-AFP levels, because sonography
plays a greater role in this group
(11,36). California physicians are re-
quired to offer MS-AFP testing to all
patients of appropriate gestational
age. The patient may not enter the
program. If the patient accepts entry
into the program, a fee of $53.00 is
charged. This fee covers the cost of
the MS-AFP test and any subsequent
genetic counseling, sonography, am-
niocentesis, or other pertinent tests
necessitated by an abnormal result,
including the right to seek a second
opinion if desired. Of course, the vast
majority of patients have results in
the normal range. The excess revenue
from their testing fee offsets the cost
of additional testing required when
an abnormal result is recorded.
General program considerations ina large-scale MS-AFP screened popu-
lation are outlined in Figure 5. Within
the California program, a limited
number of prenatal diagnostic centers
are permitted to counsel patients, per-
form amniocentesis, and perform tar-
geted sonography. All practitioners
must meet specified guidelines. How-ever, prenatal diagnostic centers are
permitted latitude in following some
: aspects of the program. A major varia-
tion is the timing of the level 2 sono-
gram in the patient’s evaluation.
Some centers recommend acquisition
of the level 2 sonogram in those pa-
j tients with elevated AF-AFF levels, as
illustrated in Figure 5. However, oth-
ers perform a level 2 examination
prior to the amniocentesis in an effort
to decrease the number of amniocen-
teses performed. At the University of
California, San Francisco (UCSF),
level 2 examinations are performed
on women with elevated AF-AFP 1ev-
els (predominant group) or women
who have an elevated MS-AFP level
but decline amniocentesis. Therefore,our data should be viewed with this
information in mind.There are considerable differences,
from the sonographic perspective, in
these two philosophies. If a center
elects to perform level 2 sonography
preceding the amniocentesis, there
are major consequences. First, there
will be a need to obtain approxi-
mately 10 times more level 2 sono-
grams. A more important conse-
quence is that the prevalence of
disease in the sonographic test popu-
lation will decrease 10-fold, thereby
placing a greater emphasis on the
“normal” result. Unfortunately, the
normal result is the less reliable sono-
graphic conclusion. It is important to
note that these examinations would
be performed earlier in gestation than
those performed after the amniocen-
tesis. All sonologists recognize the
BENEFITS
#{149}Allows many structural and chromosomalanomalies to be found
#{149}Identifies early twins#{149}Identifies early fetal demise#{149}Enables redating of many misdated
pregnancies#{149}Decreases anxiety in normal cases#{149}Identifies potential future obstetric
problems#{149}Identifies hydatidiform mote/
choriocarcinoma#{149}Identifies nonpregnant women thought to
be pregnant
PROBLEMS#{149}Anxiety caused by physiologically
increased AR’ level#{149}Affected children may be “missed” by the
screening program#{149}Affected children may be born to late
registrants or noncomplying women#{149}Probable need for 40,000 more amnloosn-
teses per year#{149}Pregnancy losses of normal fetuses due to
complications of amniocentesis#{149}Mothers may elect to abort solely on the
basis of abnormal AFP measuremen�#{149}Sonographic false-positive and false-
negative results
4 #{149}Radiology July 1993
benefits of 1-2 weeks of growth inearly pregnancy in terms of visualiza-tion of fetal structure. As noted above,
we have followed the more “tradi-tional” philosophy of performinglevel 2 examinations when the AF-AFP level is elevated. This gives usthe additional advantage of knowingthe results of ancillary tests per-formed on the amniotic fluid, amongwhich is identification of the presenceof acetylcholinesterase. This enzyme,
when found in amniotic fluid, ishighly predictive of the presence of
an anomaly, usually a neural tubedefect but sometimes also abdominalwall defects. Therefore, our resultswould serve as a useful comparisonfor institutions electing to performlevel 2 examinations in advance of theamniocentesis.
The California MS-AFP ScreeningProgram exercises very tight controlat the laboratory testing level, as well,
and the number of laboratories per-forming the assay is extremely small.Each is licensed by the state. As notedabove, all abnormally elevated sam-ples are retested, and a second sped-men is drawn from the patient forcomparative analysis if the originalspecimen was drawn at 16 menstrualweeks. If, however, the degree of ele-vation is substantial (greater than 3MOM) or the pregnancy is furtherthan 17 menstrual weeks, the lattersteps are deleted. Among the first 1.1
million women tested in the Califor-nia program, approximately 5% had
abnormal results and approximately
2% had elevated levels. Among the
cases with abnormally high results,
16% were reclassified as normal whensamples were retested. The remaining
84% of patients were referred to pre-
natal diagnostic centers for level 1sonography. As with the laboratories
that perform MS-AFP testing, the pre-
natal diagnostic centers also mustmeet stringent state requirements andundergo periodic reviews.
This, by the way, is the context in
which the term “level 1” was intro-duced into the sonologic lexicon, andsome clarification of this term is ap-propriate. A level 1 sonogram is, for
all intents and purposes, a standardobstetric sonogram as described in theAmerican Institute of Ultrasound inMedicine/American College of Radi-ology guidelines published in 1986(37). Its goals are determination offetal number, gathering of fetal bio-metric data (and the subsequent cal-culations that can be made from
these), estimation of amniotic fluidvolume, localization of the placenta,and detection of uterine and adnexal
masses. While this study is not per-
formed specifically to detect fetalanomalies, there is a reasonable prob-ability that anomalies will be detectedduring the course of the above datagathering, and a prudent effort shouldbe made to do so. This “prudent” effortis further defined by a number of
sonographic views specified in theguidelines as useful for detectinganomalies. The indication for level 1sonography is not defined by preg-nancy risk (ie, low-risk pregnancieswarrant level 1 sonography, whereashigh-risk pregnancies warrant level 2sonography). Also, the performanceof level 1 sonography is not definedby the technical capability or intellec-
tual prowess of the examiner or thecost of the sonographic machine em-
ployed. The definition rather is re-lated to the intent of the examination.Level 2 examinations are “directed”or “targeted” to answer specific ques-tions, far and away the most commonof which is, Does the fetus have amorphologic abnormality? Indeed,unless there is a reason not to do so, apatient should undergo a level 1 ex-amination every time sonography isperformed in the second or third hi-
mester. That the examination per-formed was a “level 1” study is nei-ther an excuse for failing to makeobservations that should be madeduring the course of the sonographicstudy nor an excuse to document in-adequately that the information wascarefully obtained.
In patients referred to prenatal di-agnostic centers because of a con-firmed elevated MS-AFP level, thefirst additional test to be applied afterthe patient is counseled is sonogra-phy. As noted above, individual pre-natal diagnostic centers may vary re-garding supplanting the level 1examination with a level 2 examina-tion prior to counseling regardingamniocentesis. The major purpose forlevel 1 sonography is to identify mis-dated pregnancies (18%), multiplegestations (10%), and unsuspectedfetal demise (5%) among women whohave abnormal MS-AFP levels. At thepresent time, measurement of the bi-parietal diameter is employed only toestimate age in the California MS-AFPprogram. Although composite agesfrom multiple biometric parametersare more accurate for dating, the ra-tionale in this instance is to increasedetection of myelomeningoceles. Thisanomaly is associated with smallerthan average biparietal diameter mea-surements (38). A small biparietal di-ameter makes any MS-AFP level“appear” higher. Therefore, if it is
Figure 4. Benefits of and problems in MS-
AFP screening programs.
true that fetuses with myelomeningo-
cele, as a group, have smaller thanaverage biparietal diameters, thesefetuses will be more conspicuous inthe test population.
Although the intent of the level 1examination is not to search out allpotentially diagnosable anomaliesthat might generate an elevation of
the MS-AFP level, a number of theanomalous fetuses in the group arerecognized during the course of thisexamination. Virtually all cases of an-encephaly are detected. Some of theother more conspicuous neural tubedefects are noted as well, includingcephalocele and myelomeningocele.The same is true of ventral wall de-fects. Because anencephaly is readily
diagnosed and uniformly fatal, nofurther referral is required unless the
patient wishes a second opinion.However, the other lesions have vary-ing prognoses. Further diagnostictesting can disclose features that af-
fect the prognosis. This information isvaluable in counseling parents and incase management. Therefore, suchcases should go on to level 2 sonogra-
phy.
AMNIOCENTESIS FOLLOWING
ABNORMAL MS-AFP TEST
After reclassifications are made onthe basis of the level 1 sonogram (ie,identification of misdated pregnan-
cies, multiple gestations, and unsus-
I1STMSAFPHIGH I
I ‘ 1RETEST SPECIMEN DRAW 2ND SPECIMEN
2NDMSAFPHIGH -
>3.OMOM OR>17 WEEKS
DEAD FETUS
EVACUATE
I LEVEL 1 SUNUtJKAPHY I
TWINS
REFER
OB MGMT
MISDATED
REDATE
UVING, SINGLECORRECT DATES
OB MONITORINGFOR PERINATALCOMPUCATIONS
LEVEL LI ALTERNATIVE TESTSSONOGRAM (ACETYLOIOLINESTERASE
KARYOTYPE)
Figure 5. Program considerations in a large-scale MS-AFP screened population. MGMT =management, OB = obstetric.
Volume 188 #{149}Number 1 Radiology #{149}5
pected fetal demises), approximately
65% of women will continue to have
abnormal findings. The major risk
with a low MS-AFP level is a chromo-
somal abnormality, which can be mostreliably diagnosed by means of am-
niocentesis and karyotype determina-
tion with fetal cells. Therefore, more
women (75%) offered amniocentesis
when the MS-AFP level is low elect to
proceed with this test than when the
MS-AFP is high (66%). This is in large
part because sonography can more
accurately allow identification ofanomalies in those with high MS-AFP
levels than in those with low MS-AFPlevels. Other factors that influence
women’s choices include the type ofabnormality likely to be diagnosed and
the potential risks of the procedure.
Of the first 1.1 million women
screened in the California MS-AFP
program, 38,500 (3.5%) had either an
abnormally low or high MS-AFP level
(36). Of these, 37,000 (96%) reported
for genetic counseling and sonogra-
phy at prenatal diagnostic centers,and 20,000 of the 37,000 underwentamniocentesis. This filtration process
is, of course, designed to extract from
the patient pool at large those who
have an extremely high risk of abnor-
mality. This process is highly success-
ful. Among the 1.1 million patients
screened, 1 ,390 anomalies (morpho-
logic and chromosomal) were de-
tected (prevalence of 1.3 per 1,000). Of
those patients who went to prenatal
diagnostic centers, the prevalence
increased to 38 per 1,000. If the pa-
tient underwent amniocentesis, the
risk of an anomalous fetus furtherincreased to 70 per 1,000.
Between 1987 and 1990, 1,390
anomalies were detected through the
California program. There were 710
neural tube defects: 417 cases of anen-
cephaly, 247 cases of spina bifida, and
46 cases of encephalocele. There werealso 680 cases of non-neural tube de-fects: 286 cases of ventral wall defects,
163 cases of Down syndrome, and 231cases of other chromosomal anoma-lies.
LEVEL 2 SONOGRAPHY
Conceptually, patients whose am-
niocentesis results show an elevated
level of AFP are referred for detailed
or targeted (level 2) sonography. Sim-ply stated, level 2 sonographic exami-
nation of a patient whose AF-AFPlevel is markedly increased should be
conducted in a fashion designed todetect a fetal anomaly that might ex-
plain the noted elevation. Common
causes of AF-AFP level elevation are
open neural tube defects (anencepha-
ly and its variants, encephalocele,
open spina bifida, and amniotic band
syndrome resulting in non-embryo-
logically positioned neural tube
defects), abdominal wall defects (om-
phalocele, gastroschisis, gastro-pleu-
ralschisis from amniotic band syn-
drome), cystic hygromas, and neural
axis anomalies (not associated with
open neural tube defects, eg, hydro-
cephalus, Dandy-Walker malforma-
tion). Other causes include teratomas
that contact the amniotic fluid (eg,
sacrococcygeal, lingual, and retropha-
ryngeal), renal abnormalities, esopha-geal atresia with or without tracheo-
esophageal fistula, and duodenal
obstruction.
A general obstetric examination
should be performed, which includes
documentation Df biometric data in-
cluding biparietal diameter, head cir-
cumference, abdominal circumfer-
ence, and femur length. These
parameters can then be used to calcu-
late composite sonographic age andbody proportionality ratios. It is also
important to quantitate the amount of
amniotic fluid, which will be a sec-
ondary sign of some of the above-
described disorders. Composite im-
ages should be obtained to survey the
entire uterine cavity in order to ex-dude a previously missed fetus papy-
raceous.
After these standard features have
been evaluated, images should be ob-
tamed that demonstrate specific fetal
morphologic structures. These in-
dude multiple transverse axial sono-
grams of the head to exclude enceph-
alocele and to document the size of
the lateral ventricles and the presence
of the cisterna magna. Because openspina bifida lesions are nearly always
associated with the Chian II malfor-
mation, there is an effacement of the
cisterna magna in nearly all such fe-
tuses (39) (Fig 6) and an increase in
ventricular size in approximately80%-85% of cases, although fewer(<50%) have ventnculomegaly priorto 24 weeks menstrual age. Obtaining
such images assumes, of course, that
all cases of anencephaly have previ-
ously been detected.Transverse axial sonograms of the
neck are obtained to exclude cystic
hygroma (Fig 7). These sonograms
:- � ‘��A :: � �-
6. 7.
� ‘I.
r5.L�. � �
a. b.
Figure 9. “Bowel only” omphalocele. (a) On US scan, a very small defect of the abdominal
wall (arrows) is a subtle observation. (b) Collapsed bowel loops are observed on this US scanwithin the umbilical cord (arrows) a few centimeters from the fetal abdominal wall. uv = um-bilical vein.
6 #{149}Radiology July 1993
8.
Figures 6-S. (6) Cranial findings associated with open spina bifida and the Chian II malformation. US scan shows inward scalloping of the
frontal bones (straight arrows) known as the “lemon sign.” Note the “banana” configuration of the cerebellum (c) and the effaced cisterna
magna (curved arrow). (7) Cystic hygroma. US scan shows integumentary edema is circumferential around head and neck (small arrows). Pos-tenor cystic mass (C) appears continuous with skin. N = nuchal ligament. (8) Omphalocele. Exteriorized liver (Liv) is seen on this US scan
within the omphalocele sac.
should also demonstrate a midlineposition of the hypopharynx, the tra-chea, or both, to exclude retropharyn-
geal teratoma. Transverse axial and
coronal sonograms of the face of the
fetus will exclude exophytic cranial(lingual) teratomas. Transverse axial
sonograms of the abdomen are thenobtained to document the degree offilling of the fetal stomach and the
absence of a dilated duodenum, aswell as to demonstrate one or bothkidneys and the umbilical cord inser-tion. Detection of a normal cord inser-tion and adjacent abdominal wall willexclude nearly all cases of omphalo-cele (Fig 8) and gastroschisis. How-
ever, in small hernias of the cord (es-
sentially small omphaloceles) (Fig 9),
it is possible for the cord insertion to
be nearly normal in appearance. Simi-larly, in a fetus with gastroschisis, thedefect in the abdominal wall may beobscured, and the anomaly may berecognized only on the basis of visual-
ization of bowel loops floating freelyin the amniotic fluid. The stomach is
documented, to exclude those cases of
esophageal atresia without tracheo-esophageal fistula and cases of duo-denal obstruction. A useful secondaryfinding in this regard is the quantityof amniotic fluid, which is virtuallyalways increased in cases of uppergastrointestinal tract obstruction. Un-fortunately, it is now known that
polyhydramnios is not always mani-
fest in early cases of tracheoesopha-geal fistula.
The examination is then directedtoward the spine. Open spina bifidalesions without a sac are likely to bethe most difficult abnormalities to de-tect. Thus, careful scrutiny of thespine in both longitudinal and trans-
verse axial sections is recommended.
Longitudinal views of the sacrum,
while somewhat insensitive for open
spina bifida, are excellent for the de-tection of sacrococcygeal teratoma
(Fig 10) and sacral agenesis. Trans-verse axial sonograms of the spinemust cover from the cranial cervicaljunction to the ischial ossification cen-ters. It is not necessary, however, to
record an image at every level, al-though every level should be exam-med more than one time. Any fetusmaintaining a persistently supine po-
sition must be re-examined.
A few final points should be consid-
ered. If destructive procedures will beused to evacuate the fetus and if en-cephalocele is demonstrated, special
note of the kidneys and an image of
the fetal hand are warranted to ex-
dude the Meckel syndrome (encepha-locele, polydactyly, cystic dysplastic
kidneys, microcephaly), because therecurrence risk for this autosomal re-cessive syndrome is much higher
than for encephalocele alone. When
cystic dysplasia of the kidneys is
present in the Meckel syndrome, oh-gohydramnios will virtually alwaysbe present. Some examiners look for a
clubfoot deformity as a secondarysign of a neural axis abnormality;
however, primary demonstration of
an open neural tube defect should
always be the major goal of an exami-
nation. Some examiners may want to
perform a more comprehensive exam-ination than is outlined above. Fi-
nally, consideration should be givento a later repeat examination whenthe initial study is negative (especially
T:al� � �
�,., � .�
p T ;j
Table 4
� UCSF Data from 1984 to 1990 (14,737 Amniocenteses)
(kyphosis, scoliosis), associated clubfoot deformity, associated hydroceph-
alus, postnatal complications (eg,shunt infections), and concomitantcentral nervous system or extra-cen-
tral nervous system malformations orchromosomal anomalies. Virtually allof these features can be assessed in
utero, thereby allowing parents tomake a more informed decision. In-
deed, in our experience, the level 2
examination is used more often to
further characterize anomalies than to
detect them, because a relatively high
percentage of abnormal fetuses is recog-nized on the sonogram obtained before
the amniocentesis (level 1 sonogram).
Volume 188 #{149}Number 1 Radiology #{149}7
Parameter
� AF-AFP level exceeding 2.0 MOM
Neural tube defect present with AF-AFP level > 2.0 MOM� Anomalous fetuses with AF-AFP level > 2.0 MOM
Anomalous fetuses with AF-AFP levelbetween 2.0 and 2.5 MOMAnomalous fetuses with AF-AFP level > 2.5 MOMAnomalous fetuses with AF-AFP level > 10.6 MOM
� Probability of anomalous fetus when ACHE level is positive� Including trace positive� Excluding trace positive� Probability of a normal outcome when ACHE level is negative� Anomalous fetuses detected sonographically� Combination of sonography and AF-AFP level allowed confident diagnosis of� anomalous fetus� Correct program distinction of normal versus anomalous fetus� Open neural tube defects detected sonographically
Note-ACHE = acetylcholinesterase.
if the MS-AFP or AF-AFP level wasvery high or the acetylcholinesterase
level was positive).
Obviously, a rather broad array of
anomalies is encompassed in the listof lesions that may be encountered.The prognosis varies widely in this
group. Even among single categories
of malformations, the prognosis will
vary substantially.
Myelomeningocele is an excellent
example of a serious malformationthat, nonetheless, has a wide range of
prognoses. The prognosis is affectedby the location (40) and size of thedefect (Fig 2), open versus closed le-sion, the presence of spinal deformity
After an elevated AF-AFP level isdetected, sonography can allow accu-rate assessment of the presence andtype of anomaly. The experience atthe UCSF prenatal diagnostic centerin all cases from January 1984 throughJune 1990 in which the AF-AFP levelwas elevated is detailed in Table 4(41-43). Obviously, these data wereobtained over a period of time longerthan the California AFP program has
existed. Cases of elevated AF-AFP
level discovered during amniocente-sis performed because of maternal age
are also included. Two hundred sixty-three cases in which the AF-AFP level
was elevated were obtained from atotal of 14,737 amniocenteses.
In our experience, sonography hasbeen an excellent test to identify casesof normal pregnancy and an elevatedAF-AFP concentration and segregatethem from cases of pathologic preg-
nancy. Only five of 263 fetuses seen atUCSF between 1978 and 1990 with anelevated AF-AFP level had anomaliesundetected at sonography, and threeof these are developing normally fol-lowing corrective surgery after birth
(43). The remaining two anomalous__________fetuses, although they exhibited nor-
Prevalence mal sonograms, were prospectively(%) identified as having congenital ne-__________. phrosis because of their extremely
� high levels of AF-AFP. The rule that33 “normal is the most difficult diagnosis
14 to make” clearly applies in this situa-58 tion. Although sonographic perfor-
100 mance was weakest in this area, the
81 � negative predictive value of sonogra-100 � phy alone was 97%, still a highly ac-87 curate result.
94 � Further, sonography depicts neural
97 tube defects with an extraordinarily
>99 � high degree of sensitivity and speci-100 ficity. When results of the AF-AFP
measurements and acetylcholinester-
.-� ase testing were known, no neuraltube defects were missed. Addition-ally, sonography can allow accuratediagnosis of other congenital anoma-lies that may cause an elevated AF-
AFP concentration (Table 5). Many ofthese anomalies have remarkably dif-ferent prognoses. One of the major
benefits of sonography is its ability togather valuable information and al-low fetuses to be separated into theirproper prognostic groups. For exam-
pie, a fetus with an isolated omphalo-cele has a far better prognosis than a
fetus with an omphalocele and otherassociated anomalies (Fig 11) (44).Even among fetuses with isolated le-sions, sonography can help stratify
the fetuses into prognostic categories.For example, a fetus with a sacral my-
elomeningocele has a much better
Table 5
Final Diagnoses of 263 Fetuses with Elevatedand December 1990 (UCSF)
AF-AFF Levels between January 1978
Anomalies
AF-AFP Level
2.0-2.5 MOM > 2.5 MOM
Neural axisMyelomeningocele 2 18Anencephaly 0 8Encephalocele 0 4Hydrocephalus* 3 2Dandy-Walker malformation 2 0
OtherGastroschisis I 10
Cystic hygroma 2 9
Genitourmary disease 4 5
Omphalocele 3 2Amniotic band syndrome 1 3Tracheo-esophageal fistula 1 0Pharyngeal teratoma 0 1Skeletal abnormalities I 1Hydrops (without cystic hygroma) 1 0Fetaldemise I 4
Total anomalies 22 67Normal 135 39Total 157 106
- * Not associated withmyelomeningocele.
:� � � � � � -. . �
�
a. b.
Figure 11. Amniotic band syndrome-limb body wall complex. (a) Omphalocele (o) acute an-
gulation of the spine (arrow) is seen on US scan. (b) Characteristic acute angulation of thespine (arrow) on US scan suggests this is not a simple omphalocele.
References1. Main DM, Mennuti MT. Neural tube detects:
issues in prenatal diagnosis and counseling.Obstet Gynecol 1986; 67:1-16.
2. Goldberg MF, Oakley GP. Interpreting ele-vated amniotic fluid alpha-fetoprotein levelsin clinical practice: use of the positive predic-live value concept. Am J Obstet Gynecol 1979;133:126-132.
3. Crandall BF, Matumota M. Risk associated
8 #{149}Radiology July 1993
prognosis than a fetus with a thoracicmyelomeningocele (Fig 2) (45).
Our data suggest that open neuraltube defects are generally not presentwith AF-AFP concentrations less than2.5 MOM (Table 5). Open neural tubedefects were found in only two casesover the past 12 years when the AF-
AFP concentration was less than 2.5MOM. One case was not pathologi-cally confirmed; however, the sono-graphic features were virtually pa-thognomonic for a myelomeningocele.All other fetuses with open neuraltube defects studied before 20 weekshad associated AF-AFP concentrationsgreater than 2.5 MOM. This observa-tion is consistent with previously pre-
sented data (3).In summary, our experience docu-
ments that MS-AFP screening leadingto testing of the AF-AFP level and
subsequent level 2 sonography is anexcellent method to diagnose numer-ous defects in high-risk patients (Ta-
ble 4). Pregnancies with an elevatedAF-AFP concentration clearly are inthis category. As noted earlier, it hasbeen suggested that mothers withelevated MS-AFP levels could bescreened with sonography better thanamniocentesis to confirm or deny thepresence of a fetal anomaly (46-58).These institutions elect to performlevel 2 sonography in patients with
an elevated MS-AFP level beforecounseling regarding the potential
benefits of amniocentesis. The ratio-nale is that a normal sonogram mayobviate amniocentesis. It is, of course,generally preferable to replace inva-sive tests with noninvasive tests whenappropriate. Further, amniocentesis
in our institution is associated with a0.7% risk of pregnancy loss. However,it is appropriate to review the draw-
backs of the latter approach. First, the
number of level 2 sonograms thatmust be obtained in patients with an
elevated MS-AFP level increases 10-fold. The more important conse-quence of this large influx of morpho-
logically normal fetuses is a marked
diminution of the prevalence of dis-
ease (‘/�o as many anomalous fetuses)
in the test population. Therefore, theanticipated result is a normal level 2
sonogram in the vast majority of pa-tients examined. The examiner’s sus-
picion decreases. Further, this situa-
tion increases reliance on the negative
predictive value of the sonogram: its
weakest performance parameter inour series. Additionally, the examin-ing sonologist would not be aware ofthe acetylcholinesterase level or the
karyotype, which generally are avail-
able when the level 2 sonogram is re-
served for patients demonstrating anincreased AF-AFP level. Possibly mostimportant is that level 2 sonogramsobtained in lieu of amniocentesis areobtained 1-3 weeks earlier than those
obtained after amniocentesis. All
sonologists recognize the benefit of
even short periods of additional fetal
growth when examining for anoma-lies in early pregnancy. Finally, iden-tification of which patients with a
normal initial sonogram may benefit
from a repeat examination is morestraightforward in the amniocentesisgroup. For example, a patient with aweakly positive acetylcholinesteraselevel and a normal sonogram may
benefit from repeat sonography in 2-3
weeks. It is clear that sonography hasthe capacity to depict neural tube de-
fects and other causes of AFP eleva-tion when relatively small numbers ofexaminations are performed with agreat deal of care in a population witha relatively high prevalence of fetalanomalies (59). Whether this can beachieved with the higher numbers of
examinations required and the lowerprevalence rate when screening all
patients with elevation of MS-AFPremains to be seen. #{149}
Volume 188 #{149}Number 1 Radiology #{149}9
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