4/22/05njm

**Q. What is the significance 2^nd^ trimester of ultrasound (US) markers
for Down syndrome?**

A. If US markers are negative, then decrease the risk by serum testing
in \~1/2. See the details.

**[Minor US markers]{.underline}**

Echogenic intraventricular focus (EIF), choroids plexus cyst (CPC),
'sandal-gap' toes, pyelectasis, clinodactyly, etc. are [poor
predictors]{.underline} of DS. Minor US markers are found in about 1% of
normal fetuses between 15-20 wks.

**Echogenic intraventricular focus** - Approximately 25 to 30 percent of
fetuses with Down syndrome have an echogenic intracardiac focus, while
this is seen in only 4 percent of normals (95 percent confidence
interval 2 to 8 percent). The incidence varies across races and
decreases with advancing gestational age. It is thought to be related to
microcalcification/fibrosis of the papillary muscle or chordae, often
disappears postnatally, and is not associated with myocardial
dysfunction or structural anomalies.

**Choroid plexus cysts** --- Choroid plexus cysts are present in about
one-third of fetuses with trisomy 18, compared to 1 to 2 percent of all
second trimester fetuses. The majority of large studies suggest that
choroid plexus cyst(s) with an otherwise completely normal detailed
structural survey (including examination of the face, heart, great
vessels, and extremities) is highly reassuring of a normal karyotype. In
addition, if the fetus is able to unclench its hand and hold it open,
trisomy 18 is not likely. In a meta-analysis of 748 fetuses with
isolated choroid plexus cyst(s), the risk of trisomy 18 was 1/374 and
the positive predictive value was 1/390. In another meta-analysis, there
were no cases of trisomy 18 among 1016 fetuses with isolated choroid
plexus cysts whose mothers were less than 35 years of age.

When isolated choroid plexus cyst(s) are detected in an otherwise low
risk patient, the risk of amniocentesis (1/250 chance of pregnancy loss)
is higher than the risk that the fetus has trisomy 18 (less than 1/374).
I recommend restricting amniocentesis to patients with additional
sonographic abnormalities or high risk factors (ie, advanced maternal
age (older than 32 years at delivery, abnormal serum analyte screen).
Some women may request amniocentesis after risk-benefit counseling.

In contrast, the FASTER trial (First And Second Trimester Evaluation of
Risk) found that absence of the fetal nasal bone was relatively
difficult to ascertain and not a useful marker for detecting Down
syndrome. An acceptable nasal image was obtained in only 76 percent of
6324 unselected patients undergoing evaluation of nuchal translucency in
the first trimester. None of 11 cases of Down syndrome were identified:
in nine cases, the nasal bone was described as present and in two cases
it could not be adequately imaged.

**[Other markers]{.underline}**

An enlarged nuchal thickness (NT), echogenic bowel, more than one
marker, or any anomaly, are [stronger predictors]{.underline}.

**[Discussion]{.underline}**

The echogenic intraventricular focus (EIF) is often the most worrisome
to most pregnant couples. The couple should be reassured that EIF is NOT
a marker that something is wrong with the baby's heart. With EIF alone,
the couple does NOT need fetal echocardiography for follow up.

The pregnant couple should also be reassured that a choroid plexus cyst
(CPC) does not mean there is something wrong with their baby's brain.

Table 1 below shows the relative risks of each of the markers. Please
note that a negative ultrasound, e.g., no markers found, will actually
lower the patient's risk by approximately one half (RR = 0.6), hence
should be reassuring.

Also, as more patients get 1^st^ trimester testing (to include BOTH
nuchal translucency and PAPP-A and free bHCG at 11-13 wks, not just
nuchal thickness (NT), it is important to know that that is all they
need, e.g., 2^nd^ trimester testing is NOT indicated.  

If the results of 1^st^ trimester screening are negative, then no
further (noninvasive) testing is indicated, and 2^nd^ trimester testing
will only increase the number of false positives.

**Summary**

Younger women (\<35 y/o) with a negative quad screen are at very low
risk if they have one of these minor marker. Amniocentesis is not
recommended for this group.

Older women (\>35 y/o), with or without a positive quad screen, are at
higher risk with even a minor marker however, and counseling about
amniocentesis may be appropriate for this group.

**Table 1**

# Trisomy-21 (Down syndrome) Second Trimester Ultrasonographic Markers

[RR]{.underline}

-   thickened nuchal fold\* 19.0

-   short femur 2.3

-   short humerus 2.5

-   cardiac abnormality (VSD, AV canal, Tetralogy) 25.0

-   echogenic bowel 5.5

-   choroid plexus cyst 1.5

-   hypoplasia of the middle phalanx of the 5^th^ finger (clinodactyly)
    1.5

-   widened iliac wings

-   echogenic intracardiac focus 1.5

-   pyelectasis 1.5

-   sandal gap toes

-   double bubble sign of duodenal atresia (usually 3^rd^ trimester)

-   absent nasal bone

\- 2-vessel umbilical cord

\- normal scan/no markers 0.6

\* **[Nuchal Thickness by gestational age]{.underline}**

> [Weeks]{.underline} [Mean]{.underline} [95^th^%]{.underline}
>
> 16 2.8 4
>
> 17 3.0 5
>
> 18 3.3 5
>
> 19 3.6 5
>
> 20 3.7 6
>
> 21 3.9 6

Source: FASTER Trial 2004

**Other Resources**

**The sonographic diagnosis of fetal aneuploidy**

<http://www.uptodateonline.com/application/topic.asp?file=antenatl/4468&type=A&selectedTitle=1~1>

**General principles of second trimester maternal serum screening for
Down syndrome**

<http://www.uptodateonline.com/application/topic.asp?file=antenatl/12590>

**Second trimester maternal serum screening for Down syndrome: Clinical
recommendations**

<http://www.uptodateonline.com/application/topic.asp?file=antenatl/13100>

**First trimester screening for Down syndrome and trisomy 18**

<http://www.uptodateonline.com/application/topic.asp?file=antenatl/15225>

**Pregnancy complications predicted by second trimester maternal serum
screening**

<http://www.uptodateonline.com/application/topic.asp?file=antenatl/13890>

**Etiology, prenatal diagnosis, and prevention of neural tube defects**

<http://www.uptodateonline.com/application/topic.asp?file=antenatl/9177>

**Cytogenetic abnormalities in the embryo, fetus, and infant**

<http://www.uptodateonline.com/application/topic.asp?file=antenatl/5719>

**Early amniocentesis**

<http://www.uptodateonline.com/application/topic.asp?file=antenatl/11761>

**Chorionic villus sampling: Risks, complications, and techniques**

<http://www.uptodateonline.com/application/topic.asp?file=antenatl/4910>

**Amniocentesis: Technique and complications**

<http://www.uptodateonline.com/application/topic.asp?file=antenatl/10599>

**Epidemiology; clinical features; and diagnosis of Down syndrome**

<http://www.uptodateonline.com/application/topic.asp?file=dis_chld/2412>

**Chromosomal translocations, deletions, and inversions**

<http://www.uptodateonline.com/application/topic.asp?file=leukemia/12983>

**Cytogenetic and molecular genetic diagnostic tools**

<http://www.uptodateonline.com/application/topic.asp?file=basicsci/5138>

**FASTER Trial**

Malone FD; Ball RH; Nyberg DA; Comstock CH; Saade G; Berkowitz RL;
Dugoff L; Craigo SD; Carr SR; Wolfe HM; Tripp T; D\'Alton ME.
First-trimester nasal bone evaluation for aneuploidy in the general
population. Obstet Gynecol 2004 Dec;104(6):1222-8.

Dugoff L, et al First-trimester maternal serum PAPP-A and free-beta
subunit human chorionic gonadotropin concentrations and nuchal
translucency are associated with obstetric complications: a
population-based screening study (the FASTER Trial). Am J Obstet
Gynecol. 2004 Oct;191(4):1446-51.

D\'Alton, ME, Malone, FD, Lambert-Messerlian, G, et al. Maintaining
quality assurance for nuchal translucency sonography in a prospective
multicenter study: Results from the FASTER trial. Am J Obstet Gynecol
2003; 189:S79.

**Other References**

Sotiriadis, A, Makrydimas, G, Ioannidis, JP. Diagnostic performance of
intracardiac echogenic foci for Down syndrome: a meta-analysis. Obstet
Gynecol 2003; 101:1009.

Shipp, TD, Bromley, B, Lieberman, E, Benacerraf, BR. The frequency of
the detection of fetal echogenic intracardiac foci with respect to
maternal race. Ultrasound Obstet Gynecol 2000; 15:460.

Achiron, R, Lipitz, S, Gabbay, U, Yagel, S. Prenatal ultrasonographic
diagnosis of fetal heart echogenic foci: no correlation with Down
syndrome. Obstet Gynecol 1997; 89:945.

Wax, JR, Donnelly, J, Carpenter, M, et al. Childhood cardiac function
after prenatal diagnosis of intracardiac echogenic foci. J Ultrasound
Med 2003; 22:783.

Schechter, AG, Fakhry, J, Shapiro, LR, Gewitz, MH. In utero thickening
of the chordae tendinae. A cause of intracardiac echogenic foci. J
Ultrasound Med 1987; 6:691.

Tennstedt, C, Chaoui, R, Vogel, M, et al. Pathologic correlation of
sonographic echogenic foci in the fetal heart. Prenat Diagn 2000; 20:287

Alfirevic Z, von Dadelszen P. Instruments for chorionic villus sampling
for prenatal diagnosis. *The Cochrane Database of Systematic Reviews*
2003, Issue 1. Art. No.: CD000114. DOI: 10.1002/14651858.CD000114.

Alfirevic Z, Sundberg K, Brigham S. Amniocentesis and chorionic villus
sampling for prenatal diagnosis. *The Cochrane Database of Systematic
Reviews* 2003, Issue 1. Art. No.: CD003252. DOI:
10.1002/14651858.CD003252.

**[Cochrane Library]{.underline}**

**Authors\' conclusions:** Second trimester amniocentesis is safer than
transcervical CVS and early amniocentesis. If earlier diagnosis is
required, transabdominal CVS is preferable to early amniocentesis or
transcervical CVS. In circumstances where transabdominal CVS may be
technically difficult the preferred options are transcervical CVS in the
first trimester or second trimester amniocentesis.

**Citation:** Alfirevic Z, Sundberg K, Brigham S. Amniocentesis and
chorionic villus sampling for prenatal diagnosis. *The Cochrane Database
of Systematic Reviews* 2003, Issue 1. Art. No.: CD003252. DOI:
10.1002/14651858.CD003252.

**Authors\' conclusions:** Although there is some evidence to support
the use of small forceps for transcervical chorionic villus sampling,
the evidence is not strong enough to support change in practice for
clinicians who have become familiar with aspiration cannulae.

**Citation:** Alfirevic Z, von Dadelszen P. Instruments for chorionic
villus sampling for prenatal diagnosis. *The Cochrane Database of
Systematic Reviews* 2003, Issue 1. Art. No.: CD000114. DOI:
10.1002/14651858.CD000114.