8/15/05njm

**Q. Is there an association between thyroid auto-antibodies and fetal
Down's Syndrome?**

A. Upon review no association was found. We have better methods now,
e.g., quad, NT, etc...

For years the William's Obstetrics text has mentioned that an
association between maternal serum thyroid auto-antibodies and fetal
Down Syndrome (DS) has long been suspected.

Initially, William's referenced a 1965 publication from a Canadian study
that reported on 104 families from the Winnipeg area. Both parents were
tested and 28% of the mothers were sero-positive and14 % of the
controls. The relationship became more striking when it was limited to
those women of childbearing years, 29% vs 9%.

The latest edition of William's references Chuckle and associates (1988)
which identified both types of thyroid auto-antibodies more frequently
in pregnancies with Down's syndrome versus normal controls, but the
differences were not significant.

Lastly, in 1995 Gustafasson et al reported: "There was no increase in
the relative risk of having a child with DS if the titre of either Tg or
TPO antibodies or both were positive, i.e. \> or = 1/5. The results
indicate that the presence of thyroid antibodies in the serum of a
pregnant women has no prognostic value for the birth of an infant with
DS."

In the meantime prenatal diagnostics have developed several other
markers that have been clinically successful at prenatal diagnosis of
Down's syndrome. Here is an excerpt from our Perinatology Corner module
on this:

**Serum**

"For a multiple marker screening (MMS) reported as [positive for Down
syndrome](http://www.uptodateonline.com/application/topic.asp?file=antenatl/13100&type=A&selectedTitle=2~3)
(DS), about 3-4% will be true positives. Accurate gestational dating,
maternal age, weight, diabetic status, and race, all factor in
importantly. Of note, specific normative data on Native American women
are currently not available. It is also important to know if your lab
uses a cut-off of 1:270 for a positive screen for DS (the risk of a 35
y/o woman) or the lower cut-off of 1:190, the more specific, but less
sensitive, number. Again, ultrasound is important to be sure dates are
correct. If the ultrasound indicates a date more than 10 days different
from the menstrual dates, the laboratory should be contacted to
recalculate the results with the correct information. Unlike NTD
screening however, abnormal MMS suggesting a higher risk of fetal DS
should NOT be repeated. Patients should be triaged to the next step,
high resolution ultrasound and/or amniocentesis.

Because of societal demographics, live births to women 35-49 years of
age had increased to over 12% in the year 2000. This has resulted in
almost half of the DS fetuses in the second trimester being carried by
older women (a high rate of spontaneous loss of aneuploid fetuses occurs
prior to term). MMS is thus a cost-effective way to initially evaluate
these patients, and avoid an excessive number of amniocenteses. As noted
above, amniocentesis has a 0.5% (1 in 200) procedure related pregnancy
loss rate, a very important consideration for many women.

In Practice Bulletin Number 27, [ACOG issued this Level B
recommendation](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11501567)
" Counseling for amniocentesis in a twin pregnancy in women age 33 years
is indicated because the midtrimester risk of fetal Down syndrome is
approximately the same as for that of a singleton pregnancy at age 35
years." Considering the information above the ACOG recommendation should
be considered as part of a staged diagnostic scheme may be an option to
discuss with your older pregnant patient. "

**Ultrasound**

**What about ultrasound markers of fetal DS ?**\
The so-called second trimester "[genetic
sonogram](http://www.uptodateonline.com/application/topic.asp?file=antenatl/4468&type=A&selectedTitle=6~53)"?
Ten to 40% of DS fetuses may have some anatomic abnormality, such as a
major cardiac anomaly, which can be identified antenatally and raise the
risk of aneuploidy significantly. The thickened nuchal fold (\>5 mm at
15-21 weeks) is the most reliable "soft marker" of fetal DS, raising the
likelihood ratio significantly. Other more subtle findings such as
hyperechoic bowel, pyelectasis, shortened femur or humerus, echogenic
intraventricular foci, clinodactyly, "sandle-gap toes", or choroid
plexus cysts may also be present. The positive predictive value of any
of these ultrasound indicators in isolation is very low, but the
presence of two or more positive findings, especially in the presence of
an abnormal multiple marker screen, may increase the risk enough that
many women would more strongly consider amniocentesis. On the other
hand, a negative scan, with no discernible anomalies or soft markers,
lowers the risk of aneuploidy by approximately 40%, and is very
reassuring to many women.

**How about the other less common trisomies?**\
MMS will also detect about 80% of trisomy-18 fetuses (all analytes low),
as well as Turner syndrome and triploidy, but not trisomy-13 or
translocations. Ultrasonographic anatomic abnormalities may also be much
more striking in such fetuses. **Twins** may have a higher risk of one
of the fetuses in the pregnancy having an abnormal karyotype. Since
there are two fetuses, they may be discordant for a chromosomal
abnormality, and the risk for the entire pregnancy is doubled. The
presence of multiple gestation is important information for the
laboratory to have when calculating the risks for both DS and NTD as the
levels of the analytes will be accordingly increased.

The rest of the **Prenatal Genetic Screening -- Serum and Ultrasound**
module is available at the link below as well as free continuing
education credit for completing the module. The module has a large array
of other resources available by hyperlink.

**Reference:**

Fialkow PJ, Hecht F, Uchida IA, Motulsky AG.  Increased frequency of
thyroid autoantibodies in mothers of patients with Down\'s syndrome.
Lancet. 1965 Oct 30;2(7418):868-70.\
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=4158240&query_hl=5>

Chuckle H, et al Maternal serum thyroid antibodies in early pregnancy
and fetal Down's Syndrome. Prenatal Diag 8:439-445, 1988.

<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2974954&query_hl=2>

[Gustafsson
J](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term="Gustafsson+J"%5BAuthor%5D),
et al Thyroid antibodies are not a risk factor for pregnancies with Down
syndrome. Prenat Diagn. 1995 May;15(5):451-4.\
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7644435&query_hl=4>

Williams Obstetrics. Endocrine Disorders, 21st Edition. Cunningham GF,
et al (Eds.) Section 12, No. 50, pp. 1347. McGraw-Hill, 2001 (Level
III).

**Thyroid Disorders in Pregnancy --Perinatology Corner**

<http://www.ihs.gov/MedicalPrograms/MCH/M/THYR01.cfm>

**Prenatal Genetic Screening -- Serum and Ultrasound**

<http://www.ihs.gov/MedicalPrograms/MCH/M/TM01.cfm>