Anti-M: Worth Your Time?

Q: "I hear people talking all the time about anti-M being "insignificant." What does that really mean?
Some references say that anti-M can cause HDFN or hemolytic reactions! How can an antibody like that
be insignificant?"
A: Thanks for your great question on anti-M, that antibody that causes more confusion and trouble than
it's generally worth!
Lets first take a look at the definition of "clinically significant": An antibody is considered clinically
significant if it is capable of inducing either hemolytic disease of the fetus/newborn (HDFN) or
accelerated red cell destruction. Please click this link to go to the expanded, glossary definition for
further discussion on this issue.
Note that, as discussed in the glossary entry, one of the clues as to whether or not an antibody will be
"significant" is whether or not the antibody reacts at body temperature (37C). The optimal reaction
temperature of an antibody is not always predictive of its clinical significance, but it can definitely guide
you in the right direction (see below)
With anti-M specifically, the vast majority of examples we see do not react with M-positive RBCs at 37C;
rather, they react better when at room temperature or below (usually 4C in laboratory settings). An
anti-M with this reaction pattern (in other words, a typical anti-M) is not considered clinically significant
for at least two reasons: 1) The phase of reactivity indicates that it is almost certainly not an IgG
antibody that can cross the placenta easily, and 2) Red cell destruction is highly unlikely unless the
patient with this antibody is being transfused at very cold temperatures (the assumption is that the
antibody is an IgM antibody, which can fix complement and destroy M-positive RBCs, but does not do so
at body temperatures in most cases outside of the ABO system).
There are certainly rare cases of anti-M causing severe HDFN or hemolytic transfusion reactions, as you
correctly noted. For the most part, these are due to examples of anti-M that had a high-titer IgG
component. When one hears that "anti-M is insignificant" just remember that, in the vast majority of
cases, anti-M does not meet the criteria of a clinically significant antibody. That said, an astute blood
banker takes very little at face value and will ask the pertinent questions to determine for themselves
whether, in this particular case, the anti-M can be considered insignificant: At what temperature is it
most reactive? Does the patient have a history of HDFN due to anti-M? Have the antibodys IgG and IgM
component been titered?
So, here is how I treat anti-M cases: If the patient's anti-M reacts at 37C, it should be honored in
transfusion and further investigated for the potential to cause HDFN by evaluating the sample for the
presence of an IgG component. In my experience, such cases make up the vast minority of examples of
anti-M. As a result, you can generally consider anti-M that does not react at 37C to be "insignificant."
Written by Monica LaSarre, June 2012
- See more at: http://www.bbguy.org/ask/ab-m-1.asp#sthash.BI9zhuB4.dpuf

We searched the TRIP and Medline databases as well as the Royal College of Obstetricians
and Gynaecologists website but found no guidelines on the management of patients with
anti-M antibodies in pregnancy. The NICE guideline on antenatal care does not appear to
refer to anti-M antibodies:
The main antibodies that can cause severe alloimmune anaemia in the fetus are anti-D,
anti-c and anti-Kell. Of lesser importance but still with the potential to cause HDN are anti-
e, -Ce, -Fya, -Jka and-Cw. Anti-Lea, -Leb, -Lua, -P, -N, -Xga and high-titre low-avidity
antibodies such as anti-Kna have not been associated with HDN. There is no value in
identifying group O pregnant women with high titres of anti-A or anti-B. Antenatal testing
for these antibodies has been shown to have no value in predicting the incidence of HDN
caused by ABO incompatibility. [1]
An e-Medicine article on hemolytic disease states:
Hemolysis associated with ABO incompatibility is limited to type O mothers with fetuses
who have type A or B blood. In mothers with type A and B blood, naturally occurring
antibodies are of IgM class, which do not cross the placenta, whereas in type O mothers,
the antibodies are predominantly IgG in nature. Because A and B antigens are widely
expressed in a variety of tissues besides RBCs, only small portion of antibodies crossing the
placenta is available to bind to fetal RBCs. In addition, fetal RBCs appear to have less
surface expression of A or B antigen, resulting in few reactive siteshence the low incidence
of significant hemolysis in affected neonates. [2]

In 1997, Young-Owens et al presented the findings of a review of twenty-six years of anti-M
isoiimunization:
RESULTS: Anti-M antibody was found in 90 women who had 115 pregnancies over 26
years. Among those with positive indirect antiglobulin tests, 104 pregnancies had titers at or
below 1:4. Only one patient with an initial low titer experienced more than a three-fold
increase to 1:64. Two women underwent a total of eight amniocenteses when titers were at
or above 1:128. Forty-two (60%) of the 70 infants tested were positive for M antigen. Nine
infants required phototherapy. Eight of these infants were delivered preterm. There was an
increase in the number of women seen with anti-M antibody in pregnancy at our institution,
with nearly 10% of all gravidas with a positive antibody screen having anti-M alloantibodies.
There were no cases of hemolytic disease of the newborn, mild or severe.
The authors conclude:
The prevalence of anti-M isoimmunization may be increasing. The incidence of severe
hemolytic disease of the newborn due to anti-M is extremely low. We found no cases in our
review of 115 pregnancies, although there have been several cases of severe hemolytic
disease of the newborn reported. If anti-M is detected in pregnancy, the titer is low (no
more than 1:4), and there is no history of prior pregnancy complications suggesting a
hemolytic disease process, we recommend no further testing other than an indirect
antiglobulin test at 28 weeks to look for the emergence of other alloantibodies. However, if
the initial titer is elevated or there is a concerning obstetric history, serial titers should be
performed and amniocenteses reserved for rising titers. [3]
Thompson et al review three cases of anti-M antibody in pregnancy. The Medline abstract of
this article reads:
Our three cases represent the spectrum of findings when maternal anti-M is present. In the
first case, the father's genetic makeup (NN) indicated no disease would occur. In the second
case, despite antibody capable of crossing the placenta, the infant did not become sick. In
the third case, hemolytic anemia required transfusion of the newborn, despite a negative
direct Coombs' (DAT). In summary, anti-M antibody is an uncommon cause of hemolytic
disease of the newborn. When anti-M, IgG optimally reactive at 37 degrees C, is identified in
the maternal blood, the paternal blood must be checked for the presence of M antigen. If
the father has M antigen the fetus may be at risk.
Since there is no documented body of experience that titers of anti-M predict severity of
disease, our recommendation is that amniotic fluid bilirubin studies be done, in spite of the
fact that only one prior case of hemolytic disease due to anti-M was found reported from the
United States. Anti-M is an unpredictable antibody and serial antibody titers are not reliable.
After delivery the infant's MN antigen status should be determined, because a negative
direct Coombs' test may be found even when M antigen is present in the infant and
hemolysis is occurring. Further studies are needed to determine the clinical impact of anti-M
antibody on unrecognized hemolytic disease of the newborn. [4]

References
1. NICE. Antenatal care: routine care for the healthy pregnant woman. October 2003.
(http://www.rcog.org.uk/resources/public/pdf/antenatal_care.pdf).
2. Wagle S. Hemolytic disease of the newborn. E-Medicine. June 2006.
http://www.emedicine.com/ped/topic959.htm
3. A De Young-Owens, M Kennedy, RL Rose, J Boyle, and R O'Shaughnessy
Anti-M isoimmunization: management and outcome at the Ohio State University from 1969
to 1995. Obstetrics & Gynecology 1997;90:962-966.
(http://www.greenjournal.org/cgi/content/abstract/90/6/962
4. Thompson DJ, Stults DZ, Daniel SJ et al. Anti-M antibody in pregnancy. Obstet Gynecol
Surv. 1989 Sep;44(9):637-41. (http://www.hubmed.org/display.cgi?uids=2771305).