Rh Disease.. .1970

Virginh Apgar, M.D., T4.P.li.
Vice President-Medicaf .!if fairs
The H'aeional ~o~i~~~~t~o~~~~~rch of Dimes
800 Second Avenue
Mew York, New York 10017

Presented to :
Seventh Annual I~iu~i za t ion Conference
National. Cormtinicable Disease Center
Atlanta, Georgia

March 26, 1970

Rh Disease...l970

It is unusual that a disease entity can be predicted, recognized, defined,

treated and finally prevented, all in one's 1iFetime. Siich is the case, however,
for Rh disease if you are old enough.

The prophetic statement of Dr. Theobold Sini-th in 1909 , "Passive antibody mixed

with antigen renders the antigen quite inactive as an inmunixing agent," in no way
predicted its practical application in 19GS.

   It was in 1940 that Landsteiner and Wiener discovered the Rh factor. Eight
years earlier, Diamond and his associates , on the basis of clinical observations ,
rightly observed that hydrops fetalis , icterus gravis neonatorum and congenital anemia
were all symptoms of the same clinical disease , which they labelled "erythroblas t-osis. I'
There was then a period of clinical sparring in terminology - erythroblastosis vs.
hemolytic disease of the newborn - causing great difficulties in interpreting newborn
and stillbirth death certificates. Fortunately, most of these difficulties have been
overcome by the refinement in diagnostic technics.

In 1940, it was found that injection of red blood cells of the rhesus monkey

into rabbits produced a serum factor which caused the aggLutination of monkey red cells.
When tried with red blood cells of human beings, about 857, of individuals showed
agglutination of red cells, while 15% did not. There was no sex diFference. P. Levine
and associates then cleared the vay by pointing out that incompatible transfusions , or
injections of incompatible intramuscular blood, caused sensitization. Although this
incompatibility was important in males , it was especially important in females who
were Kh negative, married to Rh positive males. Half or all of their offspring will
be' Rh positive, depending whether he has. one or two genes for Rh positiveness. This
state of affairs can !,est be ca.rried out by the determination of Rh positiveness or
negativeness in relatives. If an Rh negative woman happens to be lucky enough to
marry an Eh negative man, she need have no worries from this source.

Rh determinations were first used to prevent mismatched transfusions. By 1945 ,

it was learned that 10 to 127, of babies born alive to an Rh negative woman married
to an Kh positive nan were apt to be severely ill with anemia and post-natal jaillidice
which , if untreated , led to permanent mental damage including mental retardation,
motor disability and even cerebral palsy. Autopsy showed kernicterus , yellow staining
of the globus pallidus and other basilar nuclei. There were also many stillbirths of
hydropic babies with 'a large spongy placenta. Polyhydramnios was frequent.

After a trial of intentional premature delivery of the infant to prevent intra-

uterine death, exchange transfusion was instituted in 1947 to minimize post-natal
jaundice and neonatal death. In general, when the infant's cord blood was shown to
be Rh positive and the bilirubin level approached 20 mgs/100 cc whole blood in a
full-term infant and 12 mgs in a premature baby, 250 to 500 cc of 0 neg, low titer
A blood was injected into an infant via its umbtlical vein in 10 cc doses after with-
drawal of an equal amount of blood over a period of two hours or so. With increasing
experience, the neonatal mortality rate of sensitized babies was reduced from 50% to
5%. A number of these umbilical vein catheterizations were, in fact, unwittingly
intra-atrial transfusions , with the catheter passed through the ductus venosus, up
the inferior vena cava, into the right atriun and through the foramen ovale into the
left atrium, for it was a well known dictum among pediatric residents that "when the
blood withdrawn is really pink, the exchange transfusion works very well."

-2-

  The next advance came in the 1950's when Freda and others bravely performed
amniocentesis to determine the bilirubin content of amniotic fluid. It had been
obvious after years of experience that the mother's blood anti-D titers during the
last trimester had little to do with the condition of the infant. Serial amniotic
fluid bilirubin determinations resulted in a number of graphs which were useful in
deciding when to do i? premature induction of labor or a caesarian section to prevent
an intra-uterine death from erythroblastosis.

In 1963, Liley added the last dramatic touch to treatment of erythroblcstosis -

intra-uterine transfusion - which reduced the fetal mortality from erythroblastosis
from 100% to 60%. Now it appears that there is no need for further improvement in
therapy, for complete prevention is at hand.

' Shortly before 1950, Wiener had suggested a plausible mechanism of the sensitiza-

tion of an Rh negative woman by her Rh positive baby - transplacental bleeding.

Even in the first trimester, it has been demonstrated that trophoblast cells can

be found in maternal blood and, later, that atabrine-tagged maternal red cells can
be found in the fetus. There finally is a consensus of opinion that at the time of
delivery, a varying amount: of fetal blood cells finds its way into the maternal
intervillous space and veins d.raining the placenta as it separates from the uterine
wall. Kleiauer devised a comparatively simple chemical test to quantitate the number
of fetal cells which enter the mother's bloodstream. The basis is the difference betwen
Hgb F and Hgb A. Some clinics take the trouble to determine the relative fetal-maternal
transfusion after delivery, but most do not.

The elimination of Rh disease in infants and serrsitization of their mothers began

with the recognition that women incoIupatihle with their infants in the AT50 system,
of ten were protected From being sensitized by Rh imcoinpatibility. It seemed 1-ogical
to develop an anti-1311 globulin. Men ~~ho were Rh negative were given Rh positive blood
cells plus anti-Rh antibodies. None became sensitized, while those receiving Ith positive
cells al-one did.

Ro doubt, as public health specialists you are more interested in the present

state of affairs than historical backgrouad.

About one in eight marriages involves one of an Rh negative woman and an Rh

positive man. It is estimated that 2-300,000 women are at risk annually of being
s ens i t ized .

The estimated number of candidates depends on race and on previous isoimmunization
The expected number of white Americans of European descent and of Negroes are

either by a mismatched blood transfusion or intramuscular blood, or by an Rh positive
baby.
as follows:

White Negro

A. Rh negati.ve (r.r) 15%
A. Homozygous RIi positive (R,R) 3 7%
C. Heterozygous Rh positive (R,r) 48%

all A x B matings will be positive .15 x .37 = .0555
                            .15 )i .68 = .0360

                                       .091.5
                                      .0079

--

% A x C matings will be positive

---

2

--

Minus previously iinmunized (085~. 0915)

. G836

0 r 8 .[I 74

The number of Orientals at risk is Filightiy less than that of Negroes.

Rh imm1me globulin was licensed in April 1968. A second vaccine is about to be

licensed. Its use in susceptible women within 72 hours of the birth of an Rh positive
baby, stillbirth or miscarriage is remarkably successful in preventing isoimiiunization
of the mother, as evidenced by her lack of antibodies and the health of the succeeding
positive baby. Of course, its use is contraindicated in women already sensitized to
the D antigen. Exchange or intrauterine transfusion will still be needed in their
babies until the end of their reproductive period.

How many women who need this vaccine are receiving it? A s.urvey of 99 maternity

hospitals conducted by Mr. S tick1.e and myself, of The National Foundation, in December
1968 showed a 77% utilization in white women and a 61% utilization in non-white women.

What are the reasons for these low figures?

1. Cost. The original vaccine cost $65.00 a dose (300 micrograms of immune globulin).

This figure is now down to $35.00 in the United States, while in Canada it has always
been $10.03. Ideally, a number of laboratory tests shoilld be performed before the
vaccine is given to see if the mother's red cells are compatible with the vaccine, to
see if she has no unusual rare antibodi.es, etc. etc. These tests often cost as much
as the vaccine, if not: more. In case of doubt as to the results of these tests, the
advice of most hematologists is to give the vaccine anyway, since there seem to be no
ill effects due to it. Thus, some hospitals are giving the vaccine intramuscularly to
every Rh negative woriian following miscarriage, ectopic pregnancy, stillbirth or live
birth.

. 2. Objection tro receivj.ng - blood pro.duct.s I such as by Jehovah's tJitnesses.

3. Declaration 19- the woman rhat sbc [rill have nc inare pregpancies. It is unsafe

-- -

to accept this statcme:ic unless sterilization is perloriilcd.

  4. Resistance of the physician to introdlice a new treatment and lack of education
of the public to denniarid jt. In our survey, it was mentioned frequently that the pliystcinn
tras unailarc of the eriste!ice and beiiefits of this new vaccine. Often, his patient was
the one F:~O brought it to his attention.

As for meeting the cost of the vaccine, several avenues are hopeful. The cost of

one dose is coming down as competition becomes keener. One state, Ilassachusetts, has
enough vaccine prepared to cover all its needs, at $10.00 a dose, and is awaiting
official approval of its product. The vaccine assistance act, passed by the Senate
and now before the House, includes Rh vaccine. An increasing number of hospital.
insurance plans are including the cost of the vaccine and, occasionally, the laboratory
work in their benefits.

   It is obvious that blood grouping, at least of the AB0 and Rh systems should be
performed on premarital blood samples drawn for the diagnosis .of syphilis. The presence
of rubella antibodies also should be determined OE this sample.
is under way in the New York City Health Department, assisted by The National Foundation-
March of Dimes, although Diamond states that blood grouping was routine in Massachusetts
on premarital blood samples in the early 1950's.

Such a pilot project

-4-

  The risk of hepatitis from use of the vaccine is a logical question to ask.
Gorman states that as of April 1, 1970, hepatitis has occurred fol.lowing vaccination
in not more than a dozen women. Sone of these were in areas where hepatitis is c.idemic.
A causal relation between administration of the vaccine and occurrence of hepatitis
has not been established. Gzmmaglobi1li1~ as it .is prepared for this vaccine has been
shown to be remarkably free of the hepatitis virus.

Many aspects of the Rh problem have not been covered because of time limitations.

It would be wishful thinking to state that the Rh problem will soon be a thing of the
past. As Liley points out, the negative allele, which in due time will disappear,
will now persist.
subdued.

By diligent and conscientious effort, we can keep hemolytic disease

o

Liley, R.W. "Gaining on the Rh problem. " Obstetrics and Gynecology, MEDICAL WORLD

NEWS 1970, p. 48-52.

Lin-Fu, J. "New Hope for babies of Rh negative mothers." CHILDREN, Vol. 16/1,
January-February 1969.

Gorman, J. Personal Communication, 3/31/70.