Anti-D Immunoglobulins
(Anti-D (Rh, Immunoglobulin (BP 1998); Immunoglobulinum Humanun
Anti-D) is a liquid or freeze-dried preparation containing im
Munoglobulins, mainly immunoglobulin G (lgG). It is ob
lained from plasma from D-negative donors who have been
immunised against the D-antigen. It contains specific anti
bodies against the erythrocyte D-antigen and may also con
tain small quantities of other blood group antibodies, such as
anti-C, anti-E, anti-A, and anti-B. Normal immunoglobulin
may be added. The liquid and freeze-dried preparation:
should be stored, protected from light, in a colourless, glass
container. The freeze-dried preparation should be stored un
der vacuum or under an inert gas.
Rh, (D) Immune Globulin (USP 23) is a sterile solution of
globulins derived from human plasma containing antibody to
the erythrocyte factor Rh, (D). It contains 10 to 18% of pro
tein. of which not less than 90% is gamma globulin. It con
tains glycine as a stabilising agent, and a suitable
preservative. It should be stored at 2Β° to 8Β°.
Adverse Effects and Precautions
As for immunoglobulins in general.
Anti-D immunoglobulin should be administered
with caution to rhesus-positive persons for the treat
ment of blood disorders: the resultant haemolysis
may exacerbate pre-existing anaemia.
Interactions
As for immunoglobulins in general.
Uses and Administration
Anti-D immunoglobulin is used to prevent a rhesus
negative mother actively forming antibodies to fetal
rhesus-positive red blood cells that may pass into the
maternal circulation during childbirth, abortion, or
certain other sensitising events. In subsequent rhe-
sus-positive pregnancies these antibodies could
produce haemolytic disease of the newborn
(erythroblastosis foetalis). The injection of anti-D
immunoglobulin is not effective once the mother has
formed anti-D antibodies. Anti-D immunoglobulin
is also used in the management of some blood dis
orders, primarily idiopathic thrombocytopenic
purpura.
Anti-D immunoglobulin should always be given to
rhesus-negative mothers with no anti-D antibodies
in their serum and who have just delivered rhesus
positive infants. It should be given as soon as possi-
ble after delivery but may give some protection even
if administration is delayed beyond 72 hours. In the
UK, the Blood Transfusion Services recommend a
dose of 500 units (100 ng) by intramuscular inject-
tion although an additional dose may be required de-
pending on the amount of transplacental bleeding as
assessed by the Kleihauer test: for bleeds exceeding
4 to 5 mL an additional 100 to 125 units is given for
each mL.
For routine antenatal prophylaxis 500 units of anti-
D immunoglobulin may be given at 28 and 34 weeks
gestation. Alternatively a single dose, usually of
1500 units, may be given at 28 to 30 weeks. Postna-
tal prophylaxis is still necessary.
There is also a risk of sensitisation during pregnancy
from spontaneous, induced, or threatened abortion,
amniocentesis, or external version. Any rhesus-neg-
ative woman at risk of transplacental haemorrhage
during pregnancy and not known to be sensitised
should be given 250 units at up to 20 weeks gesta-
tion and 500 units of anti-D immunoglobulin after
20 weeks gestation.
Anti-D immunoglobulin is also given to rhesus-neg-
ative women of child-bearing potential after the in-
advertent transfusion of Rh-incompatible blood, or
after receiving blood components containing rhe-
sus-positive red cells or organ donations from rhe-
sus-positive donors. The dose is based on the
amount of red blood cells transfused.
In Europe and the USA doses of anti-D immu-
noglobulins have traditionally been higher than in
the UK; WHO and the European Commissions
Committee for Proprietary Medicinal Products have
recommended a standard dose of 200 to 300 ng
(1000 to 1500 units) but do not include a require-
ment for Kleihauer screening. A dose of approxi-
mately 250 ng (1250 units) will suppress the
immune response to up to 10 mL of red blood cells.
In the USA the dosage recommendations are based
on a standard dose which is capable of suppressing
the immune response to 15 mL of incompatible red
blood cells. One sixth of this dose may be used up to
12 weeks of gestation for sensitizing episodes.
For idiopathic thrombocytopenic purpura, an initial
dose of 250 units (50~g) per kg body-weight of
anti-D immunoglobulin by intravenous injection has
been suggested. Maintenance doses will depend on
the clinical response.
Haemolytic disease of the newborn. Rhesus (Rh) in-
compatibility, in particular Rh(D) incompatibility, is a
major
cause of potentially severe haemolytic disease of the new-
born, although other blood group antibodies may also cause
the diseased The use of anti-D immunoglobulin to suppress
the production of anti-D antibodies in a Rh(D)-negative
mother in response to leakage of red blood cells across the
placenta from a Rh(D)-positive fetus has produced a major
reduction in the incidence of this disorder.
Postnatal prophylaxis of Rh(D)-negative mothers following
the birth of a Rh(D)-positive infant is well established. In
1971 WHO suggested a standard dose of 200 to 300 mcg but
stated that a 100-mcg dose is likely lo have a success rate
only
slightly inferior to that of a 200-mcg dose, thus allowing
optimum use to be made of a limited resource. Clinical
experience in the UK has confirmed the efficacy of the 100-
mcg dose and this is the amount officially recommended in
the UK in such situations.
Despite the success of anti-D prophylaxis, sensitisations
have continued to occur. There are several possible reasons for
this. Failures may occur when an inadequate dose has been
administered or when anti-D prophylaxis is omitted following
a sensitising event. Postpartum doses may be omitted due
to oversight or loss to follow-up. Sensitisation may occur
spontaneously during the first pregnancy without any identi-
fiable event causing feto-matemal haemorrhage. Inadequate
dosing can be avoided by application of the Kleihauer test to
estimate the size of any transplacental haemorrhage,'
Significant feto-matemal transfusion may also occur follow-
ing still-birth, abortion (both therapeutic and
spontaneous),
threatened abortion, external fetal version, abdominal
injury, or amniocentesis.
The efficacy of postpartum prophylaxis is not in question but
opinions differ on the need for prophylaxis during pregnancy.
It is generally agreed that prophylaxis is necessary
following therapeutic terminations at any stage of pregnancy,
including medical termination utilising mifepristone, but there
is no generally accepted policy for other possibly sensitising
events. A study of 655 Rh(D)-negative women in Denmark,"
where antepartum prophylaxis is not common practice, sug-
gested that the sensilisation rate following amniocentesis was
no higher than the spontaneous sensitisation rate. Surveys of
general medical practitioners and consultant obstetricians and
haematologists in the UK have suggested that many do
not recommend routine prophylaxis following early complete
or threatened miscarriages; 74% of general practitioners in
one survey never gave anti-D after threatened miscarriages.
Spontaneous miscarriages during early pregnancy might not
cause sensilisation so long as there is no surgical interven-
tion. Nonetheless some authorities in the UK urge rou-
tine antenatal prophylaxis for all Rh(D)-negative women.
Everett and Hussey represent the alternative opinion that.
with the shortage of anti-D, indiscriminate use of anti-D
should be avoided and attention should be focussed upon
administration of adequate doses following term deliveries
and terminations of pregnancy in Rh(D)-negative women.
Further debate arises over the significance of spontaneous
sensitisation during the first pregnancy. Tovey and
colleagues" found that administration of anti-D to 2069
Rh(D)-negative primigravidas at 28 and 34 weeks as well as
standard postpartum administration was more effective at
preventing immunization than standard postpartum prophy-
laxis in 2000 primigravidas. In a subsequent analysis of wom-
en from this study following further pregnancies.
comparison with a group of Rh(D)-positive mothers showed
no detrimental effects to mothers or infants. In addition anie-
natal prophylaxis may not need to be given beyond the first
pregnancy. Nevertheless, concerns have been expressed
over the consequent unnecessary administration of anti-D to
women who are carrying Rh(D)-negative fetuses and the pos-
sible long-term effects, although anti-D has had a good safety
record. Both factions agree on the desirability of identi-
fying high-risk women to reduce the indiscriminate use of
anti-D. A remaining major stumbling block, in the UK at
least, is the continuing expense and scarcity of anti-D immu-
noglobulin. Supplies are derived from plasma collected from
Rh-negative donors who have to undergo potentially hazard-
ous sensitisation with Rh-positive red blood cells. The devel-
opment of genetically-engineered anti-D should help to
improve availability. The UK and WH0 guidelines may
represent a counsel of perfection, but until difficulties with
supply are overcome, prophylaxis during the first pregnancy
for Rh(D)-negative women, thus ensuring the possibility of
two unaffected infants, would seem a reasonable priority.
IVtatment. In mild cases, the resultant hyperbilirubinemia
can be managed with phototherapy. In severe cases, exchange
transfusions may be necessary and intra-uterine transfusions
may be considered in pregnancies of less than about 34 weeks
gestation: beyond this. premature delivery is often prefera-
ble.21 Some clinicians have reported treatment failures with
intia-uterine transfusions but have found the intravenous ad-
ministration of normal immunoglobulin 400 mg per kg body-
weight daily for 5 days every 2 lo 3 weeks to the mother to be
effective. There are several case reports of beneficial re-
sponses using similar doses, but no benefit was seen in 4 pa-
tients receiving 1000 mg per kg once a week. This dose.
however, appeared to reduce the severity of the disease in a
patient with Kell sensitisation. Reductions in bilirubin con-
centrations have been reported following intravenous admin-
istration of normal immunoglobulin 500 mg per kg as a single
dose to newborn infants. Preliminary studies in small num-
bers of infants suggest that epoetins may be of value in
controlling anaemia which develops 2 to 8 weeks after birth.
Idlopathic thrombocytopenic purpura. Although corti-
costeroids or splenectomy are established as the usual therapy
for chronic idiopathic thrombocytopenic purpura,
normal immunoglobulin is also used in some circumstances,
and anti-D immunoglobulin has been found to have similar
properties. Treatment of an Rh(D)-positive patient with a
long history of severe immune thrombocytopenic purpura
with a single dose of 500 units (100 ng) of anti-D irnmu-
nuglobulin intravenously was reported to result in a steady
rise in platelet count and rapid resolution of a cephalic
haematoma.2 Responses to anti-D immunoglobulin were re-
ported in 23 of 25 children with chronic idiopathic
thrombocytopenia following treatment with 25 ng per kg
body-weight on each of two consecutive days. However, in
children with acute disease, a similar dose of anti-D immu-
noglobulin was less effective in restoring platelet count and
produced a greater fall in haemoglobin than either normal im-
munoglobulin or corticosteroids. (Most children with the
acute form do not in any case require therapy.)
Beneficial results in both rhesus-positive and rhesus-negative
patients with HIV-related thrombocytopenia were reported~
with doses in the order of I to 3 mg daily, given intravenously.