REVIEW

The role of antenatal immunoprophylaxis in the prevention

of maternal-foetal anti-Rh(D) alloimmunisation
Giancarlo Maria Liumbruno1,2, Angelo D'Alessandro1, Federica Rea3, Vanessa Piccinini1,
Liviana Catalano1, Gabriele Calizzani1, Simonetta Pupella1, Giuliano Grazzini1
1

Centro Nazionale Sangue, Istituto Superiore di Sanit, Roma. 2UU. OO. CC. di Immunoematologia e
Medicina Trasfusionale e di Patologia Clinica, Ospedale San Gi ovanni Calibita Fatebenefratelli, Roma.
3
U. O. C. di Immunoematologia e Medicina Trasfusionale, Ospedale San Giovanni Calibita
Fatebenefratelli, Roma, Italy.

Introduction
The first description of haemolytic disease of the
newborn (HDN) can be traced back to 1609 and was
made by a French midwife, Louise Bourgeois, who,
from 1600, worked at the royal court of King Henry
IV and Queen Marie de Medicis1-4. In the treatise that
Bourgeois wrote in 1609 she described the birth of
two twins3: the first had hydrops and died immediately,
while the second, initially in a better condition, rapidly
became jaundiced and, after having developed
neurological symptoms (kernicterus), died 3 days after
being born.
Hydrops foetalis and kernicterus were correctly
interpreted as two aspects of the same pathology only
in 1932 5 , when Diamond described foetal
erythroblastosis secondary to severe haemolysis,
although the cause was still unknown. A few years
later, in 1938, Ruth Darrow correctly identified the
(antibody-related) pathogenesis of HDN6, although
erroneously attributing foetal haemoglobin the role
of the culprit antigen, which was suggested to have
induced a maternal antibody response after crossing
the placenta. The true pathogenesis of the disease was
definitively clarified in 1940 with the discovery of
the Rhesus (Rh) blood group system by Landsteiner
and Wiener7 and with the subsequent identification,
in 1941, by Levine8, of the Rh(D) antigen. This antigen
was, in fact, identified, in D-negative mothers, as
being the cause of the immunisation occurring
following transplacental passage of foetal D-positive
red blood cells. The subsequent passage of maternal
anti-D immunoglobulin G (IgG) across the placenta
into the foetal circulation was recognised as the final
event able to cause the spectrum of clinical events

that characterise HDN.

It did not take long before the risk of immunisation
could be quantified1,3: i) 16% in the case of a Rh(D)negative mother and a Rh(D)-positive, ABOcompatible foetus; ii) 2% in the case of a Rh(D)negative mother and a Rh(D)-positive, ABOincompatible foetus (about 20% of the cases); iii)
overall risk of immunisation: 13.2%.
Before 1945, about 50% of all foetuses with HDN
died of kernicterus or hydrops foetalis. Subsequently,
thanks to the progress in treatment, in industrialised
countries the mortality decreased to 2-3%; this
mortality rate was then very considerably further
reduced (100-fold) with the introduction of anti-D
immunoprophylaxis to prevent maternal-foetal antiRh(D) alloimmunisation 9.
At the beginning of the 1960s, Stern demonstrated
experimentally that the administration of anti-D IgG
could prevent sensitisation to the Rh(D) antigen10; in
the same period, other studies clarified the mechanism
of Rh iso-immunisation in pregnancy and introduced
the clinical practice of passive immunisation with antiD IgG to protect Rh(D)-negative women from
sensitisation against Rh(D)-positive red blood cells1114
. The successes obtained in studies of Rh(D)-negative
male volunteers formed the experimental basis for
clinical trials in pregnant Rh(D)-negative women15;
these trials demonstrated that post-partum
immunoprophylaxis decreased the incidence of postpregnancy anti-Rh(D) immunisation from 12-13% to
1-2%15,16.
Subsequently, in 1977, it was shown that 1.8% of
Rh(D)-negative women, despite post-natal
prophylaxis, continued to develop anti-D antibodies

Blood Transfus 2010; 8:8-16 DOI 10.2450/2009.0108-09

SIMTI Servizi Srl

Antenatal anti-D immunoprophylaxis

because of small transplacental haemorrhages during

pregnancy17,18.
One year later, a Canadian study by Bowman et al.
showed, in 1,357 Rh(D)-negative primagravida, that the
incidence of Rh(D) alloimmunisation could be reduced
to 0.1% by prophylaxis with antenatal anti-D IgG, in
addition to post-partum prophylaxis19. There is currently
sufficient evidence demonstrating that antenatal anti-D
prophylaxis also reduces the risk of Rh(D) immunisation
in the next pregnancy to below the level of 0.4%.
Forty years after Zipursky and Israels first
proposed the use of anti-D IgG to reduce the incidence
of Rh alloimmunisation in pregnancy 14 ,
immunoprophylaxis has drastically reduced the cases
of Rh-induced HDN; nevertheless, this pathology
continues to be relevant in 0.4 of 1,000 births
(0.04%)20, for various reasons21: i) the possible
occurrence of anti-D immunisation during the
pregnancy (which occurs in about 1% of Rh(D)negative women carrying a Rh(D)-positive foetus22);
ii) the lack of efficacy of immunoprophylaxis because
of the administration of an insufficient dose of anti-D
IgG that is not congruent with the volume of the foetalmaternal haemorrhage; iii) immunoprophylaxis not
administered; iv) possible errors in typing the pregnant
or puerperal woman or the neonate; v) possible errors
in transfusion therapy in women of child-bearing age.

Antenatal prophylaxis
Rationale
Systematic anti-D prophylaxis was proposed in the
1970s with the aim of reducing the percentage of
Rh(D)-negative women who could be sensitised during
pregnancy, despite the use of post-partum prophylaxis.
This percentage ranged from 0.9-2.2% in a series of
studies carried out between 1977 and 198917-19,23-28, and
from 0.8-1.5% in subsequent studies carried out
between 1995 and 199929-32; this latter modest reduction
is probably due to intercurrent changes in obstetric care
and the wider use of anti-D prophylaxis following
sensitising events during pregnancy33.
The D antigen has been demonstrated to be present
on foetal red blood cells from the 7th week of
pregnancy onwards34. There is a direct, proportional
relationship between the volume of Rh(D)-positive
red blood cells to which the Rh(D)-negative subject
is exposed and the incidence of anti-Rh immunisation,
although it has been estimated that 0.1 mL is already

sufficient to induce the formation of antibodies14,33.

During the first trimester of a normal pregnancy,
foetal red blood cells can be found in the maternal
circulation of about 3% of women, albeit in amounts
less than 0.1 mL35. As the pregnancy proceeds, the
frequency and volume of foetal red blood cells in the
maternal circulation increase, such that during the
second and third trimesters these cells can be detected
in 12% and 45% of women, respectively. At the time
of delivering an ABO-compatible neonate, foetal red
blood cells can be found in the maternal circulation
in as many as 50% of cases12. However, the main
sensitising event for Rh(D)-negative women, in whom
prevention is based on post-natal prophylaxis, occurs
at the end of the pregnancy, with detachment of the
placenta during delivery33.
Other sensitising events, in the form of occult or
silent transplacental haemorrhages, are probably the
principal cause of the approximately 1% residual rate
of immunisation. These events provide the rationale
for the strategy, adopted in many countries, of
systemic antenatal anti-D prophylaxis for all nonimmunised Rh(D)-negative pregnant women, as a
complementary measure to post-partum prophylaxis36.
Numerous studies have demonstrated that the
antenatal administration of anti-D IgG does not have
adverse effects on the foetus, even though small amounts
of anti-D can cross the placenta and, by binding to foetal
D-positive red blood cells, can cause weak positivity at
birth in the direct Coombs' test16,23,37-40.
Antenatal anti-D prophylaxis is generally
recommended from the 28th week of pregnancy
onwards, because transplacental haemorrhages large
enough to cause sensitisation do not occur until the
third trimester and, therefore, anti-D antibodies usually
develop after the 28th week of gestation17,41,42; studies
showing that 92% of Rh(D)-negative women who
develop anti-D do so after the 28th week of gestation
lend support to this recommendation16,37.
Anti-D
prophylaxis
has
a
strong
immunosuppressive effect, such that subsequent
exposure to the D antigen does not cause a secondary
immune response, but rather a primary response, as if
the immune system has never encountered the D
antigen43. Numerous mechanisms of action have been
proposed to explain the efficacy of this strategy,
including : (i) accelerated clearance of D-positive cells,
(ii) epitope masking, (iii) inhibition due to antibodies

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Liumbruno GM et al.

against FcRIIB (the specific activating receptor for

the Fc fragment of IgG) or anti-idiotype44, (iv) inhibition
of immature dendritic cells, and (v) inhibition of Bcell clones specific for the D antigen43; this last, recently
proposed, mechanism was suggested by the finding of
an increase in the levels of transforming growth factor and prostaglandin E2, found in a cohort of pregnant
women who were given antenatal prophylaxis.
However, the accelerated destruction of D-positive red
blood cells remains, according to some authors, the
main mechanism of action45.
Dose
A dose of 20 g (100 UI) of anti-D IgG protects
against 1 mL of D-positive red blood cells or 2 mL of
whole blood 10,20 . However, the World Health
Organisation (WHO) and the British Medical Research
Council consider that 25 g (125 UI) are needed to
protect against the same volume of D-positive red blood
cells46; according to Bowman and Pollock, this is
equivalent to having a concentration of anti-D IgG in
the maternal circulation of 2.4 ng/mL26.
There are essentially two approaches to antenatal
prophylaxis: i) a single injection of 300 g (1,500
UI) in the 28th week of pregnancy19,28,47, or ii) two
injections of 100-125 g (500-625 UI), one in the
28th week, the other in the 34th week24,32,40.
In pharmacokinetic studies, the half-life of the IgG
was estimated to be, on average, 17-22 days (range:
11-29)48,49; a recently published pharmacokinetic study46
reported that both protocols are effective and able to
ensure, 12 weeks after administration, the minimum
residual concentration of 25 g (2.4 ng/mL) of anti-D
IgG indicated by the WHO as a protective level. This
is probably an overcautious estimate because it is
extremely unlikely that the volume of a transplacental
haemorrhage in the antenatal period exceeds 1 mL of
foetal red blood, which is equivalent to the volume of
foetal-maternal haemorrhage occurring at the time of
delivery in 98% of women46,50.
A recent systematic review of the literature on the
clinical efficacy of anti-D prophylaxis during
pregnancy33 found 11 studies that compared the
outcome of Rh(D)-negative women (and their
babies) 19,23-32 not immunised to D antigen who
underwent antenatal prophylaxis in the 28th week of
pregnancy or subsequently, with the outcome of
Rh(D)-negative controls (and their babies) who did

not receive prophylaxis. Table I reports the

characteristics of the studies analysed in the review,
which showed that the percentage of sensitised women
decreased from 1.9-2.2% to 0-0.2% with the use of
antenatal prophylaxis; the data also showed that the
main clinical benefit that a Rh(D)-negative woman
can have from antenatal prophylaxis is the possibility
of avoiding HDN in subsequent pregnancies with
Rh(D)-positive foetuses.
A meta-analysis, carried out on two of the 11 studies
included in the review, demonstrated a notable reduction
in relative risk of sensitisation in women treated with the
antenatal prophylaxis; indeed, the odds ratio (OR) was
0.37 (95% CI: 0.2-0.65), while the absolute reduction in
risk of sensitisation in mothers at risk (carrying a Rh(D)positive foetus) was 0.6%; the number of women who
had to be treated to avoid one case of sensitisation (i.e.
the NNT, number needed to treat) was 278.
A meta-analysis by the Cochrane Collaboration in
200042 also included only two studies27,29, for a total
of more than 4,500 women treated with
immunoprophylaxis in the 28th and 34th weeks of
pregnancy; the doses of anti-D IgG used were 100 g
(500 UI) x 2 in the French trial27, and 50 g (250 UI)
x 2 in the British trial29. Three outcomes were
evaluated and for each of these the reduction in the
relative risk was statistically significant. As far as
concerns positivity for the Kleihauer test, which
detects foetal red blood cells in the maternal
circulation, the OR was 0.6 (95% CI: 0.41-0.88)
during pregnancy and 0.6 (95% CI: 0,46-0,79) also
after the delivery of a Rh(D)-positive baby. The OR
for the incidence of anti-D alloimmunisation was 0.42
(95% CI: 0.15-1.17) both during pregnancy and after
the birth of a Rh(D)-positive baby; the OR became
0.41 (95% CI: 0.16-1.04) within 12 months of the
birth, while the OR for women at a first pregnancy,
within 12 months after the delivery, was 0.11 (95%
CI: 0.01-2.04). The reduction in the relative risk of
neonatal jaundice was considerably greater, with an
OR of 0.26 (95% CI: 0.03-2.3).
According to the Cochrane reviewers, as a result of
antenatal prophylaxis [100 g (500 UI) of anti-D IgG
in the 28th to 34th weeks], the risk of alloimmunisation
of Rh(D)-negative pregnant women drops from about
1% to 0.2% and the probability of immunisation in
subsequent pregnancies is also reduced; the NNT to
avoid one case of sensitisation is 213.
Blood Transfus 2010; 8:8-16 DOI 10.2450/2009.0108-09

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Antenatal anti-D immunoprophylaxis

Table I

Summary of the results of the clinical efficacy of antenatal anti-D prophylaxis

(adapted from: Jones ML et al.33).

Study
[Study desing]

Dosage

Patient selection

Bowman et al. (1978)

[NRCT]19

2 x 1500 IU (28 and 34 weeks) Primigravidae

Bowman and Pollock (1978)

[NRCT]23

1 x 1500 IU (28 weeks)

Unselected

Tovey et al. (1983)

[NRCT]24

2 x 500 IU (28 and 34 weeks)

Primigravidae

Hermann et al. (1984)

[NRCT]25

1 x 1250 IU (34 weeks)

Anti-D prophylaxis group

% Sensitised or
r/n
sensibilised
(95% CI)

r/n

Control group
% Sensitised or
sensibilised
(95% CI)

1/1357

0.1 (0.1 to 0.2)

45/2768

1.6 (1.6 to 2.1)

11/1805

0.6 (0.3 to 1.0)

62/3533

1.8 (1.3 to 2.2)

5/1238

0.4 (0.1 to 0.8)

30/2000

1.5 (1.0 to 2.0)

Primigravid primiparae

4/236

1.7 (0.0 to 3.3)

5/286

1.7 (0.2 to 3.3)

Multigravid primiparae

1/332

0.3 (0.3 to 0.9)

7/359

1.9 (0.2 to 2.6)

Unselected primiparae

5/568

0.9 (0.1 to 1.6)

12/645

1.9 (0.8 to 2.9)

Bowman and Pollock (1987)

[NRCT]26

1 x 1500 IU (28 weeks)

Unselected

30/9295

0.3 (0.2 to 0.4)

62/3533

1.8 (1.3 to 2.2)

Huchet et al. (1987)

[Quasi RCT]27

2 x 500 IU (28 and 34 weeks)

Primiparae

0/461

0.0 (0.0 to 0.0)

4/454

0.9 (0.0 to 1.7)

Multiparae

1/138

0.7 (0.7 to 2.1)

3/136

2.2 (0.3 to 4.7)

Unselected

1/599

0.2 (0.2 to 0.5)

7/590

1.2 (0.3 to 2.1)

Trolle (1989)
[NRCT]28

1 x 1500 IU (28 weeks)

Unselected

0/291

0.0 (0.0 to 0.0)

6/322

1.9 (0.4 to3.3)

Lee and Rawlinson (1995)

[RCT] 29

2 x 250 IU (28 and 34 weeks)

Primigravidae

5/513

1.0 (0.1 to 1.8)

9/595

1.5 (0.5 to 2.5)

Mayne et al. (1997)

[Before and after study]30

2 x 500 IU (28 and 34 weeks)

Primiparae

4/1425

0.3 (0.0 to 0.6)

16/1426

1.1 (0.6 to 1.7)

Parsons et al. (1998)

[NRCT]31

Not stated* (28 weeks)

Not stated

72/9684

0.7 (0.6 to 0.9)

No data

0.8 (not given)

Mackenzie et al. (1999)

[Controlled before and
after study]32

2 x 500 IU (28 and 34 weeks)

Primiparae

12/3320

0.4 (0.2 to 0.6)

26/3146

0.8 (0.5 to 1.1)

NRCT = non randomised controlled trial.; RCT = randomised controlled trial; n = number of deliveries of RhD-positive babies to RhD-negative women;
r = number of sensitised RhD-negative women in the trial group. * Most probably the standard Canadian dose of 1500 IU.

International recommendations
Various international recommendations (table II)
suggest antenatal anti-D prophylaxis (i.m. or i.v.) in
unsensitised Rh(D)-negative women as a complement
to post-partum prophylaxis.
1) The Society of Obstetricians and Gynaecologists
of Canada (SOGC) suggests 300 g in the 28th
week (grade of recommendation: A) or two doses
of 100-120 g in the 28th and 34th weeks of
pregnancy20.
2) The Italian Society of Transfusion Medicine and
Immunohaematology (SIMTI), together with the

3)
4)

5)

6)

Italian Society of Gynaecology and Obstetrics

(SIGO) recommends 250-300 g in the 28th week21.
The American Society of Clinical Pathologists
(ASCP) suggests 300 g in the 28th-30th week16.
The American College of Obstetrician and
Gynaecologists (ACOG) recommends
prophylaxis51, around the 28th week, but does not
specify the dose (grade of recommendation: A).
The U.S. Preventive Services Task Force
(USPSTF) (USA) recommends 300 g in the
24th-28th week52.
The National Institute for Clinical Excellence

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Liumbruno GM et al.
Table II

Recommended antenatal anti-D prophylaxis in

the main international recommendations
Recommended dose

Week

300 (or 100-120)

28 (or 28 and 34)

250-300

28

USA (ASCP)16

300

28-30

USA (ACOG)51

Not specified

28

USA (USPSTF)52

300

24-28

UK (NICE) 53

100

28 and 34

UK (BCSH)54

100

28 and 34

Australia (NHMRC)56

125

28 and 34

Australia (RANZCOG)57

125

28 and 34

France (CNGOF)58

300

28

The Netherlands (CHI)59

200

30

Spain (SETS-SEOG)60

300

28

Canada (SOGC)20
Italy (SIMTI-SIGO)21

SOGC: Society of Obstetricians and Gynaecologists of Canada

SIMTI: Societ Italiana di Medicina Trasfusionale e Immunoematologia
[Italian Society of Transfusion Medicine and Immunohaematology]
SIGO: Societ Italiana di Ginecologia e Ostetricia [Italian Society of
Obstetrics and Gynaecology]
ASCP: American Society of Clinical Pathologists
ACOG: The American College of Obstetricians and Gynecologists
USPSTF: U.S. Preventive Services Task Force
NICE: National Institute of Clinical Excellence
BCSH: British Committee for Standards in Haematology
NHMRC: National Health and Medical Research Council
RANZCOG: Royal Australian and New Zealand College of Obstetricians
and Gynaecologists
CNGOF: Collge National des Gyncologues et Obsttriciens Francais
[French College of Obstetricians and Gynaecologists]
CHI: Council of Health Insurances
SETS: Sociedad Espaola de Transfusin Sangunea[Spanish Society of
Blood Transfusion]
SEOG: Sociedad Espaola de Obstetricia y Ginecologa [Spanish Society
of Obstetrics and Gynaecology]

7)

8)

(NICE) (UK), in guidelines published in 2002

and revised in 2005, indicates 100 g (500 UI)
in the 28th and 34th weeks53; the NICE states that
this scheme is equivalent to a single dose of 300
g (1,500 UI) in the 34th week.
The same indications are included in the recent
guidelines from the British Committee for
Standards in Haematology (BCSH)54, which
replaced the preceding recommendations by Lee
et al. in 199955.
The National Health and Medical Research

Council (NHMRC) (Australia) suggests 125 g

(625 UI) in the 28th and 34th weeks56.
9) The Royal Australian and New Zealand College
of Obstetricians and Gynaecologists
(RANZCOG)
confirms
the
above
57
recommendation .
10) The French recommendations are for a dose of
300 g in the 28th ( 1) week of pregnancy58.
11) The Dutch authorities recommend a single dose
of 200 g in the 30th week59.
12) The Spanish Society of Blood Transfusion
(SETS) and the Spanish Society of Obstetrics
and Gynaecology indicate a single dose of 300
g in the 28th week60.
Prophylaxis should not be given to women with a
"weak" D phenotype, in that such women are actually
D-positive21; however, the use of anti-D IgG in these
women does not have significant side effects.

Conclusions
HDN has become a rare disorder since the
introduction of anti-D prophylaxis. The foetal Rh(D)
antigen is already well developed after 30-40 days of
gestation and the risk of antenatal foeto-maternal
haemorrhage, already possible from the 6th week61,
increases exponentially as a pregnancy progresses22,35.
Although the risk of foetal blood entering the maternal
circulation is high, the average volume of is very small,
being 0.07 mL in the first trimester, 0.08 mL in the
second and 0.13 mL in the third62. A Rh(D)-negative
woman not immunised and who does not receive
prophylaxis has, in every pregnancy, a 16% risk of
becoming immunised to a Rh(D)-positive foetus63.
However, the global success rate of post-natal Rh
immunoprophylaxis has now reached 98.4 - 99%1,3.
Given that anti-D prophylaxis is effective for about
12 weeks, as indicated by pharmacokinetic studies
on anti-D IgG46, and given the relatively low risk of
significant foeto-maternal haemorrhage before the 28th
week of gestation, antenatal prophylaxis is carried out
from the 28th week onwards41.
The currently available evidence demonstrates that
antenatal anti-D prophylaxis, besides being a costeffective strategy36,64, is able to further reduce the
incidence of sensitisation to D antigen down to about
0.2%33,42; a variety of prophylactic regimens are used
in different countries, although 300 g of anti-D IgG
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Antenatal anti-D immunoprophylaxis

Abortion (spontaneous or
therapeutic)

Ectopicpregnancy

Amniocentesis

Cordocentesis

Rh(D)positive

Villocentesis

(60%)

Abdominaltrauma

Antenatalhaemorrhage

Sensitising
events

AntiDprophylaxis
within72hoursof
theevent

AntiDprophylaxis
within72hoursof
theevent

Foetalgenotyping

Nosensitising
events

(firsttrimester)

Rh(D)negative
(40%)

Figure 1 -

AntenatalantiD
prophylaxisin
28thweek

Postpartum
antiD
prophylaxis

Noprophylaxis

Anti-D prophylaxis in Rh(D) negative pregnant women: possible scenario following the introduction of
foetal genotyping

in the 28th week is the dose most commonly indicated

in international recommendations16,20,52,58.
It is not, however, possible to completely eliminate
the risk of sensitisation because, despite increased
adherence to antenatal immunoprophylaxis65, and
although most foeto-maternal haemorrhages able to
cause immunisation occur in the last trimester of
pregnancy, sensitisation does occur before the 28th
week in a small percentage of women; alternatively,
there may be cases in which intramuscular
administration of the anti-D IgG is insufficient to
provide passive prophylaxis.
Furthermore, the risk of intrauterine foetal death
of Rh(D)-positive foetuses of Rh(D)-negative mothers
appears to be increased despite antenatal
immunoprophylaxis, as indicated by a recent,
retrospective observational study carried out in Israel
on more than 140,000 deliveries occurring between
1988 and 200366; although the subject undoubtedly
needs further investigation, this retrospective study
seems to suggest a possible pathogenic scenario not
limited
to
maternal-foetal
serological
alloimmunisation but also involving the maternal-

foetal interface (i.e. the placenta), which could

undergo immune-mediated damage leading to
intrauterine foetal death.
The IgG subclasses with anti-D activity are IgG1
and IgG3; the anti-D IgG are produced by industrial
fractionation from pools of donor plasma containing
a high titre of anti-D antibodies; chromatographic
procedures, which are well suited to processing small
quantities of plasma and guarantee an excellent yield,
are used for the fractionation67.
Antenatal prophylaxis with anti-D IgG does not
have side effects on the foetus and can be considered
complementary to post-partum prophylaxis, but the
decision on whether to undertake a programme of
prophylaxis during pregnancy can be influenced by
the commercial availability of anti-D IgG. The raw
material is a limited resource because the
hyperimmune plasma comes exclusively from the
USA, the only country that still carries out active
immunisation of donors which, until about 10 years
ago, was also performed in Switzerland and Slovenia
(Italian National Blood Centre, unpublished data).
An economic analysis carried out in the United

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Liumbruno GM et al.

Kingdom36,64 demonstrated that the cost per year of

life gained from using antenatal anti-D prophylaxis
for women in their first pregnancy was low compared
to that of other interventions normally offered by the
health care service in that country; the same
prophylaxis, given to all pregnant women, although
costing more, maintained a relatively low cost per year
of life gained, thus confirming that antenatal anti-D
prophylaxis is a decidedly cost-effective strategy.
Methods of foetal genotyping on maternal
plasma68-74 are able to detect foetal DNA sequences in
the maternal plasma; used on a large scale, these
methods could enable elimination of unnecessary
antenatal prophylaxis with anti-D IgG in Rh(D)negative mothers of Rh(D)-negative foetuses, who
represent about 40% of all cases, thus sparing this
blood derivative and reserving its appropriate use
exclusively to those women at risk of maternal-foetal
alloimmunisation (Figure 1). In addition to this
benefit, a further advantage of foetal genotyping
would be that of knowing whether, in a women already
immunised in an early stage of a pregnancy, the foetus
of the current pregnancy is Rh(D)-negative or positive,
providing important information for the management
of the pregnancy.
The possible use of monoclonal or recombinant
anti-D antibodies in clinical practice remains very
uncertain75. These antibodies could, in the future, be
an alternative to the prophylactic use of plasmaderived polyclonal anti-D IgG76-78; unfortunately,
however, none of the products developed by industry
so far has been demonstrated to be effective in the
numerous phase I clinical trials that have been carried
out79,80. During the last 20 years, 19 monoclonal or
recombinant antibodies, produced by different cell
lines, have been tested in humans75, but the in vivo
clinical efficacy and side effects were very
heterogeneous. Most of the side effects are probably
related to the type of glycosylation to which the IgG
molecule is subjected in the various different cell
systems used for its production75,80.
The drafting and adoption of national
recommendations on the systematic use of antenatal
immunoprophylaxis must, however, take into
consideration both clinical and organisational
implications81, and the potential financial impact of
using this blood derivative which, already in the 3
years from 2002 to 2005, led to a 56% increase in

costs, for a 15% rise in sales (Italian National Blood

Centre, unpublished data), caused presumably also
by the increase in the sale price of the product.
Key words: antenatal immunoprophylaxis,
maternal-foetal alloimmunisation, haemolytic disease
of the newborn, Rh(D).

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Received: 12 May 2009 - Revision accepted: 6 August 2009

Correspondence: Dr. Giancarlo Maria Liumbruno,
Viale Italia, 19
57126 Livorno, Italy.
e-mail: iancarlo@liumbruno.it; ricerca.cns@iss.it

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