Acog Practice Bullet In: Management of Alloimmunization During Pregnancy

interim update
The American College of

Obstetricians and Gynecologists
WOMEN’S HEALTH CARE PHYSICIANS
ACOG P RACTICE BULLET IN

Clinical Management Guidelines for Obstetrician–Gynecologists
Number 192, March 2018 (Replaces Practice Bulletin Number 75, August 2006)
Committee on Practice Bulletins—Obstetrics. This Practice Bulletin was developed by the American College of Obstetricians and Gynecologists’
Committee on Practice Bulletins—Obstetrics with the assistance of Calla Holmgren, MD, and T. Flint Porter, MD.
INTERIM UPDATE: This Practice Bulletin is updated as highlighted to reflect a limited, focused change to align with Practice
Bulletin No. 181, Prevention of Rh D Alloimmunization.
Management of Alloimmunization During

Pregnancy
When any fetal blood group factor inherited from the father is not possessed by the mother, antepartum or intrapartum
fetal–maternal bleeding may stimulate an immune reaction in the mother. Maternal immune reactions also can occur
from blood product transfusion. The formation of maternal antibodies, or “alloimmunization,” may lead to various
degrees of transplacental passage of these antibodies into the fetal circulation. Depending on the degree of antige-
nicity and the amount and type of antibodies involved, this transplacental passage may lead to hemolytic disease in
the fetus and neonate. Undiagnosed and untreated, alloimmunization can lead to significant perinatal morbidity and
mortality. Advances in Doppler ultrasonography have led to the development of noninvasive methods of management
of alloimmunization in pregnant women. Together with more established protocols, Doppler ultrasound evaluation
may allow for a more thorough and less invasive workup with fewer risks to the mother and fetus. Prevention of allo-
immunization is addressed in another Practice Bulletin (1).
Background found, and use of the letter “d” indicates the absence of
an evident allelic product. Anti-C, anti-c, anti-D, anti-E,
Nomenclature and anti-e designate specific antibodies directed against
The nomenclature for the Rh (CDE) blood group system their respective antigens.
is complex and often confusing. Five major antigens can An Rh gene complex is described by the three appro-
be identified with known typing sera, and there are many priate letters. Eight gene complexes are possible (listed in
variant antigens. Of the numerous nomenclature systems decreasing order of frequency among whites): CDe, cde,
that have been developed, the Fisher–Race nomenclature cDE, cDe, Cde, cdE, CDE, and CdE. Genotypes are indi-
is best known and most compatible with our understand- cated as pairs of these gene complexes, such as CDe/cde.
ing of the inheritance of the Rho (or D) antigen and the Certain genotypes, and thus certain phenotypes, are more
clinical management of Rh alloimmunization (2). The prevalent than others. The genotypes CDe/cde and CDe/
Fisher–Race nomenclature presumes the presence of CDe are the most common, with approximately 55% of
three genetic loci, each with two major alleles. The anti- all whites having the CcDe or CDe phenotype (3). The
gens produced by these alleles originally were identified genotype CdE has never been demonstrated in vivo (2).
by specific antisera and have been lettered C, c, D, E, Most of the cases of Rh alloimmunization causing
and e. No antiserum specific for a “d” antigen has been transfusion reactions or serious hemolytic disease in the
e82 VOL. 131, NO. 3, MARCH 2018 OBSTETRICS & GYNECOLOGY
Copyright Ó by American College of Obstetricians

and Gynecologists. Published by Wolters Kluwer Health, Inc.
Unauthorized reproduction of this article is prohibited.
fetus and newborn are the result of incompatibility with necessary to cause alloimmunization varies from patient
respect to the D antigen. For this reason, the designation to patient and is probably related to the immunogenic
Rh positive usually indicates the presence of the D anti- capacity of the Rh-positive erythrocytes and the immune
gen and Rh negative indicates the absence of D antigen responsiveness of the mother. Fetomaternal hemorrhage
on erythrocytes. sufficient to cause alloimmunization occurs most com-
In addition to the five major antigens of the Rh monly at delivery, in 15–50% of births (5–8). Specific
system, more than 30 antigenic variants have been clinical factors such as cesarean delivery, multifetal
identified. Among these are the Cw antigen and the Du gestation, bleeding placenta previa or abruption, manual
antigen, which is now referred to as weak D. The latter is removal of the placenta, and intrauterine manipulation
a heterogeneous group of clinically important D antigen may increase the volume of fetomaternal hemorrhage. In
variants. Some weak D-positive patients are capable of most cases, though, excessive fetomaternal hemorrhage
producing the anti-D antibody, although alloimmuniza- occurs with uncomplicated vaginal delivery (9, 10). The
tion rarely occurs. volume of fetal blood entering the maternal circulation
is 0.1 mL or less in most cases resulting in alloimmuni-
Other Antibodies zation (8, 11). Approximately 1–2% of Rh alloimmuniza-
The most frequently encountered antibodies other than D tion is caused by antepartum fetomaternal hemorrhage
are Lewis (Lea and Leb) and I antibodies. Like most cold (12). In one large series, fetomaternal hemorrhage was
agglutinins, Lewis and I antigens do not cause erythro- detected in 7% of patients during the first trimester, in
blastosis fetalis because they are predominantly of the 16% of patients during the second trimester, and in 29%
immunoglobulin M type and they are poorly expressed of patients during the third trimester (5). Detectable
on fetal and newborn erythrocytes. In contrast, Kell fetomaternal hemorrhage resulting in alloimmunization
antibodies (anti-K) can produce erythroblastosis fetalis. may occur in first-trimester spontaneous and induced
A more complete list of antibodies and their effects can abortion (13). Alloimmunization also has been reported
be found in Table 1. Often, Kell alloimmunization is after threatened abortion and ectopic pregnancy (14, 15).
caused by prior transfusion because Kell compatibility Several obstetric procedures may lead to fetomaternal
was not considered when the blood was cross-matched. hemorrhage and, in turn, maternal alloimmunization.
Care of patients with sensitization to antigens other than These include chorionic villus sampling, pregnancy ter-
D that are known to cause hemolytic disease should be mination, amniocentesis, and external cephalic version
the same as that for patients with D alloimmunization. A (16–18).
possible exception is Kell sensitization, in which amni-
otic fluid analysis has been reported to correlate poorly Anti-D Immune Globulin to Prevent
with the severity of fetal anemia (4). These patients may Alloimmunization
benefit from more aggressive fetal assessment, such as Anti-D immune globulin is not indicated for patients
measurement of the peak systolic velocity in the fetal previously sensitized to D. However, it is indicated for
middle cerebral artery; however, optimal care of Kell- patients who might be sensitized to other blood group
sensitized patients is controversial (4). antigens.
Incidence of Rh-Incompatible
Pregnancy
The incidence of Rh incompatibility varies by race and
Clinical Considerations and
ethnicity. Approximately 15% of whites are Rh negative, Recommendations
compared with only 5–8% of African Americans and
1–2% of Asians and Native Americans. Among whites,
What are the best screening methods for
an Rh-negative woman has an approximate 85% chance detecting alloimmunization in women?
of mating with an Rh-positive man, 60% of whom are All pregnant women should be tested at the time of the
heterozygous and 40% of whom are homozygous at the first prenatal visit for ABO blood group and Rh-D type
D locus. and screened for the presence of erythrocyte antibod-
ies. These laboratory assessments should be repeated in
Causes of Rh Alloimmunization each subsequent pregnancy. The American Association
Rh alloimmunization can occur only if a sufficient num- of Blood Banks also recommends repeated antibody
ber of erythrocytes from an Rh-positive fetus gain access screening before administration of anti-D immune glob-
to the circulation of its Rh-negative mother. The volume ulin at 28 weeks of gestation, postpartum, and at the time
VOL. 131, NO. 3, MARCH 2018 Practice Bulletin Management of Alloimmunization During Pregnancy e83

Table 1. Atypical Antibodies and Their Relationship to Fetal Hemolytic Disease
Blood Group Antigens Related to

System Hemolytic Disease Hemolytic Disease Severity Proposed Management
Lewis *
I *
Kell K Mild to severe† Fetal assessment
k Mild Routine obstetric care
Ko Mild Routine obstetric care
Kpa Mild Routine obstetric care
Kpb Mild Routine obstetric care
Jsa Mild Routine obstetric care
Jsb Mild Routine obstetric care
Rh (non-D) E Mild to severe† Fetal assessment
C Mild to severe† Fetal assessment
C Mild to severe† Fetal assessment
Duffy Fya Mild to severe† Fetal assessment
Fyb ‡ Routine obstetric care
By3 Mild Routine obstetric care
Kidd Jka Mild to severe Fetal assessment
Jkb Mild Routine obstetric care
Jk3 Mild Routine obstetric care
MNSs M Mild to severe Fetal assessment
N Mild Routine obstetric care
S Mild to severe Fetal assessment
s Mild to severe Fetal assessment
U Mild to severe Fetal assessment
Mia Moderate Fetal assessment
MSSs Mta Moderate Fetal assessment
Vw Mild Routine obstetric care
Mur Mild Routine obstetric care
Hil Mild Routine obstetric care
Hut Mild Routine obstetric care
Lutheran Lua Mild Routine obstetric care
Lub Mild Routine obstetric care
Diego D1a Mild to severe Fetal assessment
Dib Mild to severe Fetal assessment
Xg Xga Mild Routine obstetric care
P PP1pk (Tja ) Mild to severe Fetal assessment
Public antigens Yta Moderate to severe Fetal assessment
Ytb Mild Routine obstetric care
Lan Mild Routine obstetric care
Ena Moderate Fetal assessment
Ge Mild Routine obstetric care
Jra Mild Routine obstetric care
Coa Severe Fetal assessment
Co1-b- Mild Routine obstetric care
Private antigens Batty Mild Routine obstetric care
Becker Mild Routine obstetric care
Berrens Mild Routine obstetric care
(continued)
e84 Practice
ACOG Bulletin
Practice Management
Bulletin No. 75 of Alloimmunization During Pregnancy OBSTETRICS & GYNECOLOGY
3

Table 1. Atypical Antibodies and Their Relationship to Fetal Hemolytic Disease (continued)
Blood Group Antigens Related to

System Hemolytic Disease Hemolytic Disease Severity Proposed Management
Private antigens Biles Moderate Fetal assessment
Evans Mild Routine obstetric care
Gonzales Mild Routine obstetric care
Good Severe Fetal assessment
Heibel Moderate Fetal assessment
Hunt Mild Routine obstetric care
Jobbins Mild Routine obstetric care
Radin Moderate Fetal assessment
Rm Mild Routine obstetric care
Ven Mild Routine obstetric care
Wrighta Severe Fetal assessment
Wrightb Mild Routine obstetric care
Zd Moderate Fetal assessment
*Not a proven cause of hemolytic disease of the newborn
†Withhydrops fetalis
‡Nota cause of hemolytic disease of the newborn
Modified from Weinstein L. Irregular antibodies causing hemolytic disease of the newborn: a continuing problem. Clin Obstet Gynecol 1982;25:321.
Anti-D Immune Globulin to Prevent with a history of a previously affected fetus or neonate,
Alloimmunization serial titer assessment is inadequate for surveillance of
of any event in pregnancy. Patients who are weak D (Du) Determination of Paternal Genotype
fetal anemia. Titer values are reported as the integer of
positiveimmune
Anti-D are not globulin
at risk for
is alloimmunization and should
not indicated for patients pre- Thegreatest
initial management
the tube dilution ofwith a pregnancy
a positive involving
agglutination an
not receive anti-D immunoprophylaxis.
viously sensitized to D. However, it is indicated for alloimmunized patient is determination of the paternal
reaction. Variation in titer results from different laborato-
patients who might be sensitized to other blood group erythrocyte antigen status. If the father
At what antibody titer should an additional ries is not uncommon, so titers should be is negative
obtained in for
the
antigens. the erythrocyte antigen in question (and it is certain
same laboratory when monitoring a patient, and a change
evaluation be initiated? thatmore
he isthan
the one
father of the isfetus), furtherAassessment and
of dilution significant. critical titer is
intervention are unnecessary. In cases of Rh-D
that titer associated with a significant risk for severe alloim-
The usefulness of maternal serum antibody titers is deter-
Clinical Considerations
mined by the patient’s reproductive history. For aand
woman
munization in which the father is Rh positive, the prob-
erythroblastosis fetalis and hydrops, and in most centers
ability that he is heterozygous for the D antigen can be
Recommendations
with a history of a previously affected fetus or neonate, this is between 1:8 and 1:32. If the initial antibody titer is
reliably estimated by using Rh-D antisera to determine
serial titer assessment is inadequate for surveillance of 1:8 or less, the patient may be monitored with titer
his most likely genotype. This involves mixing antisera,
fetalWhat areTiter
the values
best screening methods for
▲
anemia. are reported as the integer of assessment every 4 weeks. For patients with alloimmu-
containing antibodies to the D antigen, with the father’s
detecting
the greatest alloimmunization
tube in women?
dilution with a positive agglutination nization involving antigens other than D, similar titer lev-
cells to determine if the D antigen is present. A posi-
reaction. Variation in titer results from different labo- els should be used to guide care except in Kell-sensitized
All pregnant women should be tested at the time of the tive result is determined by agglutination caused by the
ratories is not uncommon, so titers should be obtained patients because Kell antibodies do not correlate with
first prenatal visit for ABO blood group and Rh-D type cross-linking of the antibody with the corresponding
in the same laboratory when monitoring a patient, and a fetal status
and screened for the presence of erythrocyte antibodies. antigen. If (19).
the father is homozygous for the D antigen,
change of more than one dilution is significant. A critical all his children will be Rh positive; if he is heterozygous,
These laboratory assessments should be repeated in each
titer is that titer associated with a significant risk for thereWhat ancillary teststhat
should
each follow identifica-
▲
subsequent pregnancy. The American Association of is a 50% likelihood pregnancy will have
severe erythroblastosis fetalis and hydrops, and in
Blood Banks also recommends repeated antibody screen-
tion of maternal antibodies to diagnose
an Rh-negative fetus that is not at risk of anemia. Given
most centers this is between 1:8 and 1:32. If the initial that hemolytic diseasefor
the genes coding in the
the Dfetus?
antigen are known, a
ing before administration of anti-D immune globulin at
antibody titer is 1:8 or less, the patient may be moni- DNA-based diagnosis is commercially available. This
28 weeks of gestation, postpartum, and at the time of any
tored with titer assessment every 4 weeks. For patients form of diagnosis alsoofcan be used to Genotype
identify a number
event in pregnancy. Patients who are weak D (Du) posi- Determination Paternal
with alloimmunization involving antigens other than D, of minor antigens (C, c, E, and e). Evaluation of alloim-
tive are not at risk for alloimmunization and should not
similar titer levels should be used to guide care except in The initial management
munization of a pregnancy
to other erythrocyte involving
antigens known an
to be
receive anti-D immunoprophylaxis.
Kell-sensitized patients because Kell antibodies do not alloimmunized patient is determination of the
associated with erythroblastosis fetalis (Table 1) should paternal
correlate withantibody
At what fetal statustiter
(19).should an additional erythrocyte
be performed antigen
in thestatus. If the father is negative for the
same manner.
▲
erythrocyte antigen in question (and it is certain that he is

evaluation be initiated?
What ancillary tests should follow identifica- Determination
the father of the fetus), offurther
Fetalassessment
Genotype and interven-
tion of maternal
The usefulness antibodies
of maternal to diagnose
serum antibody titers is deter- tion
The are unnecessary.
fetal antigen typeIn cases
shouldof Rh-D alloimmunization
be assessed when the
hemolytic
mined disease
by the patient’s in the fetus?
reproductive history. For a woman in which genotype
paternal the father is Rh positive,
thought to betheheterozygous
probability thator he
is
4
VOL. 131, NO. 3, MARCH 2018 ACOG Practice
Practice Bulletin Management of Alloimmunization During Bulletin
PregnancyNo.e85
75

unknown. Amniocentesis is the primary modality used Spectral Analysis of Amniotic Fluid
to determine fetal blood type using polymerase chain Historically, measurement of amniotic fluid bilirubin
reaction (PCR) on uncultured amniocytes in 2 mL of levels using spectral analysis at 450 nm (ΔOD450) has
amniotic fluid. The sensitivity and specificity of PCR been the accepted method of assessing the severity of
typing are reported as 98.7% and 100%, respectively, erythroblastosis in utero. Fetal status was determined
with positive and negative predictive values of 100% by plotting the ΔOD450 measurement on either a
and 96.9% (20). Chorionic villus biopsy also has been Liley graph in the late second and third trimesters (25)
employed for this purpose, but its use should be dis- or on the Queenan curve for earlier gestational ages
couraged because disruption of the villi may result (19–25 weeks). The current trend is management with
in unnecessary fetomaternal hemorrhage and worsen- middle cerebral artery Doppler ultrasonography.
ing alloimmunization (21). If the fetus is found to be
negative for the erythrocyte antigen in question, fur- What is the role of middle cerebral artery
ther testing may not be warranted (20). Although the
Doppler testing to predict fetal anemia?
false-negative rate is low (1–3%), periodic noninvasive
assessment may be warranted (20). Recent advances in Doppler technology have lead to the
Detection of fetal D by molecular analysis of development of noninvasive methods to assess the
maternal plasma or serum can be assessed in the second degree of fetal anemia. Doppler was used to measure the
trimester with greater than 99% accuracy (22, 23). This peak systolic velocity in the fetal middle cerebral artery
is possible because of high concentrations of fetal DNA in 111 fetuses at risk for fetal anemia secondary to red
found in maternal plasma (24). It should be noted, how- cell alloimmunization (Fig. 1) (26). Moderate or severe
ever, that this is not a widely used clinical tool. anemia was predicted by values of peak systolic velocity
18
17
16 1.16
15
14
Median
13
12
Multiples of the median

Hemoglobin (g/dL)
11 0.84
10
Mild anemia
9 0.65
8 Moderate anemia
7 0.55
Severe anemia
6
5
4
3
2
1
0
16 18 20 22 24 26 28 30 32 34 36
Gestational age (weeks)
Figure 1. Hemoglobin concentrations in 265 healthy fetuses and 111 fetuses that underwent cor-
docentesis. The reference range in the healthy fetuses was between 0.84 and 1.16 times the median
(corresponding to the 5th and 95th percentiles). Values for the 111 fetuses that underwent cordo-
centesis are plotted individually. Solid circles indicate fetuses with hydrops. (Reprinted from
Mari G, Deter RL, Carpenter RL, Rahman F, Zimmerman R, Moise KJ Jr, et al. Noninvasive
diagnosis by Doppler ultra-sonography of fetal anemia due to maternal red-cell alloimmuniza-
tion. Collaborative Group for Doppler Assessment of the Blood Velocity of Anemic Fetuses. N Engl J
Med 2000:342:9–14. Copyright 2000 Massachusetts Medical Society. All rights reserved.)
e86 Practice Bulletin Management of Alloimmunization During Pregnancy OBSTETRICS & GYNECOLOGY
tion to the K or K1 antigens of the Kell blood group sys- If the history and antenatal studies indicate only mild
in the fetal middle cerebral artery above 1.5 times the Amniotic fluid bilirubin measurements may be mis-
median for gestational age with a sensitivity of 100% leading in cases of Kell alloimmunization. Doppler mea-
and a false-positive rate of 12%. Correct technique is a surements, however, appear to be accurate in predicting
critical factor when determining peak systolic velocity in severe fetal anemia (29).
the fetal middle cerebral artery with Doppler ultrasonog-
raphy. This procedure should be used only by those with When is the best time to deliver the infant of
adequate training and clinical experience. an alloimmunized patient?
Studies have reported a good correlation between
Delivery of the infant of an alloimmunized patient is a
the peak systolic velocity in the fetal middle cerebral
controversial subject, and literature on the subject is lim-
artery and hemoglobin in fetuses that have undergone
ited. Standard treatment is to prolong the pregnancy until
two previous transfusions, expanding the clinical use of
the fetus reaches a gestational age necessary for survival.
this Doppler test (27, 28).
If the history and antenatal studies indicate only mild
There are some limitations of this technology.
fetal hemolysis, it is reasonable to proceed with deliv-
Multiple studies have suggested that there is a higher
ery by induction of labor at 37–38 weeks of gestation.
false-positive rate after 34–35 weeks of gestation (21). In
Induction may be considered earlier if fetal pulmonary
addition, as with any new technology, the measurements
maturity is documented by amniocentesis.
must be done by a practitioner specifically trained to per-
With severely sensitized pregnancies requiring mul-
form Doppler for measurement of peak systolic velocity
tiple invasive procedures, the risks of continued cord
in the fetal middle cerebral artery. In a center with trained
blood sampling and transfusions must be considered and
personnel and when the fetus is at an appropriate gesta-
compared with those neonatal risks associated with early
tional age, middle cerebral artery Doppler measurements
delivery. Given that the overall neonatal survival rate
seem to be an appropriate noninvasive means to monitor
after 32 weeks of gestation in most neonatal intensive
pregnancies complicated by red cell alloimmunization.
care nurseries is greater than 95%, it is prudent to time
procedures so that the last transfusion is performed at
What are strategies for care of a patient
30–32 weeks of gestation, with delivery at 32–34 weeks
positive for non-D antigens at the first of gestation after maternal steroid administration to
prenatal visit? enhance fetal pulmonary maturity (30). Several authors
The use of anti-D immune globulin to prevent red cell recommend intrauterine transfusion up to 36 weeks of
alloimmunization has led to a relative increase in the gestation when intravascular transfusion is feasible in
number of non-Rh-D alloimmunizations causing fetal order to limit neonatal morbidity (31). Delivery can
anemia and hemolytic disease of the newborn. Hundreds then be accomplished between 37 and 38 weeks of
of other distinct antigens, known as “minor” antigens, gestation.
exist on the red blood cell surface. Most cases of alloim-
munization due to these minor antigens are caused by
incompatible blood transfusion. Overall, antibodies to Recommendations and
minor antigens occur in 1.5–2.5% of obstetric patients. Conclusions
Although many antibodies directed against minor
antigens do not cause erythroblastosis fetalis, some do The following recommendations are based on
(Table 1). In general, care of the pregnant patient with good and consistent scientific evidence (Level A):
antibodies to one of the clinically significant minor anti-
In a center with trained personnel and when the fetus
gens is similar to care of Rh-D alloimmunized pregnant is at an appropriate gestational age, Doppler mea-
women. An important exception involves alloimmuniza- surement of peak systolic velocity in the fetal middle
tion to the K or K1 antigens of the Kell blood group cerebral artery is an appropriate noninvasive means
system. Kell alloimmunization appears to be less pre- to monitor pregnancies complicated by red cell allo-
dictable and often results in more severe fetal anemia immunization.
than alloimmunization due to other erythrocyte antigens.
Some authorities believe the mechanism of anemia due The initial management of a pregnancy involving an
to Kell alloimmunization to be different than with Rh-D alloimmunized patient is determination of the pater-
alloimmunization, and experience suggests that maternal nal erythrocyte antigen status.
Kell antibody titers and amniotic fluid ΔOD450 values Serial titers are not useful for monitoring fetal status
are not as predictive of the degree of fetal anemia as with when the mother has had a previously affected fetus
Rh-D sensitization (4). or neonate.

Antibody titers are not appropriate for monitoring 15. Dayton VD, Anderson DS, Crosson JT, Cruikshank SH.
A case of Rh isoimmunization: should threatened firsttri-
Kell-sensitized patients because Kell antibodies do mester abortion be an indication for Rh immune globulin
not correlate with fetal status. prophylaxis? Am J Obstet Gynecol 1990;163:63–4. (Level
Anti-D immune globulin is indicated only in III)
Rh-negative women who are not previously sensi- 16. Leong M, Duby S, Kinch RA. Fetal-maternal transfusion
tized to D. following early abortion. Obstet Gynecol 1979;54:424–6.
(Level II)
17. Katz J, Marcus RG. The risk of Rh isoimmunization in
Proposed Performance ruptured tubal pregnancy. Br Med J 1972;3(828):667–9.
(Level III)
Measure 18. Mennuti MT, Brummond W, Crombleholme WR, Schwarz
Further evaluation of patients found to have significant RH, Arvan DA. Fetal-maternal bleeding associated with
antibodies associated with fetal anemia genetic amniocentesis. Obstet Gynecol 1980; 55:48–54.
(Level II-3)
19. Hackney DN, Knudtson EJ, Rossi KQ, Krugh D,

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cles pub lished in the English lan guage.
(Level III) Priority was given to articles reporting results of original
31. Boggs TR Jr. Survival rates in Rh sensitizations: 140 inter- research, although review articles and commentaries also
rupted versus 141 uninterrupted pregnancies. Pediatrics were consulted. Abstracts of research presented at sympo
1964;33:758–62. (Level III) sia and scientific conferences were not considered adequate
for inclusion in this document. Guidelines published by
organizations or institutions such as the National Institutes
of Health and the American College of Obstetricians and
Gynecologists were reviewed, and additional studies were
located by reviewing bibliographies of identified articles.
When reliable research was not available, expert opinions
from obstetrician–gynecologists were used.
Studies were reviewed and evaluated for quality according
to the method outlined by the U.S. Preventive Services
Task Force:
I Evidence obtained from at least one prop er
ly
designed randomized controlled trial.
II-1 Evidence obtained from well-designed con trolled
trials without randomization.
II-2 Evidence obtained from well-designed co hort or
case–control analytic studies, preferably from more
than one center or research group.
II-3 Evidence obtained from multiple time series with or
without the intervention. Dramatic results in uncon
trolled experiments also could be regarded as this
type of evidence.
III Opinions of respected authorities, based on clinical
experience, descriptive studies, or reports of expert
committees.
Based on the highest level of evidence found in the data,
recommendations are provided and graded according to the
following categories:
Level A—Recommendations are based on good and con
sistent scientific evidence.
Level B—Recommendations are based on limited or incon
sistent scientific evidence.
Level C—Recommendations are based primarily on con
sensus and expert opinion.
Copyright March 2018 by the American College of Obstetri

cians and Gynecologists. All rights reserved. No part of this
publication may be reproduced, stored in a retrieval system,
posted on the Internet, or transmitted, in any form or by any
means, electronic, mechanical, photocopying, recording, or
otherwise, without prior written permission from the publisher.
Requests for authorization to make photocopies should be
directed to Copyright Clearance Center, 222 Rosewood Drive,
Danvers, MA 01923, (978) 750-8400.
American College of Obstetricians and Gynecologists
409 12th Street, SW, PO Box 96920, Washington, DC 20090-6920
Management of alloimmunization during pregnancy. ACOG Practice
Bulletin No. 192. American College of Obstetricians and Gyne-
cologists. Obstet Gynecol 2018;131:e82–90.

This information is designed as an educational resource to aid clinicians in providing obstetric and gynecologic care, and use of this information is vol-
untary. This information should not be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. It is
not intended to substitute for the independent professional judgment of the treating clinician. Variations in practice may be warranted when, in the reason-
able judgment of the treating clinician, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in
knowledge or technology. The American College of Obstetricians and Gynecologists reviews its publications regularly; however, its publications may not
reflect the most recent evidence. Any updates to this document can be found on www.acog.org or by calling the ACOG Resource Center.
While ACOG makes every effort to present accurate and reliable information, this publication is provided “as is” without any warranty of accuracy, reli-
ability, or otherwise, either express or implied. ACOG does not guarantee, warrant, or endorse the products or services of any firm, organization, or person.
Neither ACOG nor its officers, directors, members, employees, or agents will be liable for any loss, damage, or claim with respect to any liabilities, including
direct, special, indirect, or consequential damages, incurred in connection with this publication or reliance on the information presented.


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