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Regular Article

TRANSFUSION MEDICINE

CME Article
Prophylactic transfusion for pregnant women with sickle cell disease:
a systematic review and meta-analysis
Ann Kinga Malinowski,1,2 Nadine Shehata,2-6 Rohan D’Souza,1,2 Kevin H. M. Kuo,2,5 Richard Ward,2,5 Prakesh S. Shah,2,3,7
and Kellie Murphy1,2
1
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, Toronto, Canada; 2Department of Medicine and
3
Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Canada; 4Division of Haematology, Department of Medicine, Mount
Sinai Hospital, Toronto, Canada; 5Division of Medical Oncology and Haematology, Department of Medicine, University Health Network, Toronto, Canada;
and 6Department of Laboratory Medicine and Pathobiology, and 7Department of Paediatrics, Mount Sinai Hospital, Toronto, Canada

Pregnancy in women with sickle cell disease is associated with adverse maternal and neo-
Key Points
natal outcomes. Studies assessing the effects of prophylactic red blood cell transfusions on
• Prophylactic transfusion these outcomes have drawn inconsistent conclusions. The objective of this systematic re-
in pregnant women with view was to assess the effect of prophylactic compared with on-demand red blood cell
SCD may reduce maternal transfusions on maternal and neonatal outcomes in women with sickle cell disease. A sys-
mortality, vaso-occlusive tematic search of several medical literature databases was conducted. Twelve studies
involving 1291 participants met inclusion criteria. The studies had moderate to high risk of
pain events, and pulmonary
bias. Meta-analysis demonstrated that prophylactic transfusion was associated with
complications.
a reduction in maternal mortality (7 studies, 955 participants; odds ratio [OR], 0.23; 95%
• Prophylactic transfusion in confidence interval [CI], 0.06-0.91), vaso-occlusive pain episodes (11 studies, 1219 par-
pregnant women with SCD ticipants; OR, 0.26; 95% CI, 0.09-0.76), pulmonary complications (9 studies, 1019 partic-
may similarly reduce perinatal ipants; OR, 0.25; 95% CI, 0.09-0.72), pulmonary embolism (3 studies, 237 participants; OR,
mortality, neonatal death, and 0.07; 95% CI, 0.01-0.41), pyelonephritis (6 studies, 455 participants; OR, 0.19; 95% CI, 0.07-0.51),
preterm birth. perinatal mortality (8 studies, 1140 participants; OR, 0.43; 95% CI, 0.19-0.99), neonatal
death (5 studies, 374 participants; OR, 0.26; 95% CI, 0.07-0.93), and preterm birth (9 studies,
1123 participants; OR, 0.59; 95% CI, 0.37-0.96). Event rates for most of the results were low. Prophylactic transfusions may positively impact
several adverse maternal and neonatal outcomes in women with sickle cell disease; however, the evidence stems from a relatively small
number of studies with methodologic limitations. A prospective, multicenter, randomized trial is needed to determine whether the potential
benefits balance the risks of prophylactic transfusions. (Blood. 2015;126(21):2424-2435)

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The online version of this article contains a data supplement. © 2015 by The American Society of Hematology

2424 BLOOD, 19 NOVEMBER 2015 x VOLUME 126, NUMBER 21

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BLOOD, 19 NOVEMBER 2015 x VOLUME 126, NUMBER 21 TRANSFUSION FOR SICKLE CELL DISEASE IN PREGNANCY 2425

Medscape Continuing Medical Education online

Learning objectives
1. Describe the effects of prophylactic transfusion in pregnant women with sickle cell disease (SCD) on maternal outcomes,
based on a systematic review.
2. Discuss the effects of prophylactic transfusion in pregnant women with SCD on perinatal outcomes.
3. Determine potential mechanisms by which prophylactic transfusion may benefit pregnant women with SCD and their infants,
and potential adverse effects.
Release date: November 19, 2015; Expiration date: November 19, 2016

Introduction
Sickle cell disease (SCD) is characterized by deformation of red
blood cells (RBCs) into rigid, sickle shapes under conditions of hyp-
oxic stress, leading to ischemia-reperfusion injury, hemolysis-mediated
endotheliopathy, and multiorgan damage.1 Recent estimates in 2010
identified SCD to be responsible for ;28 600 deaths annually world-
wide.2 Disease course depends in part on SCD genotype, with greater
severity encountered in HbSS and HbS/b0 thalassemia and a more
benign course in HbSC and HbS/b1 thalassemia, although adverse
events have been observed in all subtypes.3
With advancement in comprehensive care, most women now reach
their reproductive years. Pregnancy in women with SCD is currently
viewed more favorably4 than it was during the 1970s, when its avoidance
was recommended.5 Nevertheless, maternal and fetal morbidity and
mortality6-9 are still encountered, and further examination of interven-
tions capable of mitigating these adverse pregnancy outcomes is needed.
Prophylactic RBC transfusion has been proposed to reduce com-
plications by correcting severe anemia and the extent of sickling in both
the maternal and placental circulation,10 thereby improving blood flow
and oxygenation. The benefits of prophylactic transfusion in SCD have
been established for stroke prophylaxis11 and as part of preoperative
optimization.12 However, the use of prophylactic transfusion beyond
these indications is tempered by concerns over acute and delayed trans-
fusion reactions, alloimmunization, transfusion-related infections, and iron
overload.13 Furthermore, reports assessing the effect of prophylactic RBC
transfusions on pregnancy outcomes in SCD have been inconsistent.14-19
Thus, the objective of this study was to systematically review the impact
of prophylactic transfusion compared with on-demand transfusion
(defined as transfusion instituted to treat complications) on maternal
and neonatal adverse pregnancy outcomes in pregnant women with SCD.
Methods
The systematic review protocol was registered on PROSPERO (CRD42014007277),
and the review was conducted according to PRISMA guidelines20 and

Figure 1. Search results for prophylactic transfusion

in sickle cell disease in pregnancy.
 2426

Table 1. Characteristics and risk of bias assessment for cohort studies on transfusion therapy in pregnant women with sickle cell disease
Risk of bias assessment (NOS)
Risk of bias
Author (year), (1-3: high; 4-6:
country, setting Single vs multicenter Design Years of study Inclusion criteria Selection ++++ Comparability ++ Outcome +++ Total/9 moderate; 7-9: low)
Morrison (1976)28* Single Prospective cohort, matched Apr. 1970 – Mar. 1974 SCD ++ — + 3 High
MALINOWSKI et al

United States retrospectively with Apr 1965 – Mar. 1970 - Historical

historical controls controls
Tertiary care
Miller (1981)26 Single Retrospective cohort with 1978-1980 (PT) SCD ++ — + 3 High
United States historical controls 1974-1979 (ODT) Historical
controls
Tertiary care
Cunningham (1983)19 Single Retrospective cohort with 1973-1982 (PT) SCD ++ — + 3 High
United States historical controls 1955-1972 (ODT)
Tertiary care
Tuck (1987)30 Multi Retrospective cohort 1978-1984 (PT) SCD + — — 1 High
United Kingdom 1975-1981 (Un-transfused)
Tertiary care
Koshy (1991)15† Single Retrospective cohort 1986-1990 SCD + — + 2 High
United States
Tertiary care
Morrison (1991)27 Single Retrospective cohort with Jan 1981-Dec 1990 HbSS, HbSC ++ — + 3 High
United States historical controls
Tertiary care
Howard (1995)10 Multi Retrospective cohort 1991-1993 SCD ++ — ++ 4 Moderate
United Kingdom
Hospitals England &Wales
El-Shafei (1995)18 Single Mixed retrospective and May 1988 – Oct. 1994 SCD ++ — + 3 High
Bahrain prospective cohort (prospective) vs Nov.
MoH Hospital 1986 – Oct. 1988
(retrospective)
Moussaoui (2002)29 Single Retrospective cohort Not stated HbSS ++ — — 2 High
Libreville, Gabon
Not stated
Gilli (2007)17 Single Retrospective cohort 1994-2004 HbSS, HbSC ++ + + 4 Moderate
Brazil
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Tertiary care
Asma (2015)14 Single Retrospective cohort 2000-2013 SCD + — + 2 High
Turkey
Tertiary care

MoH, Ministry of Health; NOS, Newcastle-Ottawa Scale; ODT, on-demand transfusion; PNM, perinatal mortality; PT, prophylactic transfusion.
*Data include Morrison (1976) J Pediatr.
†Data for patients in the prophylactic transfusion arm also previously reported as part of RCT (Koshy 1988).
BLOOD, 19 NOVEMBER 2015 x VOLUME 126, NUMBER 21
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BLOOD, 19 NOVEMBER 2015 x VOLUME 126, NUMBER 21
Table 2. Characteristics and risk of bias assessment for RCT on transfusion therapy in pregnant women with sickle cell disease
Author (year), Single vs
country, setting multicenter Design Years of study
Koshy (1988)16 Multi RCT Jan 1979 to Mar
United States Only HbSS randomized 1986
Tertiary care 28 with HbSS not randomized;
of those, 7 continued long-
term PT initiated prior to study
reported in accordance with the MOOSE guidelines.21 Studies were included
if they (1) involved pregnant women with SCD (HbSS, HbSC, HbS/b0/1
thalassemia); (2) examined the role of simple transfusions (transfusion of
$1 unit of RBCs) or partial or full exchange transfusions (either manually or
involving automated erythrocytapheresis) given prophylactically or on-
demand for obstetric or hematologic indications; and (3) were randomized
controlled trials (RCTs), controlled trials, and noncontrolled comparative
studies with 10 or more participants. Case reports of ,10 participants,
reviews, letters to the editor, animal studies, studies of laboratory inves-
tigations, and noncomparative studies were excluded.
Primary maternal outcomes were mortality; SCD-related morbidity, in-
cluding vaso-occlusive pain episodes, acute chest syndrome, thromboem-
bolic events (venous and arterial), systemic infections (sepsis/multiorgan
failure), and local infections (renal [urinary tract infections/pyelonephritis],
pulmonary [pneumonia], uterine [endometritis], and wound); and obstetric
morbidity in the form of preeclampsia (as reported by authors). Primary neo-
natal outcomes were mortality (intrauterine fetal demise or neonatal death);
small for gestational age/low birth weight infants (defined as weight below
10th percentile for gestational age [GA]/weight ,2500 g); and preterm birth
(defined as birth prior to 37 weeks GA). Secondary outcomes included
transfusion-related alloimmunization (defined as newly formed alloanti-
bodies following transfusion in pregnancy), need for induction of labor, and
mode of delivery.
The literature search was conducted using the OvidSP search platform in the
following databases: MEDLINE, EMBASE, and EBM Reviews containing the
Cochrane Central Register of Controlled Trials, as well as the EBSCOHost
search platform in CINAHL, to include articles indexed as of February 19, 2015
(supplemental Table 1 available on the Blood Web site). The search was limited
to human data, without language restrictions. Additional articles were identified
by scanning reference lists and searching the gray literature, for the last 5 years,
for relevant abstracts from conference proceedings of the American Society of
Hematology, the Society for Maternal Fetal Medicine, the Society of Obste-
tricians and Gynecologists of Canada, and the Royal College of Obstetricians
and Gynecologists.
Title and abstract screening, data extraction for studies meeting inclusion
criteria, and risk of bias assessment were independently carried out by 2 re-
viewers (A.K.M. and N.S.). Disagreements were resolved by discussion and
consensus. When disagreement persisted, a third author (R.D.) adjudicated. Risk
of bias was assessed at the individual study level according to the Cochrane
collaboration’s risk of bias tool22 for RCTs and the Newcastle-Ottawa Scale23 for
nonrandomized studies.
Data were analyzed according to the type of intervention. For dichotomous
variables, relative effect measures, primarily consisting of odds ratios (ORs) and
relative risk (RR) and their 95% confidence intervals (CIs), were calculated.
A random effects model was chosen given the diversity of individual studies,
particularly concerning study population, as well as protocols and targets of the
intervention.24 For continuous variables, the mean difference was calculated. The
degree of heterogeneity across the studies was examined using I2 values,25
TRANSFUSION FOR SICKLE CELL DISEASE IN PREGNANCY 2427
Inclusion criteria Risk of bias assessment
HbSS ,28 weeks GA Selection bias: Unclear
Excluded neurologic dysfunction,
nephrotic syndrome, chronic renal
failure, persistent liver disease,
chronic lung disease, coagulopathy,
or presence of multiple RBC
antibodies
Performance bias: High risk
Detection bias: Unclear
Attrition bias: Low risk
Reporting bias: Unclear risk
Overall: High risk of bias
classifying .50% as moderate heterogeneity, and .75% as high heterogeneity.
Review Manager Software (version 5.3; the Cochrane Collaboration, Oxford,
United Kingdom) was used to complete the meta-analysis. A subgroup analysis
by type of SCD was conducted.
Results
The flow diagram detailing selection of studies included in this review
is provided in Figure 1. A total of 12 articles met inclusion criteria
(11 cohort studies10,14,15,17-19,26-30 and 1 RCT16).
Description of study characteristics
Study characteristics are described in Tables 1 and 2. Only 2 of the
cohort studies were multicenter,10,30 and all but 218,28 used a retrospec-
tive design with historical controls.19,26,27 Historical controls from the
1950s and 1960s were included in 2 studies.19,28 Seven studies spec-
ified outcomes based on b-globin genotype.10,15,18,19,26,28,30 Con-
founding variables were generally not addressed in the study design or
analysis.
The RCT16 was a multicenter study conducted in the United States
of pregnancies with HbSS recruited before 28 weeks of gestation. Of
note, participants with history of neurologic dysfunction, persistent
liver disease, chronic lung disease, nephrotic syndrome, chronic renal
failure, coagulopathy, or presence of multiple RBC antibodies were
excluded, of whom 25% were on long-term transfusion therapy prior
to pregnancy.
Risk of bias assessment
Nine cohort studies were deemed to be at high risk of bias and 2 at
moderate risk (Tables 1 and 2). Most studies did not report whether the
outcome of interest was present at the start of the study. Only 2 studies
controlled for relevant confounders, but none controlled for the burden
of disease prior to pregnancy. The duration of follow-up was not ex-
plicitly stated in most studies.
The only included RCT was deemed to be at high risk of bias due
to high risk of selection bias (unclear randomization method), high
risk of detection bias (unreported method of allocation conceal-
ment), low risk of attrition bias (all outcome data were obtained), and
unclear risk of reporting bias (protocol outlining the prespecified out-
comes was not available).
Table 3. Summary of management and transfusion protocols
2428

Prophylactic transfusion ODT

Timing of Proportion Timing of Proportion
initiation, requiring Initial targets subsequent initiation, requiring
Author, year, journal Type of transfusion weeks GA MUT ODT, n (%) triggers Reason for transfusion weeks GA MUT ODT, %
Cohort studies
Morrison 197627 Partial exchange 28 3-6 per 2/36 (5.6%) Target Severe anemia (Hct ,15%) NR 1 38%
Obstet Gynecol* transfusion from transfusion Hct 35% with crisis &/or infection
MALINOWSKI et al

28 wks (routine HbA 40%

admission) Trigger
a) Hct ,25% & HbA ,20%
b) 36-38 wks
c) with crisis
d) in labor
Miller 198126 Initially partial exchange 22.3 6 8.4 13 NR Target Hb ,70 g/L or anemia-related NR 3.7 NR
Am J Obstet transfusion, NR symptoms
Gynecol subsequently EA Trigger
Hct or HbA ,25%
Cunningham 198319 Simple transfusion ;20 HbSS - 13 NR Target Hb ,70 g/L or Hct , 20% NR NR NR
Obstet Gynecol or partial exchange HbSC - 15 HbA 50% or infection, hypoxia,
transfusion depending HbS/B-Thal – NR HbS 50% excessive blood loss
on degree of anemia Trigger
Hct ,25% HbA ,40%
Tuck 198730 BJOG Simple or partial ,20 or 12 (4-28) NR Target NR NR NR NR
exchange transfusion
depending on
degree of anemia
Dulwich: PT for all .20 in HbSS Hb 110 g/L &
SCD types
St. Thomas: depending HbS 25%
PT for HbSS on time of
presentation
Trigger
NR
Koshy 199115 J Clin Simple or partial “Early 12 NR Target Prior to C/S, ACS, PET, NR 4 74%
Apher exchange transfusion pregnancy” Hb 100-110 g/L severe anemia
HbS ,35%
Trigger
NR
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Morrison 199127 Partial exchange 19.4 NR NR Target Severe and symptomatic NR NR 58%
J Clin Apher transfusion or EA HbA .50% anemia, or crisis
if severe crisis Trigger un-responsive to treatment
or morbidity HbA ,20% or “significant crisis,
severe morbidity”

ACS, acute chest syndrome; C/S, Caesarean section; EA, erythrocytapheresis; Hb, hemoglobin, MUT, mean units transfused; NR, not reported; ODT, on-demand transfusion; PET, preeclampsia; PPH, postpartum hemorrhage; PT,
prophylactic transfusion; Retics, reticulocyte count; RBCs, red blood cells.
*Data include Morrison (1976) J Pediatr.
†Data for patients in the prophylactic transfusion arm also previously reported as part of RCT (Koshy 1988).
BLOOD, 19 NOVEMBER 2015 x VOLUME 126, NUMBER 21
Table 3. (continued)
Prophylactic transfusion ODT
Timing of Proportion Timing of Proportion
initiation, requiring Initial targets subsequent initiation, requiring
Author, year, journal Type of transfusion weeks GA MUT ODT, n (%) triggers Reason for transfusion weeks GA MUT ODT, %
10
Howard 1995 Simple or partial “First or NR NR Target Sickling complications NR NR 26%
BJOG exchange transfusion second NR
depending on trimester” Trigger
severity of anemia NR
El-Shafei 199518 PT for anemia NR NR 148 (60.7%) Target Hb ,60 g/L, ongoing crisis, NR NR 29.4%
Aust NZ J Obstet (Hb ,100 g/L) NR Hb ,80 g/L prior to
Gynaecol Trigger C/S, or PPH
NR
Moussaoui 200229 Simple transfusion 16 12 2/10 (for PPH) Target Severe anemia in pregnancy, NR 7.83 NR
Trop Med Hb .100 g/L severe anemia peripartum,
BLOOD, 19 NOVEMBER 2015 x VOLUME 126, NUMBER 21

HbS ,40% or to treat PPH

Trigger
NR
Gilli 200717 Erythro-cytapheresis 28 8.14 6 4.31 NR Target Acute SCD complications NR 3.76 6 2.70 NR
Int J Gyn Ob NR
Trigger
NR
Asma 201514 Continuous flow Variable 6.2 6 0.6 4/24 (16.7%) Target Simple transfusion - Hb ,70g/L One in NR 15%
Transfusion apheresis; 60-70% HbS ,30% leukocytosis in absence first & one in
RBCs exchanged Trigger of infection, and underlying third trimester
Clinical deterioration, Hb ,70g/L, pulmonary or cardiac disease
leukocytosis with no infection, and
underlying pulmonary or cardiac
disease - hyper-transfusion with
target Hct of 27%
RCT
Koshy 198816 Simple or partial 8-14 wks 12 NR Hb 100-110 g/L or Hematologic or obstetric NR 6.5 44%
NEJM† exchange transfusion indications
(78%) Hct near 33% and Hematologic
20-26 wks HbS ,35% Hb ,60g/L
(22%)
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Hct ,18%
Retics ,3%

ACS, acute chest syndrome; C/S, Caesarean section; EA, erythrocytapheresis; Hb, hemoglobin, MUT, mean units transfused; NR, not reported; ODT, on-demand transfusion; PET, preeclampsia; PPH, postpartum hemorrhage; PT,
prophylactic transfusion; Retics, reticulocyte count; RBCs, red blood cells.
*Data include Morrison (1976) J Pediatr.
†Data for patients in the prophylactic transfusion arm also previously reported as part of RCT (Koshy 1988).
TRANSFUSION FOR SICKLE CELL DISEASE IN PREGNANCY
2429
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2430 MALINOWSKI et al BLOOD, 19 NOVEMBER 2015 x VOLUME 126, NUMBER 21

Table 4. Outcomes in cohort studies of prophylactic transfusion compared with on-demand transfusion in pregnant women with SCD
(cohort studies)
Group Outcomes Studies, n Study subject, n OR (95% CI) Significance (heterogeneity), P (I2)
14,15,18,26-29
Maternal Mortality 7 955 0.23 (0.06-0.91) .04 (20%)
Vaso-occlusive pain episodes 1110,15,17-19,26-30 1219 0.26 (0.09-0.76) .01 (90%)
Pulmonary complications* 910,15,17-19,26-28,30 1019 0.25 (0.09-0.72) .01 (77%)
Pulmonary infection 518,19,26-28 792 0.26 (0.05-1.27) .10 (83%)
Pulmonary embolism 319,26,28 237 0.07 (0.01-0.41) ,.01 (1%)
Acute chest syndrome 215,17 102 0.28 (0.06-1.26) .10 (0%)
Urinary tract infection 315,29,30 149 1.09 (0.22-5.42) .92 (61%)
Pyelonephritis 615,19,26-29 455 0.19 (0.07-0.51) ,.01 (34%)
Endometritis 226,29 80 0.76 (0.17-3.44) .72 (40%)
Preeclampsia 610,14,15,17,26,29 282 1.01 (0.49-2.08) .98 (0%)
Fetal Perinatal mortality 810,15,18,19,26-28,30 1140 0.43 (0.19-0.99) ,.05 (58%)
Intrauterine fetal demise 814,15,17,19,26,28-30 458 0.47 (0.17-1.33) .15 (32%)
Neonatal death 515,19,26,28,30 374 0.26 (0.07-0.93) .04 (0%)
Small for gestational age/low birth weight 1010,15,17-19,26-30 1187 0.71 (0.44-1.16) .17 (35%)
Preterm delivery 910,15,17-19,27-30 1123 0.59 (0.37-0.96) .03 (38%)

*Pulmonary complications (infections, infarctions, and/or embolism).

Summary of management and transfusion protocols
Transfusion protocols are detailed in Table 3. Protocols varied across
reports and the type of transfusion depended on the degree of anemia
in 5 studies.10,15,16,19,30 Timing of prophylactic transfusion differed,
with only 2 studies instituting the intervention in early to mid-
pregnancy.10,15 The proportion of patients receiving prophylactic
transfusion and needing additional on-demand transfusions was not
reported in the majority of studies and varied widely in the studies in
which it was reported (5.6-60.7%).14,18,28,29 Initial transfusion targets
and subsequent transfusion triggers in the prophylactic transfusion
group differed between studies and involved a combination of values,
including hemoglobin of 100 to 110 g/L,15,29,30 hematocrit (Hct)
#35%,19,26,28 HbA .40% to .50%,19,27,28 and/or HbS ,25% to
,50%14,15,19,29,30 for the former and hemoglobin ,70 g/L, 14
hematocrit ,25%,19,26,28 and/or HbA ,20% to ,40%19,26-28 for
the latter. In the on-demand transfusion group, severe anemia,
which was variably defined, was the indication for transfusion in
6 studies,14,15,18,26,27,29 acute SCD-related complications (including
acute chest syndrome or nonresolving vaso-occlusive pain episodes)
were the indications in 4 studies,15,17,18,27 and the indication was not
defined in 4 studies.10,19,28,30 None of the cohort studies explicitly listed
obstetric indications as reason for on-demand transfusion.10,14,15,17-19,26-30
In the single RCT conducted by Koshy et al,16 the prophylactic
transfusion group received simple or partial exchange transfusions to
achieve the following targets: hemoglobin of 100 to 110 g/L, Hct of

Figure 2. Comparison of mortality between the prophylactic transfusion and on-demand transfusion groups. (A) Maternal mortality. (B) Perinatal mortality.
 From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
BLOOD, 19 NOVEMBER 2015 x VOLUME 126, NUMBER 21
Figure 3. Comparison of selected maternal morbidity indices between the prophylactic transfusion and on-demand transfusion groups. (A) Vaso-occlusive pain
episodes. (B) Pulmonary complications. (C) Pulmonary embolism.
33%, and HbS ,35%. Transfusions were initiated between 8 and 14
weeks of GA in three quarters and between 20 and 26 weeks in one
quarter of participants. The proportion of women in the prophylactic
transfusion group that required on-demand transfusion was not spec-
ified. Indications for transfusion in the on-demand transfusion group
were listed as obstetric or hematologic and were not defined beyond
the transfusion triggers that included hemoglobin ,60 g/L, Hct ,18%,
and reticulocyte count ,3%. Transfusion in the on-demand trans-
fusion group was required by 44% of participants.
Meta-analysis
A summary of the ORs for the cohort studies is detailed in Table 4 and
individual study results in supplemental Table 2. Thromboembolic
events (aside from pulmonary emboli) and systemic infections (sepsis/
multiorgan failure) could not be evaluated. Pulmonary infections, pul-
monary embolism, and acute chest syndrome were assessed separately
by some studies and in varying combinations by others; thus, the out-
come of overall pulmonary complications was added to reflect this
TRANSFUSION FOR SICKLE CELL DISEASE IN PREGNANCY 2431
variability. Furthermore, an evaluation of alloimmunization, need for
induction of labor, and mode of delivery was not completed secondary
to lack of detail across studies. Figures 2–4 illustrate the effects of pro-
phylactic transfusion on maternal and fetal mortality, maternal mor-
bidities, and obstetric morbidities, respectively. Odds of maternal
mortality, vaso-occlusive pain episodes, overall pulmonary complica-
tions, pulmonary embolism, pyelonephritis, perinatal mortality,
neonatal death, and preterm birth were significantly lower in the
prophylactic transfusion group compared with the on-demand trans-
fusion group, whereas there was no difference between the groups in
odds of pulmonary infection, acute chest syndrome, urinary tract in-
fection, endometritis, preeclampsia, intrauterine fetal demise, and small
for gestational age infants or low-birth-weight infants.
The RCT16 did not include maternal mortality as an outcome,
and there was no difference in the risk of perinatal mortality (RR,
3.0; 95% CI, 0.65-13.88), intrauterine fetal demise (RR, 2.0; 95%
CI, 0.39-10.24), or neonatal death (RR, 5.0; 95% CI, 0.25-100.64)
between the prophylactic transfusion and on-demand transfusion
groups. With respect to maternal morbidity, the prophylactic transfusion
 From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2432 MALINOWSKI et al
Figure 4. Comparison of obstetric morbidity between the prophylactic transfusion and on-demand transfusion groups. (A) Pre-eclampsia. (B) Small for gestational
age/low birth-weight infants. (C) Preterm birth.
group had a lower risk of vaso-occlusive pain events (RR, 0.28; 95% CI,
0.12-0.67) and acute chest syndrome (RR, 0.11; 95% CI, 0.03-0.44),
whereas there were no pulmonary embolic events in either group.
There was no difference between groups in the risk of urinary tract
infection (RR, 0.33; 95% CI, 0.07-1.54), pyelonephritis (RR, 1.00;
95% CI, 0.07-15.38), endometritis (RR, 0.33; 95% CI, 0.01-7.92), or
preeclampsia (RR, 0.75; 95% CI, 0.29-1.94). Similarly, there were no
differences between groups in the risk of fetal morbidity, including
small for gestational age and low-birth-weight infants (RR, 0.71; 95%
CI, 0.25-2.04) or preterm birth (RR, 2.33; 95% CI, 1.0 1-5.39).
Subgroup analysis
Subgroup analysis of nonrandomized studies based on common
b-globin genotypes, HbSS, HbSC, and HbS/b thalassemia (supple-
mental Table 3), demonstrated that among patients with HbSS
in the prophylactic transfusion group, there was a significant reduc-
tion in odds of vaso-occlusive pain episodes, overall pulmonary
BLOOD, 19 NOVEMBER 2015 x VOLUME 126, NUMBER 21
complications, pulmonary embolism, and pulmonary infections
compared with the on-demand transfusion group, but no significant
difference in odds of maternal mortality, pyelonephritis, perinatal
mortality, neonatal death, or preterm birth. Among patients with
HbSC in the prophylactic transfusion group, there was a significant
reduction in odds of vaso-occlusive pain events and pulmonary
embolism compared with the on-demand transfusion group, but no
significant difference in any of the remaining outcomes. Among
patients with HbS/b thalassemia, no significant difference in odds was
identified for any of the outcomes between the prophylactic transfusion
and the on-demand transfusion groups; however, numbers were small.
Discussion
In contrast to recently drawn conclusions,31 this systematic review and
meta-analysis invites further investigation into the merits of prophylactic
 From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
BLOOD, 19 NOVEMBER 2015 x VOLUME 126, NUMBER 21
transfusion in pregnant women with SCD. Although constrained
by methodologic limitations of original study designs, the analysis
suggested a reduction in vaso-occlusive pain episodes, maternal
mortality, overall pulmonary complications, pulmonary embo-
lism, neonatal mortality, and preterm birth, favoring institution of
prophylactic transfusion.
The potential of prophylactic transfusion to reduce adverse preg-
nancy outcomes in women with SCD stems from its capacity to remedy
SCD-driven physiologic derangements through (1) correction of
anemia, enhancing RBC oxygen-carrying capacity; (2) reduction in
the proportion of sickle hemoglobin carrying erythrocytes, diminishing
vaso-occlusive episodes; (3) reduction in blood viscosity, if provided
via RBC exchange transfusion; and to a lesser extent, (4) suppression
of endogenous erythropoiesis.32,33 Although indiscriminate use of
transfusion must be avoided, given its potential adverse effects of
alloimmunization, acute and delayed transfusion reactions, transfusion-
related infectious morbidity, and iron overload,13 transfusion in the
appropriate context has merit and may even be lifesaving.
Studies to date have consistently supported the effectiveness of
prophylactic transfusion in reducing the frequency of vaso-occlusive
pain episodes,14,15,17,19,27-30 which tend to increase in pregnancy.3 As
this systematic review demonstrates, maternal mortality in a majority
of women with SCD occurred in the setting of vaso-occlusive pain
episodes,14,18,28 with pulmonary embolism and acute chest syndrome
accounting for 2 additional cases each.14,28 The positive impact of
prophylactic transfusion on maternal morbidity may thus be the conse-
quence of reducing the frequency of vaso-occlusive pain episodes.
However, uncomplicated vaso-occlusive events in the nonpregnant
state are typically self-limited and of themselves are not considered
an indication for transfusion.34 To rationalize the use of prophylactic
transfusion to address vaso-occlusive pain events in pregnant women,
it may thus be useful to classify them as complicated when they occur in
the setting of pregnancy.
The utility of prophylactic transfusion in stabilizing the pregnancy
course in women with SCD may further be judged by the proportion
of women who, given the institution of prophylactic transfusion,
are able to avoid the need for urgent on-demand transfusion.
Unfortunately, most studies did not address this variable, and
those that did demonstrated significant variability in their estimates,
ranging from 5.6% to 60.7%. Moreover, none of the cohort stud-
ies listed obstetric indications explicitly as a reason for on-demand
transfusion, where their inclusion may have yielded higher rates of
transfusion in the on-demand transfusion group. Precise estimates of
these parameters are needed, as on-demand transfusion is often pro-
vided in urgent circumstances, whereas prophylactic transfusion
allows for a nonurgent, planned approach, which may decrease the
rate of transfusion-related complications. A recent study found that
the proinflammatory state characteristic of SCD-related challenges,
when present at the time of transfusion, was associated with an
increased risk of alloimmunization, with acute chest syndrome and
vaso-occlusive episodes demonstrating the strongest relationship
with alloantibody formation.35 Although this finding needs repli-
cation in prospective studies, it may lend further credence to a
preemptive approach aimed at preventing the need for transfusion
in the acute setting.
Having considered possible mechanisms underlying the ob-
served favorable impact of prophylactic transfusion on maternal
mortality and morbidity, its seeming lack of effect on preeclampsia
and fetal growth restriction is incongruous and deserves explora-
tion. Although the etiology of fetal growth restriction can be
heterogeneous,36 the most likely process in the context of SCD is
placental insufficiency, which is supported by the recognition of
TRANSFUSION FOR SICKLE CELL DISEASE IN PREGNANCY 2433
a strong relationship between placental weight and birth weight for
infants of mothers with homozygous SCD,37 and by reports of
pathologic placental features consisting of calcifications, infarcts,
intervillous hemorrhage, fibrin necrosis, and syncytial knots.38 Pla-
cental dysfunction in this setting is likely a consequence of both
vaso-occlusion and impaired placental development,4,39 creating
a condition of relative fetal hypoxia.40,41
The lack of impact of prophylactic transfusion on fetal growth
restriction and preeclampsia demonstrated in this systematic review
may potentially be explained by the circumstances under which
prophylactic transfusion was instituted. The wide variation among
studies in the timing of prophylactic transfusion commencement
is of specific relevance, given that aberrant early placentation is
typically the pathophysiologic origin of these conditions. In the first
weeks of pregnancy, abnormal differentiation of the villous syncytio-
trophoblast will lead to compromise in the placental barrier, inciting an
inflammatory response and culminating in features of preeclampsia.
However, abnormal extravillous trophoblast invasion will result in
altered differentiation of spiral arteries, compromising uterine blood
flow, consequently affecting umbilical blood flow, and culminating in
growth restriction.42 The events of early trophoblast development are
well underway by 3 weeks after conception.42,43 Given that none of the
studies included in this review initiated the treatment early enough
to have an effect on early placental development, the lack of effect
on growth restriction and preeclampsia, both driven by abnormal
placentation, becomes less surprising.
However, it must be considered that if prophylactic transfusion is
to positively impact the downstream events of growth restriction and
preeclampsia in sickle cell patients, it may need to be instituted as soon
as pregnancy is diagnosed and perhaps even peri-conceptionally. Fur-
ther studies are needed to advance these hypotheses.
The results of this study are largely contrary to results of the single
RCT of prophylactic transfusion in pregnant women with SCD,16 which
found that, aside from decreasing vaso-occlusive pain episodes, the
rate of medical/obstetric complications did not differ between the
prophylactic and on-demand transfusion groups. However, it is worth
considering that the RCT’s sample size was very small, with 36 partic-
ipants in each arm, and event rates were low; thus, the study was under-
powered to assess the outcomes of interest. In addition, it excluded
participants with considerable sickle cell-related comorbidities, who
arguably comprise a group at higher risk of pregnancy-related com-
plications. Similarly, a recent systematic review31 concluded that pro-
phylactic transfusion carried no clinical benefit. Two trials, deemed to
be at moderate risk of bias, were included.16,44 Further appraisal of these
2 trials reveals that participants for both were selected as part of the Co-
operative Study and that the 26 pregnancies from the first trial were
included in the analysis of the second trial, which reported a total of 36
pregnancies, thus potentially overestimating the sample size and rising
questions with regard to the accuracy of analyses.
Strengths and limitations
Strengths of this review include the fact that it is a comprehensive
objective appraisal of the available scientific literature. Addition-
ally, the evidence from both RCT and non-RCT study designs was
carefully evaluated. Limitations include the suboptimal methodo-
logic quality of the included studies, the majority of which are at
moderate to high risk of bias, and the absence and/or heteroge-
neity of definitions for exposure and the outcomes of interest.
Furthermore, the subgroup analysis based on SCD genotypes was
limited by very small sample sizes and low event rates. The lack of
information from original studies pertaining to transfusion risks,
 From www.bloodjournal.org by guest on September 11, 2016. For personal use only.

2434 MALINOWSKI et al BLOOD, 19 NOVEMBER 2015 x VOLUME 126, NUMBER 21

particularly relating to alloimmunization, delayed hemolytic

transfusion reactions, and iron overload precluded analysis of these
important variables.
In conclusion, this systematic review advances the possibility that
prophylactic transfusion might benefit pregnant women with SCD,
leading to a decrease in maternal and neonatal morbidity and mortality.
However, the review is limited by the quality and paucity of available
research and the lack of studies addressing the impact of transfusion
complications on maternal and fetal outcomes. This underscores the
need to conduct a rigorously designed, multicenter RCT to conclusively
settle this important concern.
Acknowledgments
The authors thank Elizabeth Uleryk for invaluable assistance with
the development and execution of the search strategy.
N.S. was supported by a Canadian Institute of Health Research/
Canadian Blood Services New Investigator Award.
Authorship
Contribution: A.K.M. and N.S. contributed to study concept design,
protocol development, independent review of all studies, data col-
lection, data interpretation, drafting of manuscript, manuscript revision,
and approval of final version; R.D. contributed to study concept de-
sign, adjudication, data interpretation, manuscript revision, and ap-
proval of final version; K.H.M.K. and K.M. contributed to study
concept design, protocol development, data interpretation, manu-
script revision, and approval of final version; R.W. contributed to
study concept design, data interpretation, drafting of manuscript,
manuscript revision, and approval of final version; and P.S.S. contrib-
uted to study concept design, data interpretation, manuscript revision,
and approval of final version.
Conflict-of-interest disclosure: The authors declare no competing
financial interests.
Correspondence: Ann Kinga Malinowski, 700 University Ave,
3rd Floor, Suite 3-909,Toronto, ON, Canada M5G 1Z5; e-mail:
amalinowski@mtsinai.on.ca.

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 From www.bloodjournal.org by guest on September 11, 2016. For personal use only.

2015 126: 2424-2435

doi:10.1182/blood-2015-06-649319 originally published
online August 24, 2015

Prophylactic transfusion for pregnant women with sickle cell disease: a

systematic review and meta-analysis
Ann Kinga Malinowski, Nadine Shehata, Rohan D'Souza, Kevin H. M. Kuo, Richard Ward, Prakesh
S. Shah and Kellie Murphy

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