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Regular Article RED CELLS, IRON, AND ERYTHROPOIESIS
Adverse maternal and perinatal outcomes in pregnant women with sickle cell disease: systematic review and meta-analysis Eugene Oteng-Ntim,1,2,3 Daveena Meeks,1 Paul T. Seed,1 Louise Webster,1 Jo Howard,4 Pat Doyle,3 and Lucy C. Chappell1,2 1
Women’s Health Academic Centre, King’s College London, London, United Kingdom; 2Women’s Services, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom; 3London School of Hygiene and Tropical Medicine, London, United Kingdom; and 4Department of Haematology, Guy’s and St. Thomas’ National Health Service Foundation Trust, London, United Kingdom
A systematic review and meta-analysis of observational studies were conducted to quantify the association between sickle cell disease in pregnancy and adverse maternal and perinatal outcomes. Data sources (Medline, Embase, Maternity and Infant care, • Pregnant women with sickle Cochrane, Web of Science, Popline) were searched for publications to June 2014. Elicell disease have high risks gibility criteria included observational studies reporting maternal and perinatal health of adverse maternal and outcomes in pregnant women with sickle cell disease against a comparative group perinatal outcomes. of pregnant women without sickle cell disease. Twenty-one studies (including 26 349 • The risks are greatest for women with sickle cell disease; 26 151 746 women without sickle cell disease) were elithose with HbSS disease (vs gible for inclusion. Pregnancies in women with HbSS genotype, compared with women HbSC disease) and those in without sickle cell disease, were at increased risk of maternal mortality (relative risk [RR], low income (vs high income) 5.98; 95% confidence interval [CI], 1.94-18.44), preeclampsia (RR, 2.43; 95% CI, 1.75-3.39), countries. stillbirth (RR, 3.94; 95% CI, 2.60-5.96), preterm delivery (RR, 2.21; 95% CI, 1.47-3.31), and small for gestational age infants (RR, 3.72; 95% CI, 2.32-5.98). Meta-regression demonstrated that genotype (HbSS vs HbSC), low gross national income, and high study quality were associated with increased RRs. Despite advances in the management of sickle cell disease, obstetrics, and neonatal medicine, pregnancies complicated by the disease remain associated with increased risk of adverse maternal and perinatal outcomes. (Blood. 2015;125(21):3316-3325)
Key Points
Introduction Sickle cell disease (SCD) is defined as an autosomal recessive hemoglobinopathy that includes sickle cell HbSS disease and various compound heterozygous genotypes (eg, sickle cell HbSC disease or sickle cell b-thalassemia disease [HbSb thal]) characterized by chronic hemolytic anemia and vaso-occlusive complications.1 It is one of the most common genetic disorders globally, with .300 000 children born with the condition each year.2,3 The disease is associated with high lifetime morbidity and premature mortality,4 as described in the most recent Global Burden of Disease study.5 Better quality of care for individuals with SCD has improved survival, and thus there are increasing numbers of women reaching reproductive age.6 Individual studies have shown that pregnant women with SCD are at increased risk of maternal and fetal adverse outcomes; however, the heterogeneity inherent in the pathophysiology of SCD and in the setting of these studies leads to uncertainty when estimating the risk associated with pregnancy for women with the disease.7 The lack of comprehensive data on pregnancy outcomes in these women has made provision of antenatal counseling, clinical care pathways, and benchmarks for health care in institutions worldwide challenging. The aim of this study was to systematically review and meta-analyze maternal and perinatal outcomes in pregnant women with SCD, with consideration of factors that may influence heterogeneity between studies.
Methods Search strategy A systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Meta-Analysis of Observational Studies in Epidemiology Group criteria.8 The following data sources were interrogated: MEDLINE, EMBASE, Cochrane, Popline, Web of Science, and Maternity and Infant Care. Where the option existed, literature searches were restricted to between January 1995 and June 1, 2014 publication. The search terms are shown in Table 1. Abstracts and full text articles were inspected by 2 authors (E.O.-N., D.M.) to identify those articles that met inclusion criteria (Figure 1). In addition, we interrogated references from relevant original papers and review articles to identify further relevant studies. There were no language restrictions. Study selection Studies were included in the systematic review if they met the following criteria: the study design was observational; the exposure of interest was SCD in pregnancy (stratified into SS disease, SC disease, and those reported as SCD but with the genotype not specified); maternal and/ or perinatal outcomes were included; and the investigators reported absolute numbers or relative risks with 95% confidence intervals. We excluded reviews, editorials,
Submitted November 17, 2014; accepted February 10, 2015. Prepublished online as Blood First Edition paper, March 23, 2015; DOI 10.1182/blood-201411-607317.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
There is an Inside Blood Commentary on this article in this issue.
© 2015 by The American Society of Hematology
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Table 1. Search strategy for databases No. 1
Maternity and Infant Care, Medline, and Embase search strategy exp Hemoglobin, Sickle/ or sickle.mp. or exp Anemia, Sickle Cell/
2
hemoglobinopathy.mp. or exp Hemoglobinopathies/
3
Hemoglobinopathies/ or Hemoglobins, Abnormal/ or haemoglobinopathy.mp.
4
exp Pregnancy Complications/ or exp Pregnancy Trimesters/ or pregnancy.mp. or exp Pregnancy Complications, Cardiovascular/ or exp Pregnancy Complications, Infectious/ or exp Pregnancy, High-Risk/ or exp Pregnancy Complications, Hematologic/ or exp Pregnancy/ or exp Hypertension, Pregnancy-Induced/ or exp Pregnancy Trimester, Second/ or exp Pregnancy Outcome/ or exp Pregnancy Trimester, First/ or exp Pregnancy Trimester, Third/
5
1 or 2 or 3
6
(pregnancy adj3 outcome).mp. [mp5title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]
7
exp Maternal Mortality/ or maternal.mp. or exp Maternal Death/
8
exp Obstetrics/ or exp Prenatal Care/ or maternity.mp.
9
pregnant.mp. or exp Placenta/ or exp Infant, Newborn/ or exp Pregnancy Complications/ or exp Fetus/ or exp Pregnancy Complications,
SICKLE CELL DISEASE IN PREGNANCY: META-ANALYSIS
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analysis on the outcomes of interest: maternal mortality, preeclampsia, eclampsia, caesarean delivery, stillbirth, neonatal death, preterm delivery (delivery before 37 completed weeks of gestation), and delivery of a small for gestational age infant (,10th centile). Details on use of blood transfusion (routine/for clinical indications and top-up/exchange) were collected for each study. We obtained the gross national income per capita for each study location from World Bank data. Quality assessment Quality assessment was performed using the Newcastle-Ottawa (NOS) scale.9 Studies were judged on 3 broad perspectives, with a maximum of 9 stars available: the selection of the study groups (4 stars allocated to selection based on a representativeness of the exposed, selection of the nonexposed, ascertainment of the exposed, and demonstration that the outcome of interest was not present at the start of the study); comparability of the groups (2 stars allocated to comparability of the groups in terms of appropriate study comparison group); and ascertainment of either the exposure or the outcome of interest for case-control or cohort studies, respectively (3 stars allocated for assessment of outcome, length of follow-up, and adequacy of follow-up). The papers were categorized into high- (7-9), medium- (4-6), and low-grade (1-3) quality.
Infectious/ or exp Pregnancy/ or exp Pregnant Women/ 10
exp Fetal Diseases/ or antenatal.mp.
11
exp Fetal Growth Retardation/ or fetal.mp. or exp Fetal Development/ or exp Fetal Death/ or exp Fetal Weight/ or exp Fetal Diseases/ or exp Fetal Mortality/
12
foetus.mp. or Fetus/
13
gestation.mp. or Pregnancy/
14
4 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13
15
5 and 14 Web of Science and Cochrane search strategy
1
Sickle or sickle cell
2
Hemoglobinopathy or haemoglobinopathy
3
Hemoglobinopathies or haemoglobinopathies
4
1 or 2 or 3
5
Pregnancy or pregnant
6
Maternal or maternity
7
Obstetrics
8
Antenatal
9
Fetal or foetal
10
Fetus or foetus
11
Gestation
12
5 or 6 or 7 or 8 or 9 or 10 or 11 Popline search strategy
1
Sickle or sickle cell
2
Hemoglobinopathy or haemoglobinopathy or hemoglobinopathies or
3
1 or 2
4
Pregnancy or pregnant or maternal or maternity or obstetrics or antenatal
5
3 and 4
haemoglobinopathies
or fetal or foetal or fetus or foetus or gestation
studies without a comparator group (with no SCD), nonhuman studies, and letters without sufficient data. Studies where women with a sickle cell trait were included as cases were also excluded. If study populations were reported more than once across several papers, we used the dataset with the longest follow-up period to avoid duplication. Data extraction Data extraction was carried out independently by 2 authors (D.M. and L.W.) using a standard extraction form. The following information from each study was extracted: authors; year of publication; study name; study design; study location; number of women in exposed and comparator groups; genotype; and outcomes. For each included study, data were retrieved for the meta-
Statistical analysis Analyses were pregnancy based. The main measure of effect of maternal SCD on maternal and pregnancy outcome was the unadjusted risk ratio, calculated from the given numbers of pregnancies and events. Separate comparisons were made for women with HbSS, HbSC, and genotype not specified. In each analysis, the reference group was women without SCD. A small proportion of women contributed .1 pregnancy to a study, but without individual patient data, it was not possible to adjust the confidence intervals for the relatively small amount of clustering caused by including .1 pregnancy per woman. Depending on the outcome under consideration, studies with no events in either arm were excluded. We used statistical meta-analysis with a random effects model10 to assess the association between SCD and adverse pregnancy outcome. The level of heterogeneity is expressed using t2 (rather than I2),11 a measure of the absolute level of unexplained variation between the studies. As with I2, a t2 value of 0 indicates no unexplained variation, whereas values of t2 ;0.5 indicate a typical ratio of 2 between study estimates of the risk ratio; higher values indicate higher levels of variation. Unlike I2, there is no artificial upper limit of 100%. We also conducted analysis stratified by sickle cell genotype (as specified above) and high vs low/medium resources health care, as well as quality of study based on NOS. Where substantial heterogeneity existed (by t2), multilevel mixed-effects logistic regression10 was used to test for study differences using the following variables: genotype (SC vs SS and SCD genotype not specified vs SS); gross national income (GNI) per capita; and NOS. The results are expressed as odds ratios. All statistical analyses were performed in the statistical package Stata, version 12.1 (StataCorp, College Station, TX) using the commands metan and xtmelogit.11
Results A flow diagram for identification of papers and subsequent evaluation is shown in Figure 1; after excluding ineligible papers (as shown), 21 papers remained. Study characteristics
The characteristics of the 21 studies included in the meta-analysis are outlined in Table 2 (HbSS disease12-23), Table 3 (HbSC disease6,17,18,20,23), and Table 4 (SCD with genotype not specified).24-31 All studies were categorized as pregnancy cohort studies. Thirteen studies originated
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Figure 1. Flowchart of study selection.
from high income countries, with the remaining 8 studies from medium/low income countries. Five studies were considered to be of high quality, 15 of medium quality, and 1 of low quality (Table 5). The meta-analysis included 26 349 women (26 823 pregnancies) with SCD in pregnancy, including 1276 women (1523 pregnancies) in women with HbSS disease, 279 women (331 pregnancies) in women with HbSC disease, and 24 794 (24 969 pregnancies) in women with SCD with genotype not specified, together with 26 151 746 women without SCD or women from the general population assumed not to have SCD (26 185 638 pregnancies). It was estimated that 1.8% of women contributed .1 pregnancy to the total pregnancy numbers. Of the 21 studies, 10 stated that the comparator population was matched for ethnicity; of the remaining 11 studies, 10 were
from countries with a relatively low degree of diversity such that women in the control group were likely to be comparable to the women with SCD. Association between SCD and maternal outcome. There was an increased risk of maternal mortality in women with HbSS disease (relative risk [RR], 5.98; 95% confidence interval [CI], 1.94-18.44) and in women with nonspecified SCD (RR, 18.51; 95% CI, 8.63-39.72) compared with women without SCD, but there was much greater heterogeneity between studies in the latter group (Figure 2). There was only 1 death (of 279 women in total) in studies reporting women with HbSC disease as a separate group.17 There was an approximate doubling in the risk of preeclampsia in women with HbSS disease (RR, 2.43; 95% CI, 1.75-3.39), HbSC
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Table 2. Characteristics of studies comparing pregnancy outcome in women with HbSS against women with no SCD GNI per capita $ (year)
Country
Duration of study
Total N
HbSS women, N (N pregnancies)
No. SCD women, N (N pregnancies)
1276 (1523)
2848 (3183)
75 (75)
150 (150)
Transfusion details
Quality of reporting (NOS) of 9
First author and year of publication Afolabi 200912
Nigeria
2450 (2012)
1996-2000
40% HbSS transfused (on
6
clinical indications) vs 1.9% controls Al Jama 200913
Saudi Arabia
30 160 (2011)
2000-2007
145 (255)
500 (500)
34% HbSS transfused (on
7
clinical indications) vs 5.6% controls Al Kahtani 201214
Saudi Arabia
30 160 (2011)
2001-2010
392 (392)
784 (784)
Top-up transfusion: 33.7%
7
HbSS; exchange transfusion: 3.6% HbSS (on clinical indications) Balgir 199715
India
3910 (2012)
1991-1992
51 (146)
73 (251)
No data on transfusion for
4
study population Daigavane 2013*16
India
3910 (2012)
2010-2012
60 (60)
100 (100)
46.6% HbSS (on clinical
4
indications) vs 3.3% controls Howard 199517
United Kingdom
37 340 (2012)
1991-1993
39 (39)
100 (100)
56.4% HbSS transfused in
4
1st or 2nd trimester (prophylactic) Ngo 201018
France
36 720 (2012)
1994-2004
95 (95)
128 (128)
Prophylactic transfusion for all
7
HbSS Serjeant 2004*19
Jamaica
5120 (2012)
1973-2004
52 (94)
68 (157)
17.3% HbSS transfused (on
7
clinical indications) vs 5.8% controls Sun 200120
United States
52 610 (2012)
1980-1995
69 (69)
61 (129)
59% of HbSS transfused (on
6
clinical indications) vs 0% controls Thame 2013*21
Jamaica
5120 (2012)
2005-2008
41 (41)
41 (41)
No data on transfusion for
6
study population Thame 200722
Jamaica
5120 (2012)
1992-2002
126 (126)
126 (126)
No data on transfusion for
7
study population Wilson 201223
Ghana
1910 (2012)
2007-2008
131 (131)
717 (717)
No data on transfusion for
5
study population All studies were historical cohort of pregnancy studies except for those marked with an asterisk, which were prospective pregnancy cohort studies.
disease (RR, 2.03; 95% CI, 1.17-3.54), and those with nonspecified SCD (RR, 2.06; 95% CI, 1.49-2.85) compared with women without SCD (Figure 3), with low heterogeneity between studies. There was a similarly increased risk of eclampsia in women with HbSS disease (RR, 4.89; 95% CI, 1.97-12.16), but no significantly increased risk in women with HbSC disease or nonspecified SCD compared with women without SCD.
Women with HbSS disease had a small increase in risk of being delivered by Caesarean section (RR, 1.50; 95% CI, 1.26-1.79), as did those with HbSC disease (RR, 1.56; 95% CI, 1.31-1.87) and nonspecified SCD (RR, 1.27; 95% CI, 1.18-1.36) compared with those without SCD. Association between SCD and adverse perinatal outcome. There was a fourfold increased risk of stillbirth in women with HbSS disease (RR, 3.94; 95% CI, 2.60-5.96) and an approximately twofold
Table 3. Characteristics of studies comparing pregnancy outcome in women with HbSC against women with no SCD Country
GNI $ (year)
Duration of study
Total N
HbSC women, N (N pregnancies)
No SCD, N (N pregnancies)
279 (331)
1074 (1231)
33 (33)
100 (100)
Transfusion details
Quality of reporting (NOS) of 9
First author and year of publication Howard 199517
United
37 340 (2012)
1991-1993
Kingdom
21.2% HbSC transfused in
4
1st or 2nd trimester (prophylactic);
Ngo 201018
France
36 720 (2012)
1994-2004
33 (33)
128 (128)
Prophylactic transfusion for
7
all HbSC Serjeant 2005*6
Jamaica
5120 (2012)
1973-2004
43 (95)
68 (157)
11.6% HbSC (on clinical
6
indications) Sun 200120
United
52 610 (2012)
1980-1995
58 (58)
61 (129)
States Wilson 201223
Ghana
21% of HbSC (on clinical
6
indications) vs 0% controls 1910 (2012)
2007-2008
112 (112)
717 (717)
No data on transfusion for study population
All studies were historical cohort studies of pregnancy except for those marked *, which were prospective pregnancy cohort studies.
5
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Table 4. Characteristics of studies comparing pregnancy outcome in women with SCD (genotype unspecified) against women with no sickle cell disease
Country
GNI $ (year)
Duration of study
Total N
Unspecified SCD women, N (N pregnancies)
No SCD women, N (N pregnancies)
24 794 (24 969)
26 147 824 (26 181 224)
4262 (4262)
8 817 059 (8 817 059)
Transfusion details
Quality of reporting (NOS) of 9
First author and year of publication Alayed 201324
Canada
42 530 (2012)
1999-2008
No data on transfusion for
6
study population Al Mulhim 200025
Saudi
30 160 (2011)
1997-1998
61 (61)
84 (84)
Arabia
45.9% SCD (on clinical
5
indications) vs 1.1% controls
Barfield 201026
United
52 610 (2012)
1998-2006
488 (663)
83 877 (115 160)
States Boulet 201327
5
study population
United
52 610 (2012)
2004-2010
1526 (1526)
333 822 (333 822)
States Muganyizi 201328
No data on transfusion for 12.9% SCD vs 1.2% controls
3
(indication not given)
Tanzania
1,560 (2012)
1999-2011
149 (149)
155 207 (157 324)
No data on transfusion for
5
study population Natu 201429
India
3,910 (2012)
2012
25 (25)
500 (500)
60.0% SCD (prophylactic)
4
and 40.0% (on clinical indications) vs 0% controls Rajab 200630
Bahrain
18 910 (2010)
1998-2002
331 (331)
331 (331)
48.9% SCD (top-up
6
transfusion); 3% SCD (exchange transfusion) for prophylaxis Villers 200831
United
52 610 (2012)
2000-2003
17 952 (17 952)
16 756,944 (16 756,944)
States
No raw data on transfusion
4
for study population
All studies were historical cohort studies of pregnancy.
increased risk in women with HbSC disease (RR, 1.78; 95% CI, 1.05-3.02) compared with women without SCD (Figure 4). There was a similar increased risk of neonatal death in women with HbSS disease (RR, 2.68; 95% CI, 1.49-4.82). Only 1 study reported neonatal deaths in women with HbSC disease, giving an RR of 1.78 (95% CI, 0.52-12.41). The risks of preterm delivery were increased in a similar manner, with more than twofold increased risk in women with HbSS disease (RR, 2.21; 95% CI, 1.47-3.31) and a lower, nonsignificant increase in women with HbSC disease (RR, 1.45; 95% CI, 0.86-2.43) compared with women without SCD (Figure 5); there was
greater heterogeneity in the studies in HbSC disease, with 1 study reporting no increase. Most studies did not differentiate between spontaneous preterm deliveries and those where labor and delivery were initiated by medical staff for maternal or fetal complications. There was a nearly fourfold increased risk of infants being born small for gestational age (,10th centile) in women with HbSS disease (RR, 3.72; 95% CI, 2.32-5.98) and a twofold risk in women with HbSC disease (RR, 1.98; 95% CI, 1.04-3.77) compared with women without SCD (Figure 6); heterogeneity was low across studies.
Table 5. Newcastle-Ottawa quality appraisal First author (year)
Study design
Selection
Comparability
Exposure/outcome
Afolabi 200912
Historical cohort
****
*
*
6
Alayed 201324
Historical cohort
***
**
*
6
Al Jama 200913
Historical cohort
****
**
*
7
Al Kahtani 201214
Historical cohort
****
**
*
7
Al Mulhim 200025
Historical cohort
***
*
*
5
Balgir 199715
Historical cohort
*
**
*
4
Barfield 201026
Historical cohort
**
*
**
5
Boulet 201327
Historical cohort
*
*
*
3
Daigavane 201316
Total of 9
Prospective cohort
**
*
*
4
Howard 199517
Historical cohort
**
*
*
4
Muganyizi 201328
Historical cohort
***
*
*
5
Natu 201429
Historical cohort
**
*
*
4
Ngo 201018
Historical cohort
****
*
**
7
Rajab 200630
Historical cohort
***
*
**
6
Serjeant 200419
Prospective cohort
****
**
*
7
Serjeant 20056
Prospective cohort
***
**
*
6
Sun 200120
Historical cohort
***
**
*
6
Prospective cohort
***
**
*
6
Thame 200722
Historical cohort
****
*
**
7
Villers 200831
Historical Cohort
*
*
**
4
Wilson 201223
Historical Cohort
**
*
**
5
Thame 201321
Each asterisk corresponds to a score of one.
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Figure 2. Forest plot of studies investigating the association of SCD with maternal mortality.
Meta-regression demonstrated that genotype (HbSS vs HbSC) had a significant influence on adverse perinatal outcomes (stillbirth, preterm delivery, and small for gestational age infants), but not on the
occurrence of preeclampsia (Table 6). There was substantially and significantly lower maternal mortality (odds ratio, 0.15; 95% CI, 0.02-0.86) and stillbirth (odds ratio, 0.28; 95% CI, 0.14-0.55) in women with
Figure 3. Forest plot of studies investigating the association of SCD with preeclampsia.
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Figure 4. Forest plot of studies investigating the association of SCD with stillbirth.
SCD from countries with a gross national income of $30 000 or greater, but no significant impact of meta-regression by gross national income on preeclampsia, preterm delivery, or small for gestational age infants.
Figure 5. Forest plot of studies investigating the association of SCD with preterm delivery.
There was an impact of quality of reporting, with higher odds ratios being reported for all outcomes in high-quality studies compared with low-quality studies.
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Figure 6. Forest plot of studies investigating the association of SCD with delivery of small for gestational age infant.
Discussion This systematic review and meta-analysis identified a strong association between SCD and adverse outcome for the mother (including maternal mortality and preeclampsia) and baby (including perinatal death, preterm delivery, and small for gestational age infants). Women with HbSS disease had significantly worse perinatal outcomes compared with those with HbSC disease, in a similar pattern to complications outside of pregnancy, and maternal mortality and stillbirth were substantially lower in high-income countries; studies rated as high quality reported increased relative risks that were generally double those of the low-quality studies. This may reflect better ascertainment of outcome data in the high-quality studies. To the best of our knowledge, this study represents the first systematic review and meta-analysis of outcomes for pregnancies complicated by SCD. We used a comprehensive and systematic literature search, not limited by language or setting. The pooled sample size of .26 000 pregnancies in women with SCD increases the reliability of the pooled estimates for each outcome. It remains a limitation of the source data that most of the included studies were of historical design, single institution origin, and of mixed quality rating. Furthermore, a number of studies failed to define the precise genotypic diagnosis of the participants or analyze pregnancy outcomes by genotype separately. However, we tried to mitigate this limitation by stratifying the study populations into the specific genotypes (together with a SCD nonspecified group) where
possible. It was also not possible to adjust the confidence intervals for the relatively small amount of clustering caused by 1.8% of women being included in the study more than once with different pregnancies, and confidence intervals might be slightly too narrow in consequence. The meta-analysis includes 5 population-wide studies; the larger sample sizes and greater number of institutions included allow increased generalizability and precision in the generation of pooled risk ratios estimates, but are subject to caution over accuracy of coding. Variation in management strategies across settings may have influenced the pregnancy outcomes; this may either have occurred through a direct impact on ameliorating pregnancy outcomes (eg, there is an uncertain benefit of prophylactic vs clinically indicated exchange transfusion in women with SCD) or through different thresholds for delivery depending on availability of neonatal care facilities (which may influence gestation of delivery in a woman with preeclampsia). Most studies included in the review did not provide comprehensive details of their management pathway for pregnant women with SCD, and the considerable heterogeneity of transfusion management plans precluded formal statistical comparison of the influence of this factor. We limited the review and meta-analysis to well-delineated outcomes, reported across the majority of the studies as other end points (such as maternal jaundice, pulmonary hypertension, sepsis, thromboembolism, abruption, postpartum hemorrhage, and congenital fetal abnormality) were not reported consistently and the data on increased occurrence in SCD are conflicting).
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Table 6. Meta-regression by disease genotype, country gross national income, and quality of study reporting Odds ratios Nonspecified SCD
P value (x2)
HbSS
HbSC
P value (LR test*)
Preeclampsia
2.7 (1.8-3.9)
1.9 (1.1-3.2)
2.6 (2.4-2.8)
.43*
Stillbirth
4.0 (2.8-5.6)
1.9 (1.04-3.4)
3.7 (2.8-4.9)
.04*
Preterm delivery
2.2 (1.8-2.7)
1.2 (0.8-1.6)
1.6 (1.4-1.7)
Small for gestational age infants
4.0 (3.1-5.2)
1.6 (0.79-3.1)
1.5 (1.2-1.8)
Disease genotype Maternal mortality
Country gross national income
No deaths
.0007* ,.001
GNI $ $30 000 ,.001
Maternal mortality
0.15 (0.02-0.86)
Preeclampsia
0.59 (0.24-1.42)
.24
Stillbirth
0.28 (0.14-0.55)
,.001
Preterm delivery
0.78 (0.40-1.51)
.46
Small for gestational age infants
0.89 (0.42-1.92)
Quality of study reporting
.77
High quality
Low quality
23.2 (13.5-40.1)
11.2 (8.2-15.4)
,.001
Preeclampsia
3.1 (2.8-3.4)
2.0 (1.7-2.2)
,.001
Stillbirth
6.5 (3.7-11.6)
3.2 (2.6-4.1)
.03
Preterm delivery
2.7 (2.1-3.4)
1.5 (1.4-1.6)
,.001
Small for gestational age infants
3.9 (3.0-5.0)
1.5 (1.2-1.8)
,.001
Maternal mortality
The P value for the likelihood ratio (LR) test is for a comparison between the HbSS and HbSC group results.
With improvements in clinical management that have focused on early identification and treatment of manifestations with the aim of reducing complications, women with SCD are surviving into adulthood and actively considering reproductive options. Previous narrative reviews2,32,33 have summarized the studies, but a systematic review permits quantification of the risks for use in prepregnancy and pregnancy counseling. It is of particular concern that women with SCD have a markedly increased risk in maternal mortality. Studies from Europe and Jamaica looking at patterns of mortality in SCD highlight acute chest syndrome, sepsis, and multiorgan failure as the 3 major causes of death.17,34 Many studies in our systematic review did not elaborate on the precise cause of maternal death or to what extent SCD contributed directly or indirectly. The risk of maternal mortality in HbSS women was quantified as being sixfold compared with women without SCD, whereas in the studies of women with HbSC disease, there was 1 maternal death (of 279 women reported), and the risk of maternal morbidity in both groups remains substantial. There is a substantial difference in magnitude of risk of maternal death and stillbirth between countries with high and low gross national income (dichotomized at $30 000), even though the odds ratios for preeclampsia, preterm delivery, and small for gestational age infants were not significantly different, suggesting that the risk of death is dependent on the availability of adequate health care resources and expertise and the variable implementation of prophylactic or indicated exchange blood transfusion practices. This may be aggravated by the difficulties in identification of those at greatest risk of mortality; a recent Jamaican study showed that a third of those dying from multiorgan failure and acute chest syndrome had had only mild disease before the final events.34 SCD has been proposed to be a chronic inflammatory state35,36; endothelial damage secondary to sickled red blood cells and the subsequent release of proinflammatory cytokines may contribute to microvascular damage.37 Normal vascular, endothelial, and inflammatory adaptations in pregnancy may lead to exacerbation of these pathophysiologic changes, with manifestation of resulting maternal complications such as preeclampsia and fetal growth restriction. There are data from a small case-control study to demonstrate an association between SCD, abnormal mid-trimester uterine artery Doppler waveforms,38,39 abnormal placental histology, including placental
lesions of moderate-to-severe villous sclerosis, intervillous fibrin deposits, and infarction,40 and subsequent delivery of small for gestational age infants. Prophylactic interventions to reduce preeclampsia are limited, but low-dose aspirin from mid-trimester to the end of pregnancy has been shown to decrease the occurrence of preeclampsia in other groups of high-risk women41; although never formally tested in a randomized controlled trial specifically in women with SCD, it is highly likely that aspirin is similarly beneficial in these women. Regular third trimester screening for fetal growth may also represent a strategy to reduce adverse outcome such as stillbirth linked to fetal growth restriction, but it is accepted that this resource would be of limited availability to less privileged health care providers.42 Further research, with appropriately powered prospective studies and strict genotype diagnosis and outcome ascertainment, is needed to understand the reasons behind the increased risks of morbidity and mortality in women with SCD, particularly those with HbSS genotype and in low income countries. There is interest in strategies such as selective prophylactic exchange transfusion43; the most recent Cochrane systematic review and meta-analysis of 2 trials in this population concluded that there was no clear benefit of prophylactic transfusion over a selective (emergency) approach.44 There is an urgent need for adequately powered trials of transfusion modalities in this high-risk group of pregnant women with appropriate choice of maternal and perinatal outcome measures. In high-income countries, women with SCD are usually managed by a multidisciplinary team of obstetricians, hematologists, specialist midwives, and anesthetists, but the greatest burden of morbidity and mortality undoubtedly lies within low and middle income countries, where access to specialist antenatal care may be limited. This systematic review and meta-analysis provides useful estimates of the morbidity and mortality associated with the condition and should encourage global health care policy makers, researchers, and clinicians to work together to reduce the maternal and perinatal adverse outcomes described.
Acknowledgment The authors thank the librarian at the Royal College of Obstetricians and Gynaecologists (Lisa Xue) for help with obtaining some of the articles.
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SICKLE CELL DISEASE IN PREGNANCY: META-ANALYSIS
Authorship Contribution: E.O.-N., L.C.C., and P.D. designed the study; E.O.-N., D.M., and L.W. conducted the literature searches; and all authors contributed to the writing of the manuscript and approved the final version.
3325
Conflict-of-interest disclosure: J.H. has been on the advisory board for Novartis and AesRx. All other authors declare no competing financial interests. Correspondence: Eugene Oteng-Ntim, Women’s Health Directorate, Guy’s and St Thomas’ NHS Foundation Trust, London SE1 7EH, United Kingdom; e-mail: [email protected].
References 1. Weatherall DJ. ABC of clinical haematology. The hereditary anaemias. BMJ. 1997;314(7079): 492-496.
16. Daigavane MM, Jena RK, Kar TJ. Perinatal outcome in sickle cell anemia: a prospective study from India. Hemoglobin. 2013;37(6):507-515.
30. Rajab KE, Issa AA, Mohammed AM, Ajami AA. Sickle cell disease and pregnancy in Bahrain. Int J Gynaecol Obstet. 2006;93(2):171-175.
2. Howard J, Oteng-Ntim E. The obstetric management of sickle cell disease. Best Pract Res Clin Obstet Gynaecol. 2012;26(1):25-36.
17. Howard RJ, Tuck SM, Pearson TC. Pregnancy in sickle cell disease in the UK: results of a multicentre survey of the effect of prophylactic blood transfusion on maternal and fetal outcome. Br J Obstet Gynaecol. 1995;102(12):947-951.
31. Villers MS, Jamison MG, De Castro LM, James AH. Morbidity associated with sickle cell disease in pregnancy. Am J Obstet Gynecol 2008;199(2): 125e1-125e5.
3. Piel FB, Patil AP, Howes RE, et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet. 2013; 381(9861):142-151. 4. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376(9757):2018-2031. 5. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095-2128. 6. Serjeant GR, Hambleton I, Thame M. Fecundity and pregnancy outcome in a cohort with sickle cell-haemoglobin C disease followed from birth. BJOG. 2005;112(9):1308-1314. 7. Adekile AD. What’s new in the pathophysiology of sickle cell disease? Med Princ Pract. 2013;22(4): 311-312. 8. Stroup DF, Berlin JA, Morton SC, et al. Metaanalysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008-2012. 9. Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa scale (NOS) for assessing the quality of non-randomised studies in metaanalyses. Available at: http://www.ohri.ca/ programs/clinical_epidemiology/oxford.asp. Accessed September 1, 2014. 10. Rabe-Hesketh S, Skrondal A, Pickles A. Maximum likelihood estimation of limited and discrete dependent variable models with nested random effects. J Econom. 2005;128(2):23. 11. Harbord R, Higgins J. Metaregression in Stata. Stata J. 2008;8(4):493-519. 12. Afolabi BB, Iwuala NC, Iwuala IC, Ogedengbe OK. Morbidity and mortality in sickle cell pregnancies in Lagos, Nigeria: a case control study. J Obstet Gynaecol. 2009;29(2):104-106. 13. Al Jama FE, Gasem T, Burshaid S, Rahman J, Al Suleiman SA, Rahman MS. Pregnancy outcome in patients with homozygous sickle cell disease in a university hospital, Eastern Saudi Arabia. Arch Gynecol Obstet. 2009;280(5):793-797. 14. Al Kahtani MA, AlQahtani M, Alshebaily MM, Abd Elzaher M, Moawad A, Aljohani N. Morbidity and pregnancy outcomes associated with sickle cell anemia among Saudi women. Int J Gynaecol Obstet. 2012;119(3):224-226. 15. Balgir RS, Dash BP, Das RK. Fetal outcome and childhood mortality in offspring of mothers with sickle cell trait and disease. Indian J Pediatr. 1997;64(1):79-84.
18. Ngoˆ C, Kayem G, Habibi A, et al. Pregnancy in sickle cell disease: maternal and fetal outcomes in a population receiving prophylactic partial exchange transfusions. Eur J Obstet Gynecol Reprod Biol. 2010;152(2):138-142. 19. Serjeant GR, Loy LL, Crowther M, Hambleton IR, Thame M. Outcome of pregnancy in homozygous sickle cell disease. Obstet Gynecol. 2004;103(6): 1278-1285. 20. Sun PM, Wilburn W, Raynor BD, Jamieson D. Sickle cell disease in pregnancy: twenty years of experience at Grady Memorial Hospital, Atlanta, Georgia. Am J Obstet Gynecol. 2001;184(6): 1127-1130. 21. Thame MM, Osmond C, Serjeant GR. Fetal growth in women with homozygous sickle cell disease: an observational study. Eur J Obstet Gynecol Reprod Biol. 2013;170(1):62-66. 22. Thame M, Lewis J, Trotman H, Hambleton I, Serjeant G. The mechanisms of low birth weight in infants of mothers with homozygous sickle cell disease. Pediatrics. 2007;120(3):e686-e693. 23. Wilson NO, Ceesay FK, Hibbert JM, et al. Pregnancy outcomes among patients with sickle cell disease at Korle-Bu Teaching Hospital, Accra, Ghana: retrospective cohort study. Am J Trop Med Hyg. 2012;86(6):936-942. 24. Alayed N, Kezouh A, Oddy L, Abenhaim HA. Sickle cell disease and pregnancy outcomes: population-based study on 8.8 million births. J Perinat Med. 2014;42(4):487-492.
32. de Montalembert M. Management of sickle cell disease. BMJ. 2008;337:a1397. 33. Serjeant GR. Sickle-cell disease. Lancet. 1997; 350(9079):725-730. 34. Asnani MR, McCaw-Binns AM, Reid ME. Excess risk of maternal death from sickle cell disease in Jamaica: 1998-2007. PLoS ONE. 2011;6(10): e26281. 35. Sparkenbaugh E, Pawlinski R. Interplay between coagulation and vascular inflammation in sickle cell disease. Br J Haematol. 2013;162(1):3-14. 36. Litos M, Sarris I, Bewley S, Seed P, Okpala I, Oteng-Ntim E. White blood cell count as a predictor of the severity of sickle cell disease during pregnancy. Eur J Obstet Gynecol Reprod Biol. 2007;133(2):169-172. 37. Chirico EN, Pialoux V. Role of oxidative stress in the pathogenesis of sickle cell disease. IUBMB Life. 2012;64(1):72-80. 38. Anyaegbunam A, Langer O, Brustman L, Damus K, Halpert R, Merkatz IR. The application of uterine and umbilical artery velocimetry to the antenatal supervision of pregnancies complicated by maternal sickle hemoglobinopathies. Am J Obstet Gynecol. 1988;159(3):544-547. 39. Billett HH, Langer O, Regan OT, Merkatz I, Anyaegbunam A. Doppler velocimetry in pregnant patients with sickle cell anemia. Am J Hematol. 1993;42(3):305-308.
25. Al Mulhim K. Pregnancy in sickle cell disease in the Al Hassa Region of Saudi Arabia. Ann Saudi Med. 2000;20(5-6):471-473.
40. Anyaegbunam A, Mikhail M, Axioitis C, Morel MI, Merkatz IR. Placental histology and placental/fetal weight ratios in pregnant women with sickle cell disease: relationship to pregnancy outcome. J Assoc Academic Minority Physicians. 1994;5(3): 123-125.
26. Barfield WD, Barradas DT, Manning SE, Kotelchuck M, Shapiro-Mendoza CK. Sickle cell disease and pregnancy outcomes: women of African descent. Am J Prev Med. 2010; 38(4 Suppl):S542-S549.
41. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA, Group PC; PARIS Collaborative Group. Antiplatelet agents for prevention of preeclampsia: a meta-analysis of individual patient data. Lancet. 2007;369(9575):1791-1798.
27. Boulet SL, Okoroh EM, Azonobi I, Grant A, Craig Hooper W. Sickle cell disease in pregnancy: maternal complications in a Medicaid-enrolled population. Matern Child Health J. 2013;17(2): 200-207.
42. Hofmeyr GJ, Haws RA, Bergstrom S, et al. Obstetric care in low-resource settings: what, who, and how to overcome challenges to scale up? Int J Gynaecol Obstet. 2009;107(Suppl 1): S21-S44.
28. Muganyizi PS, Kidanto H. Sickle cell disease in pregnancy: trend and pregnancy outcomes at a tertiary hospital in Tanzania. PLoS ONE. 2013; 8(2):e56541.
43. Asma S, Kozanoglu I, Tarım E, et al. Prophylactic red blood cell exchange may be beneficial in the management of sickle cell disease in pregnancy. Transfusion. 2015;55(1):36-44.
29. Natu N, Khandelwal S, Kumar R, Dave A. Maternal and perinatal outcome of women with sickle cell disease of a tribal population in Central India. Hemoglobin. 2014;38(2):91-94.
44. Okusanya BO, Oladapo OT. Prophylactic versus selective blood transfusion for sickle cell disease in pregnancy. Cochrane Database Syst Rev. 2013;12:CD010378.
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2015 125: 3316-3325 doi:10.1182/blood-2014-11-607317 originally published online March 23, 2015
Adverse maternal and perinatal outcomes in pregnant women with sickle cell disease: systematic review and meta-analysis Eugene Oteng-Ntim, Daveena Meeks, Paul T. Seed, Louise Webster, Jo Howard, Pat Doyle and Lucy C. Chappell
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Regular Article RED CELLS, IRON, AND ERYTHROPOIESIS
Adverse maternal and perinatal outcomes in pregnant women with sickle cell disease: systematic review and meta-analysis Eugene Oteng-Ntim,1,2,3 Daveena Meeks,1 Paul T. Seed,1 Louise Webster,1 Jo Howard,4 Pat Doyle,3 and Lucy C. Chappell1,2 1
Women’s Health Academic Centre, King’s College London, London, United Kingdom; 2Women’s Services, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom; 3London School of Hygiene and Tropical Medicine, London, United Kingdom; and 4Department of Haematology, Guy’s and St. Thomas’ National Health Service Foundation Trust, London, United Kingdom
A systematic review and meta-analysis of observational studies were conducted to quantify the association between sickle cell disease in pregnancy and adverse maternal and perinatal outcomes. Data sources (Medline, Embase, Maternity and Infant care, • Pregnant women with sickle Cochrane, Web of Science, Popline) were searched for publications to June 2014. Elicell disease have high risks gibility criteria included observational studies reporting maternal and perinatal health of adverse maternal and outcomes in pregnant women with sickle cell disease against a comparative group perinatal outcomes. of pregnant women without sickle cell disease. Twenty-one studies (including 26 349 • The risks are greatest for women with sickle cell disease; 26 151 746 women without sickle cell disease) were elithose with HbSS disease (vs gible for inclusion. Pregnancies in women with HbSS genotype, compared with women HbSC disease) and those in without sickle cell disease, were at increased risk of maternal mortality (relative risk [RR], low income (vs high income) 5.98; 95% confidence interval [CI], 1.94-18.44), preeclampsia (RR, 2.43; 95% CI, 1.75-3.39), countries. stillbirth (RR, 3.94; 95% CI, 2.60-5.96), preterm delivery (RR, 2.21; 95% CI, 1.47-3.31), and small for gestational age infants (RR, 3.72; 95% CI, 2.32-5.98). Meta-regression demonstrated that genotype (HbSS vs HbSC), low gross national income, and high study quality were associated with increased RRs. Despite advances in the management of sickle cell disease, obstetrics, and neonatal medicine, pregnancies complicated by the disease remain associated with increased risk of adverse maternal and perinatal outcomes. (Blood. 2015;125(21):3316-3325)
Key Points
Introduction Sickle cell disease (SCD) is defined as an autosomal recessive hemoglobinopathy that includes sickle cell HbSS disease and various compound heterozygous genotypes (eg, sickle cell HbSC disease or sickle cell b-thalassemia disease [HbSb thal]) characterized by chronic hemolytic anemia and vaso-occlusive complications.1 It is one of the most common genetic disorders globally, with .300 000 children born with the condition each year.2,3 The disease is associated with high lifetime morbidity and premature mortality,4 as described in the most recent Global Burden of Disease study.5 Better quality of care for individuals with SCD has improved survival, and thus there are increasing numbers of women reaching reproductive age.6 Individual studies have shown that pregnant women with SCD are at increased risk of maternal and fetal adverse outcomes; however, the heterogeneity inherent in the pathophysiology of SCD and in the setting of these studies leads to uncertainty when estimating the risk associated with pregnancy for women with the disease.7 The lack of comprehensive data on pregnancy outcomes in these women has made provision of antenatal counseling, clinical care pathways, and benchmarks for health care in institutions worldwide challenging. The aim of this study was to systematically review and meta-analyze maternal and perinatal outcomes in pregnant women with SCD, with consideration of factors that may influence heterogeneity between studies.
Methods Search strategy A systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Meta-Analysis of Observational Studies in Epidemiology Group criteria.8 The following data sources were interrogated: MEDLINE, EMBASE, Cochrane, Popline, Web of Science, and Maternity and Infant Care. Where the option existed, literature searches were restricted to between January 1995 and June 1, 2014 publication. The search terms are shown in Table 1. Abstracts and full text articles were inspected by 2 authors (E.O.-N., D.M.) to identify those articles that met inclusion criteria (Figure 1). In addition, we interrogated references from relevant original papers and review articles to identify further relevant studies. There were no language restrictions. Study selection Studies were included in the systematic review if they met the following criteria: the study design was observational; the exposure of interest was SCD in pregnancy (stratified into SS disease, SC disease, and those reported as SCD but with the genotype not specified); maternal and/ or perinatal outcomes were included; and the investigators reported absolute numbers or relative risks with 95% confidence intervals. We excluded reviews, editorials,
Submitted November 17, 2014; accepted February 10, 2015. Prepublished online as Blood First Edition paper, March 23, 2015; DOI 10.1182/blood-201411-607317.
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Table 1. Search strategy for databases No. 1
Maternity and Infant Care, Medline, and Embase search strategy exp Hemoglobin, Sickle/ or sickle.mp. or exp Anemia, Sickle Cell/
2
hemoglobinopathy.mp. or exp Hemoglobinopathies/
3
Hemoglobinopathies/ or Hemoglobins, Abnormal/ or haemoglobinopathy.mp.
4
exp Pregnancy Complications/ or exp Pregnancy Trimesters/ or pregnancy.mp. or exp Pregnancy Complications, Cardiovascular/ or exp Pregnancy Complications, Infectious/ or exp Pregnancy, High-Risk/ or exp Pregnancy Complications, Hematologic/ or exp Pregnancy/ or exp Hypertension, Pregnancy-Induced/ or exp Pregnancy Trimester, Second/ or exp Pregnancy Outcome/ or exp Pregnancy Trimester, First/ or exp Pregnancy Trimester, Third/
5
1 or 2 or 3
6
(pregnancy adj3 outcome).mp. [mp5title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier]
7
exp Maternal Mortality/ or maternal.mp. or exp Maternal Death/
8
exp Obstetrics/ or exp Prenatal Care/ or maternity.mp.
9
pregnant.mp. or exp Placenta/ or exp Infant, Newborn/ or exp Pregnancy Complications/ or exp Fetus/ or exp Pregnancy Complications,
SICKLE CELL DISEASE IN PREGNANCY: META-ANALYSIS
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analysis on the outcomes of interest: maternal mortality, preeclampsia, eclampsia, caesarean delivery, stillbirth, neonatal death, preterm delivery (delivery before 37 completed weeks of gestation), and delivery of a small for gestational age infant (,10th centile). Details on use of blood transfusion (routine/for clinical indications and top-up/exchange) were collected for each study. We obtained the gross national income per capita for each study location from World Bank data. Quality assessment Quality assessment was performed using the Newcastle-Ottawa (NOS) scale.9 Studies were judged on 3 broad perspectives, with a maximum of 9 stars available: the selection of the study groups (4 stars allocated to selection based on a representativeness of the exposed, selection of the nonexposed, ascertainment of the exposed, and demonstration that the outcome of interest was not present at the start of the study); comparability of the groups (2 stars allocated to comparability of the groups in terms of appropriate study comparison group); and ascertainment of either the exposure or the outcome of interest for case-control or cohort studies, respectively (3 stars allocated for assessment of outcome, length of follow-up, and adequacy of follow-up). The papers were categorized into high- (7-9), medium- (4-6), and low-grade (1-3) quality.
Infectious/ or exp Pregnancy/ or exp Pregnant Women/ 10
exp Fetal Diseases/ or antenatal.mp.
11
exp Fetal Growth Retardation/ or fetal.mp. or exp Fetal Development/ or exp Fetal Death/ or exp Fetal Weight/ or exp Fetal Diseases/ or exp Fetal Mortality/
12
foetus.mp. or Fetus/
13
gestation.mp. or Pregnancy/
14
4 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13
15
5 and 14 Web of Science and Cochrane search strategy
1
Sickle or sickle cell
2
Hemoglobinopathy or haemoglobinopathy
3
Hemoglobinopathies or haemoglobinopathies
4
1 or 2 or 3
5
Pregnancy or pregnant
6
Maternal or maternity
7
Obstetrics
8
Antenatal
9
Fetal or foetal
10
Fetus or foetus
11
Gestation
12
5 or 6 or 7 or 8 or 9 or 10 or 11 Popline search strategy
1
Sickle or sickle cell
2
Hemoglobinopathy or haemoglobinopathy or hemoglobinopathies or
3
1 or 2
4
Pregnancy or pregnant or maternal or maternity or obstetrics or antenatal
5
3 and 4
haemoglobinopathies
or fetal or foetal or fetus or foetus or gestation
studies without a comparator group (with no SCD), nonhuman studies, and letters without sufficient data. Studies where women with a sickle cell trait were included as cases were also excluded. If study populations were reported more than once across several papers, we used the dataset with the longest follow-up period to avoid duplication. Data extraction Data extraction was carried out independently by 2 authors (D.M. and L.W.) using a standard extraction form. The following information from each study was extracted: authors; year of publication; study name; study design; study location; number of women in exposed and comparator groups; genotype; and outcomes. For each included study, data were retrieved for the meta-
Statistical analysis Analyses were pregnancy based. The main measure of effect of maternal SCD on maternal and pregnancy outcome was the unadjusted risk ratio, calculated from the given numbers of pregnancies and events. Separate comparisons were made for women with HbSS, HbSC, and genotype not specified. In each analysis, the reference group was women without SCD. A small proportion of women contributed .1 pregnancy to a study, but without individual patient data, it was not possible to adjust the confidence intervals for the relatively small amount of clustering caused by including .1 pregnancy per woman. Depending on the outcome under consideration, studies with no events in either arm were excluded. We used statistical meta-analysis with a random effects model10 to assess the association between SCD and adverse pregnancy outcome. The level of heterogeneity is expressed using t2 (rather than I2),11 a measure of the absolute level of unexplained variation between the studies. As with I2, a t2 value of 0 indicates no unexplained variation, whereas values of t2 ;0.5 indicate a typical ratio of 2 between study estimates of the risk ratio; higher values indicate higher levels of variation. Unlike I2, there is no artificial upper limit of 100%. We also conducted analysis stratified by sickle cell genotype (as specified above) and high vs low/medium resources health care, as well as quality of study based on NOS. Where substantial heterogeneity existed (by t2), multilevel mixed-effects logistic regression10 was used to test for study differences using the following variables: genotype (SC vs SS and SCD genotype not specified vs SS); gross national income (GNI) per capita; and NOS. The results are expressed as odds ratios. All statistical analyses were performed in the statistical package Stata, version 12.1 (StataCorp, College Station, TX) using the commands metan and xtmelogit.11
Results A flow diagram for identification of papers and subsequent evaluation is shown in Figure 1; after excluding ineligible papers (as shown), 21 papers remained. Study characteristics
The characteristics of the 21 studies included in the meta-analysis are outlined in Table 2 (HbSS disease12-23), Table 3 (HbSC disease6,17,18,20,23), and Table 4 (SCD with genotype not specified).24-31 All studies were categorized as pregnancy cohort studies. Thirteen studies originated
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OTENG-NTIM et al
Figure 1. Flowchart of study selection.
from high income countries, with the remaining 8 studies from medium/low income countries. Five studies were considered to be of high quality, 15 of medium quality, and 1 of low quality (Table 5). The meta-analysis included 26 349 women (26 823 pregnancies) with SCD in pregnancy, including 1276 women (1523 pregnancies) in women with HbSS disease, 279 women (331 pregnancies) in women with HbSC disease, and 24 794 (24 969 pregnancies) in women with SCD with genotype not specified, together with 26 151 746 women without SCD or women from the general population assumed not to have SCD (26 185 638 pregnancies). It was estimated that 1.8% of women contributed .1 pregnancy to the total pregnancy numbers. Of the 21 studies, 10 stated that the comparator population was matched for ethnicity; of the remaining 11 studies, 10 were
from countries with a relatively low degree of diversity such that women in the control group were likely to be comparable to the women with SCD. Association between SCD and maternal outcome. There was an increased risk of maternal mortality in women with HbSS disease (relative risk [RR], 5.98; 95% confidence interval [CI], 1.94-18.44) and in women with nonspecified SCD (RR, 18.51; 95% CI, 8.63-39.72) compared with women without SCD, but there was much greater heterogeneity between studies in the latter group (Figure 2). There was only 1 death (of 279 women in total) in studies reporting women with HbSC disease as a separate group.17 There was an approximate doubling in the risk of preeclampsia in women with HbSS disease (RR, 2.43; 95% CI, 1.75-3.39), HbSC
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Table 2. Characteristics of studies comparing pregnancy outcome in women with HbSS against women with no SCD GNI per capita $ (year)
Country
Duration of study
Total N
HbSS women, N (N pregnancies)
No. SCD women, N (N pregnancies)
1276 (1523)
2848 (3183)
75 (75)
150 (150)
Transfusion details
Quality of reporting (NOS) of 9
First author and year of publication Afolabi 200912
Nigeria
2450 (2012)
1996-2000
40% HbSS transfused (on
6
clinical indications) vs 1.9% controls Al Jama 200913
Saudi Arabia
30 160 (2011)
2000-2007
145 (255)
500 (500)
34% HbSS transfused (on
7
clinical indications) vs 5.6% controls Al Kahtani 201214
Saudi Arabia
30 160 (2011)
2001-2010
392 (392)
784 (784)
Top-up transfusion: 33.7%
7
HbSS; exchange transfusion: 3.6% HbSS (on clinical indications) Balgir 199715
India
3910 (2012)
1991-1992
51 (146)
73 (251)
No data on transfusion for
4
study population Daigavane 2013*16
India
3910 (2012)
2010-2012
60 (60)
100 (100)
46.6% HbSS (on clinical
4
indications) vs 3.3% controls Howard 199517
United Kingdom
37 340 (2012)
1991-1993
39 (39)
100 (100)
56.4% HbSS transfused in
4
1st or 2nd trimester (prophylactic) Ngo 201018
France
36 720 (2012)
1994-2004
95 (95)
128 (128)
Prophylactic transfusion for all
7
HbSS Serjeant 2004*19
Jamaica
5120 (2012)
1973-2004
52 (94)
68 (157)
17.3% HbSS transfused (on
7
clinical indications) vs 5.8% controls Sun 200120
United States
52 610 (2012)
1980-1995
69 (69)
61 (129)
59% of HbSS transfused (on
6
clinical indications) vs 0% controls Thame 2013*21
Jamaica
5120 (2012)
2005-2008
41 (41)
41 (41)
No data on transfusion for
6
study population Thame 200722
Jamaica
5120 (2012)
1992-2002
126 (126)
126 (126)
No data on transfusion for
7
study population Wilson 201223
Ghana
1910 (2012)
2007-2008
131 (131)
717 (717)
No data on transfusion for
5
study population All studies were historical cohort of pregnancy studies except for those marked with an asterisk, which were prospective pregnancy cohort studies.
disease (RR, 2.03; 95% CI, 1.17-3.54), and those with nonspecified SCD (RR, 2.06; 95% CI, 1.49-2.85) compared with women without SCD (Figure 3), with low heterogeneity between studies. There was a similarly increased risk of eclampsia in women with HbSS disease (RR, 4.89; 95% CI, 1.97-12.16), but no significantly increased risk in women with HbSC disease or nonspecified SCD compared with women without SCD.
Women with HbSS disease had a small increase in risk of being delivered by Caesarean section (RR, 1.50; 95% CI, 1.26-1.79), as did those with HbSC disease (RR, 1.56; 95% CI, 1.31-1.87) and nonspecified SCD (RR, 1.27; 95% CI, 1.18-1.36) compared with those without SCD. Association between SCD and adverse perinatal outcome. There was a fourfold increased risk of stillbirth in women with HbSS disease (RR, 3.94; 95% CI, 2.60-5.96) and an approximately twofold
Table 3. Characteristics of studies comparing pregnancy outcome in women with HbSC against women with no SCD Country
GNI $ (year)
Duration of study
Total N
HbSC women, N (N pregnancies)
No SCD, N (N pregnancies)
279 (331)
1074 (1231)
33 (33)
100 (100)
Transfusion details
Quality of reporting (NOS) of 9
First author and year of publication Howard 199517
United
37 340 (2012)
1991-1993
Kingdom
21.2% HbSC transfused in
4
1st or 2nd trimester (prophylactic);
Ngo 201018
France
36 720 (2012)
1994-2004
33 (33)
128 (128)
Prophylactic transfusion for
7
all HbSC Serjeant 2005*6
Jamaica
5120 (2012)
1973-2004
43 (95)
68 (157)
11.6% HbSC (on clinical
6
indications) Sun 200120
United
52 610 (2012)
1980-1995
58 (58)
61 (129)
States Wilson 201223
Ghana
21% of HbSC (on clinical
6
indications) vs 0% controls 1910 (2012)
2007-2008
112 (112)
717 (717)
No data on transfusion for study population
All studies were historical cohort studies of pregnancy except for those marked *, which were prospective pregnancy cohort studies.
5
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Table 4. Characteristics of studies comparing pregnancy outcome in women with SCD (genotype unspecified) against women with no sickle cell disease
Country
GNI $ (year)
Duration of study
Total N
Unspecified SCD women, N (N pregnancies)
No SCD women, N (N pregnancies)
24 794 (24 969)
26 147 824 (26 181 224)
4262 (4262)
8 817 059 (8 817 059)
Transfusion details
Quality of reporting (NOS) of 9
First author and year of publication Alayed 201324
Canada
42 530 (2012)
1999-2008
No data on transfusion for
6
study population Al Mulhim 200025
Saudi
30 160 (2011)
1997-1998
61 (61)
84 (84)
Arabia
45.9% SCD (on clinical
5
indications) vs 1.1% controls
Barfield 201026
United
52 610 (2012)
1998-2006
488 (663)
83 877 (115 160)
States Boulet 201327
5
study population
United
52 610 (2012)
2004-2010
1526 (1526)
333 822 (333 822)
States Muganyizi 201328
No data on transfusion for 12.9% SCD vs 1.2% controls
3
(indication not given)
Tanzania
1,560 (2012)
1999-2011
149 (149)
155 207 (157 324)
No data on transfusion for
5
study population Natu 201429
India
3,910 (2012)
2012
25 (25)
500 (500)
60.0% SCD (prophylactic)
4
and 40.0% (on clinical indications) vs 0% controls Rajab 200630
Bahrain
18 910 (2010)
1998-2002
331 (331)
331 (331)
48.9% SCD (top-up
6
transfusion); 3% SCD (exchange transfusion) for prophylaxis Villers 200831
United
52 610 (2012)
2000-2003
17 952 (17 952)
16 756,944 (16 756,944)
States
No raw data on transfusion
4
for study population
All studies were historical cohort studies of pregnancy.
increased risk in women with HbSC disease (RR, 1.78; 95% CI, 1.05-3.02) compared with women without SCD (Figure 4). There was a similar increased risk of neonatal death in women with HbSS disease (RR, 2.68; 95% CI, 1.49-4.82). Only 1 study reported neonatal deaths in women with HbSC disease, giving an RR of 1.78 (95% CI, 0.52-12.41). The risks of preterm delivery were increased in a similar manner, with more than twofold increased risk in women with HbSS disease (RR, 2.21; 95% CI, 1.47-3.31) and a lower, nonsignificant increase in women with HbSC disease (RR, 1.45; 95% CI, 0.86-2.43) compared with women without SCD (Figure 5); there was
greater heterogeneity in the studies in HbSC disease, with 1 study reporting no increase. Most studies did not differentiate between spontaneous preterm deliveries and those where labor and delivery were initiated by medical staff for maternal or fetal complications. There was a nearly fourfold increased risk of infants being born small for gestational age (,10th centile) in women with HbSS disease (RR, 3.72; 95% CI, 2.32-5.98) and a twofold risk in women with HbSC disease (RR, 1.98; 95% CI, 1.04-3.77) compared with women without SCD (Figure 6); heterogeneity was low across studies.
Table 5. Newcastle-Ottawa quality appraisal First author (year)
Study design
Selection
Comparability
Exposure/outcome
Afolabi 200912
Historical cohort
****
*
*
6
Alayed 201324
Historical cohort
***
**
*
6
Al Jama 200913
Historical cohort
****
**
*
7
Al Kahtani 201214
Historical cohort
****
**
*
7
Al Mulhim 200025
Historical cohort
***
*
*
5
Balgir 199715
Historical cohort
*
**
*
4
Barfield 201026
Historical cohort
**
*
**
5
Boulet 201327
Historical cohort
*
*
*
3
Daigavane 201316
Total of 9
Prospective cohort
**
*
*
4
Howard 199517
Historical cohort
**
*
*
4
Muganyizi 201328
Historical cohort
***
*
*
5
Natu 201429
Historical cohort
**
*
*
4
Ngo 201018
Historical cohort
****
*
**
7
Rajab 200630
Historical cohort
***
*
**
6
Serjeant 200419
Prospective cohort
****
**
*
7
Serjeant 20056
Prospective cohort
***
**
*
6
Sun 200120
Historical cohort
***
**
*
6
Prospective cohort
***
**
*
6
Thame 200722
Historical cohort
****
*
**
7
Villers 200831
Historical Cohort
*
*
**
4
Wilson 201223
Historical Cohort
**
*
**
5
Thame 201321
Each asterisk corresponds to a score of one.
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SICKLE CELL DISEASE IN PREGNANCY: META-ANALYSIS
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Figure 2. Forest plot of studies investigating the association of SCD with maternal mortality.
Meta-regression demonstrated that genotype (HbSS vs HbSC) had a significant influence on adverse perinatal outcomes (stillbirth, preterm delivery, and small for gestational age infants), but not on the
occurrence of preeclampsia (Table 6). There was substantially and significantly lower maternal mortality (odds ratio, 0.15; 95% CI, 0.02-0.86) and stillbirth (odds ratio, 0.28; 95% CI, 0.14-0.55) in women with
Figure 3. Forest plot of studies investigating the association of SCD with preeclampsia.
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BLOOD, 21 MAY 2015 x VOLUME 125, NUMBER 21
Figure 4. Forest plot of studies investigating the association of SCD with stillbirth.
SCD from countries with a gross national income of $30 000 or greater, but no significant impact of meta-regression by gross national income on preeclampsia, preterm delivery, or small for gestational age infants.
Figure 5. Forest plot of studies investigating the association of SCD with preterm delivery.
There was an impact of quality of reporting, with higher odds ratios being reported for all outcomes in high-quality studies compared with low-quality studies.
From www.bloodjournal.org by guest on September 11, 2016. For personal use only. BLOOD, 21 MAY 2015 x VOLUME 125, NUMBER 21
SICKLE CELL DISEASE IN PREGNANCY: META-ANALYSIS
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Figure 6. Forest plot of studies investigating the association of SCD with delivery of small for gestational age infant.
Discussion This systematic review and meta-analysis identified a strong association between SCD and adverse outcome for the mother (including maternal mortality and preeclampsia) and baby (including perinatal death, preterm delivery, and small for gestational age infants). Women with HbSS disease had significantly worse perinatal outcomes compared with those with HbSC disease, in a similar pattern to complications outside of pregnancy, and maternal mortality and stillbirth were substantially lower in high-income countries; studies rated as high quality reported increased relative risks that were generally double those of the low-quality studies. This may reflect better ascertainment of outcome data in the high-quality studies. To the best of our knowledge, this study represents the first systematic review and meta-analysis of outcomes for pregnancies complicated by SCD. We used a comprehensive and systematic literature search, not limited by language or setting. The pooled sample size of .26 000 pregnancies in women with SCD increases the reliability of the pooled estimates for each outcome. It remains a limitation of the source data that most of the included studies were of historical design, single institution origin, and of mixed quality rating. Furthermore, a number of studies failed to define the precise genotypic diagnosis of the participants or analyze pregnancy outcomes by genotype separately. However, we tried to mitigate this limitation by stratifying the study populations into the specific genotypes (together with a SCD nonspecified group) where
possible. It was also not possible to adjust the confidence intervals for the relatively small amount of clustering caused by 1.8% of women being included in the study more than once with different pregnancies, and confidence intervals might be slightly too narrow in consequence. The meta-analysis includes 5 population-wide studies; the larger sample sizes and greater number of institutions included allow increased generalizability and precision in the generation of pooled risk ratios estimates, but are subject to caution over accuracy of coding. Variation in management strategies across settings may have influenced the pregnancy outcomes; this may either have occurred through a direct impact on ameliorating pregnancy outcomes (eg, there is an uncertain benefit of prophylactic vs clinically indicated exchange transfusion in women with SCD) or through different thresholds for delivery depending on availability of neonatal care facilities (which may influence gestation of delivery in a woman with preeclampsia). Most studies included in the review did not provide comprehensive details of their management pathway for pregnant women with SCD, and the considerable heterogeneity of transfusion management plans precluded formal statistical comparison of the influence of this factor. We limited the review and meta-analysis to well-delineated outcomes, reported across the majority of the studies as other end points (such as maternal jaundice, pulmonary hypertension, sepsis, thromboembolism, abruption, postpartum hemorrhage, and congenital fetal abnormality) were not reported consistently and the data on increased occurrence in SCD are conflicting).
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Table 6. Meta-regression by disease genotype, country gross national income, and quality of study reporting Odds ratios Nonspecified SCD
P value (x2)
HbSS
HbSC
P value (LR test*)
Preeclampsia
2.7 (1.8-3.9)
1.9 (1.1-3.2)
2.6 (2.4-2.8)
.43*
Stillbirth
4.0 (2.8-5.6)
1.9 (1.04-3.4)
3.7 (2.8-4.9)
.04*
Preterm delivery
2.2 (1.8-2.7)
1.2 (0.8-1.6)
1.6 (1.4-1.7)
Small for gestational age infants
4.0 (3.1-5.2)
1.6 (0.79-3.1)
1.5 (1.2-1.8)
Disease genotype Maternal mortality
Country gross national income
No deaths
.0007* ,.001
GNI $ $30 000 ,.001
Maternal mortality
0.15 (0.02-0.86)
Preeclampsia
0.59 (0.24-1.42)
.24
Stillbirth
0.28 (0.14-0.55)
,.001
Preterm delivery
0.78 (0.40-1.51)
.46
Small for gestational age infants
0.89 (0.42-1.92)
Quality of study reporting
.77
High quality
Low quality
23.2 (13.5-40.1)
11.2 (8.2-15.4)
,.001
Preeclampsia
3.1 (2.8-3.4)
2.0 (1.7-2.2)
,.001
Stillbirth
6.5 (3.7-11.6)
3.2 (2.6-4.1)
.03
Preterm delivery
2.7 (2.1-3.4)
1.5 (1.4-1.6)
,.001
Small for gestational age infants
3.9 (3.0-5.0)
1.5 (1.2-1.8)
,.001
Maternal mortality
The P value for the likelihood ratio (LR) test is for a comparison between the HbSS and HbSC group results.
With improvements in clinical management that have focused on early identification and treatment of manifestations with the aim of reducing complications, women with SCD are surviving into adulthood and actively considering reproductive options. Previous narrative reviews2,32,33 have summarized the studies, but a systematic review permits quantification of the risks for use in prepregnancy and pregnancy counseling. It is of particular concern that women with SCD have a markedly increased risk in maternal mortality. Studies from Europe and Jamaica looking at patterns of mortality in SCD highlight acute chest syndrome, sepsis, and multiorgan failure as the 3 major causes of death.17,34 Many studies in our systematic review did not elaborate on the precise cause of maternal death or to what extent SCD contributed directly or indirectly. The risk of maternal mortality in HbSS women was quantified as being sixfold compared with women without SCD, whereas in the studies of women with HbSC disease, there was 1 maternal death (of 279 women reported), and the risk of maternal morbidity in both groups remains substantial. There is a substantial difference in magnitude of risk of maternal death and stillbirth between countries with high and low gross national income (dichotomized at $30 000), even though the odds ratios for preeclampsia, preterm delivery, and small for gestational age infants were not significantly different, suggesting that the risk of death is dependent on the availability of adequate health care resources and expertise and the variable implementation of prophylactic or indicated exchange blood transfusion practices. This may be aggravated by the difficulties in identification of those at greatest risk of mortality; a recent Jamaican study showed that a third of those dying from multiorgan failure and acute chest syndrome had had only mild disease before the final events.34 SCD has been proposed to be a chronic inflammatory state35,36; endothelial damage secondary to sickled red blood cells and the subsequent release of proinflammatory cytokines may contribute to microvascular damage.37 Normal vascular, endothelial, and inflammatory adaptations in pregnancy may lead to exacerbation of these pathophysiologic changes, with manifestation of resulting maternal complications such as preeclampsia and fetal growth restriction. There are data from a small case-control study to demonstrate an association between SCD, abnormal mid-trimester uterine artery Doppler waveforms,38,39 abnormal placental histology, including placental
lesions of moderate-to-severe villous sclerosis, intervillous fibrin deposits, and infarction,40 and subsequent delivery of small for gestational age infants. Prophylactic interventions to reduce preeclampsia are limited, but low-dose aspirin from mid-trimester to the end of pregnancy has been shown to decrease the occurrence of preeclampsia in other groups of high-risk women41; although never formally tested in a randomized controlled trial specifically in women with SCD, it is highly likely that aspirin is similarly beneficial in these women. Regular third trimester screening for fetal growth may also represent a strategy to reduce adverse outcome such as stillbirth linked to fetal growth restriction, but it is accepted that this resource would be of limited availability to less privileged health care providers.42 Further research, with appropriately powered prospective studies and strict genotype diagnosis and outcome ascertainment, is needed to understand the reasons behind the increased risks of morbidity and mortality in women with SCD, particularly those with HbSS genotype and in low income countries. There is interest in strategies such as selective prophylactic exchange transfusion43; the most recent Cochrane systematic review and meta-analysis of 2 trials in this population concluded that there was no clear benefit of prophylactic transfusion over a selective (emergency) approach.44 There is an urgent need for adequately powered trials of transfusion modalities in this high-risk group of pregnant women with appropriate choice of maternal and perinatal outcome measures. In high-income countries, women with SCD are usually managed by a multidisciplinary team of obstetricians, hematologists, specialist midwives, and anesthetists, but the greatest burden of morbidity and mortality undoubtedly lies within low and middle income countries, where access to specialist antenatal care may be limited. This systematic review and meta-analysis provides useful estimates of the morbidity and mortality associated with the condition and should encourage global health care policy makers, researchers, and clinicians to work together to reduce the maternal and perinatal adverse outcomes described.
Acknowledgment The authors thank the librarian at the Royal College of Obstetricians and Gynaecologists (Lisa Xue) for help with obtaining some of the articles.
From www.bloodjournal.org by guest on September 11, 2016. For personal use only. BLOOD, 21 MAY 2015 x VOLUME 125, NUMBER 21
SICKLE CELL DISEASE IN PREGNANCY: META-ANALYSIS
Authorship Contribution: E.O.-N., L.C.C., and P.D. designed the study; E.O.-N., D.M., and L.W. conducted the literature searches; and all authors contributed to the writing of the manuscript and approved the final version.
3325
Conflict-of-interest disclosure: J.H. has been on the advisory board for Novartis and AesRx. All other authors declare no competing financial interests. Correspondence: Eugene Oteng-Ntim, Women’s Health Directorate, Guy’s and St Thomas’ NHS Foundation Trust, London SE1 7EH, United Kingdom; e-mail: [email protected].
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3. Piel FB, Patil AP, Howes RE, et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet. 2013; 381(9861):142-151. 4. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376(9757):2018-2031. 5. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095-2128. 6. Serjeant GR, Hambleton I, Thame M. Fecundity and pregnancy outcome in a cohort with sickle cell-haemoglobin C disease followed from birth. BJOG. 2005;112(9):1308-1314. 7. Adekile AD. What’s new in the pathophysiology of sickle cell disease? Med Princ Pract. 2013;22(4): 311-312. 8. Stroup DF, Berlin JA, Morton SC, et al. Metaanalysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008-2012. 9. Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa scale (NOS) for assessing the quality of non-randomised studies in metaanalyses. Available at: http://www.ohri.ca/ programs/clinical_epidemiology/oxford.asp. Accessed September 1, 2014. 10. Rabe-Hesketh S, Skrondal A, Pickles A. Maximum likelihood estimation of limited and discrete dependent variable models with nested random effects. J Econom. 2005;128(2):23. 11. Harbord R, Higgins J. Metaregression in Stata. Stata J. 2008;8(4):493-519. 12. Afolabi BB, Iwuala NC, Iwuala IC, Ogedengbe OK. Morbidity and mortality in sickle cell pregnancies in Lagos, Nigeria: a case control study. J Obstet Gynaecol. 2009;29(2):104-106. 13. Al Jama FE, Gasem T, Burshaid S, Rahman J, Al Suleiman SA, Rahman MS. Pregnancy outcome in patients with homozygous sickle cell disease in a university hospital, Eastern Saudi Arabia. Arch Gynecol Obstet. 2009;280(5):793-797. 14. Al Kahtani MA, AlQahtani M, Alshebaily MM, Abd Elzaher M, Moawad A, Aljohani N. Morbidity and pregnancy outcomes associated with sickle cell anemia among Saudi women. Int J Gynaecol Obstet. 2012;119(3):224-226. 15. Balgir RS, Dash BP, Das RK. Fetal outcome and childhood mortality in offspring of mothers with sickle cell trait and disease. Indian J Pediatr. 1997;64(1):79-84.
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43. Asma S, Kozanoglu I, Tarım E, et al. Prophylactic red blood cell exchange may be beneficial in the management of sickle cell disease in pregnancy. Transfusion. 2015;55(1):36-44.
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2015 125: 3316-3325 doi:10.1182/blood-2014-11-607317 originally published online March 23, 2015
Adverse maternal and perinatal outcomes in pregnant women with sickle cell disease: systematic review and meta-analysis Eugene Oteng-Ntim, Daveena Meeks, Paul T. Seed, Louise Webster, Jo Howard, Pat Doyle and Lucy C. Chappell
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