research paper

Improvement of medical care in a cohort of newborns with

sickle-cell disease in North Paris: impact of national guidelines

Nathalie Couque,1 Delphine Girard,2,3 Summary

Rolande Ducrocq,1 Priscilla Boizeau,2
We conducted a retrospective study on newborns with sickle-cell disease
Zinedine Haouari,4,5 Florence Missud,4,5
Laurent Holvoet,4,5 Ghislaine Ithier,4,5 (SCD), born 1995–2009, followed in a multicentre hospital-based network.
Marie Belloy,6 Marie-H
el
ene Odievre,7 We assessed patient outcomes, medical care and compliance with the
Michel Benemou,8 Patricia Benhaim,9 national guidelines published in December 2005. Data from 1033 patients
Brigitte Retali,10 Philippe Bensaid,11 (742 SS/Sb°-thalassaemia) with 6776 patient-years of follow-up were anal-
Brigitte Monier,12 Valentine Brousse,13 ysed (mean age 7
1  3
9 years). SCD-related deaths (n = 13) occurred
Roger Amira,14 Christine Orzechowski,15 only in SS-genotype patients at a median age of 23
1 months, mainly due
Emmanuelle Lesprit,16 Laurent Man- to acute anaemia (n = 5, including 2 acute splenic sequestrations) and
gyanda,17 Nathalie Garrec,18 Jacques infection (n = 3). Treatment non-compliance was associated with a 10-fold
Elion,1,3,19 Corinne Alberti,2,3,20 André higher risk of SCD-related death (P = 0
01). Therapeutic intensification
Baruchel4,3,21 and Malika Benkerrou4,5,20
1
was provided for all stroke patients (n = 12), almost all patients with
G
en
etique Mol
eculaire et Biochimie, AP-HP,
abnormal transcranial Doppler (TCD) (n = 76) or with >1 acute chest syn-
H^opital Robert-Debr
e, 2Unit
e d’Epid
emiologie
drome/lifetime (n = 64) and/or ≥3 severe vaso-occlusive crises/year
Clinique, AP-HP, H^opital Robert-Debr
e, 3Univ
Paris Diderot, Sorbonne Paris Cit
e, 4Service
(n = 100). Only 2/3 of patients with baseline haemoglobin <70 g/l received
d’H
ematologie P
ediatrique, AP-HP, H^opital intensification, mainly for other severity criteria. Overall, hydroxycarbamide
Robert-Debr
e, 5Centre de R
ef
erence de la was under-prescribed, given to 2/3 of severe vaso-occlusive patients and 1/3
Dr
epanocytose, 6H^opital Robert Ballanger, Aul- of severely anaemic patients. Nevertheless, introduction of the on-line
nay sous Bois, France, 7AP-HP, H^opital Louis guidelines was concomitant with an improvement in medical care in the
Mourier, Colombes, France, 8H^opital de Gonesse, 2006–2009 cohort with a trend towards increased survival at 5 years, from
Gonesse, France, 9AP-HP, H^opital Jean Verdier, 98
3% to 99
2%, significantly increased TCD coverage (P = 0
004) and ear-
10
Bondy, France, Centre Hospitalier Ren
e Dubos, lier initiation of intensification of therapy (P ≤ 0
01).
11
Pontoise, France, Centre Hospitalier Victor
Dupouy, Argenteuil, France, 12
Hôpital Simone Keywords: hydroxycarbamide, mortality, newborn screening, sickle cell dis-
Veil, Montmorency, France, AP-HP, Hôpital 13 ease, transfusion.
Necker-Enfants Malades, 14Centre Hospitalier
Intercommunal de Saint-Denis, Saint-Denis,
15
France, Centre Hospitalier de Bry-sur-Marne,
16
Bry-sur-Marne, France, AP-HP, Hôpital
17
Armand Trousseau, CHI des Portes de l’Oise,
18
Beaumont-sur-Oise, France, Centre Hospitalier
19
de Marne-la-Vallée, Jossigny, France, Inserm
20 21
UMR S1134, Inserm 1123, and Institut
Universitaire d’Hématologie (EA3518), Univer-
sité Paris Diderot, Paris, France

Received 2 October 2015; accepted for

publication 27 December 2015
Correspondence: Malika Benkerrou, Centre de
R
ef
erence de la Dr
epanocytose, H^
opital
Robert-Debr
e, 48 boulevard S
erurier, 75019

ª 2016 John Wiley & Sons Ltd First published online 7 April 2016
British Journal of Haematology, 2016, 173, 927–937 doi: 10.1111/bjh.14015
N. Couque et al
Paris, France.
E-mail: malika.benkerrou@rdb.aphp.fr
Sickle-cell disease (SCD) is a group of genetic haemoglobin
disorders characterized by a mutation in the HBB gene (HBB
E6V, also termed HbS mutation). It causes multiple-system
morbidity and an increased risk of mortality, starting in the
first years of life. Patients with sickle-cell anaemia (SS) or
sickle b°-thalassaemia (Sb°) have the most severe disease,
whereas patients with sickle haemoglobin C disease (SC) or
sickle b+-thalassaemia (Sb+) tend to have less severe disease
(Powars et al, 1990; Gill et al, 1995). Newborn screening
with early implementation of preventive therapies has dra-
matically improved survival in children with SCD (Vichinsky
et al, 1988; Lee et al, 1995; Almeida et al, 2001; Kmietowicz,
2004). Preventive measures include prophylaxis of infection
with penicillin V (Gaston et al, 1986), vaccination against
Streptococcus pneumoniae, parental education about preven-
tive handling of potentially life-threatening events such as
infection and splenic sequestration, as well as transcranial
Doppler (TCD) screening in order to detect cerebrovascular
stenosis and to implement chronic transfusion (CT) to pre-
vent stroke (Adams et al, 1998).
In France, SCD has become the most common genetic
disease, with an overall prevalence of 1/2221 newborns
[Association Francßaise de D
epistage et de Pr
evention des
Handicaps de l’Enfant (AFDPHE) 2013]. Screening of new-
borns for SCD was started in the French West Indies in
1985 (Bardakdjian-Michau et al, 2009). In 1995, screening
targeted to at-risk newborns became part of the French
national newborn screening programmes in metropolitan
areas, including the Paris area, and was extended nation-
wide in 2000 by AFDPHE. Recently, data from single-cen-
tre cohorts of newborns in the USA (Quinn et al, 2004,
2010), England (Telfer et al, 2007) and France (Bernaudin
et al, 2011) have documented improved overall survival in
children with SCD. These results are confirmed by sequen-
tial overall mortality rates in the USA (Hamideh &
Alvarez, 2013). The two smaller cohorts also analysed
either the occurrence of specific events, i.e. micro- and
macro-vasculopathy in the Cr
eteil cohort (Bernaudin et al,
2011), or age at first SCD-related event in the East Lon-
don cohort (Telfer et al, 2007). Our aim was to assess the
extent to which current care follows national and interna-
tional guidelines (HAS 2010, Yawn et al, 2014), as well as
the impact of national on-line guidelines, published at the
end of 2005, on patient outcomes and care between the
two periods in a large cohort of newborns with SCD.
Thus, we retrospectively analysed patients born between
1995 and 2009 diagnosed with SCD through newborn
screening in the national reference laboratory at Robert-
Debr
e Teaching Hospital (Paris, France) and followed
928
through a multicentre hospital-based network in the north
of Paris.
Patients and methods
Patients
Patients with SCD were identified through newborn screen-
ing at the national reference laboratory of Robert-Debr
e
Hospital, as previously described (Galacteros et al, 1980;
Ducrocq et al, 2001).
The paediatric reference centre at Robert-Debr
e Teaching
Hospital is the referral centre for children with SCD in the
northern part of the Paris area, coordinating a hospital-based
network of local paediatric teams belonging to the national
SCD network.
In the North Paris area, parents and newborns with results
indicating a major haemoglobin disorder are given an
appointment with the local hospital’s reference paediatrician
for SCD, who explains the disease, performs confirmatory
laboratory tests, initiates preventive therapy and provides
follow-up.
We retrospectively analysed the cohort of patients with
SCD born between 1995 and 2009 whose follow-up was
coordinated by the paediatric SCD reference centre at
Robert-Debr
e Hospital.
Ethics statement
The Institutional Review Board of North Paris Hospitals,
University Paris 7, Paris Public Hospital Network
(IRB00006477, no. 11-076) approved the study protocol,
including the information sheet and oral consent procedure.
Oral consent was recorded in the patient’s medical file. The
study database was approved by the French National Com-
mittee for Computerized Databases (CNIL-911449). Patient
data were rendered anonymous in the database.
Patient management
Patient management was recorded and compared to interna-
tional and national guidelines for treating children with
SCD, available on-line since December 2005 (HAS 2010).
Standard treatment protocols included prophylaxis with
penicillin V, folic acid supplementation, pneumococcal and
hepatitis B vaccinations. The 23-valent pneumococcal
polysaccharide vaccine was considered to have been appro-
priately administered when it was given between 18 and
28 months of age with boosters every 3–5 years, and the
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2016, 173, 927–937

heptavalent pneumococcal conjugate vaccine, available since
2000, was appropriately administered when patients received
at least 3 doses before 18 months of age with at least two
doses prior to 6 months of age.
Medical visits were recommended at 2, 4 and 6 months
and then every 3 months. Laboratory data were collected at
2 months and then at least every 6 months. TCD was per-
formed in Robert-Debr
e Hospital starting in 1996, initially
between 12 and 24 months of age and then annually. TCD
was progressively implemented in other hospitals after 1998.
Annual follow-up was considered to have been appropri-
ately performed when the following data where available: at
least (i) two physical examinations per year, (ii) one set of
steady-state laboratory tests every year, (iii) in SS/Sb°
patients, one TCD every 2 years, (iv) abdominal ultrasonog-
raphy every 2 years starting at 3 years of age, and (v) one
ophthalmic examination every 2 years after 6 years of age in
SC patients, after the first decade in the other patients.
Vaso-occlusive crisis (VOC) was defined as acute non-
infectious, non-traumatic pain requiring analgaesics for more
than 12 h. For the purposes of the study, we recorded only
severe VOC requiring admission and opioids. Acute chest
syndrome (ACS) was defined as a new pulmonary infiltrate
on chest x-ray, with or without pain, cough, fever (≥38
5°C)
or hypoxaemia. For the purposes of the study, we recorded
only severe ACS involving at least one entire lobe on chest x-
ray. Acute anaemic events were reductions in haemoglobin
(Hb) ≥20% versus steady state. Acute splenic sequestration
(ASS) was defined as splenic enlargement with palpated
spleen size increased ≥2 cm from baseline associated with
acute anaemia. Cerebrovascular disease was defined as abnor-
mal findings on two consecutive TCDs, performed 1–
3 months apart, or conditional TCD with abnormal magnetic
resonance angiography or overt stroke confirmed by mag-
netic resonance imaging. TCD velocities were considered
abnormal when ≥2 m/s and conditional when ≥1
7 m/s but
<2 m/s (Adams et al, 1992).
Patients with cerebrovascular disease or more than two
episodes of ASS before 2 years of age received CT, mainly
partial exchange transfusion. Patients who had ≥3 severe
VOCs/year or >1 ACS/lifetime received CT until 2 years of
age and hydroxycarbamide (HC) after 2 years of age. Geno-
identical haematopoietic stem-cell transplantation (HSCT)
was proposed for patients with confirmed cerebrovascular
disease or patients with persistent vaso-occlusive disease
despite well-conducted HC therapy.
Data collection
Data were collected from the patients’ medical files until
December 2010 by a team of expert MDs and PhDs, using a
web-based case report form specifically developed for the study.
The parents’ geographic origin was classified as West Africa
(Senegal, Mali, Mauritania, Guinea-Conakry, Guinea-Bissau,
Cape Verde and Gambia), Benin Gulf (Ivory Coast, Ghana,
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2016, 173, 927–937
Newborn screening in North Paris
Togo, Benin, Nigeria, Niger and Burkina Faso), Central Africa
(Democratic Republic of Congo, Congo-Brazzaville, Central
African Republic, Angola, Gabon, Cameroon and Chad), the
Caribbean, other (both parents from other geographic regions)
and mixed (parents from different geographic regions).
Demographic data were recorded, confirmatory results,
outcome and criteria of severe disease, defined as at least one
of the following: >1 ACS/lifetime or ≥3 severe VOCs/year,
overt stroke, confirmed TCD abnormality, as well as steady-
state Hb <70 g/l at least 3 weeks after a clinical event and
3 months after transfusion. Specific therapies, including CT,
HC and HSCT, were recorded.
Patients were considered non-compliant when they
attended one or fewer medical visits per year and/or did not
comply with vaccination schedules or did not take preventive
medication as instructed by their paediatrician.
Patients were considered to be lost to follow-up when more
than 2 years had elapsed between the last medical visit and the
end of the study. The national blood-bank registry was con-
sulted in order to ensure that these patients were still alive.
Statistical analysis
The results are expressed as numbers and percentages for cat-
egorical variables and as a mean ( standard deviation) or
median (25th quartile; 75th quartile) for continuous variables,
depending on their distribution.
Given that patients with SS or Sb° tend to have a more sev-
ere clinical course than those with SC or Sb+, we stratified the
analysis into two groups, SS/Sb° (including SDPundjab) and SC/
Sb+ (including HbSE) patients. Furthermore, in order to assess
the impact of the on-line guidelines, published at the end of
2005, a further analysis was stratified by period of entry into
the cohort, i.e. pre- or post-publication of the guidelines.
The distribution of variables regarding (i) genotype, and
(ii) period of entry into the cohort was assessed using the
chi-square test (or Fisher’s test, when appropriate) for cate-
gorical variables, and the t-test (or Wilcoxon test, when
appropriate) for continuous variables.
Entry into the cohort was defined as the date of the birth.
Data were censored at the date of the last clinic visit (be-
tween 31 December 2008 and 31 December 2010), or at the
date of loss to follow-up (if the date of the last clinic visit
was before 31 December 2008), or at the date of death or
HSCT. Overall survival was defined as time from birth to
date of last follow-up, HSCT or death. We calculated the
overall and age-specific incidence rates per 100 patient-years
of observation for overall death, SCD-related death, SCD-
related death depending on the period of entry into the
cohort, stroke and abnormal TCD.
Survival curves were computed by the Kaplan-Meier
method and compared by the log-rank test. All tests were
two-sided with a significance level of 0
05. Statistical analyses
were performed using SAS statistical software Version 9.3
(SAS Institute, Cary, NC, USA).
929
N. Couque et al

deaths occurred in SS patients. The primary cause of SCD-

Results
Characteristics of the cohort
Between 1995 and 2009, 1047 consecutive newborns with
SCD were identified through newborn screening. Despite all
efforts, 14 children (1
3%) could not be located and were
excluded from the analysis. Data from 1033 patients, with
6776 patient-years of follow-up, were analysed. The charac-
teristics of the cohort are shown in Table I. The mean age of
the cohort was 7
1  3
9 years. Sixty patients were lost to
follow-up, half of whom because of relocation. The mean age
at loss to follow-up was 3
2  3
4 years.
Mortality
Overall, 17 children died. The median age at death was
14
9 months (5
4;56
0) (range 0
2–89
0). Overall survival at
15
8 years was 97
1% [95% confidence interval (CI):
(95
2;98
3)] in SS/Sb° patients and 99
6% [95%CI:
(97
4;99
9)] in SC/Sb+ patients.
The causes of death and age at death are summarized in
Table II.
Four deaths were unrelated to SCD, 3 deaths in the
neonatal period and 1 death involving maternal suicide with
infanticide.
Thirteen deaths were SCD-related, at a median age of
23
1 months (10
0;57
2) (range 5
5–89
0). All SCD-related
related death was acute anaemia in 5 patients, two of which
occurred while the patients were in rural or urban settings in
West Africa. Three patients died of pneumococcal infection.
All three had irregular follow-up and interruption of prophy-
laxis with penicillin V. The two children born prior to the
conjugate vaccine received the recommended schedule of the
polysaccharide vaccine. The third child received a full sched-
ule with the conjugate vaccine, with no polysaccharide vac-
cine booster, prior to death at 36 months. Two deaths were
of unknown origin: one child died at 6 months of age in a
rural sub-Saharan setting; the other died at 9 months of age,
at home, of a non-anaemic non-septic acute seizure event.
Among SS/Sb° patients, 6% (n = 44) were assessed as
non-compliant based on their files, as well as by their paedia-
trician. They were over-represented among patients with
SCD-related mortality (P = 0
01).
SCD-related complications requiring specific
intensification therapies
We focused on some early SCD-related complications,
namely recurrent VOC, recurrent ACS, abnormal TCD,
stroke and chronic anaemia with Hb <70 g/l, which require
specific therapeutic intensification. The results are summa-
rized in Table III.
In the SC/Sb+ group, 1% of patients (n = 3) had ≥3 sev-
ere VOCs/year. None received intensified therapy.

Table I. Characteristics of the North Paris cohort

SS/Sb° group SC/Sb+ group Total

n = 742 n = 291 n = 1033

Genotype
SS 713 (96
1%) – 713 (69
0%)
Sb° 28 (3
8%) – 28 (2
7%)
SDPunjab 1 (0
1%) – 1 (0
1%)
SC – 215 (73
9%) 215 (20
8%)
Sb+ – 74 (25
4%) 74 (7
2%)
SE – 2 (0
7%) 2 (0
2%)
Male gender 384 (51
8%) 156 (53
6%) 540 (52
3%)
Family origin
West Africa 256 (34
5%) 119 (41%)
Benin Gulf 101 (13
5%) 85 (29%)
Central Africa 216 (29%) 13 (4
5%)
Caribbean 93 (13%) 47 (16%)
Other 22 (3%) 14 (5%)
Mixed 54 (7%) 13 (4
5%)
Age (years) 7
2  3
9 7
1  3
9 7
1  3
9
Patient-years of observation 4938 1838 6776
Actively evaluated within the 684 + 14*(94
1%) 257 + 1*(88
6%) 941 + 15*(92
5%)
past 2 years + vital status only*
Lost to follow-up 28 (3
8%) 32 (11
0%) 60 (5
8%)
Deceased 16 (2
2%) 1 (0
3%) 17 (1
7%)

Values shown are mean  standard deviation and numbers (percentages).

*Patients for whom only vital status was retrieved.

930 ª 2016 John Wiley & Sons Ltd

British Journal of Haematology, 2016, 173, 927–937
 Newborn screening in North Paris

Table II. Deaths in the North Paris cohort ≥3 VOCs/year and/or >1 ACS/lifetime, occurred respectively
in 13% (n = 97) and 8
6% (n = 64) of SS/Sb° patients.
Age at
Causes of death Number Genotype death (months)
Overt stroke was observed in 1
6% of patients (n = 12), all
with the SS genotype, at a median age of 3
5 years (range
SCD-related deaths 1
8–11
6). Two of the patients had no cerebral micro- or
Acute anaemia*,† 5 SS 8, 8, 17, 57, 86 macro-vasculopathy: one of the strokes occurred during
Pneumococcal infection 3 SS 23, 36, 89
extracorporeal circulation and membrane oxygenation for
Recurrent strokes 1 SS 56
acute respiratory distress syndrome, following ACS, with sub-
Acute chest syndrome 1 SS 84
sequent cerebral blood-clot embolism, and the other
Dehydration 1 SS 5
5
Unknown† 2 SS 6, 9 occurred during parvovirus-B19 infection with a concomitant
Total 13 23
1‡ acute anaemic event and ACS.
Non-SCD related deaths Furthermore, 10
2% of patients (n = 76) in the SS/Sb°
Congenital cardiopathy 1 SS 1 group had an abnormal TCD, with a median age of 4
4 years
Prematurity 1 SS 0
23 (3
4;6
5), 4 of whom previously had a conditional result. The
Maternal-foetal infection 1 SS 1 incidences of stroke and abnormal TCD are presented in
Maternal suicide + 1 SC 15 Table IV.
infanticide Eighty patients, representing 10
8% of SS/Sb° patients,
Total 4 1‡
had chronic severe anaemia with Hb <70 g/l.
Overall deaths 17 14
9‡
Concerning specific intensification therapies, CT was per-
SCD, sickle cell disease. formed at least once in 141 patients, all in the SS/Sb° group.
*Causes of acute anaemia were acute splenic sequestration (n = 2), Mean age at initiation was 4
9  2
6 years. Median duration
parvovirus B19 erythroblastopenia (n = 1) in sub-Saharan Africa, was 19 months (9
2;89
2), and the main reasons were cerebral
post-cholecystectomy haemorrhage (n = 1), unknown mechanism vasculopathy without stroke (n = 73), stroke (n = 12) or con-
(n = 1) in sub-Saharan Africa. ditional TCD together with stenosis on magnetic resonance
†Three deaths occurred during unprepared visits to sub-Saharan
angiography (n = 10). Other frequent reasons for CT were
Africa (two acute anaemic events and 1 of unknown cause).
recurrent ASS, in 16 patients, and chronic anaemia in 6.
‡Median age.
HC was prescribed to 136 patients, all in the SS/Sb°
Table III. SCD-related complications and specific therapies among group, mainly for severe vaso-occlusive disease (n = 76, 39
SS/Sb° patients ACS and 37 VOC) at a mean age of 6
6  2
6 years. Only
14 had stopped it during follow-up.
First period Second
(<2006) period (≥2006)* Total
HSCT was performed in 11 patients, 10 for cerebrovascu-
n = 480 n = 260 n = 740* lar disease and 1 for severe vaso-occlusive disease, with a
median age of 7
8 years (5
5;11
8).
SCD-related complications†
≥3 VOCs/year 79 (17
6%) 18 (7
2%) 97 (13
9%)
>1 ACS 54 (12
1%) 10 (4
0%) 64 (9
2%) Compliance of specific intensification of therapy with
overt stroke 11 (2
5%) 1 (0
4%) 12 (1
7%) national and international guidelines
abnormal TCD 65 (14
5%) 11 (4
4%) 76 (10
9%)
anaemia 62 (13
8%) 18 (7
2%) 80 (11
4%) Among the 100 patients who experienced ≥3 VOCs/year, 64
(haemoglobin received therapeutic intensification: HC alone in 44 patients,
<70 g/l) HC and CT in 16, CT alone in 3 and geno-identical HSCT
Specific therapies in 1. Therapeutic intensification was declined in 2 patients.
HSCT 10 1 11 Sixteen additional patients received therapeutic intensifica-
HC 126 10 136 tion shortly after data were censored (HC in 14 and CT
CT 116 25 141 alone in 2). Overall, 18% of patients (n = 18) received no
Values are number (percentage). specific intensification of therapy, including all 3 patients
SCD, Sickle-Cell Disease, VOC, vaso-occlusive crisis, ACS, acute with the SC genotype. HC was prescribed as first-line therapy
chest syndrome, TCD, transcranial Doppler, HSCT, haematopoietic in only 60% of eligible patients with severe VOC in the SS/
stem cell transplantation, HC, hydroxycarbamide, CT, chronic trans- Sb° group.
fusion. Among the 64 patients with >1 ACS/lifetime, 48 received
*Two patients excluded because died in the first days of life. therapeutic intensification: HC alone in 32 patients, HC and
†A given patient could have several complications. CT in 13, CT alone in 2 and geno-identical HSCT in 1 (who
also had >2 severe VOCs). Therapeutic intensification was
In the SS/Sb° group, 69
9% of patients (n = 517) were declined in 1 patient. Ten additional patients received thera-
free from early SCD-related complications and alive at the peutic intensification shortly after data were censored (HC in
time of censoring. Severe vaso-occlusive disease, namely 9 and CT in 1 with concomitant abnormal TCD). Overall,

ª 2016 John Wiley & Sons Ltd 931

British Journal of Haematology, 2016, 173, 927–937
N. Couque et al

Table IV. Incidence of death, stroke and abnormal TCD among SS/Sb° patients in the cohort

Death SCD-related death Stroke Abnormal TCD

(all causes) First period Second period
Age group years PY 1995–2009 (<2006) PY (≥2006) PY

0–2 0
71 (0
27;1
16) 1400 0
50 (0
13;0
87) 0
64 (0
13;1
15) 939 0
22 (0
00;0
64) 462 0
07 (0
00;0
21) 0
14 (0
00;0
34)
n = 10 n=7 n=6 n=1 n=1 n=2
2–4 0
09 (0
00;0
26) 1157 0
09 (0
00;0
26) 0
11 (0
00;0
33) 913 – 245 0
52 (0
10;0
94) 2
17 (1
32;3
02)
n=1 n=1 n=1 n=6 n = 25
4–6 0
22 (0
00;0
53) 897 0
22 (0
00;0
53) 0
23 (0
00;0
55) 868 – 29 0
23 (0
00;0
54) 3
14 (1
95;4
32)
n=2 n=2 n=2 n=2 n = 27
6–8 0
45 (0
00;0
96) 668 0
45 (0
00;0
96) 0
33 (0
00;0
71) 668 – – 0
15 (0
00;0
45) 2
62 (1
34;3
90)
n=3 n=3 n=3 n=1 n = 16
8–10 430 – 430 – 0
24 (0
00;0
71) 1
32 (0
16;2
48)
n=1 n=5
10–12 262 – 262 – 0
40 (0
00;1
18) 0
45 (0
00; 1
32)
n=1 n=1
Overall 0
32 (0
17;0
48) 4938 0
26 (0
12;0
41) 0
29 (0
12;0
45) 4204 0
14 (0
00;0
40) 733 0
25 (0
11;0
39) 1
63 (1
26;1
99)
n = 13 n = 13 n = 12 n=1 n = 12 n = 76

Incidence (95% confidence interval), number of events/100 patient-years; no deaths, stroke or abnormal TCD occurred among patients 12–
14 years old (110 patient-years) or among patients 14–16 years old (19 patient-years), among the SS/Sb° patients in the cohort.
TCD, transcranial Doppler, SCD, sickle-cell disease, PY, patient-years of observation.

only 7
8% of patients (n = 5) received no therapeutic inten-
sification. HC was prescribed as first-line therapy in 64% of
eligible patients.
All 12 patients with stroke received secondary prevention
consisting of CT. Only two of them had geno-identical
donors and received subsequent HSCT. The two without
intra-cranial cerebral vasculopathy were switched to HC with
no further SCD-related events in more than 12 years of fol-
low-up on HC.
Among the 76 patients with confirmed abnormal TCD, 73
received therapeutic intensification: CT alone in 32 patients,
CT followed by HC in 23, HC alone in 9 and geno-identical
HSCT in 9. Therapeutic intensification was declined in 1
patient. One additional patient received CT shortly after data
were censored. Overall, only 2
7% of patients (n = 2)
received no therapeutic intensification. Eight patients with
conditional TCD (n = 39) received short duration transfu-
sion (median 3 months; range 3 months - on-going).
Among the patients with chronic anaemia, a relatively
low percentage of the patients i.e. 62
5% (n = 50), received
specific therapies, mainly for reasons other than anaemia: 12
for abnormal TCD, 10 for vaso-occlusive disease (VOC and/
or ACS), 9 for chronic splenic sequestration (all of whom
were subsequently splenectomized) and 19 for isolated anae-
mia. Therapeutic intensification was declined in 3 patients.
Overall, HC was prescribed as first-line therapy in only 18
patients, which represents 30
5% of eligible patients (n = 59)
with no abnormal TCD or chronic splenic sequestration.
Impact of on-line guidelines on quality of care
We compared initial care between the two periods, i.e. for
children born before 2006 (n = 667 with 5754 patient-years
of follow-up) and patients born thereafter (n = 366 with
1022 patient-years). There was a trend towards increased sur-
vival at 5 years, from 98
3% to 99
2% [95%CI: (96
9;99
1)
and (97
4;99
7) respectively] after 2005.
Twelve of the 13 SCD-related deaths occurred in patients
born before 2006. There was a trend towards a lower cumu-
lative incidence of SCD-related death for SS/Sb° patients
born in the second period [RR=0
14, 95%CI (0
00;0
40) vs.
RR=0
29, 95%CI (0
12;0
45) in the first period] (Fig 1A).
Given the younger mean age of patients in the second per-
iod, i.e. 32  15 months, and the higher mortality rate
observed in the 24-month-old age group (Table IV), we
focused on this age group in which we also found a trend
towards fewer SCD-related deaths when the two time periods
were compared: 0
64 deaths/100 patient-years in the first per-
iod (n = 6) versus 0
22 deaths/100 patient-years (n = 1) in
the second period (P = 0
28 (log rank)).
Median age at first evaluation, i.e. 2 months of age, was
similar in the two periods as was prophylaxis with penicillin
V and folic acid supplementation (data not shown). The
number of patients seen before 3
5 months was, however,
statistically higher in the second period (97%, vs. 90% in the
first period, P < 0
001). Before 28 months of age, only 84%
of patients in the second period received a full schedule of
pneumococcal vaccination compared to 94% in the first per-
iod. Overall, a full schedule was provided in 80% of children
in the two periods. The rate of hospitalization in the first
year of life was higher in the second period (47
4% vs.
36
6% in the first period, P = 0
004).
Overall, conditional and abnormal TCD results occurred
significantly earlier in the second period (P = 0
004)
(Fig 1B), increasing from 8% to 20% after 4 years of age.
Median age at first abnormal TCD was 2
9 years (2
3;3
3) in

932 ª 2016 John Wiley & Sons Ltd

British Journal of Haematology, 2016, 173, 927–937
 Newborn screening in North Paris

Fig 1. Impact of on-line guidelines on outcome and care of SS/Sb° patients. (A) Age at sickle cell disease (SCD)-related death. Trend towards
lower cumulative incidence of SCD-related death for SS/Sb° patients born in the second period [RR=0
14, 95%CI (0
00;0
40) vs. RR=0
29, 95%
CI (0
12;0
45) in the first period] was even stronger among patients 0–2 years of age, with, respectively, 0
64 deaths/100 patient-years before 2006
(n = 6) vs. 0
22 deaths/100 patient-years (n = 1) after 2006, P = 0
28 (log rank). (B) Age at first conditional or abnormal transcranial Doppler
(TCD). Younger age of patients in the second period indirectly reflects increased TCD coverage, P = 0
004. (C) Age at initiation of chronic trans-
fusion, showing earlier implementation in the second period P = 0
002. (D): Age at initiation of hydroxycarbamide therapy, showing earlier
implementation in the second period starting at 2 years of age, P = 0
01.

the second period versus 4
7 years (3
7,6
7) in the first per-
iod, although the difference was not statistically significant.
Moreover, first abnormal TCD in the second period occurred
before the median age of stroke of 3
5 years (2
7;6
1) in the
cohort as a whole.
CT was also more frequent, increasing from 7
5% to
20% after 4 years of age, and was implemented earlier in
the second period with a cumulative incidence of 2
52 at
a median age of 2
3 years vs. 2
19 at a median age of
5 years (Fig 1C, p = 0
002) with a similar percentage
(29%) of iron overload in the two periods (data not
shown). The main reason for initiating CT was cerebral
macro-vasculopathy in both periods with increased CT for
ASS in the second period (10/25 patients versus 12/116 in
the first period).
In the second period, HC was introduced earlier, at a
median age of 3
7 years vs. 6
6 years with an increase from
3
9% to 13% at 4
5 years of age (Fig 1D), primarily for
vaso-occlusive complications in both periods (P = 0
01).
In the first period, HSCT was performed (n = 10), at a
median age of 8
4 years (7
2;11
8) vs. 3
4 years of age for the
only patient in the second period.
Discussion
The North Paris cohort is the largest European cohort identi-
fied through newborn screening with systematic pneumococ-
cal prophylaxis through penicillin-V administration and anti-
pneumococcal vaccines. The cohort was followed by a net-
work of paediatric hospital teams coordinated by a teaching
hospital. Initial evaluation and follow-up were performed by
the local hospital-based paediatrician, a member of the
national SCD network. The cohort resided in an urban com-
munity characterized by significant socio-economic difficul-
ties, with a high proportion of recently immigrated families
and a lack of general practitioners (ARS 2011).
Although cross-study comparison of the incidence of
death is potentially problematic due to the varying patient

ª 2016 John Wiley & Sons Ltd 933

British Journal of Haematology, 2016, 173, 927–937
N. Couque et al
numbers, duration of follow-up and age categories, as sum-
marized in Table V, our incidence nevertheless appears to be
similar to the rates in the most recently reported SCD
cohorts (Telfer et al, 2007; Quinn et al, 2010; Bernaudin
et al, 2011). It should be emphasised that, in our cohort,
deaths not related to SCD occurred in early infancy, mainly
in the neonatal period. The rate and causes of death are in
accordance with those described in recently immigrated pop-
ulations with a low socio-economic level, as is the case in
North Paris where both neonatal and infant mortality are
1
5-fold higher than the rest of France (ARS 2011).
In our cohort, SCD-related deaths occurred mainly in
early childhood. The main causes of SCD-related death
were acute anaemia and infection. A significant number of
deaths, specifically involving acute anaemic events (2/3),
occurred during unprepared visits to tropical areas, mainly
in young infants. This feature was not reported in the East
London or Dallas cohorts, but was also described in
another newborn cohort in France (Bernaudin et al, 2011).
As visits to friends and relatives are part of the family’s
needs, it should be explained early during follow-up that
such trips must be prepared in advance. This has been
reported to limit such fatal outcomes (Runel-Belliard et al,
2009; Sommet et al, 2013). The number of deaths due to
pneumococcal infection continued to be significant in our
cohort, even after completing a full schedule with the pneu-
mococcal conjugate vaccine, all in the non-compliant group.
This was in contrast with the reported elimination of early
pneumococcal deaths after the introduction of pneumococ-
cal conjugate vaccines (Quinn et al, 2010; Hamideh &
Alvarez, 2013) and the reported two-thirds reduction in
invasive pneumococcal infections (Adamkiewicz et al, 2008).
Nevertheless, late rebound of non-vaccinal invasive pneu-
mococcal disease has been reported (McCavit et al, 2011).
More generally, we found a ten-fold higher rate of SCD-
related death among non-compliant families. In this urban
area, sociomedical needs are not met by existing medical
infrastructures, particularly general practitioners and home-
call nurses (ARS 2011). More extensive information on the
socio-cultural and economic background of the families is
needed in this mainly first-generation immigrant commu-
nity in order to implement more appropriate community-
based educational programmes, as described in the British
system (Telfer et al, 2007).
Table V. Overall Incidence of Death (all Causes of Mortality) Among SS/Sb° Patients Diagnosed Through Newborn Screening
Reference Cohort Setting Centre Type Enrolment
Quinn et al (2010) Dallas Single 1983–2007
Telfer et al (2007) East London Single 1983–2005
Bernaudin et al (2011) Cr
eteil Single 1988–2007
Our study North Paris Multi 1995–2009
FU, follow-up, PY, patient-years of observation.
*Number of events/100 patient-years.
934
Both the frequency (1
6%) and incidence (0
25 per 100
patient-years) of stroke in our cohort were comparable to
the most recently published cohorts (Telfer et al, 2007; Ber-
naudin et al, 2011). Stroke prevention requires both system-
atic early TCD and CT initiation (Adams et al, 1998). In our
cohort, almost all patients with abnormal TCDs received
intensification of therapy. Our results seem to suggest better
stroke prevention in the second period. Indeed, indirect
proof of improved TCD coverage may be the younger med-
ian age of children identified with abnormal TCD after the
on-line guidelines were published, as well as the 2
5-fold
increase over time in conditional and abnormal TCD results
after 4 years of age. We also found an increased rate of early
CT. Direct proof should become available with further
follow-up.
The rates of recurrent VOC, recurrent severe ACS and
severe chronic anaemia in our cohort were comparable to
published reports (Platt et al, 1991, 1994; Vichinsky et al,
1997). Almost all patients with recurrent ACS received thera-
peutic intensification. On the other hand, only two-thirds of
patients with severe chronic anaemia were offered specific
therapies, mainly for associated complications (abnormal
TCD, VOC, ACS). Severe chronic anaemia is a risk factor for
early death and organ damage, as well as stroke (Platt et al,
1994; Miller et al, 2000). Specific therapies should, therefore,
be more frequently planned for severely anaemic patients to
prevent the occurrence of the known cerebrovascular compli-
cations and late organ damage (Platt et al, 1994; Ohene-
Frempong et al, 1998; McKie et al, 2007).
HC is a recommended, safe and effective treatment for
VOC and ACS prevention, as well as for correction of
chronic anaemia, even in children (Wang et al, 2011; Thorn-
burg et al, 2012; Hankins et al, 2014; Yawn et al, 2014;
Stettler et al, 2015). It has also been shown to decrease long-
term morbidity and mortality in children and adults (Stein-
berg et al, 2010; Voskaridou et al, 2010; Lobo et al, 2013).
Overall, in our cohort, prescription of HC could be further
extended, as it was offered as first-line therapy to only 60%
of the eligible patients with VOC, 64% with ACS and 30
5%
with chronic anaemia. Indeed, only a minority of non-inten-
sified patients with VOC, ACS or chronic anaemia, declined
the proposed intensification therapy. Moreover, a significant
number of HC-eligible patients were offered exclusive or
associated CT. Extension of HC will require identifying and
Median FU (years) Number PY Number of Events Mortality*
9
2 593 5819 29 0
52
7
4 180 1542 4 0
26
6
2 217 1609 4 0
25
7
2 742 4938 16 0
32
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2016, 173, 927–937
 Newborn screening in North Paris

overcoming the barriers for families and practitioners (Bran-
dow et al, 2010; Strouse & Heeney, 2012).
Nevertheless, our study showed an improvement in medi-
cal care between the two periods, with a trend towards
increased survival at 5 years, significantly increased TCD cov-
erage, earlier and increased prescription of specific intensifi-
cation therapies (2
6- to 3
3-fold increase, respectively for CT
and HC at 4
5 years of age). This could potentially be related
to the publication of national on-line guidelines, however
there is no direct causal evidence because general medical
care also improved over the 15-year period of our study
(Wheatley, 2002).
The mean age in our cohort was relatively young and,
consequently, we could not explore the transition period to
adult care, which has been shown to be critical in terms of
mortality in the USA (Quinn et al, 2010; Hamideh &
Alvarez, 2013), but not in Belgium (Le et al, 2015). The same
reservation could be put forward concerning the occurrence
of later events in the 2006–2009 cohort. This will require fur-
ther follow-up.
In conclusion, to our knowledge, this is the first attempt
to assess the extent to which current management of SCD
complies with national and international published guidelines
in a contemporary multicentre cohort of newborns with
SCD. Patients born in the second period received a higher
standard of care in terms of broader TCD coverage and ear-
lier implementation of specific therapies, which may be attri-
butable to the on-line guidelines. Nevertheless, first-line
therapy with HC for eligible patients is underused. In this
recently immigrated population, we are currently seeking to
further reduce SCD-related morbidity and mortality through
pilot programmes, combining a mobile regionalized team
with multi-ethnic staff, along with web-conferences between
referral centres and local teams, for all at-risk patients.
Funding
This work was supported in part by a grant from the French
Parisian Newborn Screening Organization (FPDPHE: No.
2011/RDB/020) and charitable funding from LVMH (2011/
RDB/018, 2013/RDB/028).
Acknowledgements
The authors would like to thank the following additional
physicians who collaborated in the study: C Allisy (Argen-
teuil), E Questiaux (Aulnay-sous-Bois), A May (Corbeil-
Essonne), M Duval-Arnould (Creil), F Bernaudin and C
Arnaud (Cr
eteil), C Guitton (Kremlin-Bic^etre), F Gouraud
(Meaux), P Ferr
e (Montreuil-sous-Bois), M de Montalembert
(Necker-Enfants Malades, Paris), B Quinet (Trousseau,
Paris), O Charara (Versailles). We are indebted to Drs M
Elmaleh and S Verlhac, neuroradiologists who contributed to
the expert training of the radiological teams in the area, as
well as the monthly multidisciplinary expert case reviews.
The authors would also like to thank Professor F
Galact
eros, coordinator of the national mainland SCD refer-
ence centre for his positive support and critical review of the
manuscript; the president and director of FPDPHE pro-
gramme, Professor P Czernichow and Mrs V Gauthereau for
their support; the staff of the national reference laboratory of
Robert-Debr
e Hospital (Mrs E Trawinski, P Wazana, S
Kwan-Hu) for their enthusiasm and professionalism; Mrs T
Kolta for excellent administrative assistance and the members
of the MIRADA association for their dedication to the equal-
ity of rights and their support for children with SCD. We
would also like to thank G Smith who provided editorial
assistance, as well as all patients, their families and care-
givers for their continuous support.
Conflict of interest
The authors report no conflicts of interest.
Authorship
All authors meet the criteria for contributing authors. NC
and RD performed newborn screening for SCD, collected
the data, analysed the results and participated in writing the
manuscript; DG designed the statistical analysis, analysed the
data and participated in manuscript writing; ZH collected
and analysed the data and participated in manuscript writ-
ing; FM, LV and GI participated in data collection and
patient follow-up, PB performed the statistical analysis. MBe,
MHO, MBene, PBe, BR, PBen, PF, BM, VB, RA, CO, EL,
LM, CA, NG, AM, CG, MDA, OC participated in patient fol-
low-up. CA participated in study design and statistical analy-
sis, and critically reviewed the manuscript. JE and AB
critically reviewed the manuscript. MB designed the study,
participated in data collection, analysed the data and wrote
the manuscript.
All authors were involved in the discussion and interpreta-
tion of data, and all approved the final version.

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