Effectiveness of Cranberry Capsules to Prevent Urinary Tract

Effectiveness of Cranberry Capsules to Prevent Urinary Tract
Infections in Vulnerable Older Persons: A Double-Blind
Randomized Placebo-Controlled Trial in Long-Term Care
Monique A. A. Caljouw, MSc,* Wilbert B. van den Hout, PhD,† Hein Putter, PhD,‡
Wilco P. Achterberg, PhD,* Herman J. M. Cools, PhD,* and Jacobijn Gussekloo, PhD*
OBJECTIVES: To determine whether cranberry capsules
prevent urinary tract infection (UTI) in long-term care
facility (LTCF) residents.
DESIGN: Double-blind randomized placebo-controlled multicenter trial.
SETTING: Long-term care facilities (LTCFs).
PARTICIPANTS: LTCF residents (N = 928; 703 women,
median age 84).
MEASUREMENTS: Cranberry and placebo capsules were
taken twice daily for 12 months. Participants were stratified according to UTI risk (risk factors included long-term
catheterization, diabetes mellitus, ≥1 UTI in preceding
year). Main outcomes were incidence of UTI according to
a clinical definition and a strict definition.
RESULTS: In participants with high UTI risk at baseline
(n = 516), the incidence of clinically defined UTI was
lower with cranberry capsules than with placebo (62.8 vs
84.8 per 100 person-years at risk, P = .04); the treatment
effect was 0.74 (95% confidence interval (CI) = 0.57–
0.97). For the strict definition, the treatment effect was
1.02 (95% CI = 0.68–1.55). No difference in UTI incidence between cranberry and placebo was found in participants with low UTI risk (n = 412).
CONCLUSION: In LTCF residents with high UTI risk at
baseline, taking cranberry capsules twice daily reduces the
incidence of clinically defined UTI, although it does not
reduce the incidence of strictly defined UTI. No difference
From the *Department of Public Health and Primary Care, Leiden
University Medical Center, †Department of Medical Decision Making,
Leiden University Medical Center, and ‡Department of Medical Statistics,
Leiden University Medical Center, Leiden, the Netherlands.
Trial Registration: www.trialregister.nl; Identifier: NTR1266
Address correspondence to Monique A.A. Caljouw, Department of Public
Health and Primary Care, Leiden University Medical Center, P.O. Box
9600, 2300 RC Leiden, the Netherlands. E-mail: [email protected]
DOI: 10.1111/jgs.12593
in incidence of UTI was found in residents with low UTI
risk. J Am Geriatr Soc 62:103–110, 2014.
Key words: geriatrics; long-term care facility; urinary
tract infection; prevention; cranberry
rinary tract infection (UTI) is a common bacterial
infection in residents of long-term care facilities
(LTCF),1,2 accounting for nearly 25% of all infections.3,4
UTI not only causes several days of illness, but may have
more-severe consequences such as delirium, dehydration,
urosepsis, hospitalization, or even death.5,6
Interventions to prevent UTI could reduce these severe
consequences,7 but there are no evidence-based interventions that decrease UTI in institutionalized populations.1
The use of prophylactic antibiotics is currently controversial
because of side-effects and antibiotic resistance.8,9 Prophylaxis with cranberry is a potential prevention strategy.10,11
Cranberries contain proanthocyanidins (PACs), which are
stable phenolic compounds with anti-adhesion activity
against Escherichia coli.12–14 In vitro, antibacterial activity
of concentrated cranberry juice against other pathogens such
Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella
pneumoniae, and Proteus mirabilis has also been demonstrated.15,16
There is aggregated evidence that cranberry juice may
lead to a decrease in the incidence of symptomatic UTIs
over a 12-month period, particularly in women with
recurrent UTIs.17,18 Another recent systematic review indicates that cranberry-containing products are associated
with a protective effect against UTI in different subgroups, albeit with heterogeneity across the included trials.19 A recent study in children without urological
abnormalities showed a 65% reduction of UTI with the
use of cranberry.20
JAGS 62:103–110, 2014
© 2014, Copyright the Authors.
Journal compilation © 2014, The American Geriatrics Society.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the original work is properly cited.
JANUARY 2014–VOL. 62, NO. 1
Two studies reported that cranberry juice may be
protective in subgroups of older adults,21,22 but the effectiveness of cranberry capsules in the protection against
UTI in vulnerable older persons in LTCFs has not been
The present study assessed the effectiveness of cranberry capsules in preventing UTI in vulnerable older persons living in LTCFs. Research in an institutionalized
population is challenging, and clinical manifestations of
UTI may be subtle.23–25 To be relevant for clinical practice
and science, a clinical definition according to international
guidelines for LTCF residents and a strict definition
according to scientific criteria were both used.
to the study capsule at baseline. The cranberry capsules
contain 500 mg of the product, with 1.8% proanthocyanidins (9 mg). The placebo was indistinguishable in color,
taste, and appearance, consisting of cellulose microcrystal
colored red with azorubin.
The physician prescribed the coded capsules, and the
pharmacist added them to the drug-dispensing systems.
Nurses distributed the capsules and recorded whether the
participant took them on a drug kardex. Adherence was
measured over 1 month by counting all capsules that the
participants took during the fifth month of intervention
and comparing that with the prescribed number of
Outcome Measures
This was a double-blind randomized placebo-controlled
multicenter trial in two strata, based on baseline UTI risk.
Twenty-one LTCF organizations from the University Nursing Home Research Network in South Holland, the Netherlands, participated.
The medical ethics committee of the Leiden University
Medical Center approved the study. Written informed consent was obtained from all participants. A guardian provided written consent for participants incapable of giving
informed consent because of cognitive impairment.
Study Participants
LTCF residents aged 65 and older were included. Exclusion criteria were use of coumarin and a life expectancy of
1 month or less. Coumarin users were excluded because of
a possible interaction between coumarin and cranberry,
leading to higher international normalized ratios and
After informed consent and before randomization,
medical records were studied to stratify participants
according to baseline UTI risk. Participants with long-term
catheterization (>1 month), diabetes mellitus, or at least
one UTI in the preceding year were considered to be at
high UTI risk.
Within two strata of UTI risk, participants were randomized into the cranberry or placebo group. Block randomization (blocks of 6) was used, stratified for risk
profile and ability to give informed consent, generated
using a computer random number generator. Participants,
family, nursing staff, physicians, pharmacists, and research
nurses were blinded to treatment, and the random numbers were put in sealed envelopes so the research nurse
could allocate to the treatment group (cranberry or placebo) directly on the ward. Only the supplier of the capsules knew the codes given to the capsules (cranberry or
Participants were randomly assigned to take cranberry or
placebo capsules twice daily for 12 months. Participants
already using a cranberry supplement stopped using their
own cranberry products before randomization and changed
The primary outcome was incidence of UTI. There is no
criterion standard in diagnosing UTI in LTCF residents.
Most clinical criteria to ascertain UTI are based on consensus.29–31 A recent study showed that micturition-related
signs and symptoms are predictive of UTI.32
Because of the absence of a criterion standard in the
study population, this study used a clinical definition and
a strict UTI definition. The clinical definition of UTI is a
broad and practical definition following clinical practice
guidelines for LTCF residents.24,25 This clinical definition
of UTI is based on the presence of a minimum of one of
the following characteristics: specific and nonspecific micturition-related symptoms and signs, a positive test (nitrite
test, leukocyte esterase test, dipslide, or culture), antibiotic treatment for UTI, or UTI reported in the medical
Specific symptoms and signs are pain before, during,
or after micturition; increased frequency of micturition;
pain in abdomen; hematuria; foul smell; and signs of common sickness (fever >37.9°C or 1.5°C above baseline temperature, chills, nausea, vomiting). Nonspecific symptoms
are anorexia, fatigue and reduced mobility, and signs of
delirium (e.g., confusion, deterioration in mental or functional status).
The strict UTI definition is based on a scientific
approach, including the presence of micturition-related
symptoms and signs confirmed with a positive dipslide or
culture. A urine dipslide or culture was considered to be
positive when there were 105 CFU/mL or more bacteria,
with no more than two species of organisms present.
The treating physicians diagnosed the UTI and
reported the presence of UTI in the medical record. For
this study, they reported the needed study information on
a prestructured case report form, including presence of
specific and nonspecific micturition-related signs and symptoms, kind of testing and results, and antibiotic treatment.
Secondary outcomes were incidence of recurrent UTI,
hospitalization, and mortality.
In a companion cost-effectiveness article, whether the
effectiveness of cranberry capsule use is attained at reasonable costs was investigated.33
At 6 and 12 months, a research nurse visited all participants in their LTCF to check their medical records for
the occurrence of UTIs and to verify that all UTIs were
collected during the study period. Side effects and reasons
for withdrawal from the study were registered.
JANUARY 2014–VOL. 62, NO. 1
Additional Measurements at Baseline
A research nurse interviewed all participants at baseline
in their LTCF, where face-to-face interviews were conducted. If participants were not able to answer, their
responsible nurse was interviewed. Information on participant sociodemographic characteristics and medical history
were obtained at baseline. Care dependency was assessed
using the Care Dependency Scale (CDS),34 which measures
15 items of basic care needs on an aggregate scale from 15
to 75.
Sample Size
Sample size was based on an expected incidence of 44 first
UTIs per 100 residents per year in the placebo group. To
demonstrate a 40% reduction in incidence of UTI with the
use of cranberries,22 500 residents needed to be included
in each stratum (2 strata of 2 groups of 250)—1,000 residents in total (dropout rate 10%, alpha 0.05, power
Statistical Analysis
Differences in baseline characteristics between treatment
groups were compared using the Student t-test for continuous variables and chi-square for categorical variables. The
incidence of UTI was calculated using the life-table
method. The number of first UTIs was assigned to the
numerator and the number of observed person-years at
risk was assigned to the denominator. The observed person-years at risk were counted from randomization to end
of study, to date of death, or to date of first UTI. The
cumulative incidence of UTI for cranberry and placebo
was calculated accounting for mortality as competing
risk.35 The difference in the cumulative incidence of UTI
in residents between cranberry and placebo was tested
using the log-rank test. The treatment effect of cranberry
with respect to placebo was investigated using Cox proportional hazards models, expressed as hazard ratios
The number needed to treat (NNT) was calculated
over 1 year of follow-up, based on the difference in proportion of being event free in the placebo and cranberry
group.36,37 The difference in NNT between treatment
groups was tested using a z-test; P ≤ .05 was considered
To investigate possible heterogeneity in UTI rates
between individuals, a gamma-frailty model was fitted,38 a
random effect model for time-to-event data in which the
random effect (frailty) has a multiplicative effect on baseline hazard function. Analyses were performed based on
intention to treat using SPSS for Windows version 17.0
(SPSS Inc., Chicago, IL) and R version 2.13.0 (R Foundation for Statistical Computing, Vienna, Austria).
Between November 2008 and August 2009, all 2,086 eligible residents were invited to participate in a letter, and then
a research nurse orally invited them. The study stopped in
June 2011. Twenty-seven of the 955 residents who gave
written informed consent died before randomization,
resulting in a study population of 928 participants (Figure 1). A nonresponder analysis for giving informed consent showed no difference between nonresponders and
responders in age, sex, or UTI risk profile. None of the
participants had end-stage renal disease.
Four hundred twelve low-UTI-risk and 516 high-UTI
risk-participants were included. There were no baseline
differences within the UTI risk groups between the cranberry and placebo groups (Table 1). Mean capsule intake
was 97% (95% confidence interval (CI) = 96.6–97.6%)
and was similar between the randomization groups and
between the risk groups.
Incidence of UTI
In the high-UTI-risk group, the curve of cumulative incidence of clinically defined UTI showed a positive treatment
effect from 2 months of follow-up onward (P = .03). No
such effect was found for strictly defined UTI (P = .91).
There was no difference between cranberry and placebo in
the low-UTI-risk group (Figure 2).
In the high-UTI-risk group, the incidence of UTI
according to the clinical definition was 62.8 per 100 person-years at risk (95% CI = 50.3–75.2) for cranberry and
84.8 per 100 person-years at risk (95% CI = 70.0–99.7)
for placebo (P = .04). The treatment effect in those at high
UTI risk was 0.74 (95% CI = 0.57–0.97). The incidence
for UTI following the strict definition was not different in
those using cranberry and placebo. The treatment effect
was 1.02 (95% CI = 0.68–1.55; Table 2). A subanalysis in
participants without long-term catheters in the high-UTIrisk group (n = 420) showed a larger treatment effect of
cranberry capsules than of placebo for clinically defined
UTI (Table 2). According to the clinical definition, five
high-risk residents need to be treated with cranberry for
1 year to prevent one resident free of UTI for 1 year
(P = .01).
In the low-UTI-risk group, the incidence of UTI
according to the clinical definition was 40.3 per 100 person-years at risk (95% CI = 30.0–50.5) for cranberry and
33.4 per 100 person-years at risk (95% CI = 24.2–42.5)
for placebo (P = .30).
Recurrent UTI
In a gamma-frailty model (a random effect model) using
all recurrent clinical UTIs, cranberry did not significantly
reduce the UTI rate in the high-UTI-risk group
(HR = 0.92, 95% CI = 0.71–1.17, frailty variance 0.62,
P < .001). In the low-UTI-risk group, the HR of cranberry
versus placebo was 1.14 (95% CI = 0.78–1.68, frailty
variance 1.50, P < .001).
Hospitalization and Mortality
Five participants (0.5%), all from the high-UTI-risk group,
were hospitalized during follow-up for UTI, with no
difference between cranberry and placebo (P = .62). In the
low-UTI-risk group, 114 (27.7%) participants died during
follow-up, of whom three died from UTI (cranberry vs placebo P = .56). In the high-UTI-risk group, 181 participants
JANUARY 2014–VOL. 62, NO. 1
Figure 1. Participant recruitment and follow-up. aDiabetes mellitus or urinary catheter or treated urinary tract infection in past
12 months. bNo adherence, withdrawn by elderly care physician or family. cIntervention stopped because of end of the study period. UTI = urinary tract infection.
(35.1%) died during follow-up, of whom 14 (7.7%) died
from UTI, with no difference between cranberry and placebo (7 vs 7 P = .91).
This double-blind randomized placebo-controlled multicenter trial investigated the effectiveness of cranberry capsules to prevent UTI in older LTCF residents. In
participants with high UTI risk, twice-daily intake of cranberry capsules resulted in a 26% lower incidence of clinically defined UTI than placebo, but no difference was
found in UTI incidence of strictly defined UTI. In residents
with low UTI risk, twice-daily intake of cranberry capsules
did not result in a lower incidence of UTI than with placebo.
A systematic review showed that cranberry-containing
products were associated with a protective effect against
UTI in certain populations.19 A Cochrane review reported
a UTI reduction of 35% (95% CI = 10–54%).17 In the
recent update of this Cochrane review in 2012, the authors
performed a meta-analysis based on two studies evaluating
cranberry in elderly adults (N = 413).18 Cranberry did not
significantly reduce UTI in this population (risk
ratio = 0.75, 95% CI = 0.39–1.44).18 In contrast with this
last review, the current study found a positive effect of
treatment with cranberry capsules on the incidence of clinically diagnosed UTI in 516 older persons with high UTI
risk. A possible explanation for this difference could be
the product used (juice vs capsules), study population (hospitalized vs institutionalized), and sample size. Another
study comparing cranberry with low-dose trimethoprim
(follow-up 6 months) showed no difference between
cranberry and low-dose antibiotics but did not include a
placebo arm.39
It could have been expected that the beneficial effect
of cranberry capsules would be fairly prompt after starting treatment, but the current study showed a beneficial
effect of cranberry capsules in the high-UTI-risk group
starting from 2 months of treatment on for clinically
defined UTI. This was shown in an earlier study that
found a reduction that started between 1 and 2 months
after initiating cranberry juice and remained stable
throughout the 6 months of follow-up.21 Cranberries with
PAC were expected to have an effect by different mechanisms, because they influence the adhesive capacity of fimbriae of bacteria and build a biofilm on the surface,
preventing adhesion. Nevertheless, bacteria could be persistent (chronic bacteriuria), and the types of bacteria
could vary over time. So cranberry protects against UTI,
but it takes some time to have an effect.
JANUARY 2014–VOL. 62, NO. 1
Table 1. Baseline Characteristics of Study Population at Randomization (Intention-to-Treat Analysis)
Low UTI Risk, n = 412
Female, n/N (%)
Age, n, median (IQR)
Length of stay, months, n, median (IQR)
Family informed consent, n/N (%)
15-item Care Dependency Scale score
(range 15–75), n, median (IQR)
Cranberry use before start of study,
n/N (%)
Urinary incontinence, n/N (%)
Urinary catheter, n/N (%)
Infections in past 12 months
Urinary tract infection, n/N (%)
Number of UTIs in past 12 months, n,
median (IQR)
Antibiotics for UTI suppression, n/N (%)
Lower respiratory tract infection, n/N (%)
Other infection, n/N (%)
Comorbidities, n/N (%)
Renal dysfunction
Urogenital surgery
Myocardial infarction
Diabetes mellitus
Chronic obstructive pulmonary disease
Cranberry, n = 205
205, 84.0
204, 18.0
199, 42.0 (30.0–56.0)
High UTI Risk, n = 516a
Placebo, n = 207
207, 83.0
205, 19.0
197, 45.0 (30.5–55.0)
Cranberry, n = 253
253, 85.0
251, 17.0
244, 44.0 (31.0–56.0)
Placebo, n = 263
263, 84.0
263, 19.0
250, 43.0 (30.0–56.0)
3/196 (1.5)
6/202 (3.0)
18/248 (7.3)
22/253 (8.7)
138/198 (69.7)
0/205 (0.0)
136/199 (68.3)
0/207 (0.0)
152/247 (61.5)
49/253 (19.4)
157/246 (63.8)
47/263 (17.9)
0/205 (0.0)
0/207 (0.0)
203/253 (80.2)
202, 1.0 (1.0–2.0)
200/263 (76.0)
199, 2.0 (1.0–2.0)
0/196 (0.0)
35/200 (17.5)
21/200 (10.5)
1/202 (0.5)
35/204 (17.2)
24/204 (11.8)
3/248 (1.2)
47/249 (18.9)
38/248 (15.3)
5/253 (2.0)
54/259 (20.8)
33/255 (12.9)
IQR = interquartile range; UTI = urinary tract infection.
Diabetes mellitus or urinary catheter or treated urinary tract infection in past 12 months.
Because the effect of preventive care depends on the
incidence of the disease, a preplanned stratification was
made at baseline on baseline UTI risk. Based on the literature, LTCF residents with diabetes mellitus,40–42 long-term
catheterization,24,43,44 or UTI in the preceding year3,42,45,46
were considered to be at high risk. Although a group of
LTCF residents with a high incidence were selected using
these criteria, it might be that other criteria would have
selected a group with even higher risks or more preventable UTIs.
Strengths and Limitations
This is the first large study of the effectiveness of cranberry
capsules in preventing UTI in LTCF residents. These residents represent a vulnerable older population, with a median age of 85 and older, severely dependent on care, high
infection rates, high levels of comorbidity, and 1-year mortality of 35%47—a population in which clinical manifestations of UTI may be subtle.23
The current study was performed in Dutch LTCFs
—intramural care settings where elderly care physicians
provided medical care.48–53 Medication prescription and
distribution are well organized. The study capsules were
added to the existing drug-dispensing system. Medication
distribution by nurses is routine in Dutch LTCFs, and participants rarely missed taking any capsule, which was
reflected in a high adherence rate, although adherence was
assessed only in the fifth month, which might not be generalizable to the other months. This high and similar level of
adherence in both treatment groups also suggests that capsules were well tolerated, side-effects were negligible, and
blinding remained adequate during the study.
A technical assessment of blinding was not performed,
although the research nurses did not receive information
about deblinding during the study visits. In addition, the
distribution and adherence of participants in the cranberry
and placebo groups were similar.
The clinical definition for UTI is based on a broad definition of UTI (symptoms and signs, positive test, antibiotic treatment, or reported in the medical record) and
relies on the clinical judgment of the elderly care physician, in accordance with international clinical guidelines
for UTIs in LTCFs.24,25 Although this UTI definition is different from the strict definition, it reflects clinical care in
LTCFs and adds knowledge to practice guidelines to assist
physicians in making decisions.
The strict definition of UTI is based on a scientific
approach, including micturition-related symptoms and
signs confirmed according to a positive culture or dipslide,
and could be used for comparisons with studies in other
populations but is difficult to generalize to clinical practice
in LTCFs. It is generally accepted that diagnosing UTI in
vulnerable older persons, especially in long-term care, is
JANUARY 2014–VOL. 62, NO. 1
Low UTI-risk group (cranberry n = 205; placebo n = 207)
High UTI-risk group (cranberry n = 253; placebo n = 263)
Figure 2. Cumulative incidence of urinary tract infection (UTI) within 1 year of follow-up depending on treatment (cranberry or
placebo) stratified for those at low and high UTI risk, accounting for mortality as competing risk. Solid line: cranberry group;
dotted line: placebo group. Clinical definition: symptom or positive testing (nitrite test, leukocyte esterase test, dipslide or culture)
or antibiotic treatment or UTI reported in the medical record. Strict definition: symptom and positive dipslide or culture.
complicated. A recent study in nursing home residents
with advanced dementia showed that symptoms and signs
of UTI are frequently not present in older persons with
dementia.51 In the current study, for example, most participants had dementia (76%) or incontinence (64%). Therefore, a clean catch urine sample for culturing is often not
available, making it impossible to diagnose UTI according
to the strictest criteria.52 The current study was doubleblinded, so the randomization itself cannot have influenced
the clinical definition. Despite the large study sample, no
treatment effect was shown in those at high UTI risk using
the strict definition. The study may have been slightly
underpowered for the rarer strictly defined UTIs.
The optimum dosage of cranberries is not clear, and a
well-designed dose-finding study is needed. An in vitro
study suggests that the administration of 72 mg of PAC
daily may offer some protection against bacterial adhesion
in the bladder.53 The daily use of 18 mg of PAC (two capsules) in this study may not have been high enough.
These results are not automatically generalizable to
vulnerable older persons living at home. Differences not
only in vulnerability and infection rates, but also in adherence and hospitalization rates were expected.
In LTCF residents with high UTI risk, taking cranberry
capsules twice daily results in a 26% lower incidence of
clinically defined UTI than with placebo, although no difference was found in UTI incidence according to a strict
JANUARY 2014–VOL. 62, NO. 1
Table 2. Incidence of Urinary Tract Infection (UTI), According to Two Definitions, Depending on Treatment with
Cranberry for Different Definitions and UTI Risk During 12 Months of Follow-Up
Person-Days at
Events, n
UTI Risk
Incidence Per 100 Person Years
at Risk (95% CI)
Risk Difference
(95% CI)
Effect, Hazard
Ratio (95% CI)
40.3 (30.0–50.5)
10.5 (5.5–15.5)
33.4 (24.2–42.5)
9.4 (4.8–14.1)
6.9 ( 6.9–20.7)
1.1 ( 5.7–7.9)
1.22 (0.84–1.77)
1.11 (0.56–2.20)
62.8 (50.3–75.2)
84.8 (70.0–99.7)
0.74 (0.57–0.97)
High without long-term cathetere
25.3 (17.9–32.7)
24.6 (17.5–31.7)
(41.4 to 2.7)
0.7 ( 9.5–11.0)
1.02 (0.68–1.55)
54.5 (41.8–67.2)
81.4 (65.4–97.5)
0.67 (0.49–0.91)
21.1 (13.7–28.5)
25.5 (17.5–33.5)
( 47.4 to 6.5)
4.4 ( 15.3–6.5)
0.83 (0.52–1.33)
CI, confidence interval.
Cranberry, n = 205; placebo, n = 207.
Symptom or positive testing (nitrite test, leukocyte esterase test, dipslide or culture) or antibiotic treatment or UTI reported in the medical record.
Symptom and positive dipslide or culture.
Cranberry, n = 253; placebo, n = 263.
Cranberry, n = 204; placebo, n = 216.
definition. Cranberry capsules may offer an opportunity to
decrease the incidence of this common infection in highUTI-risk LTCF residents by using a well-tolerated treatment.
The authors thank the organizations and members of the
University Nursing Home Research Network South Holland and the staff of the LTCFs participating in this study.
Their ongoing collaboration enabled us to perform this
Conflict of Interest: The editor in chief has reviewed
the conflict of interest checklist provided by the authors
and has determined that the authors have no financial or
any other kind of personal conflicts with this paper.
A grant was received from ZonMw Doelmatigheid,
the Dutch Organization for Health Research, the Netherlands (Project 170882501). Springfield Nutraceuticals
B.V., Oud-Beijerland, the Netherlands, supplied the cranberry and placebo capsules. A grant was received from the
Dutch Organization of Scientific Research (NWO) for
Open Access publication of this paper.
Author Contributions: Jacobijn Gussekloo had full
access to all data in the study and takes responsibility for
the integrity of the data and the accuracy of the data
analysis. Study concept and design: Caljouw, van den
Hout, Cools, Gussekloo. Analysis and interpretation of
data: Caljouw, van den Hout, Putter, Achterberg, Cools,
Gussekloo. Drafting of the manuscript: Caljouw. Critical
revision of the manuscript for important intellectual content: Caljouw, van den Hout, Putter, Achterberg, Cools,
Sponsor’s Role: All funding sources and suppliers were
independent and had no influence on study design; collection, analyses, and interpretation of data; writing the
report; or the decision to submit the manuscript for
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