Evaluation

of

patients

experiences

with

antidepressants

reported

by

means

of

a

medicine

reporting

system

Objective

To

assess

experiences

related

to

antidepressant

use

reported

to

an

internet-based

medicine

reporting

system

and

to

compare

the

nature

of

the

side

effects

reported

by

patients

with

those

reported

by

health

care

professionals

-LRB-

HCPs

-RRB-

Introduction

Non-adherence

to

prescribed

medication

regimens

is

a

persistent

problem

in

the

treatment

of

depression

with

antidepressants

Premature

discontinuation

dosing

lapses

and

partial

non-adherence

often

occur

-LSB-

-RSB-

The

illness

itself

as

well

as

physician

patient

and

treatment-related

factors

have

been

suggested

to

contribute

to

antidepressant

non-adherence

but

the

ability

of

health

care

professionals

-LRB-

HCP

-RRB-

to

predict

who

discontinues

medication

remains

poor

-LSB-

-RSB-

Earlier

studies

provide

scant

information

on

how

patients

in

clinical

practice

perceive

their

treatment

with

antidepressants

thus

insight

and

an

understanding

of

the

patients

perspectives

on

non-adherence

and

discontinuation

are

limited

Side

effects

and

ineffectiveness

are

the

major

reasons

cited

for

the

discontinuation

of

antidepressant

therapy

-LSB-

-RSB-

However

the

information

available

on

side

effects

is

mostly

based

on

controlled

clinical

trials

which

standardly

do

not

evaluate

how

bothersome

side

effects

are

to

the

individual

patient

Moreover

both

the

side

effects

and

the

effectiveness

of

the

antidepressant

therapy

observed

in

clinical

trials

may

not

reflect

the

experiences

of

the

patients

in

real

world

settings

Many

interventions

have

been

developed

to

improve

adherence

to

antidepressants

but

to

date

these

have

failed

to

demonstrate

a

clear

benefit

-LSB-

-RSB-

Treatment

non-adherence

remains

one

of

the

least

understood

health-related

behaviours

Information

received

directly

from

the

patient

may

improve

our

understanding

of

the

relative

importance

of

antidepressant

treatment

issues

and

consequently

help

to

explain

patients

behaviour

towards

antidepressant

use

Reporting

systems

have

shown

to

be

a

useful

tool

in

collecting

experiences

and

identifying

issues

related

to

the

daily

use

of

medicines

-LSB-

-RSB-

In

an

internet-based

medicine

reporting

system

was

established

in

The

Netherlands

where

users

of

medicines

are

able

to

report

all

types

of

experiences

with

medicines

side

effects

as

well

as

experiences

with

effectiveness

and

practical

and

reimbursement

issues

We

extracted

data

from

this

medicine

reporting

system

in

order

to

-LRB-

-RRB-

assess

the

type

of

experiences

related

to

antidepressant

use

reported

by

patients

-LRB-

-RRB-

assess

the

relevance

of

these

experiences

and

-LRB-

-RRB-

compare

the

nature

of

the

suspected

side

effects

reported

by

patients

with

those

reported

by

HCPs

Methods

Setting

Reports

were

obtained

from

an

internet-based

medicine

reporting

system

launched

on

May

in

The

Netherlands

This

reporting

system

was

initiated

by

DGV

The

Dutch

Institute

for

the

Proper

Use

of

Medicine

the

Science

Shop

for

Medicines

and

patient

and

consumer

organisations

Individuals

are

able

to

report

their

experiences

with

medicines

anonymously

by

completing

a

report

form

downloaded

by

accessing

a

website

-LRB-

-RRB-

Users

of

the

medicine

themselves

as

well

as

their

relatives

acquaintances

or

-LRB-

professional

-RRB-

carers

can

report

an

experience

All

reports

submitted

between

May

and

May

related

to

the

use

of

antidepressants

were

reviewed

for

the

clarity

and

completeness

of

the

description

of

the

experience

and

checked

for

multiple

reports

from

the

same

IP-address

One

duplicate

report

had

to

be

excluded

All

other

reports

were

included

in

the

study

The

data

were

stored

in

an

Access

database

Report

form

The

report

form

contained

items

which

requested

information

on

age

gender

type

of

medicine

used

nature

of

the

experience

a

description

of

the

experience

and

the

relevance

of

the

experience

Individuals

filling

in

the

report

had

to

indicate

whether

the

experience

was

related

to

either

effectiveness

a

side

effect

a

practical

issue

-LRB-

e.g.

difficulties

with

swallowing

tablets

-RRB-

or

a

reimbursement

issue

More

than

one

experience

related

to

the

same

drug

could

be

submitted

Experiences

related

to

effectiveness

had

to

be

further

specified

by

the

individual

by

selecting

one

of

the

following

categories

ineffectiveness

a

positive

effect

or

a

different

type

of

effect

-LRB-

e.g.

drug

interactions

-RRB-

Experiences

related

to

side

effects

had

to

be

further

specified

by

selecting

one

of

the

following

categories

negative

side

effects

positive

side

effects

-LRB-

e.g.

less

side

effects

as

compared

with

previous

medication

-RRB-

or

the

absence

of

side

effects

Relevance

of

the

experience

was

assessed

by

asking

the

individual

filling

in

the

report

to

indicate

both

the

impact

of

the

experience

on

a

scale

-LRB-

ranging

from

very

negative

to

very

positive

-RRB-

and

whether

the

experience

caused

a

change

in

antidepressant

use

To

specify

the

change

in

antidepressant

use

those

reporting

had

to

select

one

of

the

following

categories

discontinuation

switching

to

other

treatment

adjustment

of

dosage

or

administration

any

other

action

taken

or

no

action

taken

In

the

case

of

discontinuation

of

the

antidepressant

the

report

also

asked

whether

the

HCP

has

been

informed

Side

effects

All

reported

side

effects

-LRB-

including

experiences

on

ineffectiveness

-RRB-

were

coded

by

one

of

the

authors

-LRB-

SvdW

-RRB-

and

checked

by

a

second

author

-LRB-

EvG

-RRB-

using

preferred

terms

of

the

World

Health

Organisation

Adverse

Reaction

Terminology

-LRB-

WHO-ART

-RRB-

-LSB-

-RSB-

Preferred

terms

were

combined

into

groups

of

similar

side

effects

Spontaneous

reports

of

adverse

drug

reactions

on

antidepressants

received

from

HCPs

from

May

to

May

were

included

for

comparison

These

reports

were

received

by

The

Netherlands

Pharmacovigilance

Centre

Lareb

either

on

paper

forms

or

electronically

via

Coding

and

assessment

were

carried

out

by

qualified

assessors

from

Lareb

-LSB-

-RSB-

Data

analysis

The

relevance

of

the

side

effects

was

assessed

by

comparing

the

impact

of

the

-LRB-

grouped

-RRB-

side

effects

as

a

proportion

of

the

side

effects

that

were

perceived

as

very

negative

Relevance

was

also

assessed

by

comparing

the

proportion

of

the

side

effects

that

caused

discontinuation

of

initial

antidepressant

use

including

the

categories

discontinuation

and

switching

to

other

treatment

The

impact

and

discontinuation

proportions

of

the

different

groups

of

side

effects

were

compared

using

the

chi-square

test

For

the

comparison

between

patients

and

HCPs

the

groups

of

side

effects

were

compared

and

expressed

as

an

Odds

Ratio

-LRB-

OR

-RRB-

and

confidence

interval

-LRB-

CI

-RRB-

The

most

frequently

reported

-LRB-

groups

of

-RRB-

side

effects

by

patients

as

well

as

the

most

frequently

reported

-LRB-

groups

of

-RRB-

side

effects

by

HCPs

were

included

in

the

analysis

Results

Characteristics

In

total

individuals

submitted

a

report

to

the

medicine

reporting

system

during

the

study

period

of

whom

-LRB-

-RRB-

submitted

a

report

on

antidepressants

Of

these

individuals

-LRB-

-RRB-

reported

for

themselves

and

ten

reported

for

a

relative

or

acquaintance

The

mean

-LRB-

SD

-RRB-

age

of

the

of

the

antidepressant

users

was

-LRB-

-RRB-

years

and

were

female

The

majority

of

those

reporting

on

antidepressants

-LRB-

-RRB-

were

reporting

on

a

serotonin-reuptake

inhibitor

-LRB-

SSRI

-RRB-

were

reporting

on

a

tricyclic

antidepressant

-LRB-

TCA

-RRB-

and

on

another

type

of

antidepressant

The

antidepressants

most

frequently

reported

on

were

paroxetine

-LRB-

of

total

-RRB-

venlafaxine

-LRB-

-RRB-

citalopram

-LRB-

-RRB-

and

mirtazapine

-LRB-

-RRB-

The

use

of

a

benzodiazepine

as

a

concomitant

drug

was

reported

by

of

those

reporting

on

antidepressant

use

Nature

of

experiences

The

individuals

reporting

on

antidepressant

use

described

experiences

Table

shows

the

nature

of

the

experiences

described

Ninety-two

individuals

-LRB-

-RRB-

described

an

experience

with

effectiveness

of

whom

-LRB-

-RRB-

described

an

experience

with

ineffectiveness

Four

individuals

claimed

generic

substitution

as

the

reason

for

ineffectiveness

and

-LRB-

-RRB-

reported

a

positive

experience

with

the

effectiveness

of

an

antidepressant

Other

type

of

effects

in

terms

of

effectiveness

that

were

submitted

by

seven

-LRB-

-RRB-

individuals

included

experiences

on

suspected

drug

interactions

Table

of

the

reported

experiences

related

to

antidepressant

use

reported

to

a

medicine

reporting

system

-LRB-

-RRB-

aIssueProportion

of

total

number

of

individuals

-LRB-

n

-RRB-

reporting

on

antidepressant

useNature

of

issueProportion

individuals

reporting

on

a

specific

-LRB-

n

-RRB-

-LRB-

n

-RRB-

Positive

-LRB-

n

-RRB-

-LRB-

n

-RRB-

Side

-LRB-

n

-RRB-

Negative

side

-LRB-

n

-RRB-

Positive

side

-LRB-

n

-RRB-

Absence

of

side

-LRB-

n

-RRB-

Practical

-LRB-

n

-RRB-

Reimbursement

and

availability

-LRB-

n

-RRB-

aA

total

of

reporters

submitted

experiences

The

reported

experiences

are

expressed

as

a

percentage

of

the

total

number

of

individuals

submitting

reports

In

total

of

the

individuals

-LRB-

-RRB-

reporting

on

antidepressant

use

submitted

a

report

on

side

effects

Of

these

-LRB-

-RRB-

described

a

total

of

side

effects

that

were

experienced

as

negative

The

number

of

reported

side

effects

ranged

from

to

per

reporter

experiencing

a

negative

side

effect

Twelve

individuals

-LRB-

-RRB-

reported

that

they

had

not

experienced

any

side

effect

at

all

and

three

-LRB-

-RRB-

submitted

a

positive

experience

with

side

effects

reporting

that

their

current

antidepressant

therapy

caused

fewer

side

effects

than

their

previous

medication

Fourteen

individuals

-LRB-

-RRB-

reported

a

practical

issue

-LRB-

such

as

problems

with

swallowing

tablets

or

bad

taste

-RRB-

and

four

-LRB-

-RRB-

reported

a

reimbursement

or

availability

issue

-LRB-

receiving

treatment

for

a

relative

short

duration

-RRB-

Box

shows

a

number

of

the

reported

experiences

Relevance

of

side

effects

Table

shows

the

relevance

impact

and

discontinuation

rates

of

the

most

frequently

reported

side

effects

Of

all

side

effects

resulted

in

discontinuation

of

the

initial

antidepressant

therapy

The

proportion

of

side

effects

that

caused

discontinuation

of

the

initial

antidepressant

did

not

differ

significantly

between

the

different

side

effects

Of

those

individuals

who

simultaneously

reported

an

experience

on

side

effects

and

one

on

ineffectiveness

-LRB-

-RRB-

reported

that

their

experience

resulted

in

discontinuation

of

the

initial

antidepressant

therapy

Of

all

individuals

who

reported

discontinuation

of

therapy

did

not

inform

their

HCP

Table

of

the

most

frequently

reported

side

effects

related

to

antidepressant

useSide

effectNumber

of

reported

experiences

-LRB-

n

-RRB-

Impact

-LRB-

perceived

as

very

negative

-RRB-

Discontinuation

of

antidepressant

use

-LRB-

-RRB-

Sleep

Somnolence

drowsiness

Insomnia

attempt

thought

or

attempts

thoughts

or

tendency

is

also

included

although

the

number

of

reported

experiences

was

less

than

Of

all

side

effects

were

perceived

as

very

negative

The

impact

of

the

side

effects

differed

almost

significantly

between

the

groups

of

side

effects

-LRB-

p

-RRB-

with

headache

dizziness

and

fainting

perceived

as

most

negative

Side

effects

compared

between

patients

and

HCPs

Table

presents

those

side

effects

most

frequently

reported

by

patients

and

HCPs

Patients

and

HCPs

differed

in

the

nature

of

reported

side

effects

Compared

with

HCPs

patients

reported

significantly

more

events

such

as

apathy

excessive

sweating

ineffectiveness

discontinuation

symptoms

somnolence

insomnia

sexual

problems

and

weight

increase

HCPs

reported

significantly

more

rash

pruritis

laboratory

abnormalities

muscle

and

joint

complaints

congenital

disorders

eye

disorders

extrapyramidal

disorders

and

menstrual

disorders

than

patients

Table

side

effects

on

antidepressants

by

patients

compared

with

reported

side

effects

on

antidepressants

by

health

care

professionals

-LRB-

HCPs

-RRB-

Side

effectNumber

of

reported

side

effects

by

patientsPercentage

of

total

number

of

side

effects

-LRB-

n

-RRB-

Number

of

reported

side

effects

by

HCPsPercentage

of

total

number

of

side

effects

-LRB-

n

-RRB-

Odds

ratio

-LRB-

CI

-RRB-

aTop

most

frequently

reported

side

effects

by

patients

Weight

-LRB-

-RRB-

Sexual

-LRB-

-RRB-

Discontinuation

-LRB-

-RRB-

-LRB-

-RRB-

Somnolence

drowsiness

-LRB-

-RRB-

Insomnia

-LRB-

-RRB-

Excessive

Nausea

-LRB-

-RRB-

Dizziness

-LRB-

-RRB-

-LRB-

-RRB-

Dry

-LRB-

-RRB-

Abdominal

-LRB-

-RRB-

-LRB-

-RRB-

Depressed

-LRB-

-RRB-

Top

most

frequently

reported

side

effects

by

HCPs

Rash

urticaria

and

-LRB-

-RRB-

Laboratory

Muscle

and

joint

-LRB-

-RRB-

Congenital

Eye

and

vision

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Extrapyramidal

disorders

-LRB-

-RRB-

Menstrual

disorders

vaginal

-LRB-

-RRB-

Heart

rhythm

-LRB-

-RRB-

Convulsions

Drug

substitution

-LRB-

-RRB-

Serotonin

Nausea

-LRB-

-RRB-

Dizziness

-LRB-

-RRB-

CI

confidence

intervalaOR

Patients

were

more

likely

to

report

the

side

effect

than

the

HCPs

OR

HCPs

were

more

likely

to

report

the

side

effect

than

the

patientsbSide

effects

that

appear

in

both

the

patients

and

HCPs

list

Discussion

Both

side

effects

and

a

lack

of

effectiveness

appear

to

be

important

treatment

issues

for

patients

who

reported

on

antidepressants

in

our

study

Most

of

the

individuals

reporting

on

antidepressant

use

described

one

or

more

side

effects

of

which

the

most

frequent

were

weight

increase

sexual

problems

somnolence

insomnia

and

apathy

Ineffectiveness

was

also

reported

by

a

considerable

number

of

individuals

Ineffectiveness

is

not

often

reported

in

literature

as

an

adverse

effect

of

treatment

-LSB-

-RSB-

However

our

study

reveals

that

it

is

a

relevant

issue

for

patients

during

antidepressant

therapy

The

fact

that

side

effects

tend

to

occur

before

the

therapeutic

effect

of

the

antidepressant

is

perceived

may

play

an

important

part

in

explaining

early

discontinuation

of

the

therapy

Ineffectiveness

should

therefore

receive

attention

from

HCPs

in

order

to

prevent

early

discontinuation

of

antidepressants

One

of

the

unique

features

of

this

medicine

reporting

system

is

the

possibility

to

gather

information

on

the

relevance

of

the

experiences

that

is

the

impact

of

the

experience

and

the

change

in

initial

treatment

Overall

half

of

the

experiences

were

perceived

as

very

negative

Experience

of

one

or

more

bothersome

side

effects

means

an

individual

is

threefold

more

likely

to

stop

taking

antidepressants

-LSB-

-RSB-

Our

results

show

that

one

half

of

the

side

effects

resulted

in

discontinuation

of

the

initial

antidepressant

therapy

Moreover

of

all

those

individuals

who

reported

discontinuation

of

therapy

did

not

even

inform

their

HCP

This

supports

the

concept

that

this

medicine

reporting

system

provides

data

of

which

HCPs

are

often

not

aware

but

which

are

of

crucial

importance

to

any

understanding

of

patients

behaviour

related

to

the

use

of

antidepressants

Patients

and

HCPs

differed

in

the

nature

of

the

side

effects

reported

Patients

were

found

to

report

more

frequently

those

events

which

may

be

less

tangible

and

visible

to

HCPs

such

as

sleeping

problems

and

apathy

In

addition

HCPs

may

consider

symptoms

reported

by

patients

with

psychiatric

disorders

as

a

symptom

of

the

disease

rather

than

as

one

related

to

the

medication

Other

notable

differences

between

patients

and

HCPs

in

terms

of

the

frequency

of

reported

side

effects

were

those

of

weight

increase

sexual

problems

discontinuation

symptoms

and

excessive

sweating

The

differences

in

the

nature

of

the

reported

side

effects

show

that

patients

and

HCPs

differ

in

which

type

of

side

effects

can

be

considered

to

be

bothersome

and/or

relevant

to

report

The

burden

of

side

effects

is

clearly

underestimated

by

HCPs

-LSB-

-RSB-

Although

HCPs

are

knowledgeable

on

the

side

effects

related

to

SSRI

use

they

underestimate

the

frequency

of

these

side

effects

and

how

bothersome

they

are

to

patients

-LSB-

-RSB-

In

addition

HCPs

may

be

reticent

in

reporting

a

side

effect

to

a

reporting

system

More

than

patients

HCPs

evaluate

the

side

effect

reported

by

the

patient

according

to

perceived

relevance

and

causality

related

to

the

medication

Side

effects

which

are

considered

by

the

HCP

as

well-known

or

not

related

to

the

medication

consequently

get

lost

to

the

health

care

system

-LSB-

-RSB-

Patient

reporting

is

not

yet

widely

accepted

and

the

number

of

systems

collecting

experiences

from

patients

is

still

limited

In

the

UK

the

Prescription-Event

Monitoring

-LRB-

PEM

-RRB-

system

seeks

to

identify

adverse

events

recorded

following

the

use

of

newly

marketed

drugs

selected

for

monitoring

on

the

first

patients

given

the

new

drug

-LSB-

-RSB-

Since

the

middle

of

the

Danish

Medicines

Agency

and

the

Netherlands

Pharmacovigilance

Centre

Lareb

also

accept

reports

on

adverse

drug

reactions

from

patients

-LSB-

-RSB-

In

Sweden

the

KILEN

Consumer

Institute

for

Medicines

and

Health

started

a

consumer

database

in

that

collects

experiences

related

mainly

to

dependence

and

side

effects

of

benzodiazepine

and

antidepressant

use

-LSB-

-RSB-

However

these

systems

focus

only

on

adverse

events

while

other

aspects

of

medicine

use

including

experiences

on

ineffectiveness

practical

and

reimbursement

issues

have

also

been

shown

to

be

relevant

to

patients

A

limitation

of

this

internet-based

reporting

system

is

that

the

reporters

are

anonymous

and

therefore

further

contact

and

feedback

are

not

possible

Consequently

a

thorough

assessment

of

causality

between

the

side

effect

and

the

antidepressant

was

not

always

possible

The

Netherlands

Pharmacovigilance

Centre

Lareb

on

the

other

hand

whose

primary

aim

is

the

early

detection

of

new

adverse

drug

reactions

has

the

facilities

to

request

further

medical

information

by

contacting

the

patient

and/or

his/her

HCP

-LSB-

-RSB-

However

we

believe

this

does

not

detract

from

our

conclusion

The

individuals

reporting

through

the

internet-based

reporting

system

proved

to

be

capable

of

providing

clear

descriptions

of

their

experiences

and

of

balancing

the

benefits

and

burden

of

treatment

The

patient

experiences

provide

important

information

on

how

patients

in

clinical

practice

perceive

treatment

with

antidepressants

Such

patients

experience

sleep

disorders

weight

increase

sexual

problems

apathy

and

ineffectiveness

as

events

which

have

a

negative

impact

and

which

frequently

lead

to

discontinuation

of

the

antidepressant

therapy

Because

adherence

decisions

are

mostly

a

rational

balance

of

perceived

benefits

versus

burden

-LSB-

-RSB-

an

assessment

of

patient

experiences

may

improve

the

understanding

of

patients

behaviour

towards

antidepressant

use

This

information

can

be

used

in

the

development

of

more

targeted

adherence-enhancing

strategies

that

may

lead

to

optimisation

of

antidepressant

treatment

from

the

perspective

of

both

HCPs

and

patients

O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

adverse events
antidepressants
discontinuation
patient reporting


The Generation R Study Biobank : a resource for epidemiological studies in children and their parents The Generation R Study is a population-based prospective cohort study from fetal life until young adulthood . The study is designed to identify early environmental and genetic causes of normal and abnormal growth , development and health from fetal life until young adulthood . In total , 9,778 mothers were enrolled in the study . Prenatal and postnatal data collection is conducted by physical examinations , questionnaires , interviews , ultrasound examinations and biological samples . Major efforts have been conducted for collecting biological specimens including DNA , blood for phenotypes and urine samples . In this paper , the collection , processing and storage of these biological specimens are described . Together with detailed phenotype measurements , these biological specimens form a unique resource for epidemiological studies focused on environmental exposures , genetic determinants and their interactions in relation to growth , health and development from fetal life onwards . Introduction The Generation R Study is a population-based prospective cohort study from fetal life until young adulthood . The background and specific research projects of the study have been described in detail previously -LSB- 1 , 2 -RSB- . Briefly , the Generation R Study is designed to identify early environmental and genetic causes of normal and abnormal growth , development and health from fetal life until young adulthood . The study focuses on four primary areas of research : -LRB- 1 -RRB- growth and physical development ; -LRB- 2 -RRB- behavioural and cognitive development ; -LRB- 3 -RRB- diseases in childhood ; and -LRB- 4 -RRB- health and healthcare for pregnant women and children . The main outcomes and determinants are presented in Tables 1 and 2 . The general aims of the study are : To describe normal and abnormal growth , development and health from fetal life until young adulthood ; To identify biological , environmental and social determinants of normal and abnormal growth , development and health from fetal life until young adulthood ; To examine the effectiveness of current strategies for prevention and early identification of groups at risk.Table 1Main outcomes per research areaGrowth and physical developmentFetal growth patterns and organ developmentPregnancy complicationsPostnatal growth patternsObesityRisk factors for development of cardiovascular diseaseRisk factors for type 2 diabetesBehavioural and cognitive developmentMaternal and paternal psychopathologyFetal and postnatal brain developmentBehaviour , psychopathology and cognitionNeuromotor developmentChronic painAttachmentStress reactivityDiseases in childhoodInfectious diseases in childhoodDevelopment of the immune systemAsthma and asthma related symptomsParoxysmal neurological disordersHealth and healthcareQuality of lifeHealth care utilizationEffectiveness of screening programmesTable 2Main determinantsBiological determinantsParental anthropometrics and blood pressureFetal and postnatal growth characteristicsEndocrine and immunological factorsGenetic variantsEnvironmental determinantsMaternal and childhood dietParental life style habits -LRB- including smoking , alcohol consumption -RRB- Housing conditionsSocial determinantsParental education , employment status and household incomeParental marital statusEthnicity For these aims , a detailed and extensive data collection has been conducted in the prenatal phase of the study and is currently conducted in the early postnatal period -LSB- 2 -RSB- . This data collection comprises also biological specimens including DNA , blood for phenotypes and urine samples . These biological specimens form the Generation R Study Biobank , which enables future epidemiological studies focused on environmental exposures , genetic determinants and their interactions in relation to growth , health and development from fetal life onwards . In this paper , the design , collection , processing and storage of these biological specimens in the prenatal phase of the study are described . Design and biological samples collection The Generation R Study is a population-based prospective cohort study from fetal life until young adulthood -LSB- 2 -RSB- . Mothers with a delivery date between April 2002 and January 2006 were eligible . Enrolment was aimed in early pregnancy but was allowed until birth of the child . Extensive assessments were carried out in mothers and their partners in pregnancy and are currently performed in their children . Assessments in pregnancy were planned in early pregnancy -LRB- gestational age < 18 weeks -RRB- , mid-pregnancy -LRB- gestational age 18 -- 25 weeks -RRB- and late pregnancy -LRB- gestational age ≥ 25 weeks -RRB- and at birth . The individual time scheme of these assessments depended on the specific gestational age at enrolment -LSB- 2 -RSB- . The partners were assessed once in pregnancy . All children form a prenatally recruited birth-cohort that is currently being followed until young adulthood . Additionally , more detailed assessments of fetal and postnatal growth and development are conducted in a randomly selected subgroup of Dutch children and their parents , referred to as the Generation R Focus Cohort . Studies conducted in this subgroup examine etiological associations using more time-consuming methods that can not be applied in the whole cohort . Biological materials have been collected in early , mid - and late pregnancy and at birth . Figure 1 shows the design of the collection of biological materials in this phase . In early , mid - and late pregnancy , biological materials were collected at the visits to one of our dedicated research centres . The planned amounts of blood taken by ante-cubital venous puncture were 35 ml in early pregnancy and 20 ml in mid-pregnancy from the mother and 10 ml from her partner . When mothers were enrolled in mid - and late pregnancy , 35 ml was taken at the first visit . Urine samples of mothers have been collected in early , mid - and late pregnancy from February 2004 until November 2005 . Directly after delivery , midwives or obstetricians collected 30 ml cord blood from the umbilical vein . Fig. 1Design data collection biological specimens The Generation R Study is approved by the Medical Ethical Committee of the Erasmus Medical Center , Rotterdam . Mothers and their partners received written and oral information about the study . Participants were asked for their written informed . Study cohort In total , 9,778 mothers were enrolled in the study . Of these mothers , 91 % -LRB- n = 8,880 -RRB- was enrolled in pregnancy . Only partners from mothers enrolled during pregnancy were invited to participate . In total , 71 % -LRB- n = 6,347 -RRB- of all partners were enrolled . The general characteristics of the mothers and their partners are presented in Table 3 . Of all participating mothers , enrolment was in early pregnancy in 69 % -LRB- n = 6,748 -RRB- , in mid-pregnancy in 19 % -LRB- n = 1,857 -RRB- , in late pregnancy in 3 % -LRB- n = 275 -RRB- and at birth of their child in 9 % -LRB- n = 898 -RRB- . The cohort comprises various ethnic groups . The largest ethnic groups are the Dutch , Surinamese , Turkish , Moroccan , Dutch-Antilles and Cape Verdian mothers . Table 3Characteristics of mothers and their partners MothersPartners -LRB- n = 9,778 -RRB- -LRB- n = 6,347 -RRB- Gestational age at enrolment -LRB- % -RRB- Early pregnancy69 -- Mid-pregnancy19 -- Late pregnancy3 -- Birth9 -- Pregnancy number in study -LRB- % -RRB- 1st pregnancy 94 -- 2nd pregnancy 6 -- 3rd pregnancy 0.1 -- Age at enrolment -LRB- years -RRB- a29 .7 -LRB- 5.3 -RRB- 32.7 -LRB- 5.8 -RRB- Parity -LRB- % -RRB- 055 -- 131 -- ≥ 214 -- Ethnicity -LRB- % -RRB- Dutch , other-European 5870 Surinamese96 Moroccan 74 Turkish 96 Dutch Antilles 43 Cape Verdian 42 Others 99Education -LRB- vocational training -RRB- -LRB- % -RRB- Lower 138 Intermediate4541 Higher 4251Values are percentages aMean -LRB- standard deviation -RRB- Logistics All biological samples were bar coded with a unique laboratory number . Blood or urine samples collected at one visit have the same bar code with an additional specific tube number . This combination forms a unique registration number . All following steps in processing , storing and data management of the samples are linked to this unique number . All blood samples from the mother and partner were taken by research nurses and temporally stored at our research centre or one of the obstetric departments at room temperature for a maximum of 3 h . At least every 3 h , these blood samples were transported to a dedicated laboratory facility of the regional laboratory in Rotterdam , the Netherlands -LRB- STAR-MDC -RRB- for further processing and storage . Participants delivered their child either at home or at one of the hospitals in Rotterdam . The midwife or obstetrician collected cord blood samples . Subsequently , courier services with a 7-days and 24-h availability were responsible for transportation of these cord blood samples to our laboratory within 2 h . After collection and transportation , all blood and urine samples have been centrally processed and stored at the STAR-MDC laboratory . Samples for DNA extraction have initially been stored as EDTA whole blood samples and subsequently transported to the Erasmus Medical Center for further processing . All blood and urine samples are registered in Labosys -LRB- Philips -RRB- -LSB- 3 -RSB- . Both the anonymous person unique study numbers and all sample numbers are registered which enables matching of each sample to a study subject . Also , picking and defrosting of samples in registered in Labosys . A back-up of this registration is available at the Erasmus Medical Center . Response rates Response rates for collection of biological specimens are presented in Table 4 . Overall response rates for blood collection in mothers are high . To get these high response rates , we have used the venous punctures that were already planned in routine care for additional blood sample collection when this was possible . Blood for DNA extraction is available in 91 , 83 and 67 % of the eligible mothers , partners and children . The larger number of missings in partners and children were mainly due to lack of consent and logistical constraints during delivery , respectively . As Table 4 shows , response rates for the various blood samples at one occasion were similar . Absolute numbers of urine samples are lower than the absolute number of blood samples because the urine sample collection was performed during a limited period in the prenatal phase of the study . Tables 5 and 6 show characteristics of children and partners with and without available DNA . In children , the number of missing blood samples in children with perinatal complications including low birth weight and preterm birth is higher because of the limited possibilities and priorities during these deliveries . At this moment , efforts are carried out for completing DNA collection in the children by buccal samples . Table 4Response rates biological specimensEligibleAvailable % -LRB- n -RRB- Mother DNA8 ,88091 -LRB- 8,055 -RRB- Early pregnancy Plasma -LRB- EDTA -RRB- 6,74895 -LRB- 6,398 -RRB- Serum6 ,74894 -LRB- 6,337 -RRB- Urine2 ,79785 -LRB- 2,375 -RRB- Mid-pregnancy Plasma -LRB- EDTA -RRB- 8,24193 -LRB- 7,682 -RRB- Serum8 ,24193 -LRB- 7,631 -RRB- Urine3 ,38097 -LRB- 3,279 -RRB- Late-pregnancy Urine3 ,91896 -LRB- 3,762 -RRB- Partner DNA6 ,34783 -LRB- 5,289 -RRB- Child DNA8 ,82167 -LRB- 5,908 -RRB- Plasma -LRB- EDTA -RRB- 8,82166 -LRB- 5,857 -RRB- Serum8 ,82166 -LRB- 5,821 -RRB- Number of eligible subjects reflects those participating in the study during pregnancy -LRB- DNA mother and partner -RRB- and visit our research centre in early , mid - or late pregnancy -LRB- plasma , serum and urine -RRB- . The number of eligible subjects for urine sample collection is lower since this data-collection was added after starting the study . Number of eligible children reflects the number of live born children of mothers who were enrolled in the prenatal phase of the study with a known date of birthTable 5Characteristics of partners with and without DNA availablePartners -LRB- n = 6,347 -RRB- DNA available -LRB- n = 5,289 -RRB- No DNA available -LRB- n = 1,058 -RRB- Age -LRB- years -RRB- 32.8 -LRB- 5.7 -RRB- 32.2 -LRB- 5.7 -RRB- Ethnicity -LRB- % -RRB- Dutch , other-European 68.266.1 Surinamese6 .86.6 Moroccan 3.86.2 Turkish 6.87.2 Dutch Antilles 2.93.4 Cape Verdian 2.71.9 Others 8.88.6 Values are percentages or means -LRB- standard deviation -RRB- Table 6Characteristics of children with and without DNA availableChildren -LRB- n = 8,821 -RRB- DNA available -LRB- n = 5,908 -RRB- No DNA available -LRB- n = 2,913 -RRB- Male -LRB- % -RRB- 50.650.1 Birth weight -LRB- grams -RRB- 3,444 -LRB- 520 -RRB- 3,280 -LRB- 671 -RRB- Birth weight < 2,500 g -LRB- % -RRB- 3.310.8 Gestational age -LRB- weeks -RRB- 40.1 -LRB- 37.1 -- 42.0 -RRB- 39.9 -LRB- 34.7 -- 42.1 -RRB- Gestational age < 37 weeks -LRB- % -RRB- 3.911.2 Ethnicity -LRB- % -RRB- Dutch , other-European 64.754.6 Surinamese7 .49.0 Moroccan 6.57.9 Turkish 7.59.5 Dutch Antilles 3.84.8 Cape Verdian 2.43.5 Others 7.710.7 Values are percentages , means -LRB- standard deviation -RRB- or median -LRB- 95 % range -RRB- DNA For DNA extraction , one 10 ml EDTA tube from mothers , partners and children at birth have been collected and stored directly as whole blood sample at − 80 °C . After completion of the blood sample collection , DNA extraction was started from white blood cells . First , DNA extraction from all children has been conducted manually using the Qiagen FlexiGene Kit -LRB- Qiagen Hilden , Germany -RRB- . Currently , DNA extraction from 5 ml whole blood samples from the mothers and partners is performed by a Hamilton STAR multi-channel robot using AGOWA magnetic bead technology -LRB- at 72 samples per run -RRB- and is expected to be finished in spring 2008 . Extracted DNA is automatically collected in stock tubes -LRB- 2D Matrix , Micronic -RRB- that are organized in 96-wells format , but that can be individually addressed . These stock samples are split into two tubes that are stored at different locations . One of the stocks will then be used for normalising the DNA concentrations in 96 deep well -LRB- DW -RRB- plates . This protocol , as well as other manipulations of the DNA samples are performed on a Caliper ALH3000 pipetting robot -LRB- 8/96/384 channels -RRB- with a Twister module and a 96/384 wells Tecan GENios plus UV reader . In total , 90 DNA samples are normalised per 96 DW plate with 6 water blancs per plate . Additionally , a random selection of 5 % of the total number of samples are put into separate 96 DW plates , again with 6 blancs per plate , for control purposes . For normalisation , sample and diluent volumes are automatically calculated and produced to obtain equal DNA concentrations for all samples -LRB- 25 -- 50 ng/μl -RRB- . From these stock 96-DW plates , 384 DW plates are created , which comprise 24 blancs each . Subsequently , replica PCR plates -LRB- 384 wells -RRB- with a concentration of 1 ng/μl are created for genotype studies . Stock 96-well plates -LRB- DW and 2D Matrix , Micronic -RRB- are stored at − 20 °C at two different locations within the Erasmus Medical Center -LRB- Genetic Epidemiology Laboratory , Genetic Laboratory Internal Medicine -RRB- . The 384 DW stock and PCR plates are stored at the Genetic Laboratory Internal Medicine , Erasmus Medical Center . All genotyping studies with Generation R DNA material are performed in-house at the high throughput genotyping facility in this Laboratory . Genome Wide Association database A new approach to identify most important common genetic variants that contribute to explain variance in phenotypes by a systematic analysis of our genome has only recently become available as the Genome Wide Association -LRB- GWA -RRB- analysis -LSB- 4 -RSB- . The GWA analysis is now generally considered a critical tool to identify genes for complex diseases and traits . The GWA analysis is based on genotyping large numbers -LRB- > 500,000 -- 2,000,000 -RRB- of Single Nucleotide Polymorphisms -LRB- SNPs -RRB- , and subsequently performing association analyses of the SNP genotypes -LRB- or haplotypes thereof -RRB- with the phenotype of interest . The power of GWA analyses has been recently demonstrated with the identification of susceptibility genes involved in a wide range of disorders varying from common and rare diseases including coronary heart disease , diabetes and multiple sclerosis -LSB- 5 -- 7 -RSB- . These developments have led to a stream of novel disease genes , highlighting new etiological pathways and are expected to improve the understanding of the molecular basis of these diseases . Currently , we are preparing a GWA analysis in all children participating in the Generation R Study of whom DNA is available . For this , the infrastructure , used for the GWA analysis in Rotterdam Study , a population-based cohort study in about 15,000 adults in Rotterdam , the Netherlands is used -LSB- 8 -RSB- . Blood for phenotypes Results of analyses performed in blood samples -LRB- 5 ml EDTA plasma -RRB- for routine care for pregnant women -LRB- Hb , Ht , HIV , HBsAg , Lues , Rhesus factor and irregular antibodies -RRB- are obtained from midwife and obstetric registries . All other EDTA plasma and serum samples from mothers and children have been processed and stored for future studies . Processing was aimed to be finished within a maximum of 3 h after venous puncture . Total processing time took 15 min . The samples were spun and the plasma and serum volume was distributed into 250 μl aliquots and transferred to 0.65 ml polypropylene tubes -LRB- Micronic -RRB- by a Tecan automatic liquid handler . From the mother , a set of on average 16 aliquots tubes -LRB- with a total volume of 4 ml -RRB- each from one plasma and serum sample were divided over four different microtiter trays . From the plasma and serum samples from the children , on average 11 tubes were filled with 250 μl aliquots -LRB- in total 2.75 ml -RRB- divided over three microtiter trays . The trays were immediately stored at − 80 °C . Each Micronic tube is uniquely coded on the bottom with the Traxis ® 2D code . The aliquots were divided over 4 trays of 96 tubes for storage in the freezers . Figure 2 shows the distribution of the samples in the 96 trays . All samples are stored at − 80 °C at one location -LRB- STAR-MDC laboratory -RRB- where they are distributed over four different freezers with different power supplies . Fig. 2Distribution of blood samples in the 96 trays -LRB- see text -RRB- Urine Urine samples -LRB- 65 ml -RRB- were added to the data collection between February 2004 and November 2005 . The urine samples were kept at room temperature for a maximum of 3 h and transported to the STAR-MDC laboratory for further processing . At the laboratory , the urine was filled out manually in one 5 ml and three 20 ml tubes . Before the urine was filled out , a gravity measurement was performed . The 5 ml urine tubes were send to the Department of Medical Microbiology of the Erasmus Medical Centre for Chlamydia analysis -LSB- 9 -RSB- . The remaining urine tubes -LRB- 20 ml -RRB- were each stored at − 20 °C at the STAR-MDC laboratory . Other population-based birth cohort studies The Generation R Study is not the first birth-cohort study with an extensive collection of biological specimens . Compared to other birth-cohort studies , the size of the Generation R Study cohort is not larger but the measurements are more detailed and the study group has a large ethnic variety -LSB- 10 -- 14 -RSB- . Studies having a similar design and biological specimens collection include the Avon Longitudinal Study of Parents and Children -LRB- ALSPAC -RRB- in Bristol , UK , the Danish National Birth Cohort Study , the Norwegian mother and child Cohort Study , the Southampton Women 's Survey -LRB- SWS -RRB- in Southampton , UK and The National Children 's Study in the USA . Collaboration with these studies for funding , standardization , replication and quality management is necessary . Currently , we are exploring possibilities for formal collaboration . Requests for biological samples use The study has an open policy with regard to collaboration with other research groups . Request for collaboration and use of biological specimens should primarily be pointed to Albert Hofman -LRB- a.hofman@erasmusmc.nl -RRB- . These requests are discussed in the Generation R Study Management Team regarding their scientific merits , study aims , overlap with ongoing studies , logistic consequences and financial contributions . General policy is that collaborating researchers and groups are responsible themselves for the finances and that all laboratory tests are conducted in the Eramus Medical Center , Rotterdam . After approval of the project by the Generation R Study Management Team and the Medical Ethical Committee of the Erasmus Medical Center , the collaborative research project is embedded in one of the four research areas supervised by the specific principal investigator .

O O O O B O O O O O O O O O O B O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B I O O O O O B B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O


Low

migrant

mortality

in

Germany

for

men

aged

and

older

fact

or

artifact

Migrant

mortality

in

Europe

was

found

to

be

lower

than

mortality

of

host

populations

In

Germany

residents

with

migrant

background

constitute

nearly

one

tenth

of

the

population

aged

with

about

of

them

being

foreigners

The

German

Pension

Scheme

follows

vital

status

of

pensioners

very

accurately

Mortality

re-estimation

reveals

two-fold

underestimation

of

mortality

of

foreigners

due

to

biased

death

numerator

and

population

denominator

Introduction

Migrant

mortality

has

attracted

substantial

research

interest

First

it

provides

the

opportunity

to

look

at

the

combined

influence

of

earlier

life

conditions

in

the

country

of

origin

and

the

more

recent

life

conditions

in

the

receiving

country

Second

it

allows

one

to

see

how

cultural

and

behavioral

patterns

imported

from

the

country

of

origin

and

their

further

transformation

affect

migrant

health

Third

it

enables

the

researcher

to

gain

insight

into

selective

migration

of

healthy

people

-LRB-

the

healthy

migrant

effect

-RRB-

Indeed

at

the

very

moment

of

moving

most

migrants

are

in

good

health

because

immigration

and

assimilation

to

the

foreign

society

are

hardly

compatible

with

serious

health

problems

In

addition

migrants

often

have

to

pass

obligatory

medical

examinations

before

they

immigrate

In

Germany

and

other

European

countries

migrant

mortality

was

found

to

be

much

lower

than

the

mortality

of

the

host

population

-LSB-

-RSB-

Prior

studies

have

tended

to

consider

the

healthy

migrant

effect

as

a

central

explanation

of

very

low

immigrant

mortality

In

addition

the

possible

role

played

by

behavioral

and

psychological

factors

has

been

emphasized

-LSB-

-RSB-

At

the

same

time

there

has

also

been

serious

concern

about

the

reliability

of

demographic

data

on

the

mortality

of

migrants

The

main

problem

is

related

to

migrant

moves

between

the

home

and

host

country

If

departures

from

the

host

country

and

deaths

in

the

country

of

origin

are

under-recorded

the

moves

produce

a

numerator-denominator

bias

leading

to

the

under-estimation

of

migrant

mortality

Deaths

of

migrants

in

the

country

of

origin

unregistered

by

the

population

statistics

in

the

receiving

countries

cause

statistical

immortality

The

results

of

under-registered

return

migrations

and

deaths

abroad

may

be

particularly

problematic

at

advanced

ages

-LRB-

-RRB-

i.e.

at

ages

when

the

share

of

immortals

cumulated

over

time

can

become

significant

compared

to

the

relatively

small

remaining

population

-LSB-

-RSB-

Biases

in

the

data

can

be

substantial

even

when

micro-data

from

population

registers

or

cohort

follow-up

studies

are

used

-LSB-

-RSB-

This

is

so

because

a

segment

of

migrants

-LRB-

the

less-well-integrated

and

less

healthy

-RRB-

may

tend

to

be

at

higher

risk

of

observation

censoring

due

to

departure

-LSB-

-RSB-

In

Germany

in

million

people

-LRB-

or

of

the

total

population

-RRB-

had

a

migrant

and

million

-LRB-

-RRB-

had

foreign

citizenship

-LSB-

-RSB-

Among

the

population

aged

had

a

migrant

background

-LRB-

mostly

first-generation

immigrants

-RRB-

and

of

them

were

foreigners

-LSB-

-RSB-

Many

labor

migrants

-LRB-

Gastarbeiter

-RRB-

arrived

in

Germany

in

the

and

at

a

time

when

the

rapidly

growing

German

economy

experienced

a

labor

shortage

They

came

mainly

from

Southern

Europe

and

took

up

jobs

in

the

coal

iron

steel

and

automobile

industries

of

Germany

Many

of

them

have

been

granted

permanent

residence

in

Germany

but

not

German

citizenship

The

so-called

Aussiedler

i.e.

ethnic

Germans

mostly

coming

from

the

former

Soviet

Union

were

the

exception

They

were

granted

the

legal

right

to

receive

German

citizenship

upon

arrival

-LSB-

-RSB-

On

average

foreigners

have

higher

unemployment

rates

than

Germans

their

educational

level

is

lower

and

they

have

jobs

that

require

relatively

low

qualifications

-LSB-

-RSB-

German

population

statistics

are

not

free

of

problems

possibly

resulting

in

an

overestimation

of

the

foreign

population

-LRB-

see

also

-LSB-

-RSB-

-RRB-

The

last

West

German

and

East

German

censuses

took

place

in

the

Since

then

the

population

has

been

updated

on

the

basis

of

vital

event

registration

Foreigners

are

also

registered

by

the

Central

Registry

of

Aliens

-LRB-

Ausländerzentralregister

-RRB-

but

a

recent

update

of

this

source

has

not

been

translated

into

German

population

statistics

-LSB-

-RSB-

Departures

from

Germany

to

stay

abroad

for

long

periods

legally

should

be

notified

Nevertheless

allegedly

many

fail

to

do

so

since

an

eventual

return

to

Germany

is

facilitated

by

maintaining

a

German

address

In

studies

of

migrant

mortality

data

problems

are

usually

not

addressed

by

direct

checks

since

it

is

difficult

to

find

high-quality

data

sources

alternative

to

the

official

population

statistics

We

are

aware

of

only

one

study

that

re-estimated

migrant

mortality

This

was

done

for

Sweden

on

the

basis

of

income

and

taxation

data

-LSB-

-RSB-

The

authors

calculated

death

rates

for

foreign

migrants

aged

who

had

some

registered

income

-LRB-

either

earnings

or

social

benefits

-RRB-

and

excluded

those

who

had

no

registered

income

The

latter

category

was

considered

as

the

one

that

included

a

high

proportion

of

people

who

-LRB-

de

facto

-RRB-

resided

abroad

After

the

exclusion

the

immigrant

death

rates

substantially

increased

compared

to

the

initial

rates

calculated

from

the

whole

migrant

population

Correspondingly

the

migrants

mortality

advantage

diminished

and

became

statistically

insignificant

in

most

immigrant

groups

Our

study

is

based

on

data

of

the

scientific

use

files

of

the

Federal

German

Statutory

Pension

Scheme

-LRB-

DRV

Bund-Deutsche

Rentenversicherung

Bund

-RRB-

for

the

re-estimation

of

the

mortality

of

the

retired

German

and

foreign

populations

These

data

were

provided

by

the

DRV

Research

Data

Centre

in

Würzburg

-LSB-

-RSB-

The

data

cover

all

public

old-age

pensions

resulting

from

work

careers

in

Germany

and

all

of

the

three

former

branches

of

the

pension

insurance

workers

salaried

employees

and

miners

The

data

also

reflect

pension

terminations

due

to

the

death

of

pensioners

We

consider

only

men

because

many

women

who

are

now

retired

have

never

participated

in

the

labor

market

The

DRV

data

cover

about

of

the

German

male

population

aged

The

remaining

people

are

those

whose

working

careers

were

entirely

related

to

self-employment

or

to

the

German

Civil

Service

The

DRV

data

allow

to

identify

the

narrowly

defined

migrant

population

i.e.

pensioners

with

foreign

citizenship

In

about

-LRB-

or

-RRB-

of

the

million

male

pensioners

aged

had

foreign

citizenship

The

DRV

information

about

pensioners

nationality

is

considered

to

be

exact

-LSB-

-RSB-

The

DRV

data

on

the

insurants

vital

status

are

also

highly

reliable

As

the

function

of

pension

insurers

is

to

provide

pension

payments

they

follow

the

survival

of

pensioners

very

carefully

using

several

sources

information

from

the

pay-out

service

of

the

German

Post

-LRB-

Postrentendienst

-RRB-

which

receives

death

notices

from

the

registrar

's

office

or

from

the

undertaker

information

provided

by

surviving

dependents

or

information

about

pensions

not

delivered

Those

receivers

of

German

pensions

who

live

abroad

must

provide

annual

confirmation

of

being

alive

Nevertheless

we

excluded

pensioners

with

current

residence

abroad

in

order

to

achieve

greater

data

homogeneity

The

official

population

figures

population

and

deaths

by

age

groups

split

by

German

and

non-German

nationality

were

obtained

from

the

Federal

Statistical

Office

-LSB-

-RSB-

On

the

basis

of

the

DRV

and

official

population

data

we

computed

two

sets

of

deaths

and

population

exposures

at

ages

for

the

years

and

To

estimate

life

expectancies

at

age

abridged

life

tables

were

constructed

using

Chiang

's

method

-LSB-

-RSB-

Table

presents

population

figures

and

deaths

from

official

population

statistics

and

DRV

pension

data

For

German

men

the

death

and

population

ratios

of

population

statistics

to

DRV

statistics

are

the

same

Both

official

population

and

official

death

figures

exceed

the

figures

provided

by

DRV

by

over

the

whole

period

indicating

that

DRV

data

cover

of

the

German

population

For

foreigners

however

there

is

a

pronounced

disagreement

between

population

and

death

figures

The

national

figure

for

the

former

exceeds

the

DRV

figure

by

For

the

latter

by

contrast

the

national

figure

is

lower

by

than

that

given

by

the

DRV

This

gap

suggests

a

major

bias

in

population

statistics

on

foreigners

induced

by

an

over-stated

population

and

under-stated

deaths

Table

suggests

that

mortality

of

foreigners

in

the

official

statistics

is

about

two-fold

higher

than

its

true

value

based

on

the

DRV

data.Table

of

male

population

and

death

counts

-LRB-

age

-RRB-

between

German

official

population

statistics

and

DRV

data

for

the

years

and

yearPopulationDeathsIn

thousandsRatioIn

thousandsRatioPopulation

statisticsDRV

statisticsPopulation

statistics/DRV

statisticsPopulation

statisticsDRV

statisticsPopulation

statistics/DRV

statisticsGermans

200420,200.218,451.31.091,093.91,004.11.09

Foreigners

Calculated

from

official

population

statistics

from

the

German

Federal

Statistical

Office

-LSB-

-RSB-

pension

statistics

from

scientific

use

file

-LSB-

-RSB-

Age-specific

death

rates

-LRB-

displayed

in

Fig.

-RRB-

accordingly

show

good

agreement

for

Germans

between

the

official

population

statistics

and

the

pension

statistics

except

for

very

old

ages

i.e.

at

which

the

official

population

statistics

understate

the

male

mortality

-LSB-

-RSB-

For

foreigners

there

is

a

very

large

disagreement

in

age-specific

death

rates

Official

population

statistics

on

the

death

rates

for

foreigners

are

extremely

low

at

all

ages

and

do

not

show

the

expected

increase

over

age

The

corresponding

figures

of

DRV

data

are

similar

to

those

for

Germans.Fig

of

death

rates

between

German

official

population

statistics

and

DRV

data

pooled

data

for

the

years

and

Calculated

from

official

population

statistics

from

the

German

Federal

Statistical

Office

-LSB-

-RSB-

pension

statistics

from

scientific

use

file

-LSB-

-RSB-

Table

shows

nearly

the

same

life

expectancy

figures

for

Germans

at

age

in

both

data

sources

-LRB-

years

in

the

population

statistics

and

years

in

the

DRV

statistics

for

the

whole

observation

period

-RRB-

For

foreigners

the

population

statistics

figures

are

unrealistically

high

-LRB-

e.g.

years

-RRB-

and

very

different

from

the

figures

provided

by

the

DRV

data

-LRB-

years

-RRB-

Importantly

German

life

expectancy

in

the

DRV

data

is

slightly

higher

than

that

of

foreigners

Finally

both

in

the

population

statistics

and

the

DRV

data

overall

life

expectancy

based

on

pooled

data

on

Germans

and

foreigners

hardly

deviates

from

the

life

expectancy

of

Germans

because

the

impact

of

the

foreign

population

figure

is

small.Table

expectancy

at

age

for

men

in

Germany

for

the

years

and

in

yearsYearGermansForeignersGermans

and

foreignersPopulation

statisticsDRV

statisticsPopulation

statisticsDRV

statisticsPopulation

statisticsDRV

.714.625.914.314.714.6199815.215.229.214.815.415.2200116.016.434.115.716.216.4200416.616.237.815.016.816.11995

Calculated

from

official

population

statistics

from

the

German

Federal

Statistical

Office

-LSB-

-RSB-

pension

statistics

from

scientific

use

file

-LSB-

-RSB-

The

life

expectancy

figures

of

the

order

of

years

at

age

calculated

from

German

official

population

statistics

are

obviously

implausible

They

are

much

higher

than

the

levels

of

longevity

experienced

by

Japanese

women

-LRB-

years

in

-RRB-

the

world

's

lowest

mortality

population

The

bias

is

produced

by

the

inflated

population

denominator

and

the

under-stated

death

numerator

in

German

population

statistics

By

contrast

DRV

data

-LRB-

which

is

based

on

the

rigorous

follow-up

of

people

eligible

to

receive

German

old-age

pensions

-RRB-

show

that

the

mortality

of

foreigners

aged

is

actually

slightly

higher

than

the

mortality

of

German

men

At

least

among

men

aged

the

seemingly

large

mortality

advantage

of

foreigners

compared

to

Germans

is

a

statistical

artifact

Our

study

makes

clear

that

the

inaccuracies

in

estimation

of

the

population

denominator

and

the

death

numerator

can

result

in

serious

underestimation

of

immigrant

mortality

However

a

significant

mortality

advantage

of

immigrants

could

be

found

even

in

studies

where

the

researchers

were

well

aware

of

the

possible

bias

-LSB-

-RSB-

Even

in

the

Swedish

study

mentioned

earlier

that

revealed

a

general

underestimation

of

mortality

among

immigrants

a

statistically

significant

mortality

advantage

could

be

observed

in

some

immigrant

groups

i.e.

women

from

Southern

Europe

men

from

Latin

America

Africa

and

Asia

-LSB-

-RSB-

The

underestimated

mortality

of

foreigners

should

result

in

the

underestimation

of

mortality

in

the

broader

group

of

German

residents

who

have

a

migrant

background

As

mentioned

earlier

foreigners

constitute

about

of

all

people

with

migrant

background

at

ages

Assuming

for

simplicity

the

same

level

of

true

mortality

among

all

German

residents

with

migrant

background

and

precisely

reported

mortality

of

German

nationals

with

migrant

background

it

is

easy

to

see

that

the

two-fold

underestimation

of

mortality

of

foreigners

leads

to

a

underestimation

of

mortality

of

all

residents

with

migrant

background

How

can

the

mortality

advantage

of

the

migrant

population

found

elsewhere

-LSB-

-RSB-

be

reconciled

with

the

complete

absence

of

such

an

advantage

in

our

analysis

The

answer

may

be

found

by

considering

the

peculiarities

of

our

data

compared

to

the

previous

studies

First

our

study

considers

foreigners

or

pensioners

with

current

foreign

citizenship

Mostly

these

are

people

from

Southern

Europe

who

entered

Germany

in

the

and

to

a

much

lesser

extent

more

recent

immigrants

from

the

former

Soviet

Union

and

Eastern

Europe

Second

our

study

includes

only

people

aged

and

over

while

the

other

studies

looked

mostly

or

exclusively

at

people

of

working

age

Close

to

the

age

of

their

migration

the

health

advantage

of

immigrants

can

be

attributed

to

the

selection

effect

of

healthy

people

to

healthier

behaviors

and

dietary

habits

and

to

positive

psychological

expectations

-LSB-

-RSB-

For

many

reasons

the

initial

advantage

does

not

translate

into

a

mortality

advantage

at

ages

of

and

over

Certain

factors

affecting

immigrants

in

the

country

of

their

new

residence

can

lead

to

a

steeper

-LRB-

compared

to

the

host

population

-RRB-

health

decline

with

age

In

particular

immigrants

may

gradually

adopt

less

healthy

western

lifestyles

associated

with

higher

coronary

risk

In

old

age

they

may

also

experience

higher

mortality

from

conditions

related

to

childhood

infections

and

deprivation

such

as

stroke

and

stomach

cancer

-LSB-

-RSB-

Most

importantly

immigrants

face

the

health

consequences

of

lower

socioeconomic

status

such

as

poorer

life

conditions

restricted

life

chances

and

corresponding

psychological

stress

-LSB-

-RSB-

According

to

DRV

data

of

foreigners

but

only

of

Germans

belong

to

the

lower

of

the

lifetime

income

distribution

Our

earlier

analysis

shows

that

this

category

of

pensioners

experience

approximately

mortality

elevation

compared

to

those

belonging

to

the

upper

lifetime

earnings

quintile

-LSB-

-RSB-

Foreigners

are

also

characterized

by

a

higher

share

of

former

manual

workers

vs.

among

Germans

This

status

is

associated

with

a

mortality

excess

compared

to

the

white-collar

occupations

-LSB-

-RSB-

Speculation

about

potential

reasons

for

a

steeper

health

decline

with

age

among

the

immigrants

is

supported

by

empirical

evidence

that

confirms

that

the

initial

health

advantage

of

foreigners

wears

off

over

time

-LSB-

-RSB-

This

pattern

can

lead

to

mortality

convergence

and

even

mortality

crossover

between

the

host

and

migrant

populations

In

general

our

results

support

the

concern

about

the

reliability

of

very

low

estimates

of

migrant

mortality

at

ages

and

over

It

is

possible

that

despite

the

initial

health

advantage

the

slightly

higher

mortality

of

foreigners

in

the

population

is

a

result

of

socioeconomic

health

inequalities

This

is

a

serious

public

health

concern

that

deserves

further

investigation

O O B O B O O O O O O O O O O O O B O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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