BMJ Open...Trine Munk-Olsen, PhD (1), Bodil Hammer Bech, PhD (3), Mogens Vestergaard, PhD (2), Jiong...

For peer review only

Psychiatric disorders following fetal death

Journal: BMJ Open

Manuscript ID: bmjopen-2014-005187

Article Type: Research

Date Submitted by the Author: 04-Mar-2014

Complete List of Authors: Munk-Olsen, Trine; University of Aarhus, National Center for Register-

Based Research Bech, Bodil; Institute of Publice Health, Department of Epidemiology Vestergaard, Mogens; University of Aarhus, Denmark, Research Unit for General Practice and Department of General Practice, Institute of Public Health Li, Jiong; Aarhus University, Public Health; Institute of Publice Health, Department of Epidemiology Olsen, Jørn; Aarhus University, Section for Epidemiology; Institute of Publice Health, Department of Epidemiology Laursen , Thomas Munk ; University of Aarhus, National Centre for Register-based Research

<b>Primary Subject

Heading</b>: Epidemiology

Secondary Subject Heading: Mental health, Obstetrics and gynaecology

Keywords: EPIDEMIOLOGY, OBSTETRICS, PSYCHIATRY

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Title:

Psychiatric disorders following fetal death

Authors:

Trine Munk-Olsen, PhD (1), Bodil Hammer Bech, PhD (3), Mogens Vestergaard, PhD (2), Jiong

Li, PhD (3), Jørn Olsen, PhD (3), Thomas Munk Laursen, PhD (1)

1)

iPSYCH,

The Lundbeck Foundation Initiative for Integrative Psychiatric Research

National Center for Register-Based Research,

Fuglesangs Allé 4,

Aarhus University,

Denmark

2)

Research Unit for General Practice and Section for General Medical Practice,

Department of Public Health,

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2

Aarhus University,

Aarhus,

Denmark

3)

Section for Epidemiology,


Aarhus University,

Aarhus,

Denmark

Corresponding author:

Trine Munk-Olsen, PhD

National Centre for Register-based Research,

Department of Economics and Business,

Aarhus University,

Fuglesangs Allé 4, Building K,

8210 Aarhus V

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Denmark

E-mail: [email protected]

Phone: +45 871 65749

Fax: +45 871 64601

Word count (text only) = 2,523

Keywords:

Pregnancy loss

Mental health

Reproduction

Epidemiology

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ABSTRACT

Objectives:

Women have increased risks of severe mental disorders after childbirth and death of a child, but

it remains unclear whether this association also applies to fetal loss and, if so, to which extent.

We studied the risk of any inpatient or outpatient psychiatric treatment during the time period

from 12 months before to 12 months after fetal death.

Design:

Cohort study using Danish population-based registers.

Setting:

Denmark

Participants:

A total of 1,112,831 women born in Denmark from 1960 to 1995 were included. In total, 87,687

cases of fetal death (spontaneous abortion or stillbirth) were recorded between 1996 and 2010.

Primary and secondary outcome measures:

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The main outcome measures were incidence rate ratios (risk of first psychiatric inpatient or

outpatient treatment).

Results:

A total of 1,379 women had at least one psychiatric episode during follow-up from the year

before the fetal death to the year after. Within the first months after the loss, women had an

increased risk of psychiatric contact, IRR: 1.51 (95% CI: 1.15, 1.99). In comparison, no

increased risk of psychiatric contact was found for the period before fetal death. The risk of

experiencing a psychiatric episode was highest for women with a loss occurring after 20 weeks

of gestation (12-month probability: 1.95%, 95% CI: 1.50, 2.39).

Conclusions:

Fetal death was associated with a transient increased risk of experiencing a first-time episode of

a psychiatric disorder, primarily adjustment disorders. The risk of psychiatric episodes tended to

increase with increasing gestational age at the time of the loss.

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Article summary:

Strengths and limitations of this study:

• This study calculated the risk of first-time psychiatric episodes after fetal death using

Danish population registers, and showed that the risk of psychiatric episodes tended to


• Possible interpretations of these findings could be that fetal loss increases the risk of

psychiatric disorders, that fetal loss changes the threshold for hospitalizations, or

alternatively that factors associated with an underlying mental disorder may cause fetal

death.

• Especially early spontaneous abortion rates are difficult to measure and will be

underestimated in the present study.

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INTRODUCTION

Reproduction and mental health is associated. Childbirth is associated with an increased risk of

psychiatric disorders in the mother (1-6) and induced abortions have been linked with mental

health problems in few (7), but not in most studies (8-12). The loss of a wanted pregnancy is a

major life event, which can affect mental health, and spontaneous abortions and stillbirths have

been associated with grief, depression, anxiety and social problems (13;14). Loss of a live child

is followed by increased risk of severe episodes of psychiatric disorders (15), but it remains

unclear whether this association also applies to fetal loss and, if so, to which extent.

About 15-20% of clinically recognized pregnancies abort spontaneously (13). A similar fraction

is expected to be aborted in the preclinical time period, and 0.5% of babies reaching 22 weeks of

gestation die as stillborns. If fetal loss triggers mental health problems in some women, it could

be related to stress (15), difficulties in social functioning or changes in family dynamics related

to the event (16). We aimed to study if fetal death (spontaneous abortion or stillbirth) is

associated with an increased risk of first-time episodes of psychiatric disorders in women.

Furthermore, we aimed to study the extent to which such a potential risk may correlate with

gestational age.

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METHODS

We conducted a population-based cohort study linking information from different nationwide

population registers described below. The study population consisted of all women born in

Denmark from 1960 to 1995. Follow-up started on 1 January 1996 and ended on 31 December

2010, at emigration or death or at first psychiatric contact in the study period related to fetal

death, whichever came first. The present cohort study was based on the study population

described above and designed through the following steps:

Fetal loss cohort (cohort 1):

Firstly, we defined a cohort using the information from the national population-based registers

including women who were registered as having experienced a fetal death for the first time

between 1996 and 2010. All cohort members were followed individually from 12 months before

the date of the fetal death until a first-time psychiatric contact, 12 months after fetal death, date

of death, date of emigration or 31 December 2010, whichever came first. First-time psychiatric

contacts were recorded as either inpatient admission or outpatient/emergency treatment for any

type of mental disorder. We excluded all women with one or more psychiatric contacts at the

start of the follow-up as well as women with records of spontaneous abortions and stillbirths

prior to the start of the follow-up period.

Reference cohort (cohort 2):

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Secondly, we defined a reference cohort to study whether psychiatric morbidity was increased

among women experiencing a fetal death compared to a female background population. For each

of the exposed women in cohort 1, we identified three women who fulfilled the following criteria

which were also used for cases: They were born in the same year and the same week as the

probands; they were alive and residing in Denmark on the day the index person experienced the

fetal death (index day).

Data sources

A personal identification number is assigned to every person living in Denmark, and this number

can be used as a unique key for linking information between registries (17). The Danish Civil

Registration System was introduced in 1968 and holds information on dates of birth, death,

migration status and links to legal family members. For the present study, we also used

information on parity status (measured as number of live-born children).

Data on fetal death (spontaneous abortions and stillbirths) was obtained from The Danish

National Hospital Register (18). This register holds information on all treatments at medical

hospitals in Denmark (inpatient treatments since 1977, and outpatient treatments since 1995).

The following International Classification of Diseases (ICD) codes were used: spontaneous

abortion: ICD-10 codes: O021, O021A, O03, ICD-8 codes: 634.61, 645.1x, 643.0x, 643.8x and

643.9x; stillbirths: ICD-10 codes: Z37.1 (single stillbirth), Z37.4 (twins stillborn), Z37.7

(multiple births, all stillborn), P95, ICD-8 codes: 779.xx. Information on induced first- and

second-trimester abortions (ICD-8 codes: 640, 641, 642. ICD-10 codes: O04, O05, O06) was

also collected and included in the present study.

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Data concerning the outcome variables, psychiatric inpatient or outpatient treatment, was derived

from The Danish Psychiatric Central Register (19). This register holds information on all

treatments at psychiatric hospitals in Denmark (inpatient treatments since 1969, and outpatient

treatments since 1995). The diagnostic systems used in this register are the Danish versions of

ICD-8 and ICD-10 (20;21). For analyses on psychiatric treatments/contacts, we included all

types of psychiatric diagnoses, and for sub analyses we divided cases into three groups:

Adjustment disorders (ICD-10 codes: F43), Unipolar depression (ICD-10 codes: F32, 33, 34, 38,

39) and remaining diagnoses (remaining ICD-10 codes). Furthermore, the register was used to

derive information on treated psychiatric disorders in parents of the cohort women.

Definition of fetal death

During the period of 1977-2003, stillbirths in Denmark were defined as the death of a fetus past

28 completed gestational weeks. This definition was changed to 22 completed weeks from 2004.

An intrauterine fetal death before these gestational ages was defined as a spontaneous abortion

(22). Note that the term ‘fetal death’ is used in the remaining part of the present paper as an

‘exposure measure’ including both spontaneous abortions and stillbirths. In the present study

information on gestational age was available for 97.75% of all cases.

Design and statistical analysis

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Analysis performed in cohort 1 included calculation of incidence rates (IR) of psychiatric

hospital contacts per 1,000 person-year under risk. Furthermore, we conducted a survival

analysis (Poisson regression) and calculated incidence rate ratios (IRRs); we calculated the IRRs

of psychiatric hospital contacts (in 2-month segments) of the 2-year period surrounding the day

of the abortive event, while the incidence rate 11-12 months after the abortive event was defined

as the reference category. We adjusted the IRRs for age, calendar period, parity status, induced

abortion status, and family history of formerly treated psychiatric disorders.

By using the supplementary cohort 2, including women from the background population, we

made Kaplan-Meier plots to illustrate the probability of having a psychiatric contact within the

first 12 months after fetal death compared to incidence rates for the comparable female

population.

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RESULTS

Out of the 1,112,831 women included in the study, 87,687 were registered with a first-time

recorded spontaneous abortion or stillbirth during the study period (1996-2011). Among these,

603 women had at least one psychiatric episode during the year before experiencing the fetal

death and 776 had one during the first year after the loss. The women experienced a transient

increase in risk of a psychiatric episode during the first month after the fetal death, incidence rate

ratios (IRR): 1.51 (95% 1.15, 1.99), compared to the reference category (11-12 months after the

loss, Table 1). The majority of women with psychiatric episodes following fetal death were

diagnosed with adjustment disorders (Table 2).

Additional stratified analyses were performed to describe in further detail the risk of psychiatric

episodes within the first month after the fetal death. Results showed that risks were especially

high among childless women compared to women with one or more children at the time of the

event. Furthermore, we found that women aged 27-34 had the highest risk of experiencing a

psychiatric episode after a fetal death (Table ).

Women who experience a fetal loss faced a higher probability of a psychiatric episode during the

following 12 months compared to women of the same age who have not experienced such loss

(the reference cohort). (Figure 1). Probabilities of psychiatric episodes varied by gestational age

at the time of fetal death: 1.24% (95% CI: 0.94, 1.55) for women who experienced a fetal loss

before 6 weeks of gestation, 0.78% (95% CI: 0.71, 0.84) between 6 to 12 weeks of gestation,

0.75% (95% CI: 0.55, 0.97) between 13 to 19 weeks of gestation, and 1.95% (95% CI: 1.50,

2.39) after 20 weeks of gestation.

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DISCUSSION

This large population-based cohort study showed that women experiencing a fetal death had a

transient increased risk of primarily adjustment disorders leading to psychiatric hospital contacts

lasting for approximately one month, especially if the fetal death occured after 20 weeks of

gestation. Possible interpretations of these findings could be that fetal loss increases the risk of

psychiatric disorders, that fetal loss changes the threshold for hospitalizations, or alternatively

that factors associated with an underlying mental disorder may cause fetal death.

Our previous findings show that the risk of psychiatric conditions tend to be low during

pregnancy, which may indicate that women often plan a pregnancy when they are in good mental

health (2). In contrast, the risks of psychiatric episodes seem to be 7-fold increased after

childbirth, especially in primiparous women (23-26). In the present study, we also found that

women without children at the time of the fetal death had higher risks of experiencing mental

health problems during the first month after the fetal loss compared to women with one or more

children (Table 3).

The most common diagnoses after fetal death were adjustment disorders and acute stress

reactions (F43 chapter in ICD-10, Table 2). This contrasts diagnoses-specific findings after

deliveries in general, and in parents who experience loss of a live child, where unipolar

depression/affective disorders are the single most common diagnoses (27;28).

A previous Norwegian study also found that women who had experienced a spontaneous

abortion before 21 gestational weeks had more mental distress up to six months after the

pregnancy compared to women with induced abortion. In contrast, after two and five years of

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follow-up, women who had an induced abortion had higher scores of feelings of guilt, shame but

also relief than the miscarriage group (29) .

In the present study we found an increased risk of a psychiatric disorder within the first month

after fetal death. This finding is comparable to the risk of psychiatric episodes in mothers who

lost a young child (0-18 years of age), where the risk was highest shortly after the loss (15). A

finding which is possibly related to an acute psychological response to a stressful life event (30).

Also in the present study the risk of psychiatric episodes tended to increase with increasing

gestational age, which may indicate a stronger attachment. In contrast, we also found that the risk

of psychiatric disorders was high for women with very early losses (Figure 2). The registration of

these early losses is known to be incomplete, except for persons who have received fertility

treatment, and fetal loss may be a particularly stressful life event for women with an unfulfilled

pregnancy wish (31).

Previous studies have also found an increasing risk of psychiatric symptoms or disorders with

increasing gestational age at spontaneous abortion (32;33), but not all (34;35). Most have

measured mental health using questionnaire data, including different scales to measure

psychiatric symptoms, and most have found an increased risk of deterioration of mental health in

the months immediately after the miscarriage (32;36;37). Few studies have followed women up

to 12 months after the miscarriage. Janssen et al compared women after miscarriage with women

who gave birth to live-born babies (32). After 6 months, these two groups differed substantially

according to depression scores, anxiety scores and somatization, but the differences were not

statistically significant after 12 months, which is in line with the results reported by Beutel et al

(38). A recent study from China compared women who miscarried (miscarriage < 24 weeks of

gestation) with a group of non-pregnant women, using the 12-item General Health Questionnaire

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(GHQ-12) and the Beck Depression Inventory (BDI). The miscarrying women had a

significantly higher proportion of GHQ-12 scores of ≥ 4 initially and after 6 and 12 months

compared to non-pregnant controls, while the proportion of BDI scores ≥12 was higher at the

start of follow-up, but not at the end of follow-up 12 months after miscarriage (39). Klier et al

and Neugebauer et al found that miscarrying women had a 2.5-fold and 5-fold higher risk for an

episode of major and minor depressive disorder, respectively, 6 months after miscarriage

compared to control women (34;40). Note that, in comparison to the above mentioned results,

our study had severe endpoints, measured as psychiatric treatment at inpatient or outpatient

facilities.

We used data from The National Hospital Register where the positive predictive value of the

diagnosis of spontaneous abortions in a clinically recognized pregnancy is around 95-97% (41),

Note that early spontaneous abortion rates are notoriously difficult to measure and will be

underestimated (42). After eight weeks of gestational age, most spontaneous abortions are known

to the women and documented (43;44). In a Danish study using registry data on spontaneous

abortions, Nybo Andersen et al (45) estimated that about 13% of clinical recognized pregnancies

intended to be carried to term ended in fetal loss. However, Buss et al found that about 30% of

the spontaneous abortions reported by women are not recorded in The Danish National Patient

Register (46). If underreporting of fetal loss is related to a lower threshold for hospitalization in

women with psychiatric disorders, this could explain our results.

Our outcome measure was defined as any type of psychiatric disorder treated at an inpatient or

outpatient psychiatric treatment facility. For this reason, the rates of psychiatric disorders may be

underestimated, and our results do not provide information on minor self-treated mental

problems or mental health problems treated in primary care.

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Residual confounding cannot be ruled out since unmeasured patient characteristics may have

influenced our results. The present study did e.g. not include information on life-style factors

such as smoking or alcohol use, which has been shown to increase the risk of spontaneous

abortions (47). Moderate alcohol intake during pregnancy and risk of fetal death (48) may also

be associated with the outcome in our study. Similarly, we did not have information on use of

antidepressants and antipsychotics, which may also confound the observed results. Several other

factors have been identified as potential causes of spontaneous abortions (49), and some of these

may also be risk factors for mental disorders. However, using a design with internal comparisons

among women who experienced fetal death during a relatively short observation period reduces

confounding to a minimum, i.e. factors such as medicine use and substance abuse. There is a

potential bias in calculating incidence rate ratios before the exposure (fetal death), since the

analyses condition on the survival of the women in the 12 months prior to the event. However

such bias is unlikely given the relatively young age of the cohort.

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CONCLUSION


a psychiatric disorder measured as in- or outpatient contacts for any type of mental disorder at a

psychiatric treatment facility. The most common diagnoses after fetal death were adjustment

disorders. The risk of psychiatric episodes tended to increase with increasing gestational age at

the time of the loss, with spontaneous abortions before 6 weeks of gestation being the exception.

The excess risk period is short, but of rather high magnitude, and health care personnel should be

aware of the increased risk of mental health problems following a fetal death, regardless of its

cause.

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Table 1

Incidence rate ratios of psychiatric inpatient and outpatient treatment with any psychiatric

diagnoses in women having a pregnancy with subsequent fetal death

Timing of first psychiatric

contact around time of fetal

death

Number of

cases

Person-

years

Rate per

1000

person-years

Incidence rate

ratios

11 to 12 months before 99 13566 7.298 0.83 (0.63, 1.09)

9 to 10 months before 109 13722 7.943 0.92 (0.70, 1.20)

7 to 8 months before 114 13873 8.218 0.96 (0.74, 1.25)

5 to 6 months before 94 14024 6.703 0.79 (0.60, 1.04)

3 to 4 months before 93 14176 6.561 0.79 (0.60, 1.04)

1 to 2 months before 94 14323 6.563 0.80 (0.61, 1.05)

Fetal death

1st month after 91 7203 12.634 1.51 (1.15, 1.99)

2nd month after 71 7203 9.857 1.19 (0.88, 1.60)

3 to 4 months after 145 14412 10.061 1.23 (0.96, 1.57)

5 to 6 months after 121 14420 8.391 1.04 (0.80, 1.34)

7 to 8 months after 129 14420 8.946 1.12 (0.87, 1.44)

9 to 10 months after 107 14423 7.419 0.94 (0.72, 1.23)

11 to 12 months after 112 14433 7.760 1 (ref. category)

Cohort 1.

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Adjusted for age, calendar period, parity status, previous history of induced abortion, and family

history of psychiatric disorders.

31 of the 1379 cases had missing information on gestational age.

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Table 2

Incidence rate ratios of adjustment disorders, unipolar depression and remaining diagnoses at

inpatient and outpatient treatment in women having a pregnancy with subsequent fetal death

Timing of psychiatric

contact around time of

fetal death

Adjustment disorders

(ICD-10 codes: F43)

Unipolar depression

(ICD-10 codes:

F32,33,34,38,39)

Remaining diagnoses

N* IRR (95% CI) N* IRR (95% CI) N* IRR (95% CI)

11 to 12 months before 36

0.76

(0.49, 1.17) 23

1.10

(0.60, 2.01) 41

0.81

(0.53, 1.23)


0.80

(0.52, 1.23) 21

1.00

(0.54, 1.86) 50

0.99

(0.66, 1.47)


0.97

(0.64, 1.46) 21

1.00

(0.54, 1.85) 48

0.95

(0.64, 1.43)


0.59

(0.37, 0.95) 14

0.67

(0.34, 1.32) 52

1.04

(0.70, 1.54)


0.74

(0.47, 1.15) 19

0.91

(0.48, 1.70) 40

0.80

(0.52, 1.22)


0.53

(0.32, 0.86) 24

1.15

(0.63, 2.08) 46

0.92

(0.61, 1.39)

Fetal death

1st month after 61

2.53

(1.72, 3.72) 11

1.04

(0.50, 2.17) 21

0.82

(0.49, 1.37)

2nd month after 29

1.21

(0.76, 1.93) 11

1.05

(0.50, 2.18) 31

1.22

(0.78, 1.92)

3 to 4 months after 50

1.05

(0.70, 1.58) 34

1.64

(0.94, 2.84) 61

1.21

(0.83, 1.78)


1.15

(0.78, 1.71) 31

1.51

(0.86, 2.65) 37

0.75

(0.49, 1.15)


0.91

(0.60, 1.38) 28

1.38

(0.78, 2.46) 62

1.27

(0.87, 1.86)


1.12

(0.75, 1.67) 20

1.00

(0.54, 1.86) 38

0.79

(0.52, 1.21)


1

(ref. category) 20

1

(ref. category) 47

1

(ref. category)

* Total number of cases:

Adjustment disorders: 540 women

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Unipolar depression: 277 women

Remaining diagnoses: 574 women

Note that 12 women both received an adjustment and unipolar diagnoses at the index psychiatric

contact.



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Table 3

Stratified incidence rate ratios of psychiatric inpatient and outpatient treatment among women

experiencing a fetal death

Overall risk of psychiatric episodes

0 to 1 month after fetal death

1.51 (1.15, 1.99)

Stratified analysis

Parenthood

- Women with one or more

children at time of the fetal loss

1.19 (0.80, 1.77)

- Women with no children at time

of the fetal loss

2.01 (1.35, 3.02)

Stratified analysis

Age

- Age group <=26 years 1.30 (0.87, 1.93)

- Age group 27-34 years 2.15 (1.37, 3.38)

- Age group 35+ years 1.17 (0.55, 2.50)

Reference category: 11-12 months after exposure

Cohort 1.



Parity status, induced abortion history, and family history of psychiatric disorders: time

dependent variables.

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Figure 1

Unadjusted absolute risk measured as percentages of first-time psychiatric inpatient or outpatient

treatment following spontaneous abortion and stillbirth

Cohort 2.

Probability of psychiatric contacts 12 months after a pregnancy resulting in fetal death:

<6 weeks: 1.24% (95% CI: 0.94 - 1.55), N = 64 cases

6-12 weeks: 0.78% (95% CI: 0.71 - 0.84), N = 532 cases

13-19 weeks: 0.75% (95% CI: 0.55 - 0.97), N = 51 cases

20 weeks +: 1.95% (95% CI: 1.50 - 2.39), N = 72 cases

Controls/reference population: 0.63% (95% CI: 0.60 - 0.66)

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Note: 31 of the 776 cases had missing information on gestational age, and 26 had late entry and

were excluded from the analyses.

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Funding and acknowledgments:

This study was supported by unrestricted research grants from The Lundbeck Foundation:

iPSYCH (The Lundbeck Foundation Initiative for Integrative Psychiatric Research) and

MEPRICA (Mental Health in Primary Care). Dr. Li was supported by a grant from European

Research Council (ERC-StG-2010-260242-PROGEURO).

The grant providers had no involvement in the design or in the conduct of the study; collection,

management, analysis and interpretation of the data as well as preparation, review, and approval

of the manuscript.

Dr. Thomas Munk Laursen had full access to all the data included in the study and takes

responsibility for the integrity of the data and the accuracy of the data analysis.

Competing interests:

None declared.

Contributorship:

Dr. Trine Munk-Olsen initiated the study and wrote the first draft. Dr. Thomas Munk Laursen

analysed the data. All authors contributed to the context of the manuscript and participated in all

revisions.

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fetal loss: population based register linkage study. BMJ 2000 Jun 24;320(7251):1708-12.

(46) Buss L, Tolstrup J, Munk C, Bergholt T, Ottesen B, Gronbaek M, et al. Spontaneous

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(47) Nielsen A, Hannibal CG, Lindekilde BE, Tolstrup J, Frederiksen K, Munk C, et al.

Maternal smoking predicts the risk of spontaneous abortion. Acta Obstet Gynecol Scand

2006;85(9):1057-65.

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alcohol intake during pregnancy and risk of fetal death. Int J Epidemiol 2012

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Psychiatric disorders following fetal death, a population-based cohort study

Journal: BMJ Open

Manuscript ID: bmjopen-2014-005187.R1

Article Type: Research

Date Submitted by the Author: 13-May-2014

Complete List of Authors: Munk-Olsen, Trine; University of Aarhus, National Center for Register-Based Research Bech, Bodil; Institute of Publice Health, Department of Epidemiology Vestergaard, Mogens; University of Aarhus, Denmark, Research Unit for General Practice and Department of General Practice, Institute of Public Health Li, Jiong; Institute of Publice Health, Department of Epidemiology; Aarhus University, Public Health

Olsen, Jørn; Institute of Publice Health, Department of Epidemiology; Aarhus University, Section for Epidemiology Laursen , Thomas Munk ; University of Aarhus, National Centre for Register-based Research

<b>Primary Subject Heading</b>:

Epidemiology

Secondary Subject Heading: Mental health, Obstetrics and gynaecology

Keywords: EPIDEMIOLOGY, OBSTETRICS, PSYCHIATRY


BMJ Open on M

ay 28, 2021 by guest. Protected by copyright.

http://bmjopen.bm

j.com/

BM

J Open: first published as 10.1136/bm

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1

Title:


Authors:



1)

iPSYCH,



Fuglesangs Allé 4,

Aarhus University,

Denmark

2)



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2

Aarhus University,

Aarhus,

Denmark

3)



Aarhus University,

Aarhus,

Denmark





Aarhus University,


8210 Aarhus V

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3

Denmark


Phone: +45 871 65749

Fax: +45 871 64601


Keywords:

Pregnancy loss

Mental health

Reproduction

Epidemiology

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ABSTRACT

Objectives:





Design:


Setting:

Denmark

Participants:


cases of fetal death (ICD-10 codes for spontaneous abortion or stillbirth) were recorded between

1996 and 2010.




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Results:







Conclusions:




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Article summary:








death.



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INTRODUCTION

Reproduction and mental health is associated, which has been shown in several studies across

different study populations. Childbirth is associated with an increased risk of psychiatric

disorders in the mother (1-6). Induced abortions have in comparison to studies on childbirths

been linked with mental health problems in few (7), but not in most studies (8-12). The loss of a

wanted pregnancy is a major life event, which can affect mental health, and spontaneous

abortions and stillbirths have been associated with grief, depression, anxiety and social problems

(13;14). Loss of a live child is followed by increased risk of severe episodes of psychiatric

disorders (15), but it remains unclear whether this association also applies to fetal loss and, if so,

to which extent.








gestational age.

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METHODS





death (including both spontaneous abortions and stillbirths), whichever came first. The present

cohort study was based on the study population described above and designed through the

following steps:












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Data sources















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population.

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RESULTS













psychiatric episode after a fetal death (Table 3).








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DISCUSSION













children (Table 3).








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of psychiatric disorders was high for women with very early losses (Figure 1). The registration of

these early losses is known to be incomplete, except for persons who have received fertility














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facilities.















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CONCLUSION








cause.

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Table 1





death

Number of

cases

Person-

years

Rate per

1000

person-years

Incidence rate

ratios

11 to 12 months before 99 13566 7.298 0.83 (0.63, 1.09)

9 to 10 months before 109 13722 7.943 0.92 (0.70, 1.20)

7 to 8 months before 114 13873 8.218 0.96 (0.74, 1.25)

5 to 6 months before 94 14024 6.703 0.79 (0.60, 1.04)

3 to 4 months before 93 14176 6.561 0.79 (0.60, 1.04)

1 to 2 months before 94 14323 6.563 0.80 (0.61, 1.05)

Fetal death

1st month after 91 7203 12.634 1.51 (1.15, 1.99)

2nd month after 71 7203 9.857 1.19 (0.88, 1.60)

3 to 4 months after 145 14412 10.061 1.23 (0.96, 1.57)

5 to 6 months after 121 14420 8.391 1.04 (0.80, 1.34)

7 to 8 months after 129 14420 8.946 1.12 (0.87, 1.44)

9 to 10 months after 107 14423 7.419 0.94 (0.72, 1.23)


Cohort 1.

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Table 2





fetal death


(ICD-10 codes: F43)

Unipolar depression

(ICD-10 codes:

F32,33,34,38,39)

Remaining diagnoses



0.76

(0.49, 1.17) 23

1.10

(0.60, 2.01) 41

0.81

(0.53, 1.23)


0.80

(0.52, 1.23) 21

1.00

(0.54, 1.86) 50

0.99

(0.66, 1.47)


0.97

(0.64, 1.46) 21

1.00

(0.54, 1.85) 48

0.95

(0.64, 1.43)


0.59

(0.37, 0.95) 14

0.67

(0.34, 1.32) 52

1.04

(0.70, 1.54)


0.74

(0.47, 1.15) 19

0.91

(0.48, 1.70) 40

0.80

(0.52, 1.22)


0.53

(0.32, 0.86) 24

1.15

(0.63, 2.08) 46

0.92

(0.61, 1.39)

Fetal death

1st month after 61

2.53

(1.72, 3.72) 11

1.04

(0.50, 2.17) 21

0.82

(0.49, 1.37)

2nd month after 29

1.21

(0.76, 1.93) 11

1.05

(0.50, 2.18) 31

1.22

(0.78, 1.92)


1.05

(0.70, 1.58) 34

1.64

(0.94, 2.84) 61

1.21

(0.83, 1.78)


1.15

(0.78, 1.71) 31

1.51

(0.86, 2.65) 37

0.75

(0.49, 1.15)


0.91

(0.60, 1.38) 28

1.38

(0.78, 2.46) 62

1.27

(0.87, 1.86)


1.12

(0.75, 1.67) 20

1.00

(0.54, 1.86) 38

0.79

(0.52, 1.21)


1

(ref. category) 20

1

(ref. category) 47

1

(ref. category)



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contact.



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Table 3





1.51 (1.15, 1.99)

Stratified analysis

Parenthood



1.19 (0.80, 1.77)


of the fetal loss

2.01 (1.35, 3.02)

Stratified analysis

Age

- Age group <=26 years 1.30 (0.87, 1.93)

- Age group 27-34 years 2.15 (1.37, 3.38)

- Age group 35+ years 1.17 (0.55, 2.50)


Cohort 1.





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Cohort 2.


<6 weeks: 1.24% (95% CI: 0.94 - 1.55), N = 64 cases

6-12 weeks: 0.78% (95% CI: 0.71 - 0.84), N = 532 cases

13-19 weeks: 0.75% (95% CI: 0.55 - 0.97), N = 51 cases

20 weeks +: 1.95% (95% CI: 1.50 - 2.39), N = 72 cases




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of the manuscript.

Author contributions:

Dr. Trine Munk-Olsen and Dr. Laursen were involved in the initial phase of planing the study,

and Dr. Munk-Olsen wrote the first and subsequent drafts of the manuscript. All authors

contributed to methodological considerations and the specific design of the study as well as

making critical revisons to the all versions of the manuscript.

Dr. Thomas Munk Laursen conducted the statistical analyses and had full access to all the data

included in the study and takes responsibility for the integrity of the data and the accuracy of the

data analysis.

Ethics approval: All personal identifiers were removed and replaced with a sequential number

in the final data set, and the protocol was approved by The Danish Data Protection Agency.

Data sharing statement: No additional data available

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None declared.

Figure legend

Figure 1: Unadjusted absolute risk measured as percentages of first-time psychiatric inpatient or

outpatient treatment following spontaneous abortion and stillbirth

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Reference List

(1) Bergink V, Lambregtse-van den Berg MP, Koorengevel KM, et al. First-onset psychosis

occurring in the postpartum period: a prospective cohort study. J Clin Psychiatry 2011

Nov;72(11):1531-7.

(2) Munk-Olsen T, Laursen TM, Pedersen CB, et al. New parents and mental disorders: a

population-based register study. JAMA 2006 Dec 6;296(21):2582-9.

(3) Munk-Olsen T, Laursen TM, Mendelson T, et al. Risks and predictors of readmission for

a mental disorder during the postpartum period. Arch Gen Psychiatry 2009

Feb;66(2):189-95.


1987 May;150:662-73.

(5) Harlow BL, Vitonis AF, Sparen P, et al. Incidence of hospitalization for postpartum

psychotic and bipolar episodes in women with and without prior prepregnancy or prenatal

psychiatric hospitalizations. Arch Gen Psychiatry 2007 Jan;64(1):42-8.

(6) Wisner KL, Bogen DL, Sit D, et al. Does Fetal Exposure to SSRIs or Maternal

Depression Impact Infant Growth? Am J Psychiatry 2013 Mar 20.



(8) Charles VE, Polis CB, Sridhara SK, et al. Abortion and long-term mental health


(9) Major B, Applebaum M, Beckman L, et al. APA task Force on Mental Health and

Abortion. 2008.




2011.

(11) Munk-Olsen T, Laursen TM, Pedersen CB, et al. Induced first-trimester abortion and risk

of mental disorder. N Engl J Med 2011 Jan 27;364(4):332-9.

(12) Munk-Olsen T, Laursen TM, Pedersen CB, et al. First-time first-trimester induced

abortion and risk of readmission to a psychiatric hospital in women with a history of

treated mental disorder. Arch Gen Psychiatry 2012 Feb;69(2):159-65.

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(14) Flenady V, Middleton P, Smith GC, et al. Stillbirths: the way forward in high-income

countries. Lancet 2011 May 14;377(9778):1703-17.

(15) Li J, Laursen TM, Precht DH, Olsen J, et al. Hospitalization for mental illness among

parents after the death of a child. N Engl J Med 2005 Mar 24;352(12):1190-6.

(16) Rogers CH, Floyd FJ, Seltzer MM, et al. Long-term effects of the death of a child on

parents' adjustment in midlife. J Fam Psychol 2008 Apr;22(2):203-11.

(17) Pedersen CB, Gotzsche H, Moller JO, et al. The Danish Civil Registration System. A

cohort of eight million persons. Dan Med Bull 2006 Nov;53(4):441-9.

(18) Andersen TF, Madsen M, Jorgensen J, et al. The Danish National Hospital Register. A

valuable source of data for modern health sciences. Dan Med Bull 1999 Jun;46(3):263-8.











1994.

(22) Flenady V, Middleton P, Smith GC, et al. Stillbirths: the way forward in high-income

countries. Lancet 2011 May 14;377(9778):1703-17.




(24) Blackmore ER, Jones I, Doshi M, et al. Obstetric variables associated with bipolar

affective puerperal psychosis. Br J Psychiatry 2006 Jan;188:32-6.


1987 May;150:662-73.



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(27) Munk-Olsen T, Laursen TM, Pedersen CB, et al. New Parents and Mental Disorders. A

Population-Based Register Study. JAMA 2006;296(21):2582-9.

(28) Li J, Laursen TM, Precht DH, et al. Hospitalization for mental illness among parents after

the death of a child. N Engl J Med 2005 Mar 24;352(12):1190-6.

(29) Broen AN, Moum T, Bodtker AS, et al. The course of mental health after miscarriage and

induced abortion: a longitudinal, five-year follow-up study. BMC Med 2005;3:18.


(31) Baldur-Felskov B, Kjaer SK, Albieri V, et al. Psychiatric disorders in women with

fertility problems: results from a large Danish register-based cohort study. Hum Reprod

2012 Dec 6.

(32) Janssen HJ, Cuisinier MC, Hoogduin KA, et al. Controlled prospective study on the

mental health of women following pregnancy loss. Am J Psychiatry 1996

Feb;153(2):226-30.

(33) Cuisinier MC, Kuijpers JC, Hoogduin CA, et al. Miscarriage and stillbirth: time since the

loss, grief intensity and satisfaction with care. Eur J Obstet Gynecol Reprod Biol 1993

Dec 30;52(3):163-8.

(34) Neugebauer R, Kline J, Shrout P, et al. Major depressive disorder in the 6 months after

miscarriage. JAMA 1997 Feb 5;277(5):383-8.





2003;17(3):152-61.

(37) Boyle FM, Vance JC, Najman JM, et al. The mental health impact of stillbirth, neonatal

death or SIDS: prevalence and patterns of distress among mothers. Soc Sci Med 1996

Oct;43(8):1273-82.

(38) Beutel M, Deckardt R, von RM, et al. Grief and depression after miscarriage: their


(39) Lok IH, Yip AS, Lee DT, et al. A 1-year longitudinal study of psychological morbidity

after miscarriage. Fertil Steril 2010 Apr;93(6):1966-75.



(41) Lohse SR, Farkas DK, Lohse N, et al. Validation of spontaneous abortion diagnoses in

the Danish National Registry of Patients. Clin Epidemiol 2010;2:247-50.

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Oct;114(4):548-53.



1985;13(4):159-63.

(45) Nybo Andersen AM, Wohlfahrt J, Christens P, et al. Maternal age and fetal loss:

population based register linkage study. BMJ 2000 Jun 24;320(7251):1708-12.

(46) Buss L, Tolstrup J, Munk C, et al. Spontaneous abortion: a prospective cohort study of

younger women from the general population in Denmark. Validation, occurrence and risk

determinants. Acta Obstet Gynecol Scand 2006;85(4):467-75.

(47) Nielsen A, Hannibal CG, Lindekilde BE, et al. Maternal smoking predicts the risk of

spontaneous abortion. Acta Obstet Gynecol Scand 2006;85(9):1057-65.

(48) Andersen AM, Andersen PK, Olsen J,et al. Moderate alcohol intake during pregnancy

and risk of fetal death. Int J Epidemiol 2012 Apr;41(2):405-13.



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Title:


Authors:



1)

iPSYCH,



Fuglesangs Allé 4,

Aarhus University,

Denmark

2)



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2

Aarhus University,

Aarhus,

Denmark

3)



Aarhus University,

Aarhus,

Denmark





Aarhus University,


8210 Aarhus V

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3

Denmark


Phone: +45 871 65749

Fax: +45 871 64601


Keywords:

Pregnancy loss

Mental health

Reproduction

Epidemiology

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ABSTRACT

Objectives:





Design:


Setting:

Denmark

Participants:


cases of fetal death (ICD-10 codes for spontaneous abortion or stillbirth) were recorded between

1996 and 2010.


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Results:







Conclusions:




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Article summary:








death.



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INTRODUCTION

Reproduction and mental health is associated, which has been shown in several studies across

different study populations. Childbirth is associated with an increased risk of psychiatric

disorders in the mother (1-6). and iInduced abortions have in comparison to studies on

childbirths been linked with mental health problems in few (7), but not in most studies (8-12).

The loss of a wanted pregnancy is a major life event, which can affect mental health, and

spontaneous abortions and stillbirths have been associated with grief, depression, anxiety and

social problems (13;14). Loss of a live child is followed by increased risk of severe episodes of

psychiatric disorders (15), but it remains unclear whether this association also applies to fetal

loss and, if so, to which extent.








gestational age.

Formatted: Font: Not Italic




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METHODS





death (including both spontaneous abortions and stillbirths), whichever came first. The present

cohort study was based on the study population described above and designed through the

following steps:












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Data sources















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population.

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RESULTS













psychiatric episode after a fetal death (Table 3 ).








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DISCUSSION













children (Table 3).








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of psychiatric disorders was high for women with very early losses (Figure 12). The registration

of these early losses is known to be incomplete, except for persons who have received fertility














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facilities.















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CONCLUSION








cause.

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Table 1





death

Number of

cases

Person-

years

Rate per

1000

person-years

Incidence rate

ratios

11 to 12 months before 99 13566 7.298 0.83 (0.63, 1.09)

9 to 10 months before 109 13722 7.943 0.92 (0.70, 1.20)

7 to 8 months before 114 13873 8.218 0.96 (0.74, 1.25)

5 to 6 months before 94 14024 6.703 0.79 (0.60, 1.04)

3 to 4 months before 93 14176 6.561 0.79 (0.60, 1.04)

1 to 2 months before 94 14323 6.563 0.80 (0.61, 1.05)

Fetal death

1st month after 91 7203 12.634 1.51 (1.15, 1.99)

2nd month after 71 7203 9.857 1.19 (0.88, 1.60)

3 to 4 months after 145 14412 10.061 1.23 (0.96, 1.57)

5 to 6 months after 121 14420 8.391 1.04 (0.80, 1.34)

7 to 8 months after 129 14420 8.946 1.12 (0.87, 1.44)

9 to 10 months after 107 14423 7.419 0.94 (0.72, 1.23)


Cohort 1.

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Table 2





fetal death


(ICD-10 codes: F43)

Unipolar depression

(ICD-10 codes:

F32,33,34,38,39)

Remaining diagnoses



0.76

(0.49, 1.17) 23

1.10

(0.60, 2.01) 41

0.81

(0.53, 1.23)


0.80

(0.52, 1.23) 21

1.00

(0.54, 1.86) 50

0.99

(0.66, 1.47)


0.97

(0.64, 1.46) 21

1.00

(0.54, 1.85) 48

0.95

(0.64, 1.43)


0.59

(0.37, 0.95) 14

0.67

(0.34, 1.32) 52

1.04

(0.70, 1.54)


0.74

(0.47, 1.15) 19

0.91

(0.48, 1.70) 40

0.80

(0.52, 1.22)


0.53

(0.32, 0.86) 24

1.15

(0.63, 2.08) 46

0.92

(0.61, 1.39)

Fetal death

1st month after 61

2.53

(1.72, 3.72) 11

1.04

(0.50, 2.17) 21

0.82

(0.49, 1.37)

2nd month after 29

1.21

(0.76, 1.93) 11

1.05

(0.50, 2.18) 31

1.22

(0.78, 1.92)


1.05

(0.70, 1.58) 34

1.64

(0.94, 2.84) 61

1.21

(0.83, 1.78)


1.15

(0.78, 1.71) 31

1.51

(0.86, 2.65) 37

0.75

(0.49, 1.15)


0.91

(0.60, 1.38) 28

1.38

(0.78, 2.46) 62

1.27

(0.87, 1.86)


1.12

(0.75, 1.67) 20

1.00

(0.54, 1.86) 38

0.79

(0.52, 1.21)


1

(ref. category) 20

1

(ref. category) 47

1

(ref. category)



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contact.



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Table 3





1.51 (1.15, 1.99)

Stratified analysis

Parenthood



1.19 (0.80, 1.77)


of the fetal loss

2.01 (1.35, 3.02)

Stratified analysis

Age

- Age group <=26 years 1.30 (0.87, 1.93)

- Age group 27-34 years 2.15 (1.37, 3.38)

- Age group 35+ years 1.17 (0.55, 2.50)


Cohort 1.





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Figure 1

Unadjusted absolute risk measured as percentages of first-time psychiatric inpatient or outpatient

treatment following spontaneous abortion and stillbirth

Cohort 2.


<6 weeks: 1.24% (95% CI: 0.94 - 1.55), N = 64 cases

6-12 weeks: 0.78% (95% CI: 0.71 - 0.84), N = 532 cases

13-19 weeks: 0.75% (95% CI: 0.55 - 0.97), N = 51 cases

20 weeks +: 1.95% (95% CI: 1.50 - 2.39), N = 72 cases


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of the manuscript.

Author contributions:

Dr. Trine Munk-Olsen and Dr. Laursen were involved in the initial phase of planing the study,

and Dr. Munk-Olsen wrote the first and subsequent drafts of the manuscript. All authors

contributed to methodological considerations and the specific design of the study as well as

making critical revisons to the all versions of the manuscript.

Dr. Thomas Munk Laursen conducted the statistical analyses and had full access to all the data

included in the study and takes responsibility for the integrity of the data and the accuracy of the

data analysis.

Ethics approval: All personal identifiers were removed and replaced with a sequential number in

the final data set, and the protocol was approved by The Danish Data Protection Agency.

Data sharing statement: No additional data available


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None declared.

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Reference List




(2) Munk-Olsen T, Laursen TM, Pedersen CB, Mors O, Mortensen PB. New parents and

mental disorders: a population-based register study. JAMA 2006 Dec 6;296(21):2582-9.

(3) Munk-Olsen T, Laursen TM, Mendelson T, Pedersen CB, Mors O, Mortensen PB. Risks

and predictors of readmission for a mental disorder during the postpartum period. Arch

Gen Psychiatry 2009 Feb;66(2):189-95.


1987 May;150:662-73.

(5) Harlow BL, Vitonis AF, Sparen P, Cnattingius S, Joffe H, Hultman CM. Incidence of

hospitalization for postpartum psychotic and bipolar episodes in women with and without

prior prepregnancy or prenatal psychiatric hospitalizations. Arch Gen Psychiatry 2007

Jan;64(1):42-8.

(6) Wisner KL, Bogen DL, Sit D, McShea M, Hughes C, Rizzo D, et al. Does Fetal Exposure

to SSRIs or Maternal Depression Impact Infant Growth? Am J Psychiatry 2013 Mar 20.



(8) Charles VE, Polis CB, Sridhara SK, Blum RW. Abortion and long-term mental health


(9) Major B, Applebaum M, Beckman L, Dutton M, Russo N, West C. APA task Force on

Mental Health and Abortion. 2008.




2011.

(11) Munk-Olsen T, Laursen TM, Pedersen CB, Lidegaard O, Mortensen PB. Induced first-

trimester abortion and risk of mental disorder. N Engl J Med 2011 Jan 27;364(4):332-9.

(12) Munk-Olsen T, Laursen TM, Pedersen CB, Lidegaard O, Mortensen PB. First-time first-

trimester induced abortion and risk of readmission to a psychiatric hospital in women

with a history of treated mental disorder. Arch Gen Psychiatry 2012 Feb;69(2):159-65.

Formatted: Danish

Formatted: Danish

Formatted: Danish

Formatted: Danish

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(16) Rogers CH, Floyd FJ, Seltzer MM, Greenberg J, Hong J. Long-term effects of the death

of a child on parents' adjustment in midlife. J Fam Psychol 2008 Apr;22(2):203-11.

(17) Pedersen CB, Gotzsche H, Moller JO, Mortensen PB. The Danish Civil Registration

System. A cohort of eight million persons. Dan Med Bull 2006 Nov;53(4):441-9.

(18) Andersen TF, Madsen M, Jorgensen J, Mellemkjoer L, Olsen JH. The Danish National

Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull

1999 Jun;46(3):263-8.











1994.






(24) Blackmore ER, Jones I, Doshi M, Haque S, Holder R, Brockington I, et al. Obstetric

variables associated with bipolar affective puerperal psychosis. Br J Psychiatry 2006

Jan;188:32-6.


1987 May;150:662-73.

Formatted: Danish

Formatted: Danish

Formatted: Danish

Formatted: Danish

Formatted: Danish

Formatted: Danish

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(27) Munk-Olsen T, Laursen TM, Pedersen CB, Mors O, Mortensen PB. New Parents and

Mental Disorders. A Population-Based Register Study. JAMA 2006;296(21):2582-9.



(29) Broen AN, Moum T, Bodtker AS, Ekeberg O. The course of mental health after

miscarriage and induced abortion: a longitudinal, five-year follow-up study. BMC Med

2005;3:18.


(31) Baldur-Felskov B, Kjaer SK, Albieri V, Steding-Jessen M, Kjaer T, Johansen C, et al.

Psychiatric disorders in women with fertility problems: results from a large Danish

register-based cohort study. Hum Reprod 2012 Dec 6.

(32) Janssen HJ, Cuisinier MC, Hoogduin KA, de Graauw KP. Controlled prospective study

on the mental health of women following pregnancy loss. Am J Psychiatry 1996

Feb;153(2):226-30.

(33) Cuisinier MC, Kuijpers JC, Hoogduin CA, de Graauw CP, Janssen HJ. Miscarriage and

stillbirth: time since the loss, grief intensity and satisfaction with care. Eur J Obstet

Gynecol Reprod Biol 1993 Dec 30;52(3):163-8.

(34) Neugebauer R, Kline J, Shrout P, Skodol A, O'Connor P, Geller PA, et al. Major

depressive disorder in the 6 months after miscarriage. JAMA 1997 Feb 5;277(5):383-8.





2003;17(3):152-61.

(37) Boyle FM, Vance JC, Najman JM, Thearle MJ. The mental health impact of stillbirth,

neonatal death or SIDS: prevalence and patterns of distress among mothers. Soc Sci Med

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(38) Beutel M, Deckardt R, von RM, Weiner H. Grief and depression after miscarriage: their


(39) Lok IH, Yip AS, Lee DT, Sahota D, Chung TK. A 1-year longitudinal study of

psychological morbidity after miscarriage. Fertil Steril 2010 Apr;93(6):1966-75.

Formatted: Danish

Formatted: Danish

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(41) Lohse SR, Farkas DK, Lohse N, Skouby SO, Nielsen FE, Lash TL, et al. Validation of

spontaneous abortion diagnoses in the Danish National Registry of Patients. Clin

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fetal loss: population based register linkage study. BMJ 2000 Jun 24;320(7251):1708-12.

(46) Buss L, Tolstrup J, Munk C, Bergholt T, Ottesen B, Gronbaek M, et al. Spontaneous

abortion: a prospective cohort study of younger women from the general population in

Denmark. Validation, occurrence and risk determinants. Acta Obstet Gynecol Scand

2006;85(4):467-75.

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(48) Andersen AM, Andersen PK, Olsen J, Gronbaek M, Strandberg-Larsen K. Moderate

alcohol intake during pregnancy and risk of fetal death. Int J Epidemiol 2012

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90x67mm (300 x 300 DPI)

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1

STROBE Statement—checklist of items that should be included in reports of observational studies

Item

No Recommendation

Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract

(b) Provide in the abstract an informative and balanced summary of what was done

and what was found

Introduction

Background/rationale 2 Explain the scientific background and rationale for the investigation being reported

Objectives 3 State specific objectives, including any prespecified hypotheses

Methods

Study design 4 Present key elements of study design early in the paper

Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment,

exposure, follow-up, and data collection

Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of

selection of participants. Describe methods of follow-up

Case-control study—Give the eligibility criteria, and the sources and methods of

case ascertainment and control selection. Give the rationale for the choice of cases

and controls

Cross-sectional study—Give the eligibility criteria, and the sources and methods of

selection of participants

(b) Cohort study—For matched studies, give matching criteria and number of

exposed and unexposed

Case-control study—For matched studies, give matching criteria and the number of

controls per case

Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect

modifiers. Give diagnostic criteria, if applicable

Data sources/

measurement

8* For each variable of interest, give sources of data and details of methods of

assessment (measurement). Describe comparability of assessment methods if there

is more than one group

Bias 9 Describe any efforts to address potential sources of bias

Study size 10 Explain how the study size was arrived at

Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable,

describe which groupings were chosen and why

Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding

(b) Describe any methods used to examine subgroups and interactions

(c) Explain how missing data were addressed

(d) Cohort study—If applicable, explain how loss to follow-up was addressed

Case-control study—If applicable, explain how matching of cases and controls was

addressed

Cross-sectional study—If applicable, describe analytical methods taking account of

sampling strategy

(e) Describe any sensitivity analyses

Continued on next page

Comment [TM1]: Yes (page 1)

Comment [TM2]: Yes (page 4-5)












Comment [TM14]: Not applicable for current study


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Results

Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible,

examined for eligibility, confirmed eligible, included in the study, completing follow-up, and

analysed

(b) Give reasons for non-participation at each stage

(c) Consider use of a flow diagram

Descriptive

data

14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information

on exposures and potential confounders

(b) Indicate number of participants with missing data for each variable of interest

(c) Cohort study—Summarise follow-up time (eg, average and total amount)

Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time

Case-control study—Report numbers in each exposure category, or summary measures of

exposure

Cross-sectional study—Report numbers of outcome events or summary measures

Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their

precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and

why they were included

(b) Report category boundaries when continuous variables were categorized

(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful

time period

Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity

analyses

Discussion

Key results 18 Summarise key results with reference to study objectives

Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision.

Discuss both direction and magnitude of any potential bias

Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity

of analyses, results from similar studies, and other relevant evidence

Generalisability 21 Discuss the generalisability (external validity) of the study results

Other information

Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable,

for the original study on which the present article is based

*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and

unexposed groups in cohort and cross-sectional studies.

Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and

published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely

available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at

http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is

available at www.strobe-statement.org.






Comment [TM21]: Yes (page 12 + Tables 1-3, Figure 1)






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