bmj open...trine munk-olsen, phd (1), bodil hammer bech, phd (3), mogens vestergaard, phd (2), jiong...
TRANSCRIPT
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
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
jopen-2014-005187 on 6 June 2014. Dow
nloaded from
For peer review only
1
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,
Page 1 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
2
Aarhus University,
Aarhus,
Denmark
3)
Section for Epidemiology,
Department of Public Health,
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
Page 2 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
3
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
Page 3 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
4
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:
Page 4 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
5
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.
Page 5 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
6
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
increase with increasing gestational age at the time of the loss.
• 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.
Page 6 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
7
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.
Page 7 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
8
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):
Page 8 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
9
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.
Page 9 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
10
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
Page 10 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
11
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.
Page 11 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
12
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.
Page 12 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
13
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
Page 13 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
14
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
Page 14 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
15
(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.
Page 15 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
16
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.
Page 16 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
17
CONCLUSION
Fetal death was associated with a transient increased risk of experiencing a first-time episode of
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.
Page 17 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
18
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.
Page 18 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
19
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.
Page 19 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
20
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)
9 to 10 months before 38
0.80
(0.52, 1.23) 21
1.00
(0.54, 1.86) 50
0.99
(0.66, 1.47)
7 to 8 months before 46
0.97
(0.64, 1.46) 21
1.00
(0.54, 1.85) 48
0.95
(0.64, 1.43)
5 to 6 months before 28
0.59
(0.37, 0.95) 14
0.67
(0.34, 1.32) 52
1.04
(0.70, 1.54)
3 to 4 months before 35
0.74
(0.47, 1.15) 19
0.91
(0.48, 1.70) 40
0.80
(0.52, 1.22)
2 to 1 months before 25
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)
5 to 6 months after 54
1.15
(0.78, 1.71) 31
1.51
(0.86, 2.65) 37
0.75
(0.49, 1.15)
7 to 8 months after 42
0.91
(0.60, 1.38) 28
1.38
(0.78, 2.46) 62
1.27
(0.87, 1.86)
9 to 10 months after 51
1.12
(0.75, 1.67) 20
1.00
(0.54, 1.86) 38
0.79
(0.52, 1.21)
11 to 12 months after 45
1
(ref. category) 20
1
(ref. category) 47
1
(ref. category)
* Total number of cases:
Adjustment disorders: 540 women
Page 20 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
21
Unipolar depression: 277 women
Remaining diagnoses: 574 women
Note that 12 women both received an adjustment and unipolar diagnoses at the index psychiatric
contact.
Adjusted for age, calendar period, parity status, previous history of induced abortion, and family
history of psychiatric disorders.
Page 21 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
22
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.
Adjusted for age, calendar period, parity status, previous history of induced abortion, and family
history of psychiatric disorders.
Parity status, induced abortion history, and family history of psychiatric disorders: time
dependent variables.
Page 22 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
23
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)
Page 23 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
24
Note: 31 of the 776 cases had missing information on gestational age, and 26 had late entry and
were excluded from the analyses.
Page 24 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
25
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.
Page 25 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
26
Reference List
(1) Bergink V, Lambregtse-van den Berg MP, Koorengevel KM, Kupka R, Kushner SA.
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, 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.
(4) Kendell RE, Chalmers JC, Platz C. Epidemiology of puerperal psychoses. Br J Psychiatry
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.
(7) Coleman PK. Abortion and mental health: quantitative synthesis and analysis of research
published 1995-2009. Br J Psychiatry 2011 Sep;199(3):180-6.
(8) Charles VE, Polis CB, Sridhara SK, Blum RW. Abortion and long-term mental health
outcomes: a systematic review of the evidence. Contraception 2008 Dec;78(6):436-50.
(9) Major B, Applebaum M, Beckman L, Dutton M, Russo N, West C. APA task Force on
Mental Health and Abortion. 2008.
(10) Academy of Medical Royal Colleges. National Collaborating Centre for Mental Health.
Induced Abortion and Mental Health: A Systematic Review of the Mental Health
Outcomes of Induced Abortion, Including their Prevalence and Associated Factors.
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.
Page 26 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
27
(13) Lok IH, Neugebauer R. Psychological morbidity following miscarriage. Best Pract Res
Clin Obstet Gynaecol 2007 Apr;21(2):229-47.
(14) Flenady V, Middleton P, Smith GC, Duke W, Erwich JJ, Khong TY, 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, Mortensen PB. 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, 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.
(19) Mors O, Perto GP, Mortensen PB. The danish psychiatric central research register. Scand
J Public Health 2011 Jul;39(7 Suppl):54-7.
(20) World Health Organization. Klassifikation af sygdomme; Udvidet dansk-latinsk udgave
af verdenssundhedsorganisationens internationale klassifikation af sygdomme. 8 revision,
1965 [Classification of diseases: Extended Danish-Latin version of the World Health
Organization International Classification of Diseases, 8th revision, 1965]. 1 ed.
Copenhagen: Danish National Board of Health; 1971.
(21) World Health Organization. WHO ICD-10: Psykiske lidelser og adfærdsmæssige
forstyrrelser. Klassifikation og diagnosekriterier [WHO ICD-10: Mental and Behavioural
Disorders. Classification and Diagnostic Criteria]. Copenhagen: Munksgaard Danmark;
1994.
(22) Flenady V, Middleton P, Smith GC, Duke W, Erwich JJ, Khong TY, et al. Stillbirths: the
way forward in high-income countries. Lancet 2011 May 14;377(9778):1703-17.
(23) Bergink V, Lambregtse-van den Berg MP, Koorengevel KM, Kupka R, Kushner SA.
First-onset psychosis occurring in the postpartum period: a prospective cohort study. J
Clin Psychiatry 2011 Nov;72(11):1531-7.
(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.
(25) Kendell RE, Chalmers JC, Platz C. Epidemiology of puerperal psychoses. Br J Psychiatry
1987 May;150:662-73.
Page 27 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
28
(26) Videbech P, Gouliaev G. First admission with puerperal psychosis: 7-14 years of follow-
up. Acta Psychiatr Scand 1995 Mar;91(3):167-73.
(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.
(28) Li J, Laursen TM, Precht DH, Olsen J, Mortensen PB. 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, Ekeberg O. The course of mental health after
miscarriage and induced abortion: a longitudinal, five-year follow-up study. BMC Med
2005;3:18.
(30) McEwen BS. Protective and damaging effects of stress mediators. 1998.
(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.
(35) Klier CM, Geller PA, Neugebauer R. Minor depressive disorder in the context of
miscarriage. J Affect Disord 2000 Jul;59(1):13-21.
(36) Neugebauer R. Depressive symptoms at two months after miscarriage: interpreting study
findings from an epidemiological versus clinical perspective. Depress Anxiety
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
1996 Oct;43(8):1273-82.
(38) Beutel M, Deckardt R, von RM, Weiner H. Grief and depression after miscarriage: their
separation, antecedents, and course. Psychosom Med 1995 Nov;57(6):517-26.
(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.
Page 28 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
29
(40) Klier CM, Geller PA, Neugebauer R. Minor depressive disorder in the context of
miscarriage. J Affect Disord 2000 Jul;59(1):13-21.
(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
Epidemiol 2010;2:247-50.
(42) Wang JX, Norman RJ, Wilcox AJ. Incidence of spontaneous abortion among pregnancies
produced by assisted reproductive technology. Hum Reprod 2004 Feb;19(2):272-7.
(43) Wilcox AJ, Treloar AE, Sandler DP. Spontaneous abortion over time: comparing
occurrence in two cohorts of women a generation apart. Am J Epidemiol 1981
Oct;114(4):548-53.
(44) Heidam LZ, Olsen J. Self-reported data on spontaneous abortions compared with data
obtained by computer linkage with the hospital registry. Scand J Soc Med
1985;13(4):159-63.
(45) Nybo Andersen AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. 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, 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.
(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.
(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
Apr;41(2):405-13.
(49) Kumar S. Occupational, environmental and lifestyle factors associated with spontaneous
abortion. Reprod Sci 2011 Oct;18(10):915-30.
Page 29 of 29
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
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
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
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
jopen-2014-005187 on 6 June 2014. Dow
nloaded from
For peer review only
1
Title:
Psychiatric disorders following fetal death, a population-based cohort study
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,
Page 1 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
2
Aarhus University,
Aarhus,
Denmark
3)
Section for Epidemiology,
Department of Public Health,
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
Page 2 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
3
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
Page 3 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
4
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 (ICD-10 codes for spontaneous abortion or stillbirth) were recorded between
1996 and 2010.
Primary and secondary outcome measures:
The main outcome measures were incidence rate ratios (risk of first psychiatric inpatient or
outpatient treatment).
Page 4 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
5
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.
Page 5 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
6
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
increase with increasing gestational age at the time of the loss.
• 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.
Page 6 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
7
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.
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.
Page 7 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
8
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 (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:
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):
Page 8 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
9
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.
Page 9 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
10
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
Page 10 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
11
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.
Page 11 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
12
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 3).
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.
Page 12 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
13
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
Page 13 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
14
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 1). 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
Page 14 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
15
(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.
Page 15 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
16
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.
Page 16 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
17
CONCLUSION
Fetal death was associated with a transient increased risk of experiencing a first-time episode of
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.
Page 17 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
18
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.
Page 18 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
19
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.
Page 19 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
20
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)
9 to 10 months before 38
0.80
(0.52, 1.23) 21
1.00
(0.54, 1.86) 50
0.99
(0.66, 1.47)
7 to 8 months before 46
0.97
(0.64, 1.46) 21
1.00
(0.54, 1.85) 48
0.95
(0.64, 1.43)
5 to 6 months before 28
0.59
(0.37, 0.95) 14
0.67
(0.34, 1.32) 52
1.04
(0.70, 1.54)
3 to 4 months before 35
0.74
(0.47, 1.15) 19
0.91
(0.48, 1.70) 40
0.80
(0.52, 1.22)
2 to 1 months before 25
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)
5 to 6 months after 54
1.15
(0.78, 1.71) 31
1.51
(0.86, 2.65) 37
0.75
(0.49, 1.15)
7 to 8 months after 42
0.91
(0.60, 1.38) 28
1.38
(0.78, 2.46) 62
1.27
(0.87, 1.86)
9 to 10 months after 51
1.12
(0.75, 1.67) 20
1.00
(0.54, 1.86) 38
0.79
(0.52, 1.21)
11 to 12 months after 45
1
(ref. category) 20
1
(ref. category) 47
1
(ref. category)
* Total number of cases:
Adjustment disorders: 540 women
Page 20 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
21
Unipolar depression: 277 women
Remaining diagnoses: 574 women
Note that 12 women both received an adjustment and unipolar diagnoses at the index psychiatric
contact.
Adjusted for age, calendar period, parity status, previous history of induced abortion, and family
history of psychiatric disorders.
Page 21 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
22
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.
Adjusted for age, calendar period, parity status, previous history of induced abortion, and family
history of psychiatric disorders.
Parity status, induced abortion history, and family history of psychiatric disorders: time
dependent variables.
Page 22 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
23
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)
Note: 31 of the 776 cases had missing information on gestational age, and 26 had late entry and
were excluded from the analyses.
Page 23 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
24
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.
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
Page 24 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
25
Competing interests:
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
Page 25 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
26
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.
(4) Kendell RE, Chalmers JC, Platz C. Epidemiology of puerperal psychoses. Br J Psychiatry
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.
(7) Coleman PK. Abortion and mental health: quantitative synthesis and analysis of research
published 1995-2009. Br J Psychiatry 2011 Sep;199(3):180-6.
(8) Charles VE, Polis CB, Sridhara SK, et al. Abortion and long-term mental health
outcomes: a systematic review of the evidence. Contraception 2008 Dec;78(6):436-50.
(9) Major B, Applebaum M, Beckman L, et al. APA task Force on Mental Health and
Abortion. 2008.
(10) Academy of Medical Royal Colleges. National Collaborating Centre for Mental Health.
Induced Abortion and Mental Health: A Systematic Review of the Mental Health
Outcomes of Induced Abortion, Including their Prevalence and Associated Factors.
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.
Page 26 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
27
(13) Lok IH, Neugebauer R. Psychological morbidity following miscarriage. Best Pract Res
Clin Obstet Gynaecol 2007 Apr;21(2):229-47.
(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.
(19) Mors O, Perto GP, Mortensen PB. The danish psychiatric central research register. Scand
J Public Health 2011 Jul;39(7 Suppl):54-7.
(20) World Health Organization. Klassifikation af sygdomme; Udvidet dansk-latinsk udgave
af verdenssundhedsorganisationens internationale klassifikation af sygdomme. 8 revision,
1965 [Classification of diseases: Extended Danish-Latin version of the World Health
Organization International Classification of Diseases, 8th revision, 1965]. 1 ed.
Copenhagen: Danish National Board of Health; 1971.
(21) World Health Organization. WHO ICD-10: Psykiske lidelser og adfærdsmæssige
forstyrrelser. Klassifikation og diagnosekriterier [WHO ICD-10: Mental and Behavioural
Disorders. Classification and Diagnostic Criteria]. Copenhagen: Munksgaard Danmark;
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.
(23) Bergink V, Lambregtse-van den Berg MP, Koorengevel KM, Kupka R, Kushner SA.
First-onset psychosis occurring in the postpartum period: a prospective cohort study. J
Clin Psychiatry 2011 Nov;72(11):1531-7.
(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.
(25) Kendell RE, Chalmers JC, Platz C. Epidemiology of puerperal psychoses. Br J Psychiatry
1987 May;150:662-73.
(26) Videbech P, Gouliaev G. First admission with puerperal psychosis: 7-14 years of follow-
up. Acta Psychiatr Scand 1995 Mar;91(3):167-73.
Page 27 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
28
(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.
(30) McEwen BS. Protective and damaging effects of stress mediators. 1998.
(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.
(35) Klier CM, Geller PA, Neugebauer R. Minor depressive disorder in the context of
miscarriage. J Affect Disord 2000 Jul;59(1):13-21.
(36) Neugebauer R. Depressive symptoms at two months after miscarriage: interpreting study
findings from an epidemiological versus clinical perspective. Depress Anxiety
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
separation, antecedents, and course. Psychosom Med 1995 Nov;57(6):517-26.
(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.
(40) Klier CM, Geller PA, Neugebauer R. Minor depressive disorder in the context of
miscarriage. J Affect Disord 2000 Jul;59(1):13-21.
(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.
Page 28 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
29
(42) Wang JX, Norman RJ, Wilcox AJ. Incidence of spontaneous abortion among pregnancies
produced by assisted reproductive technology. Hum Reprod 2004 Feb;19(2):272-7.
(43) Wilcox AJ, Treloar AE, Sandler DP. Spontaneous abortion over time: comparing
occurrence in two cohorts of women a generation apart. Am J Epidemiol 1981
Oct;114(4):548-53.
(44) Heidam LZ, Olsen J. Self-reported data on spontaneous abortions compared with data
obtained by computer linkage with the hospital registry. Scand J Soc Med
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.
(49) Kumar S. Occupational, environmental and lifestyle factors associated with spontaneous
abortion. Reprod Sci 2011 Oct;18(10):915-30.
Page 29 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
1
Title:
Psychiatric disorders following fetal death, a population-based cohort study
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,
Page 30 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
2
Aarhus University,
Aarhus,
Denmark
3)
Section for Epidemiology,
Department of Public Health,
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
Page 31 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
3
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
Page 32 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
4
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 (ICD-10 codes for spontaneous abortion or stillbirth) were recorded between
1996 and 2010.
Primary and secondary outcome measures:
Page 33 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
5
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.
Page 34 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
6
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
increase with increasing gestational age at the time of the loss.
• 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.
Page 35 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
7
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.
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.
Formatted: Font: Not Italic
Formatted: Font: Not Italic
Formatted: Font: Not Italic
Formatted: Font: Not Italic
Page 36 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
8
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 (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:
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):
Page 37 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
9
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.
Page 38 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
10
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
Page 39 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
11
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.
Page 40 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
12
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 3 ).
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.
Page 41 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
13
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
Page 42 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
14
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 12). 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
Page 43 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
15
(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.
Page 44 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
16
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.
Page 45 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
17
CONCLUSION
Fetal death was associated with a transient increased risk of experiencing a first-time episode of
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.
Page 46 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
18
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.
Page 47 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
19
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.
Page 48 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
20
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)
9 to 10 months before 38
0.80
(0.52, 1.23) 21
1.00
(0.54, 1.86) 50
0.99
(0.66, 1.47)
7 to 8 months before 46
0.97
(0.64, 1.46) 21
1.00
(0.54, 1.85) 48
0.95
(0.64, 1.43)
5 to 6 months before 28
0.59
(0.37, 0.95) 14
0.67
(0.34, 1.32) 52
1.04
(0.70, 1.54)
3 to 4 months before 35
0.74
(0.47, 1.15) 19
0.91
(0.48, 1.70) 40
0.80
(0.52, 1.22)
2 to 1 months before 25
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)
5 to 6 months after 54
1.15
(0.78, 1.71) 31
1.51
(0.86, 2.65) 37
0.75
(0.49, 1.15)
7 to 8 months after 42
0.91
(0.60, 1.38) 28
1.38
(0.78, 2.46) 62
1.27
(0.87, 1.86)
9 to 10 months after 51
1.12
(0.75, 1.67) 20
1.00
(0.54, 1.86) 38
0.79
(0.52, 1.21)
11 to 12 months after 45
1
(ref. category) 20
1
(ref. category) 47
1
(ref. category)
* Total number of cases:
Adjustment disorders: 540 women
Page 49 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
21
Unipolar depression: 277 women
Remaining diagnoses: 574 women
Note that 12 women both received an adjustment and unipolar diagnoses at the index psychiatric
contact.
Adjusted for age, calendar period, parity status, previous history of induced abortion, and family
history of psychiatric disorders.
Page 50 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
22
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.
Adjusted for age, calendar period, parity status, previous history of induced abortion, and family
history of psychiatric disorders.
Parity status, induced abortion history, and family history of psychiatric disorders: time
dependent variables.
Page 51 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
23
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)
Page 52 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
24
Note: 31 of the 776 cases had missing information on gestational age, and 26 had late entry and
were excluded from the analyses.
Page 53 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
25
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.
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
Competing interests:
Page 54 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
26
None declared.
Page 55 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
27
Reference List
(1) Bergink V, Lambregtse-van den Berg MP, Koorengevel KM, Kupka R, Kushner SA.
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, 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.
(4) Kendell RE, Chalmers JC, Platz C. Epidemiology of puerperal psychoses. Br J Psychiatry
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.
(7) Coleman PK. Abortion and mental health: quantitative synthesis and analysis of research
published 1995-2009. Br J Psychiatry 2011 Sep;199(3):180-6.
(8) Charles VE, Polis CB, Sridhara SK, Blum RW. Abortion and long-term mental health
outcomes: a systematic review of the evidence. Contraception 2008 Dec;78(6):436-50.
(9) Major B, Applebaum M, Beckman L, Dutton M, Russo N, West C. APA task Force on
Mental Health and Abortion. 2008.
(10) Academy of Medical Royal Colleges. National Collaborating Centre for Mental Health.
Induced Abortion and Mental Health: A Systematic Review of the Mental Health
Outcomes of Induced Abortion, Including their Prevalence and Associated Factors.
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
Page 56 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
28
(13) Lok IH, Neugebauer R. Psychological morbidity following miscarriage. Best Pract Res
Clin Obstet Gynaecol 2007 Apr;21(2):229-47.
(14) Flenady V, Middleton P, Smith GC, Duke W, Erwich JJ, Khong TY, 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, Mortensen PB. 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, 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.
(19) Mors O, Perto GP, Mortensen PB. The danish psychiatric central research register. Scand
J Public Health 2011 Jul;39(7 Suppl):54-7.
(20) World Health Organization. Klassifikation af sygdomme; Udvidet dansk-latinsk udgave
af verdenssundhedsorganisationens internationale klassifikation af sygdomme. 8 revision,
1965 [Classification of diseases: Extended Danish-Latin version of the World Health
Organization International Classification of Diseases, 8th revision, 1965]. 1 ed.
Copenhagen: Danish National Board of Health; 1971.
(21) World Health Organization. WHO ICD-10: Psykiske lidelser og adfærdsmæssige
forstyrrelser. Klassifikation og diagnosekriterier [WHO ICD-10: Mental and Behavioural
Disorders. Classification and Diagnostic Criteria]. Copenhagen: Munksgaard Danmark;
1994.
(22) Flenady V, Middleton P, Smith GC, Duke W, Erwich JJ, Khong TY, et al. Stillbirths: the
way forward in high-income countries. Lancet 2011 May 14;377(9778):1703-17.
(23) Bergink V, Lambregtse-van den Berg MP, Koorengevel KM, Kupka R, Kushner SA.
First-onset psychosis occurring in the postpartum period: a prospective cohort study. J
Clin Psychiatry 2011 Nov;72(11):1531-7.
(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.
(25) Kendell RE, Chalmers JC, Platz C. Epidemiology of puerperal psychoses. Br J Psychiatry
1987 May;150:662-73.
Formatted: Danish
Formatted: Danish
Formatted: Danish
Formatted: Danish
Formatted: Danish
Formatted: Danish
Page 57 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
29
(26) Videbech P, Gouliaev G. First admission with puerperal psychosis: 7-14 years of follow-
up. Acta Psychiatr Scand 1995 Mar;91(3):167-73.
(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.
(28) Li J, Laursen TM, Precht DH, Olsen J, Mortensen PB. 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, Ekeberg O. The course of mental health after
miscarriage and induced abortion: a longitudinal, five-year follow-up study. BMC Med
2005;3:18.
(30) McEwen BS. Protective and damaging effects of stress mediators. 1998.
(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.
(35) Klier CM, Geller PA, Neugebauer R. Minor depressive disorder in the context of
miscarriage. J Affect Disord 2000 Jul;59(1):13-21.
(36) Neugebauer R. Depressive symptoms at two months after miscarriage: interpreting study
findings from an epidemiological versus clinical perspective. Depress Anxiety
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
1996 Oct;43(8):1273-82.
(38) Beutel M, Deckardt R, von RM, Weiner H. Grief and depression after miscarriage: their
separation, antecedents, and course. Psychosom Med 1995 Nov;57(6):517-26.
(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
Page 58 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
30
(40) Klier CM, Geller PA, Neugebauer R. Minor depressive disorder in the context of
miscarriage. J Affect Disord 2000 Jul;59(1):13-21.
(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
Epidemiol 2010;2:247-50.
(42) Wang JX, Norman RJ, Wilcox AJ. Incidence of spontaneous abortion among pregnancies
produced by assisted reproductive technology. Hum Reprod 2004 Feb;19(2):272-7.
(43) Wilcox AJ, Treloar AE, Sandler DP. Spontaneous abortion over time: comparing
occurrence in two cohorts of women a generation apart. Am J Epidemiol 1981
Oct;114(4):548-53.
(44) Heidam LZ, Olsen J. Self-reported data on spontaneous abortions compared with data
obtained by computer linkage with the hospital registry. Scand J Soc Med
1985;13(4):159-63.
(45) Nybo Andersen AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. 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, 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.
(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.
(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
Apr;41(2):405-13.
(49) Kumar S. Occupational, environmental and lifestyle factors associated with spontaneous
abortion. Reprod Sci 2011 Oct;18(10):915-30.
Formatted: Danish
Page 59 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
90x67mm (300 x 300 DPI)
Page 60 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
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 [TM3]: Yes (page 7)
Comment [TM4]: Yes (page 7)
Comment [TM5]: Yes (page 8)
Comment [TM6]: Yes (page 8-10)
Comment [TM7]: Yes (page 8-9)
Comment [TM8]: Yes (page 9-10)
Comment [TM9]: Yes (page 9-10)
Comment [TM10]: Yes (page 11)
Comment [TM11]: Yes (page 11)
Comment [TM12]: Yes (page 11)
Comment [TM13]: Yes (page 11)
Comment [TM14]: Not applicable for current study
Comment [TM15]: Not applicable for current study
Page 61 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from
For peer review only
2
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 [TM16]: Yes (page 12)
Comment [TM17]: Not applicable for current study
Comment [TM18]: Yes (page 12)
Comment [TM19]: Yes (page 12)
Comment [TM20]: Yes (page 12)
Comment [TM21]: Yes (page 12 + Tables 1-3, Figure 1)
Comment [TM22]: Yes (page 13)
Comment [TM23]: Yes (page 15-16)
Comment [TM24]: Yes (page 17)
Comment [TM25]: Yes (page 15)
Comment [TM26]: Yes (page 25)
Page 62 of 62
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on May 28, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2014-005187 on 6 June 2014. D
ownloaded from