implications of psychiatric disorders during pregnancy and...
TRANSCRIPT
UMEÅ UNIVERSITY MEDICAL DISSERTATIONS
New series No 926 ISBN 91-7305-750-9 ISSN 0346-6612
___________________________________________________________________________
From the Department of Clinical Sciences, Obstetrics and Gynecology
Umeå University, Sweden
Implications of Psychiatric Disorders during Pregnancy
and the Postpartum Period
- A Population-based Study
Liselott Andersson
Umeå 2004
Cover picture:
“Depressed” by the author
Copyright © Liselott Andersson
ISBN 91-7305-750-9
Printed by Umeå University, Print & Media, 2004:2000341
Department of Clinical Sciences, Obstetrics and Gynecology
Umeå University
S-90185 Umeå, Sweden
2
The pure and simple truth is rarely pure and never simple.
Oscar Wilde
3
4
ABSTRACT
Background: Depressive and anxiety disorders are common health problems, affecting women
at least twice as often as men. Although some studies have been made on pregnant women or,
especially, in the postpartum period, most of these studies have been performed on small
samples, mainly specific risk groups such as teenage mothers, women of low socioeconomic
status and certain ethnic groups. Also, there is a lack of studies on antenatal and postpartum
depression and/or anxiety using diagnostic criteria adhering to the Diagnostic and Statistical
Manual of Mental disorders, fourth edition (DSM-IV).
Aims and methods: The aims were to estimate the point prevalence of mood, anxiety and eating
disorders, based on DSM-IV criteria, in an unselected population during the second trimester of
pregnancy, and to assess the obstetric and neonatal outcome, as well as the health care
consumption during pregnancy, delivery and the early postpartum period among women with a
psychiatric disorder, compared to healthy subjects. Finally, we aimed to investigate depression
and anxiety, and associated maternal characteristics and events through pregnancy and the
postpartum period in the same group of women. The Primary Care Evaluation of Mental
Disorders (PRIME-MD) was used for assessment of psychiatric disorders during the second
trimester of pregnancy and three to six months after delivery. From October 2nd, 2000, to
October 1st, 2001 all women attending the second trimester routine ultrasound-screening at two
different hospitals in northern Sweden (at Umeå University Hospital and at Sunderby Central
Hospital) were approached for participation in the study. After delivery, data were extracted from
the medical records of the mothers and their offspring to evaluate obstetric and neonatal
outcome. Three to six months after delivery, the women who had an antenatal depression and/or
anxiety were contacted for an assessment using the PRIME-MD. The same procedure was made
in a control group, consisting of 500 women, randomly selected among those who did not have
any psychiatric diagnosis according to the PRIME-MD investigation during the second trimester
of pregnancy.
Results and conclusions: Of the 1555 women in the study population, 220 (14.1%) had one or
more PRIME-MD diagnoses. Living single, low socioeconomic status, smoking, multiparity and a
body mass index of 30 or more were significantly associated with a psychiatric diagnosis in the
second trimester of pregnancy. Women with antenatal depression and/or anxiety more often
suffered from nausea and vomiting during pregnancy, were more often on sick leave, and they
5
visited their obstetrician more often than healthy subjects, specifically because of fear of
childbirth and premature contractions. Also, they were more commonly delivered by elective
caesarean section, had an increased use of epidural analgesia and reported a longer self-
experienced duration of labor. Severe complications of pregnancy, delivery, and the early
postpartum period were not affected by antenatal depression and/or anxiety.
There was no significant difference in neonatal outcome depending on antenatal depressive or
anxiety disorder. Fewer cases of depressive and/or anxiety disorders were prevalent postpartum,
but there was a significant shift from a majority of sub-threshold diagnoses during pregnancy to
full DSM-IV diagnoses during the postpartum period. Previous psychiatric disorder and living
singly were significantly associated with both a new-onset and a postpartum
continuation/recurrence of depression and/or anxiety. Postpartum continuation/recurrence of a
psychiatric disorder was additionally associated with smoking, obesity, and adverse obstetric
events.
Key words: anxiety, depression, neonatal, obstetric, population-based, postpartum, pregnancy.
6
SVENSK SAMMANFATTNING
Depression och ångest är vanligt hos kvinnor, särskilt under de fertila åren. Få studier är
populationsbaserade och/eller baserade på DSM-IV (Diagnostic and Statistical Manual of Mental
disorders, fourth edition) kriterier för depression och ångesttillstånd.
Syftet med studien var: (1) att bestämma punktprevalensen av depression, ångest och ätstörning i
en oselekterad gravid population med hjälp av ett DSM-IV baserat instrument; (2) att undersöka
hur depression och ångest under graviditet påverkar obstetriskt utfall inklusive
sjukvårdskonsumtion; (3) att ta reda på om neonatalt utfall påverkas av psykiatrisk ohälsa under
graviditet; (4) att undersöka samband mellan depression och ångest under graviditet och
postpartum liksom att utforska vilka faktorer hos kvinnan som är associerade till dessa tillstånd.
Primary Care Evaluation of Mental Disorders (PRIME-MD) användes för diagnostik av psykisk
ohälsa under andra trimestern och tre till sex månader efter förlossningen. Samtliga kvinnor som
kom för ultraljudsscreening på specialistmödravårdsmottagningarna vid Umeå
Universitetssjukhus och Sunderby sjukhus under perioden 2000-10-02 – 2001-10-01 inbjöds att
delta i studien. För att undersöka obstetriskt och neonatalt utfall analyserades data ur
mödrahälsovårds- och förlossningsjournalerna efter att kvinnorna hade fött sina barn. De
kvinnor som hade en psykiatrisk diagnos under andra trimestern kontaktades tre till sex månader
efter förlossningen för utvärdering med hjälp av PRIME-MD. En likadan utvärdering gjordes i
en kontrollgrupp som bestod av 500 slumpmässigt utvalda kvinnor utan någon psykiatrisk
diagnos under andra trimestern.
Studiepopulationen kom att bestå av 1555 kvinnor varav 220 (14.1%) hade en eller flera
psykiatriska diagnoser. Maternella faktorer associerade till psykisk ohälsa under graviditet visade
sig vara civilstånd i form av att vara ensamstående, lågt socioekonomiskt status, rökning, att ha
fött ett eller flera barn och fetma (body mass index 30 eller mera). De kvinnor som hade
depression och/eller ångest under graviditeten led oftare av graviditetsillamående, var i högre
utsträckning sjukskrivna och sökte oftare på specialistmödravårdsmottagningarna, speciellt på
grund av förlossningsrädsla och livmodersammandragningar. De blev oftare förlösta med
planerat kejsarsnitt, hade oftare epiduralbedövning och upplevde ett längre värkarbete. Det fanns
inga statistiskt signifikanta samband mellan psykiatrisk ohälsa under andra trimestern och
allvarliga somatiska komplikationer under graviditet, förlossning eller postpartum. Neonatalt
utfall påverkades inte av depression och ångest under graviditeten. Färre kvinnor fick en
7
psykiatrisk diagnos postpartum men diagnoserna var tyngre än under graviditeten. Både
nyinsjuknande och fortsatt/återinsjuknande i depression och ångest postpartum hade signifikanta
samband med civilstånd (ensamstående) och tidigare psykiatrisk sjukdom. Förekomst av
depression och ångest både under graviditet och postpartum hade dessutom samband med
rökning, fetma och fler negativa obstetriska händelser.
8
CONTENTS
Abstract 5
Svensk sammanfattning 7
Abbreviations 11
Original papers 12
Introduction 13
Depression in women 13
Anxiety in women 14
Somatic symptoms and somatoforms disorders in women 15
Etiology of depression and anxiety in women 16
Sex hormones 16
Neuroactive steroids 18
Predisposing factors 20
Depression and anxiety during pregnancy and postpartum 20
Consequences of depression and anxiety 22
Obstetric outcome 22
Neonatal and child outcome 23
Postpartum depression 23
Diagnostic considerations 24
Treatment considerations 25
Non-pharmacological treatment 25
SSRI 25
Tricyclic antidepressant medication and ECT 26
Hormone therapy 26
Aims 28
Subjects and methods 29
Subjects 29
Methods 30
PRIME-MD 30
Prevalence of psychiatric disorders 31
Obstetric and neonatal outcome 32
9
Depression and anxiety through pregnancy and postpartum 33
Statistical analyses 34
Results 35
Prevalence of psychiatric disorders 35
Obstetric outcome 37
Neonatal outcome 42
Depression and anxiety through pregnancy and postpartum 44
Discussion 47
Methodological considerations 47
Ethical considerations 49
Prevalence of psychiatric disorders 49
Obstetric outcome 51
Neonatal outcome 53
Depression and anxiety through pregnancy and postpartum 56
Future perspective 58
Conclusions 9
Acknowledgements 60
References 62
Appendix 72
10
5
ABBREVIATIONS
BMI body mass index
CEG clinician evaluation guide
CES-D Center for Epidemiologic Studies Depression
DSM-IV Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
ECT electroconvulsive therapy
EPDS Edinburgh Postnatal Depression Scale
GABA gamma aminobutyric acid
NOS not otherwise specified
OCD obsessive-compulsive disorder
PPD postpartum depression
PRIME-MD Primary Care Evaluation of Mental Disorders
PQ patient questionnaire
SPSS Statistical Package for the Social Sciences
SSRI selective serotonin reuptake inhibitor
11
ORIGINAL PAPERS
This thesis is based on the following papers, which will be referred to in the text by their Roman
numerals.
I Andersson L, Sundström-Poromaa I, Wulff M, Åström M, Bixo M. Point Prevalence of
Psychiatric Disorders during the Second Trimester of Pregnancy – A Population-based Study. American
Journal of Obstetrics and Gynecology 2003; 189: 148-154.
II Andersson L, Sundström-Poromaa I, Wulff M, Åström M, Bixo M. Neonatal Outcome
following Maternal Antenatal Depression and Anxiety – A Population-based Study. American
Journal of Epidemiology 2004; 159: 872-881.
III Andersson L, Sundström-Poromaa I, Wulff M, Åström M, Bixo M. Implications of Antenatal
Depression and Anxiety for Obstetric Outcome. Obstetrics and Gynecology 2004; 104: 467-476.
IV Andersson L, Sundström-Poromaa I, Wulff M, Åström M, Bixo M. Depression and Anxiety
through Pregnancy and the Postpartum Period – A Population-based Study. Submitted.
Papers I - III are reproduced with the permission of the copyright holders.
12
INTRODUCTION
Depression in women
Major depression is a common health problem, affecting women at least twice as often as men
(Brown 2001; Nolen-Hoeksema 1987; Weissman et al. 1993). Furthermore, The World Health
Organization’s Global Burden of Disease Study has estimated major depression to be the leading
cause of disease-related disability among women in the world today (Murray and Lopez 1997).
According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-
IV) (American Psychiatric Association, 1994), major depressive disorder is a period of at least
two weeks, during which there is either depressed mood or loss of interest in nearly all activities.
Additionally, four out of eight stated symptoms have to be fulfilled. These symptoms are: (1)
marked diminished interest or pleasure in all, or almost all, activities, (2) significant weight loss or
weight gain, or decrease or increase in appetite, (3) insomnia or hypersomnia, (4) psychomotor
agitation or retardation, (5) fatigue or loss of energy, (6) feelings of worthlessness or excessive or
inappropriate guilt, (7) diminished ability to think or concentrate, or indecisiveness, (8) recurrent
thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a
specific plan for committing suicide. Moreover, all but the last symptom have to be present
nearly every day (appendix 1). The lifetime prevalence of major depression among women is 14-
21% (Kessler et al. 1993; Wittchen et al. 1992), with point prevalence estimated to be 1.4-3.5% in
Sweden (Hagnell et al. 1994), and the majority has their first onset in reproductive age (Weissman
et al. 1993).
Women are also more likely than men to suffer from atypical depression, associated with
increased distress, suicidal ideation, and disability, compared with typical depression (Matza et al.
2003). This mood disorder is, according to DSM-IV, a depression with atypical symptoms such
as hyperphagia, hypersomnia, leaden paralysis and rejection sensitivity. Also, seasonal affective
disorder is more common in women than in men (Magnusson and Boivin 2003). The symptoms
are roughly the same as in atypical depression and occurs most commonly in winter, prevalent in
4.3% to 10%, with a female-to-male ratio of 6.3 to 1 (Brown 2001).
13
Dysthymic disorder is characterized by chronic depression, but with less severity than a major
depression. The essential symptom for dysthymic disorder is an almost daily depressed mood for
appetite disturbances and low self-esteem are usually part of the clinical picture as well (appendix
1). Chronic depression, that is a major depression superimposed on dysthymia, appears to affect
women more seriously than men, as manifested by an earlier age of onset, greater family history
of affective disorders, greater symptom reporting, poorer social adjustment, and poorer quality of
life (Kornstein et al. 2000).
Minor depression is also more common in women than men, characterized by mood and
cognitive symptoms rather than neurovegetative symptoms (Rapaport et al. 2002). Although
minor depression has fewer symptoms than required for a specific DSM-IV diagnosis, this
disorder is associated with considerable impairment in function, in terms of more health care
consumption and more days of sick leave (Lepine et al. 1997; Rapaport et al. 2002). Furthermore,
recent data suggest that minor depression is not evanescent, as earlier believed, and that
depressive disorders should be regarded as a continuum of severity (Rapaport et al. 2002).
Anxiety in women
Anxiety disorders such as generalized anxiety, panic disorder, obsessive-compulsive disorder
(OCD), and social phobia are encountered at least twice as often in women than in men (Brown
2001; Steiner 1992), and the lifetime prevalence for anxiety disorders in women is approximately
31% (Cloitre et al. 2004). Also, associated anxiety disorders are known to be frequent in
depressed individuals (Breslau et al. 1995; Wilhelm et al. 1997).
Generalized anxiety disorder is characterized by anxiety and worry experienced most of the time
for at least six months (appendix 1). The lifetime prevalence rate is nearly 7% in women versus
approximately 4% in men (Brown 2001). Affected individuals find it hard to control the worry
concentrating, irritability, muscle tension, and difficulty in sleeping (appendix 1).
Panic disorder is characterized by unexpected attacks of panic and at least one attack should be
followed by one (or more) of following symptoms for at least one month: persistent concern
14
at least two years, but without the necessary criteria for a major depression. Low energy, sleep or
and at least three of the following symptoms are present: restlessness, fatigue, difficulty in
about having subsequent attacks, worry about the implications of the attack (for example, going
crazy), or a change in behavior related to the attacks (appendix 1). Lifetime prevalence is
approximately 2% in men versus 5% in women (Brown 2001). Patients with panic disorder are
five times as likely to rate their physical health as poor, twice as likely to have a general medical
visit, and 30 times more likely to use an emergency room than are healthy people (Brown 2001).
OCD is found in approximately 3% of women and 2% of men (lifetime prevalence) (Brown
2001). The symptoms include obsessions or compulsions that are excessive and unreasonable and
that lead to marked distress and functional impairment (appendix 1). Obsessions are recurrent
thoughts or images that are intrusive and inappropriate and are not simply about real-life
problems. Compulsions are repetitive behaviors (hand washing or checking) that an individual is
driven to repeat to decrease anxiety. The age of onset is earlier than in many of the other anxiety
disorders, and the disorder is frequently noted in children (Brown 2001).
Social phobia is a persistent fear of one or more situations that may lead to embarrassing scrutiny
by others, such as speaking, eating, or writing in front of other people (appendix 1), with lifetime
prevalence approximately 16% in women versus 7% in men (Brown 2001). The disorder is not
only associated with depression, but also with high rates of suicide and alcohol abuse, the latter
regarded as an attempt to self-medicate.
Somatic symptoms and somatoform disorders in women
Both depressive and anxiety disorders are strongly associated with increased reporting of somatic
symptoms, more in women than in men (Bixo et al. 2001; Kroenke and Spitzer 1998). The
tendency to emphasize somatic complaints contributes to failed recognition of depressive and
anxiety disorders by physicians (Brown 2001). Among physical symptoms frequently reported by
women in primary care are dizziness, headache, fatigue, joint and limb pain, palpitations, back
pain, and bowel complaints (Kroenke and Spitzer 1998).
Somatoform disorders are more frequent in women than men and are often hard to diagnose,
resulting in misapplied medical treatment (Snyder and Strain 1989). The somatization disorder is
defined by DSM-IV as a history of somatic complaints beginning before age 30 years and
occurring during several years, resulting in treatment being sought or impairment in social,
15
occupational or other important areas of functioning. Also, eight specified somatic symptoms
have to be fulfilled (American Psychiatric Association, 1994). Furthermore, co-morbid depressive
and anxiety disorders are often present (Leibbrand et al. 1999).
Etiology of depression and anxiety in women
Sex hormones
It has been suggested that sex hormones are involved in the onset of depression and anxiety.
Surveys of depression among children and adolescents show that the gender differences first
emerge in the age range 11 – 14 years (Angold et al. 1998). Also, other experiences related to
changes in sex hormone levels have been noted to be associated with depression. Examples of
such experiences are: use of oral contraceptives (Cullberg 1972), the premenstrual phase
(Yonkers 1997), pregnancy and the postpartum period (Buckwalter et al. 1999), perimenopause
(Bosworth et al. 2001; Freeman et al. 2004), and use of hormone replacement therapy (Zweifel
and O'Brien 1997).
Steiner and colleagues, in their review of hormones and mood, found that during puberty, the
sudden appearance of higher estrogen levels might alter the sensitivity of different
neurotransmitter systems (Steiner et al. 2003). Also, higher levels of testosterone and cortisol, and
lower levels of dehydroepiandrosterone sulphate were associated with negative affect in female
adolescents. A possible mechanism suggested is that altered distribution or function of serotonin
receptor subtypes brought on by hormonal changes at menarche may increase vulnerability to
mood disorders (Steiner et al. 2003).
The current consensus on premenstrual dysphoric disorder is that affected women may be
behaviorally or biochemically sub- or supersensitive to biological challenges of the serotonergic
and GABAergic systems. During pregnancy and delivery, dramatic changes in estrogen and
progesterone levels are seen, together with a postpartum significant suppression of the
hypothalamic-pituitary-adrenal axis. Most likely, an abnormal reaction to some of those changes
rather than the changes themselves is responsible for postpartum depression (Steiner et al. 2003).
Finally, the loss of modulating effects of estrogen and progesterone due to declining levels of
these hormones during menopause is one possible explanation for the development of
perimenopausal mood disorders in vulnerable women.
16
STRESS
CRH
ACTH
Glucocorticoidhormones
Adrenal cortex
Anterior pituitary
Hypothalamus
Brain
Figure 1. The hypothalamic-pituitary-adrenal axis.
More recent research has found associations between polycystic ovarian syndrome and mood
disorders (Rasgon et al. 2003; Weiner et al. 2004). Androgens have been suggested to be a part of
the mechanisms of depression development. Also, elevated body mass index (BMI) and insulin
resistance seem to be associated with depression. Furthermore, severe obesity per se has been
associated with depression (Dong et al. 2004; Onyike et al. 2003).
© Hilary B. Price. Reprinted with special permission of King Features Syndicate.
17
The influence of sex hormones on the development of depressive disorders has been questioned.
Systematic reviews have failed to show that rates of major depression are associated with
reproductive events other than the postpartum period (Gotlib et al. 1989; Steiner et al. 2003;
Wisner et al. 1993). Also, the puberty-related gender difference in depression was found not to be
constant across all race-ethnics groups in the US (Hayward et al. 1999). Furthermore, recent data
have shown that climacteric symptoms, rather than menopause per se, seem to be associated with
depression (Avis et al. 2001; Bosworth et al. 2001).
The causality for development of anxiety disorders has been less investigated than for depressive
disorders. A recent review found that generalized anxiety disorder seems to precede co-morbid
major depression and other anxiety disorders (Kessler et al. 2001). Supporting results were
obtained in a study of young male and female adults, where anxiety seemed to precede major
depression independent of gender, suggesting that women’s higher rates of anxiety disorders
might play a role in their higher risk of depression (Breslau et al. 1998).
Neuroactive steroids
The classical mechanism for the effects of estradiol and progesterone is receptor binding with
subsequent gene transcription and protein synthesis. These hormone receptors are uniquely
distributed in certain areas in the brain such as: the amygdala, hippocampus, basal forebrain,
cortex, cerebellum, locus ceruleus, midbrain raphe nuclei, pituitary gland and hypothalamus
(McEwen 1988; Stomati et al. 1998). The amygdala and hippocampus are members of the limbic
system, which, together with the hypothalamus is involved with feeding, sexual behavior, fear,
emotions, and motivation. Estradiol is excitatory and seems to increase brain excitability via the
glutamate system. Furthermore, the ovarian hormones also influence the functions of several
other transmitter systems, for example the serotonin system.
Besides the classic mechanism, certain progesterone metabolites such as allopregnanolone,
pregnanolone and tetra-hydro-des-oxycorticosterone are known as potent gamma aminobyturic
acid (GABA) steroids, acting more directly in modulating the GABA effects (Backstrom et al.
2003). The metabolites mentioned above are examples of neurosteriods, the name referring to
the nervous system, where they are synthesized (Baulieu 1991). Changes in plasma concentration
of estradiol, progesterone, and allopregnanolone are reflected in the brain (Bixo et al. 1997).
Allopregnanolone plasma levels are highly correlated with progesterone plasma levels, and it is
conceivable that the corpus luteum is the primary major source for progesterone metabolites in
18
fertile women. During the third trimester of pregnancy, plasma levels of allopregnanolone and
pregnanolone are about 100 nM (Paul and Purdy 1992), a level causing sedation in non-pregnant
women (Sundstrom et al. 1999).
Figure 2. The limbic system.
Allopregnanolone effects are similar to those of benzodiazepines, barbiturates and alcohol. These
effects can be characterized as: (1) symptoms induced via direct effects on GABAA receptor
function; (2) effects via indirect changes in the function of the GABAA receptor, and/or
induction of tolerance; and, (3) effects or symptoms caused by allopregnanolone abstinence. The
direct effects on mood and behavior are most likely biphasic. In high doses, allopregnanolone
and pregnanolone are sedative, hypnotic and anesthetic (Paul and Purdy 1992). Furthermore, in
animal studies these steroid metabolites have shown anxiolytic and antiepileptic effects (Gasior et
al. 1997). Additionally, negative effects such as impaired learning and memory, increasing
appetite, disturbed motor function, worsening of petit-mal epilepsy and, in very high doses, an
abuse-potential effect have been noted. In low doses, such as in physiologic situations,
allopregnanolone induces loss of impulse control, negative mood and aggression/irritability in
certain individuals (Backstrom et al. 2003). Tolerance occurs after continuous and long exposure
to benzodiazepines and GABA steroids. This phenomenon has been found to reinforce drug
dependency. Supporting findings are that women with premenstrual dysphoric disorder have
increased alcohol consumption during the luteal phase as well as increased risk for alcohol abuse
19
(Charette et al. 1990; McLeod et al. 1994). Withdrawal or abstinence symptoms often occur after
continuous exposure to GABAA agonists (Smith et al. 1998). Examples of such symptoms are
sleep disturbance, irritability, increased tension and anxiety, panic attacks, hand tremor,
clumsiness, sweating, concentration difficulties, increased stress sensitivity, loss of impulse
control, nausea, palpitations, headache, muscular pain and stiffness (Backstrom et al. 2003). Also,
more serious symptoms such as seizures, depression, and psychotic reactions have been noted
(Petursson 1994). In conclusion, effects of GABAA agonists on the CNS might to a great degree
explain the mechanisms for development of mood and anxiety disorders in women.
Predisposing factors
Since hormonal changes occur in all women, one might expect that genetic predisposition also is
required for the development of mood disorders (Steiner et al. 2003), and supporting results are
shown in studies of twins and in studies of women with postpartum depression (Kendler et al.
1999; Steiner et al. 2003). Studies of depression in twins have revealed a 36.2% affection in co-
twin (Kendler et al. 1999). Familial depression seems to be associated with intermediate levels of
recurrence, long duration of episodes, high levels of impairment, and recurrent thoughts of death
or suicide (Kendler et al. 1999). Furthermore, postpartum depressed women’s first-degree
relatives had a much higher lifetime prevalence of mood-related disorders than the population at
large, indicating a potential genetic or familial component (Steiner et al. 2003).
Besides hormonal and genetic factors, psychosocial stress, such as stressful life-events, also seems
to be associated with mood disorders (Kendler et al. 1995). Women appear to be more sensitive
to interpersonal problems in contrast to men, who seem to be more often affected by divorce or
separation and work-related problems (Kendler et al. 2001). However, the greater prevalence of
major depression in women than in men does not seem to depend on differences in the rates of
reported stressful life events or to differential sensitivity to their pathogenic effect (Kendler et al.
2001).
Depression and anxiety during pregnancy and postpartum
Recent studies have suggested depression to be at least as common in pregnant as in non-
pregnant women (Burt and Stein 2002), prevalent in 7.4% - 12.8% of women during pregnancy
(Bennett et al. 2004). In fact, in contrast to previous opinions, depression appears to be more
20
common during pregnancy than postpartum (Evans et al. 2001; Josefsson et al. 2001). During
pregnancy, mood disorders more often seem to be influenced by socio-economic status than
during the postpartum period suggesting different etiological factors (Gotlib et al. 1989). Few
studies on the subject are population-based. Among those that are, is a Swedish study performed
by Josefsson and colleagues (Josefsson et al. 2001). Their study on 1558 women displayed
depressive symptoms to be prevalent in 17% of women during pregnancy compared to 13%
postpartum. Presence of depressive symptoms was measured with the Edinburgh Postnatal
Depression Scale (EPDS). Using the same instrument in a cohort of 13,799 women, Evans and
co-workers found depressive symptoms to be present in 13.5% during late pregnancy compared
to 9.1% eight weeks postpartum (Evans et al. 2001). However, one must not forget that these
studies were made on scored symptoms, not depression as a strictly defined diagnosis.
Studies of preexisting panic disorder indicate a variable impact of pregnancy, either improvement
or status quo, but postpartum worsening seems to be a more consistent phenomenon (Northcott
and Stein 1994). Furthermore, OCD may first appear or be exacerbated during pregnancy or in
the postpartum period (Altshuler et al. 1998; Williams and Koran 1997). Less is known about
eating disorders during pregnancy but bulimia nervosa seems to improve. However, the risk of
postpartum depression seems to be higher among women with eating disorders (Morgan et al.
1999).
Postpartum depression (PPD) is probably the most studied psychiatric disorder associated with
reproduction, with a point prevalence estimated to be 10% in the early weeks after delivery
(Cooper and Murray 1998). According to DSM-IV, PPD is a non-psychotic depression that
begins or extends within the first four weeks after delivery and meets the same criteria as for a
major depression (American Psychiatric Association, 1994). The prevalence rate of depression
postpartum is not considered to be higher than in non-postpartum state (Cox et al. 1993; Harris
1993; O'Hara et al. 1990; Troutman and Cutrona 1990), but it is unique in its timing and in that it
involves at least the mother-baby dyad, and in most cases an entire family unit (Steiner et al.
2003). Similar to the natural course of major depression, the great majority remits spontaneously
within three to six months (Cooper and Murray 1995; Cox et al. 1993). However, postpartum
depressed women have been found to present more anxiety symptoms and take more time and
require higher doses to respond to antidepressant medication, compared with non-pregnant
depressed women (Hendrick et al. 2000). The possibility of screening for PPD has been studied.
For example, postpartum screening was made in a Swedish community-based sample of 1584
21
women. Using the EPDS, point prevalence of depressive symptoms turned out to be 12.5% at
eight weeks and 8.3% at 12 weeks postpartum (Wickberg and Hwang 1997).
Austin and colleagues (Austin and Lumley 2003) have recently investigated the possibility of
antenatal screening for PPD. In their systematic review of sixteen studies, they found that no
screening instrument met the criteria for routine application in the antenatal period. The majority
of the studies in the review had used different rating scales and/or criteria for diagnosing
depression and only five of those studies were population-based. Reasons suggested for failure to
screen for PPD during pregnancy were that the sample sizes were too small, that the screening
instruments were not applied to the populations from which they had been derived, and that risk
factors for PPD were not considered in the screening instruments.
In conclusion, many studies have been performed on depression and anxiety during pregnancy
and, especially, postpartum. A major disadvantage is that few of these studies were population-
based. Furthermore, there is a lack of studies on the subject, where DSM-IV based instruments
have been used for assessment of psychiatric disorders.
Consequences of depression and anxiety
The general consequences of depression are not only impaired quality of life, but also negative
effects on society in terms of increased health care utilization and lost productivity (Lepine et al.
1997). Another well-known and ultimate consequence is excess mortality due to suicide
(Davidson and Meltzer-Brody 1999).
Obstetric outcome
A few studies have investigated the impact of antenatal depression and anxiety on obstetric
outcome. For example, a weak relationship has been found between anxiety and use of
analgesia/anesthesia in the second stage of labor, but no other obstetric complications (Perkin et
al. 1993). Also, in another study, an increased use of epidural analgesia and operative deliveries
was noted in women with antenatal depressive symptoms (Chung et al. 2001). Another, more
odd, finding is the association between depression and anxiety in early pregnancy and
preeclampsia, noted in a recent study (Kurki et al. 2000). Validation and comparison of results
between studies is, however, difficult, as most studies have used different rating scales and/or
22
criteria for diagnosing depression and anxiety. Moreover, very few studies have been performed
in population-based samples.
Neonatal and child outcome
Psychiatric disorders during pregnancy have been associated with deterioration in neonatal
outcome in terms of increased risks for spontaneous premature delivery, low birth weight, and
admission to neonatal care units (Chung et al. 2001; Hoffman and Hatch 2000; Orr et al. 2002).
Moreover, prior studies have found that antenatal maternal stress tend to shorten pregnancy
length (Dole et al. 2003; Sjostrom et al. 1999). The underlying mechanism for causing premature
delivery is suggested to be through activation of the placental-maternal pituitary-adrenal axis
(Hobel et al. 1999). This hypothesis is further supported by a relationship between premature
birth and elevated levels of corticotrophin-releasing hormone in maternal plasma and in placenta
(Ellis et al. 2002; Hobel et al. 1999; McGrath et al. 2002). Nevertheless, associations between
maternal psychiatric disorder and adverse neonatal outcome might be questioned. In conformity
with studies on psychiatric disorders and obstetric outcome, most previous studies have been
performed on small samples, mainly specific risk groups such as teenage mothers, women of low
socioeconomic status, and certain ethnic groups (Miranda et al. 1998; Orr et al. 2002; Piyasil
1998). Also, there is a lack of studies on antenatal depression and/or anxiety using diagnostic
criteria adhering to DSM-IV.
Regarding long-term effects on offspring, associations have been found between antenatal
anxiety and behavioral/emotional problems in children at the age of four years (O'Connor et al.
2002), suggesting adverse long-term effects on children’s development. Furthermore, a Finnish
cohort study of 12059 children found a significant but slight increase in criminality in the male
offspring of mothers depressed during pregnancy (Maki et al. 2003).
Postpartum depression
Prior studies have emphasized the benefits of early identification and treatment of PPD. Adverse
child outcome in terms of impaired cognitive and emotional development on the basis of
disturbed mother-infant interaction is regarded as one major reason (Cooper and Murray 1998).
More adverse perinatal events and more psychiatric disorders (particularly major depression) have
been noted in children with at least one parent having a history of depression (Weissman et al.
1986). Examples of such perinatal events were injuries, accidents, and convulsive disorders. Also,
the offspring of depressed parents have been found to be at high-risk for early onset of major
23
depressive disorder and alcohol dependence in adolescence and early adulthood (Weissman et al.
1997). Moreover, if left untreated, many women still suffer from depression at the end of the first
postpartum year (Stowe and Nemeroff 1995) and women with PPD are also at high risk for
relapse of depression in a future pregnancy (Weissman and Olfson 1995).
In conclusion, prior research on associations between maternal depression and anxiety have
mostly displayed adverse obstetric and neonatal outcome, emphasizing the benefits of diagnosing
and treating those affected women as early as possible.
Diagnostic considerations
It has been estimated that at least 20% of all primary care outpatients suffer from some mental
disorder (Barrett et al. 1988; Schulberg and Burns 1988; Spitzer et al. 1994) and that more
subjects with psychiatric disorders are cared for in primary care than in the mental health sector
(Shapiro et al. 1984). Also, psychiatric disorders have been found to be frequent in gynecological
(Sundstrom et al. 2001) and obstetric-gynecologic outpatient settings (Spitzer et al. 2000),
prevalent in 30.5% and 20% respectively. Unsatisfying, failed recognition of psychiatric disorders
is a general problem in primary care (Schulberg and Burns 1988) and probably also in obstetric-
gynecologic outpatient settings (Spitzer et al. 2000).
A number of instruments have been constructed to ease diagnosis of psychiatric disorders in
outpatient settings, but most of them either focus on a single area of psychopathology, for
example depression or anxiety, or on a more general psychological distress. Among the most
used instruments for assessment of depression are the Beck Depression Inventory (Beck and
Steer 1984), the Edinburgh Postnatal Depression Scale (EPDS) (Cox et al. 1987), and Center for
Epidemiologic Studies Depression (CES-D) Scale (Weissman et al. 1977). Fewer instruments are
present for anxiety diagnosis, but Spielbergers State Trait Anxiety Inventory scale is one of the
most commonly used (Spielberger et al. 1983). An example of instruments for assessment of
psychological distress is the Life Experiences Survey (Sarason et al. 1978). However, these
instruments are mostly based on scales, only suggesting the likelihood of a mental disorder. Even
if likelihood of disease is associated with elevated scores, it is not the same as a clinical diagnosis,
therefore making study results difficult to evaluate when these instruments have been used.
24
In this study, diagnoses of psychiatric disorders were made using the Primary Care Evaluation of
Mental Disorders (PRIME-MD) (Spitzer et al. 1994). The main reasons for choosing this
diagnostic tool were that it conforms to DSM-IV criteria and is easy to use for assessment of
both depression and anxiety in large populations. Further description of PRIME-MD is given in
the methods section.
Treatment considerations
Non-pharmacological treatment
Pharmacological treatment of depression and anxiety during pregnancy is controversial as it
affects both the mother and her unborn child. In order to be sure to avoid potential harmful
medication in the fetus and newborn, one must not forget that different kinds of non-
pharmacological treatments are possible to use during pregnancy and lactation. For example,
psychotherapy has been found effective in PPD (Highet and Drummond 2004; O'Hara et al.
2000; Steinberg and Bellavance 1999), and morning light therapy has provided promising results
in antepartum depressed women (Epperson et al. 2004; Oren et al. 2002).
SSRI
Generally, no major malformations have been detected among offspring to women with antenatal
selective serotonin reuptake inhibitor (SSRI) medication (Kulin et al. 1998; Marcus et al. 2001;
Simon et al. 2002; Spigset and Hagg 2004). On the other hand, more symptoms are reported in
newborns exposed to SSRI preparations during the third trimester of pregnancy. Examples of
such symptoms are irritability, respiratory distress and muscular hypotonia (Spigset and Hagg
2004). Also, a small study of 17 SSRI-exposed and 17 non-exposed newborns showed
significantly more neurobehavioral symptoms among those who were exposed (Zeskind and
Stephens 2004). The excretion in breast milk seems in most cases to be negligible but suspected
adverse effects have been reported in a few infants (Spigset and Hagg 2004). Though there are
few studies of the long-term effects in children, the existing ones do not show adverse effects in
children exposed to SSRI substances in utero (Heikkinen et al. 2002; Heikkinen et al. 2003;
Nulman et al. 1997; Nulman et al. 2002; Simon et al. 2002). In contrast, Nulman and colleagues
found that mothers’ on-going depression per se was associated with less cognitive and language
achievement by their children (Nulman et al. 2002). Although most studies present data,
suggesting SSRI medication to be quite safe during pregnancy and lactation, an individual risk-
25
benefit-assessment should always be carried out before treatment initiation (Spigset and Hagg
2004). When treatment is ongoing or initiated, it might be useful to measure plasma
concentrations in the mother for drug monitoring, in order to avoid both maternal sub
therapeutic dosage and over dosage with more fetal exposure (Heikkinen et al. 2002; Spigset and
Hagg 2004).
A Cochrane review of treatment of postpartum depression showed that women can be effectively
treated with fluoxetine, which was as effective as a full course of cognitive-behavioral counseling
(Hoffbrand et al. 2001). However, as only one study fulfilled the criteria for inclusion (Appleby et
al. 1997), the Cochrane authors concluded that more trials with a longer follow-up period are
needed to compare different antidepressants in the treatment of postpartum depression, and to
compare antidepressant medication with psychosocial interventions.
Tricyclic antidepressant medication and ECT
Tricyclic antidepressants are effective for depression treatment, and, as with SSRIs, no adverse
neonatal or child outcome has been shown (Nulman et al. 1997; Nulman et al. 2002). However,
compared with SSRIs, tricyclics have more negative side effects such as dry mouth, blurred
vision, constipation, dizziness, cardiac symptoms, sedation or agitation, and weight gain.
Furthermore, these agents can be lethal in an overdose (Marcus et al. 2001).
Electroconvulsive therapy (ECT) is regarded effective for treatment of depression, and with
proper medical care, it is considered relatively safe both during pregnancy and the postpartum
period (Rabheru 2001). The mechanisms for effects of ECT on depression are not fully
understood but, similarly to other antidepressant therapies, ECT affects the monoaminergic
systems (Mann 1998; Newman et al. 1998). Furthermore, ECT influences the GABA system and
neuropeptides (Mathe 1999; Sackeim 1999).
Hormone therapy
The effect of hormone therapy on postpartum depression is surprisingly sparsely studied,
considering the widespread use of sex hormones in other situations, such as for contraception
and perimenopausally. A Cochrane review of the subject found only two studies that fulfilled the
criteria for evaluation (Lawrie et al. 2000). One of these studied showed that depot
norethisterone enanthate given within 48 hours after delivery was significantly associated with
higher postpartum depression scores than placebo (Lawrie et al. 1998). In the second study,
26
transdermal estrogen in severely depressed women was associated with a greater improvement in
depression scores than placebo (Gregoire et al. 1996). The Cochrane authors concluded that
there is no place for synthetic progestogens in prevention and treatment of postpartum
depression but that the role of progesterone for therapy has to be evaluated in a randomized
placebo-controlled trial. Estrogen therapy was regarded as having a modest value at a late stage of
postpartum depression.
27
AIMS
The aims of this study were to:
estimate the point prevalence of mood, anxiety and eating disorders, based on DSM-IV
criteria, in an unselected population during the second trimester of pregnancy
assess the obstetric outcome and health care consumption during pregnancy, delivery and
the early postpartum period in an unselected population-based sample of pregnant
women, diagnosed with antenatal depressive and/or anxiety disorders, compared to
healthy subjects
investigate the neonatal outcome in an unselected population-based sample of pregnant
women, diagnosed with antenatal depressive and/or anxiety disorders, compared to
healthy mothers
analyze depression and anxiety, and associated maternal characteristics and events
through pregnancy and the postpartum period
28
SUBJECTS AND METHODS
Subjects
From October 2nd, 2000, to October 1st, 2001 all women attending the second trimester routine
ultrasound-screening at two different hospitals in northern Sweden (at Umeå University Hospital
and at Sunderby Central Hospital) were approached for participation in the study. In Sweden, all
pregnant women are invited to an ultrasound examination at 16-18 weeks of gestation, mainly for
estimation of the delivery date. According to available statistics, approximately 97% of the
Swedish pregnant women participate in this screening program (The Swedish Council of
Technology Assessment in Health Care 1999). At the time-point for the beginning of the study,
Umeå University Hospital served a population of 134,428 people of whom 27,063 were women
of reproductive age. The corresponding figures for Sunderby Central Hospital were 115,600 and
19,277, respectively. There were no other available ultrasound-screening facilities or delivery
departments in these two cities.
Umeå, situated in the county of Västerbotten, is the biggest town in Northern Sweden. It is
characterized by being a university city, with approximately 27,000 students living there during
the academic year. The municipality has 108,153 inhabitants with a mean age of 37 years.
Approximately 4% of the inhabitants have foreign citizenship. During 2001 and 2002, the
number of deliveries at the University Hospital was 1435 and 1433, respectively. Referrals to the
hospital are made from the whole Northern Region in Sweden and the hospital’s neonatal
intensive care unit takes care of extremely premature infants (from 23 completed weeks of
gestation).
Sunderby Central Hospital is situated in Luleå municipality, and serves mainly the inhabitants of
Luleå and Boden, which is the neighboring town. Luleå municipality, situated in the county of
Norrbotten, has 71,139 inhabitants. Luleå town is well-known for its metallurgic industries and
its harbor, which is among the biggest in Sweden. A Technical University is situated in Luleå and
serves approximately 11,000 students. The mean age of all inhabitants is 40 years and about 4%
of them have foreign citizenship. Boden is one of Sweden’s largest and most important military
towns and approximately 28,000 people live in the municipality. During the study period, the
29
delivery department at the neighboring hospital in Kalix closed down, resulting in more deliveries
at Sunderby Central Hospital. The number of deliveries at the Central Hospital was 1220 in 2001,
and 1715 in 2002. Women at risk of premature deliveries and prematurely delivered newborns
from 28 completed weeks of gestation are referred to Sunderby Central Hospital from the rest of
the county of Norrbotten.
Baseline-study exclusion criteria were: (1) detection of malformation or miscarriage during the
ultrasound examination, (2) inability to read and understand the questionnaire because of
language difficulties, (3) not providing informed written consent.
Methods
PRIME-MD
Psychiatric disorders were diagnosed using the PRIME-MD system. The PRIME-MD system
conforms to DSM-IV criteria and has been validated for use in primary care settings. The
agreement between PRIME-MD diagnoses and those of independent mental health professionals
is excellent with a sensitivity of 83%, a specificity of 88%, a positive predictive value of 80% and
an overall accuracy of 88% (Spitzer et al. 1994). Given its utility and ease of use, the instrument
was considered to be a suitable tool for assessing the prevalence of psychiatric disorders in an
obstetric outpatient setting. Furthermore, a self-administered version of PRIME-MD, the
PRIME-MD Patient Health Questionnaire, has been validated for use with obstetric-gynecologic
patients (Spitzer et al. 2000). The instrument, which is fully described elsewhere (Spitzer et al.
1994), consists of two components: a one-page patient questionnaire (PQ) (appendix 2) and a 12-
page clinician evaluation guide (CEG), which is a structured interview for the clinician to follow
when evaluating the responses on the PQ. The original CEG contains modules for mood,
anxiety, eating disorders, alcohol abuse, social phobia, and obsessive-compulsive disorder.
Clinicians administer only those modules that are indicated by the patient on the PQ. The
PRIME-MD system evaluates the presence of 20 possible mental disorders, of which this study
focused on 13 diagnoses. Among these 13 diagnoses of interest, eight correspond to the specific
requirements of DSM-IV (major depressive disorder, dysthymia, partial remission of major
depressive disorder, generalized anxiety disorder, panic disorder, obsessive-compulsive disorder
(OCD), social phobia and bulimia nervosa). An additional four diagnoses are considered to be
“sub-threshold“diagnoses, such as minor depressive disorder, anxiety not otherwise specified
30
(NOS), eating disorder NOS, and binge eating disorder. Sub-threshold diagnoses have fewer
symptoms than required for a specific DSM-IV diagnosis, but are included as they are associated
with considerable impairment in function (Lepine et al. 1997). Finally, a rule-out diagnosis of
bipolar disorder was included. The DSM-IV criteria for major depression, dysthymia, generalized
anxiety disorder, panic disorder, OCD, and social phobia are specified in appendix 1.
Prevalence of psychiatric disorders
A modified form of the PQ was used for this study (appendix 3), containing 25 questions
evaluating somatoform disorder, mood disorders, anxiety disorders (including social phobia and
OCD), and eating disorders. Somatoform disorders and alcohol abuse were not assessed. Before
attending the ultrasound examination, the women completed the PQ. In order to pursue a
diagnosis, a telephone interview, using a computerized version of the CEG was conducted with
the screen-positive women. Along with the PQ, the women were asked to provide name, date of
birth, and telephone number. Furthermore, they were asked to sign an informed consent allowing
for a telephone interview. The women were considered to be screen-positive if any key question
for mental disorders was indicated. As mentioned above, the questions in the PQ concerning
somatoform disorders were not followed up in the interview. The reason for this is that pregnant
women normally have a lot of physical symptoms related to the pregnancy, which makes it more
difficult to diagnose somatoform disorders.
© Hilary B. Price. Reprinted with special permission of King Features Syndicate.
The telephone interview with the screen-positive women was made within one to two weeks after
the visit. At the time of the telephone interview, the interviewer had no knowledge of the
woman’s psychiatric and medical history including problems concerning the actual pregnancy. In
case of a PRIME-MD diagnosis, the woman was asked about current antidepressant drug therapy
and/or psychotherapy. Those who were asking for help and/or had thoughts about committing
suicide were immediately referred to psychiatric specialist care. One research nurse and four
31
obstetricians performed the telephone interviews. All had participated in a training session with
PRIME-MD instructors and a psychiatrist prior to the study and one of the obstetricians had
prior experience with the instrument.
Obstetric and neonatal outcome
After delivery, data were extracted from the medical records of the mothers and their offspring.
Only complete medical records were assessed and, furthermore, stillbirths and multiples were
excluded in the neonatal analyses. Investigated maternal sociodemographic and medical
characteristics were age, parity, BMI at the first trimester, marital status, socioeconomic status
(appendix 4), smoking and tobacco habits, alcohol consumption, and prevalence of chronic
disease. Chronic diseases were considered to be prevalent when a history of heart disease,
diabetes mellitus, hypertension or renal disease was recorded at the first antenatal visit. Data on
previous psychiatric disorder were extracted from the medical records of the mothers.
Data on previous miscarriage and infertility treatment in the actual pregnancy were assessed.
Pregnancy data obtained from the medical charts included number of midwife visits, nausea and
vomiting (defined as doctors visits and/or disability days because of nausea and vomiting),
incidence of sick leave during the first trimester, total amount of sick leave before 36 weeks of
gestation, number of ultrasound examinations, total number of visits to the obstetrician and
specific visits for amniocentesis or chorion villi sampling, pain, fear of childbirth, and premature
contractions. Pregnancy complications assessed were hypertensive disorder including
preeclampsia, prolonged pregnancy, oligohydramnion, third trimester bleeding (including
placenta previa and abruption placenta), intrauterine growth restriction, fetal hypoxia, and
premature delivery.
Delivery data were obtained on induced labor, elective or acute caesarean delivery, instrumental
delivery, use of oxytocin and epidural analgesia during labor, time from self-experienced start of
labor to delivery, and time from arrival in the delivery unit to delivery. Data on poor progress in
labor, postpartum bleeding, fetal distress and rupture of the anal sphincter were recorded for
assessment of delivery complications. Finally, data were recorded on early postpartum
complications such as postpartum infection, postpartum re-admission, mastitis, other postpartum
complications and duration of stay at the maternity ward.
32
The study population and the group of eligible but not included women were compared
regarding age, parity, marital status, socioeconomic status, smoking, snuff taking, and history of
psychiatric disorder. Also, comparison regarding overall premature delivery was made between
these groups. Hospital-to-hospital variation was evaluated regarding the distribution of PRIME-
MD diagnoses.
Neonatal data regarding length, weight, pH and base deficit in the umbilical artery blood, Apgar
score at one and five minutes, neonatal intensive care, and the most common pediatric diagnoses
were recorded from the pediatric medical charts. The diagnoses recorded for the study were
overall premature birth, spontaneous premature birth, small-for-gestational-age birth, respiratory
distress, asphyxia, and malformation.
Depression and anxiety through pregnancy and postpartum
The postpartum selected group of women followed-up consisted of 720 subjects, recruited the
following way: The women who had an antenatal depressive and/or anxiety diagnosis (n = 220)
were contacted for a telephone interview three to six months after delivery. If an oral informed
consent was given, the PQ was used for screening immediately. In cases where the woman was
screen-positive, the interview proceeded using the computerized version of the CEG. The same
procedure was made in a control group, consisting of 500 women, randomly selected among
those who did not have any psychiatric diagnosis according to the PRIME-MD investigation
during the second trimester of pregnancy. Of these, 250 women had been screen-negative and
250 women had been screen-positive, according to the second trimester PQ. An oral informed
consent was obtained before starting the telephone interview. If the woman received a depression
and/or anxiety diagnosis at the postpartum assessment, help was offered for treatment of her
psychiatric condition. On-going psychiatric treatment was noted for all interviewed women. The
presence of a psychiatric diagnosis both during pregnancy and postpartum was regarded as a
postpartum continuation/recurrence of disorder. If the woman received a depression and/or
anxiety diagnosis only at the postpartum assessment, the disorder was considered as a new
development.
33
STATISTICAL ANALYSES
Continuous variables were compared using the t-test, and are displayed as mean standard
deviation. Frequencies were compared between groups by Chi-square test and Fisher’s exact test.
The statistical analyses were performed using Statistical Package for the Social Sciences (SPSS)
for Windows, version 10.0 or 12.0 (SPSS Inc, Chicago, IL). A two-sided p value less than 0.05
was considered significant. Maternal and neonatal variables were generally dichotomized.
Adjusted odds ratios for all variables regarding neonatal and obstetric outcome were computed
using a multiple logistic regression model, which included maternal factors and mediators,
associated with a psychiatric diagnosis. Regarding neonatal outcome, the study was designed to
detect an increase in the rate of overall premature births from 6.0 percent to 12.0 percent in
women with depressive and/or anxiety disorders compared to controls, with an alpha coefficient
of 0.05 and a beta coefficient of 0.20. The prevalence of psychiatric disorders before and after
delivery was compared using McNemar test. For estimation of odds ratios, psychiatric disorders
were categorized according to the presence of any PRIME-MD diagnosis, minor depressive
disorder, DSM-IV defined depression (major depressive disorder, dysthymia and partial
remission of major depressive disorder) and anxiety disorder (anxiety NOS, generalized anxiety
disorder, panic disorder, OCD and social phobia).
34
RESULTS
Prevalence of psychiatric disorders (Paper I)
During the inclusion period, 2263 women were examined by ultrasound-screening (figure 3).
After exclusion for refusal to participate (10 women), language difficulties (82 women), too
intense patient flow (362 women) and other reasons (14 women), 1795 women received the PQ.
Sixty-four women did not answer the questionnaire and 105 women did not sign the informed
consent. Furthermore, 22 women were excluded due to missed abortion or malformation and 49
women were not reached within the stipulated 14 days. Thus, the response rate was 90.2 percent.
Among women not consenting to a telephone interview, the prevalence of screen-positive
subjects (n = 62, 59.0%) was higher than in the study population. The mean age of the study
population was 29.4 4.6 years, whereas excluded women were significantly older, 30.2 5.3
years, p < 0.005. Pronounced fear of childbirth was noted in 390 (25.1%) women, 1149 (73.8%)
did not display any fear and 17 (1.1%) women did not answer this question.
Of the 1555 women in the study population, 220 (14.1%) had one or more PRIME-MD
diagnoses. The distribution of the psychiatric disorders detected by PRIME-MD in the total
sample is summarized in table 1. Overall, major depressive disorder was present in 52 (3.3%) of
the women and additionally 107 (6.9 %) had a minor depressive disorder. The most common
psychiatric symptom was fatigue or loss of energy, which was found in 88.7 % of depressed
women. Between the two key symptoms for major depression, the pregnant women in the study
more often complained of diminished interest in daily activities (82.4% of depressed women)
than of depressed mood (44.7 % of depressed women).
Anxiety disorders were present in 102 (6.6%) of the women and anxiety NOS was most
common, found in 69 (4.4%). OCD was diagnosed in 20 (1.3%) women, social phobia in six
(0.4%) and eating disorders in three (0.2%). Pronounced fear of the approaching childbirth was
significantly more common in the women with psychiatric diagnoses than those without,
prevalent in 44.5% and 22.1%, respectively, p < 0.005.
35
Exc
lud
edn
= 4
6 8
No
t co
mp
lete
d q
ue
stio
nna
ireo
r in
form
ed
co
nse
ntn
= 2
18
Exc
lud
ed
du
e to
mis
carr
iage
or
mal
form
atio
nn
= 2
2
Psy
chia
tric
dia
gn
osi
sn
= 2
20
Lo
st f
or
follo
w u
pn
= 6
6E
xclu
ded
n =
4
Inte
rvie
wed
n =
650
Te
lep
ho
ne in
terv
iew
po
stpa
rtum
n =
720
Ra
ndo
m s
amp
len
= 2
50
No
dia
gno
sis
and
no
t se
lect
edn
= 2
96
Scr
een
-pos
itive
n =
766
Ra
ndo
m s
amp
len
= 2
50
No
t se
lect
edn
= 5
39
Scr
een
-ne
gativ
en
= 7
89
Co
mp
lete
d q
ue
stio
nna
irea
nd
info
rme
d c
on
sent
n =
15
55
Re
cie v
ed
qu
e stio
n na
iren
= 1
795
Exa
min
e d w
ith u
ltra
sou
n dn
= 2
263
Fi
gure
3. F
low
char
t
36
.
Table 1. Prevalence of psychiatric disorders detected by PRIME-MD.
Mental disorder Total sample
n = 1555
Any psychiatric diagnosis 220 (14.1%)
Any mood disorder 181 (11.6%)
Major depressive disorder 52 (3.3 %)
Dysthymia 10 (0.6%)
Partial remission of major depressive disorder 11 (0.7%)
Minor depressive disorder 107 (6.9%)
Bipolar disorder 1
Any anxiety disorder 102 (6.6%)
Anxiety NOS 69 (4.4%)
Generalized anxiety disorder 4 (0.3%)
Panic disorder 3 (0.2%)
Obsessive-compulsive disorder 20 (1.3%)
Social phobia 6 (0.4%)
Eating disorder 3 (0.2%)
Co-morbidity was often encountered. Of the 220 women with a psychiatric diagnosis, 53 (24.1%)
had two or more diagnoses, 11 (5.0%) women had three or more diagnoses and one woman had
five diagnoses. Very few of the women who received a PRIME-MD diagnosis during the study
course had treatment for their psychiatric condition at the time point for assessment; 208 (94.5%)
of the women received no treatment for their mental disorder, 11 (5.0%) received some form of
psychotherapy, and one had been prescribed antidepressant treatment. Physical symptoms were
significantly more common in the women with some form of psychiatric diagnosis than in
women without a diagnosis. This was, however, not true regarding pelvic pain and sexual
problems.
Obstetric outcome (Paper II)
Incomplete medical records were present in 60 women, thus leaving 1495 women, of whom 211
(14.1%) had one or more psychiatric diagnoses. A total number of 11 (5.2%) of the women with
37
a diagnosis had some sort of treatment for their psychiatric condition. Only one of them used
any antidepressant therapy at the time for second trimester ultrasound-screening. One additional
woman was prescribed antidepressant therapy later in pregnancy. In both these cases the drug
was an SSRI preparation. None of the women without any psychiatric diagnosis were noted to use
psychoactive medication. Regarding sociodemographic and medical characteristics, comparisons
between the study group and the group of women not included in the study are given in table 2.
The distribution of psychiatric disorders did not differ between hospitals.
Maternal factors associated with depressive and/or anxiety disorders were used in the
multivariate analyses of obstetric outcome. Single living, low socioeconomic status, smoking,
multiparity and BMI more than 30 kg/m2 were significantly and independently associated with
the presence of a diagnosis of depression and/or anxiety in the second trimester of pregnancy
(table 3).
Women with an antenatal depressive and/or anxiety disorder more often suffered from nausea
and vomiting (table 4). They more often had their first sick leave already during the first trimester
and they had a significantly higher number of disability days throughout the entire pregnancy
compared to the group without a diagnosis (table 4). Moreover, women with an antenatal
psychiatric diagnosis visited their obstetrician more often than healthy subjects and, specifically,
they more frequently attended the obstetrics-gynecology clinic because of fear of childbirth and
premature contractions (table 4). Also, they were more commonly delivered by elective caesarean
section, had an increased use of epidural analgesia and reported a longer self-experienced time of
labor (table 5). Severe complications of pregnancy, delivery and the early postpartum period were
not affected by antenatal depression and/or anxiety.
38
Table 2. Selected demographic, behavioral and medical characteristics associated with the presence of anantenatal psychiatric diagnosis.Variable Psychiatric
diagnosis(n = 211†)
Nopsychiatricdiagnosis(n = 1284†)
Oddsratio
95%Confidenceinterval
Age 19 years or less 4 (1.9%) 15 (1.2%) 1.78 0.58, 5.48 20-29 years 93 (44.1%) 621 (48.4%) Referent30-39 111 (52.6%) 631 (49.1%) 1.18 0.87, 1.58 40 years or more 3 (1.4%) 17 (1.3%) 1.18 0.34, 4.10
Marital status*** Married or cohabiting 193 (91.5%) 1240 (97.4%) ReferentSingle living 18 (8.5%) 33 (2.6%) 3.50 1.94, 6.35
Socioeconomic* Professional employee 63 (29.9%) 512 (40.4%) Referentstatus Laborer 148 (70.1%) 755 (59.6%) 1.59 1.16, 2.18
Smoking*** Non-smoker 182 (86.7%) 1192 (93.9%) ReferentSmoker 28 (13.3% 78 (6.1%) 2.35 1.49, 3.72
Snuff taking Not snuff-taker 198 (94.3%) 1194 (94.0%) ReferentSnuff-taker 12 (5.7%) 76 (6.0%) 0.95 0.51, 1.78
Parity** Primiparous 77 (36.5%) 572 (44.6%) ReferentMultiparous 134 (63.5%) 710 (55.4%) 1.40 1.04, 1.90
Alcohol Rarely/never 210 (99.5%) 1268 (99.9%) Referentuse Yes 1 (0.5%) 1 (0.1%) 6.04 0.38, 96.91
Chronic disease No 198 (97.1%) 1229 (97.9%) ReferentYes 6 (2.9%) 27 (2.1%) 1.36 0.55, 3.32
BMI first <18.5 (kg/m2) 4 (2.0%) 22 (1.8%) 1.25 0.42, 3.70 trimester* 18.5 – 24.9 (kg/m2) 108 (12.7%) 744 (61.8%) Referent
25.0 – 29.9 (kg/m2) 54 (27.1%) 328 (27.3%) 1.13 0.80, 1.61 30.0 (kg/m2) or more 33 (16.6%) 109 (9.1%) 2.09 1.34, 3.23
Previous No 169 (80.1%) 1045 (81.7%) Referentmiscarriage Yes 42 (19.9%) 234 (18.3%) 1.11 0.77, 1.60
Infertility No 207 (98.1%) 1237 (96.8%) Referenttreatment Yes 4 (1.9%) 41 (3.2%) 0.58 0.21, 1.64
* p 0.05; ** p 0.01; *** p 0.001. † Data for the BMI variable were missing in 93 (6.2%) women. For the variables marital status,socioeconomic status, smoking, snuff taking, alcohol consumption, chronic disease, previous miscarriageand infertility treatment, missing data was prevalent in 0.1 – 1.1%.
39
Table 3. The study population compared to the group of women not included in the study.Variable Study population
(n = 1495†) Not included women(n = 768†)
p value
Age (years) 29.6 4.6 29.7 5.2 0.42
Marital status Married or cohabiting 1433 (96.6%) 650 (95.4%) 0.22Single living 51 (3.4%) 31 (4.6%)
Socioeconomic Professional employee 687 (46.5%) 265 (38.9%) < 0.01 status Laborer 791 (53.5%) 416 (61.1%)
Smoking Non-smoker 1374 (92.8%) 615 (91.1%) 0.16Smoker 106 (7.2%) 60 (8.9%)
Snuff taking Not snuff-taker 1392 (94.1%) 654 (96.9%) < 0.01 Snuff-taker 88 (5.9%) 21 (3.1%)
Parity Primiparous 649 (43.5%) 308 (44.3%) 0.75Multiparous 844 (56.5%) 388 (55.7%)
Previous psychiatric disorder
NoYes
1424 (95.8%) 63 (4.2%)
656 (95.1%) 34 (4.9%)
0.50
† For all variables, missing data was prevalent in 1.9–4.8%.
40
Table 4. Pregnancy data associated with the presence of an antenatal psychiatric diagnosis.Variable Psychiatric
diagnosis(n = 211†)
No psychiatricdiagnosis(n = 1284†)
Oddsratio‡
95%Confidenceinterval
Midwife visits 10 114 (54.3%) 671 (53.0%) Referent
10 96 (45.7%) 596 (47.0%) 0.99 0.73, 1.35
Nausea and vomiting*** No 169 (81.3%) 1171 (92.2%) ReferentYes 39 (18.8%) 99 (7.8%) 2.04 1.40, 2.98
Sick leave during first No 126 (68.9%) 946 (84.3%) Referenttrimester*** Yes 57 (31.3%) 176 (15.7%) 2.06 1.41, 2.96
Sick leave before 36weeks of gestation***
7 weeks 7 weeks
80 (44.2%) 101 (55.8%)
731 (66.0%) 376 (34.0%)
Referent2.10 1.49, 3.00
Ultrasound examinations 2 119 (56.4%) 787 (61.4%) Referent
2 92 (43.6%) 495 (38.6%) 1.16 0.85, 1.59
Visits to the obstetrician** 2 137 (64.9%) 954 (74.5%) Referent
2 74 (35.1%) 327 (25.5%) 1.52 1.10, 2.12
Amniocentesis or chorion villisampling
NoYes
196 (92.9%) 15 (7.1%)
1182 (92.3%) 99 (7.7%)
Referent0.82 0.44, 1.53
Visits due to pain No 184 (87.2%) 1176 (91.8%) ReferentYes 27 (12.8%) 105 (8.2%) 1.56 0.97, 2.51
Visits due to fear of No 187 (88.6%) 1218 (95.1%) Referentchildbirth* Yes 24 (11.4%) 63 (4.9%) 2.38 1.41, 4.02
Visits due to premature No 185 (87.7%) 1186 (92.6%) Referentcontractions** Yes 26 (12.3%) 95 (7.4%) 1.68 1.03, 2.75
* p 0.05; ** p 0.01; *** p 0.05. † Data for the sick leave variable were missing in 207 (13.8%) women and data for the variable sick leaveduring first trimester were missing in 190 (12.7%) For all other variables missing data was prevalent in 0.1– 1.2%.
index.
41
‡ Odds ratio adjusted for age, marital status, socioeconomic status, smoking habits, parity and body mass
Table 5. Delivery data associated with the presence of an antenatal psychiatric diagnosis.Variable Psychiatric
diagnosis(n = 211†)
No psychiatricdiagnosis(n = 1284†)
Oddsratio‡
95%Confidenceinterval
Induced labor No 180 (85.3%) 1103 (86.0%) ReferentYes 31 (14.7%) 180 (14.0%) 0.97 0.63, 1.50
Elective caesarean No 187 (88.6%) 1198 (93.3%) Referentsection** Yes 24 (11.4%) 86 (6.7%) 1.76 1.05, 2.93
Acute caesarean section No 190 (90.9%) 1169 (91.0%) ReferentYes 21 (10.0%) 115 (9.0%) 1.07 0.62, 1.82
Instrumental delivery No 199 (94.3%) 1187 (92.4%) ReferentYes 12 (5.7%) 97 (7.6%) 0.66 0.32, 1.37
Normal vaginal delivery Yes 125 (59.2%) 788 (61.4%) Referentwithout complications No 86 (40.8%) 496 (38.6%) 1.17 0.84, 1.63
Oxytocin during labor No 101 (56.1%) 648 (55.6%) ReferentYes 79 (43.9%) 517 (44.4%) 1.13 0.79, 1.62
Epidural analgesia** No 121 (65.1%) 855 (72.0%) ReferentYes 65 (34.9%) 333 (28.0%) 1.56 1.08, 2.56
Time from start of laborto delivery*
12 hours 12 hours
100 (58.1%) 72 (48.9%)
750 (69.3%) 332 (30.7%)
Referent1.88 1.30, 2.73
Time from arrival in 12 hours 130 (72.6%) 891 (78.1%) Referentdelivery unit to delivery 12 hours 49 (27.4%) 250 (21.9%) 1.42 0.96, 2.13
* p 0.05; ** p 0.01. † Data for the variable time from start of labor to delivery were missing in 133 (9.6%) women and data forthe variable time from arrival in delivery department to delivery were missing in 67 (4.8%) women. Forthe variables induced labor, oxytocin during labor and epidural analgesia, missing data was prevalent in 0.1– 3.0%.‡ Odds ratio adjusted for age, marital status, socioeconomic status, smoking habits, parity and body massindex.
Neonatal outcome (Paper III)
Complete medical records regarding the newborns were retrieved in 1492 women who delivered
1513 children. Six children were excluded due to stillbirth and 42 twins were removed from the
analyses, thus leaving 1465 women and newborns to be investigated. Pre-pregnant antidepressant
medication was noted in 18 (1.2%) women. However, all women with pre-pregnant
antidepressant therapy had withdrawn from therapy prior to the first midwife visit. Comparison
between the group of not included women and the study population revealed no significant
42
Table 6. The neonatal outcome associated with the presence of an antenatal psychiatric diagnosis. Variable Psychiatric
diagnosis(n= 204†)
No psychiatric diagnosis(n = 1261†)
Oddsratio‡
95%Confidenceinterval
Birth weight 2500 g 6 (2.9%) 28 (2.2%) 1.47 0.58, 3.70 2500 – 3999 g 147 (72.1%) 974 (77.5%) Referent
4000 g 51 (25.0%) 255 (20.3%) 1.26 0.86, 1.84
Umbilical artery pH 7.2 139 (81.8%) 883 (83.5%) Referent< 7.2 31 (18.2%) 174 (16.5%) 1.17 0.75, 1.83
Umbilical artery base -12 165 (99.4%) 1012 (98.2%) Referentdeficit (mmol/l) < -12 1 (0.6%) 19 (1.8%) 0.42 0.05, 3.19
Apgar score at one 4 201 (98.5%) 1240 (98.8%) Referentminute < 4 3 (1.5%) 15 (1.2%) 1.51 0.43, 5.30
Apgar score at five 4 204 (100%) 1251 (99.7%) Referentminutes < 4 0 4 (0.3%) 0.04 Not calculated
Neonatal intensive care No 184 (90.2%) 1113 (88.3%) ReferentYes 20 (9.8%) 147 (11.7%) 0.84 0.50, 1.42
Overall premature birth No 193 (94.6%) 1196 (94.8%) ReferentYes 11 (5.4%) 65 (5.2%) 0.96 0.47, 1.92
Spontaneous premature No 199 (97.5%) 1224 (97.1%) Referentbirth Yes 5 (2.5%) 37 (2.9%) 0.74 0.26, 2.12
Small-for-gestational-age No 202 (99.0%) 1243 (98.6%) ReferentYes 2 (1.0%) 18 (1.4%) 0.52 0.11, 2.41
Respiratory distress No 199 (97.5%) 1225 (97.1%) ReferentYes 5 (2.5%) 36 (2.9%) 0.98 0.37, 2.60
Asphyxia No 201 (98.5%) 1251 (99.2%) ReferentYes 3 (1.5%) 10 (0.8%) 2.14 0.58, 7.96
Malformation No 203 (99.5%) 1238 (98.2%) ReferentYes 1 (0.5%) 23 (1.8%) 0.25 0.03, 1.93
† Data for the base excess variable were missing in 268 (18.3%) newborns and data for the pH variable were missing in 238 (16.2%) newborns. For the variables birth weight, neonatal intensive care, Apgar score at one and five minutes, missing data was prevalent in 0.1 – 0.4%. ‡ Odds ratio adjusted for age, marital status, socioeconomic status, smoking habits and body mass index.
differences regarding overall premature births. Significant maternal characteristics associated with
a PRIME-MD diagnosis were, with the exception of parity, the same as in the analysis of
obstetric outcome.
A borderline significant bivariate association was revealed between antenatal depressive disorder
and increased birth weight, p = 0.05. In the multiple regression analyses there were no significant
43
differences in any of the studied variables between newborns of women with a depressive and/or
anxiety disorder and newborns of women without a diagnosis (table 6). Neither did newborns of
women with exclusively depressive disorders or anxiety disorders differ significantly from
newborns of women without a diagnosis.
Depression and anxiety through pregnancy and
postpartum (Paper IV)
Of the 720 included women, 650 were reached for a telephone interview and 66 (9.2%) women
were lost for follow-up. Additionally four women were excluded due to stillbirth (two women)
and missed abortion (two women), detected during data collection from the medical records.
These four women did not have any psychiatric diagnosis during the second trimester of
pregnancy. The 66 women, who were lost to follow-up had a significantly lower socioeconomic
status, were more seldom tobacco snuffers and more often had a depression and/or anxiety
diagnosis during the second trimester of pregnancy.
The prevalence of a psychiatric diagnosis, in this selected sample of high-risk women, decreased
significantly after the delivery, present in 190 (29.2%) versus 107 (16.5%) women, p 0.001,
mainly due to a decrease in minor depressive disorders from 14.5% to 3.2% (table 7). Also,
anxiety NOS was significantly more common antenatally, whereas the opposite was noted for
panic disorder.
Psychiatric treatment was statistically more common three to six months after delivery, noted in
24 women, p 0.05. Postpartum antidepressant medication consisted exclusively of SSRI
preparations. Two women additionally used benzodiazepines. Of the 83 diagnosed women
without ongoing treatment, 20 women wanted help. Three of them were booked for a visit to an
obstetrician, 12 were referred to a psychiatrist and five were referred to a therapist. The most
common reason for treatment unwillingness was that the women wanted to wait and see if their
condition would spontaneously improve. The associations between antenatal and postpartum
diagnoses are illustrated in table 8.
44
Table 7. Antenatal and postpartum psychiatric disorder in a selected sample of women (n=650)
PRIME-MD diagnosis Antenatal Postpartum p value
Any psychiatric diagnosis 190 (29.2%) 107 (16.5%) < 0.001
Any mood disorder 152 (23.4%) 78 (12.0%) < 0.001
Major depressive disorder 46 (7.1%) 39 (6.0%) 0.39
Dysthymia 8 (1.2%) 8 (1.2%) 1.00
Partial remission of major depressive disorder 10 (1.5%) 18 (2.8%) 0.13
Minor depressive disorder 95 (14.5%) 21 (3.2%) < 0.001
Bipolar disorder 1 2 (0.3%) 1.00
Any anxiety disorder 74 (11.4%) 52 (8.0%) 0.02
Anxiety NOS 58 (8.9%) 23 (3.8%) < 0.001
Generalized anxiety disorder 3 (0.5%) 6 (0.9%) 0.51
Panic disorder 1 9 (1.4%) 0.02
Obsessive-compulsive disorder 15 (2.5%) 18 (2.8%) 0.65
Social phobia 6 (0.9%) 10 (1.5%) 0.42
Eating disorder 3 (0.5%) 5 (0.8%) 0.73
Table 8. Associations between antenatal and postpartum psychiatric disorders. Antenatal Postpartum depression and/or anxiety Odds ratio* 95% Confidence interval
No Yes
Depression and/or No 414 (76.4%) 128 (23.6%) Referentanxiety Yes 46 (43.0%) 61 (57.0%) 3.99 2.47, 6.46
Minor depression No 414 (85.5%) 70 (14.5%) ReferentYes 46 (65.7%) 24 (34.3%) 3.45 1.84, 6.48
DSM-IV depression No 414 (92.8%) 32 (7.2%) ReferentYes 46 (63.0%) 27 (37.0%) 6.42 3.25, 12.69
Anxiety disorder No 414 (90.6%) 43 (9.4%) ReferentYes 46 (59.7%) 31 (40.3%) 6.28 3.24, 12.17
* Adjusted for maternal age, marital status, smoking, previous psychiatric disorder and BMI.
The adjusted oddsratio for postpartum depression and anxiety was highest, 6.42, when a DSM-
IV depression was present during the second trimester of pregnancy. Previous psychiatric
disorder and single living was significantly associated with both a new-onset and a postpartum
continuation/recurrence of depression and/or anxiety. Postpartum continuation/recurrence of a
45
psychiatric disorder was additionally associated with smoking and obesity. Women with
postpartum continuation/recurrence of an antenatal depressive or anxiety disorder significantly
more often visited their obstetrician due to fear of childbirth, were more often on sick leave
during the first trimester of pregnancy, and more often suffered from nausea and vomiting.
Furthermore, planned caesarean section was more common among them and labor induction
was less common. Finally, gestational length was significantly shorter in women with postpartum
continuation/recurrence of a psychiatric disorder compared to healthy subjects, 38.8 ± 2.4 weeks
and 39.5 ± 1.5 weeks, respectively. Women with a new-onset psychiatric disorder did not differ
significantly regarding obstetric or neonatal outcome when compared with healthy subjects.
Postpartum depressive and/or anxiety disorders were significantly more common in antenatally
screen-positive women compared with those who were screen-negative, present in 33 (14.3%)
and in 13 (5.7%) subjects.
46
DISCUSSION
The present study is probably unique in being based on an unselected population of pregnant
women using modern DSM-IV criteria for psychiatric diagnosis. Most other studies on pregnant
women are based on smaller samples where the women are attending physicians for apprehended
or manifest pregnancy complication. Also, rating scales with focus on a single disorder have
mostly been used. Nevertheless, there are some methodological considerations that might bias
the strengths of our conclusions and they are discussed below. Also, an ethical reflection is made.
Methodological considerations
A limitation to the present study is that the assessment of psychiatric diagnoses was made at one
time point only during pregnancy, raising questions whether symptoms were unchanged,
transitory or might have developed after the time of screening. A significant increase in
depression scores between 18 to 32 weeks of pregnancy has previously been noted (Evans et al.
2001), but it remains uncertain if the same phenomenon is applicable to other psychiatric
disorders. On the other hand, in choosing the second trimester as the occasion for assessment,
we most certainly did not overestimate the prevalence of psychiatric disorders. Moreover, the
second trimester ultrasound-screening was considered as a suitable point of time, mainly due to
the high participation rate (almost 100%).
The present study design made it impossible to include women with language difficulties. As
rates of anxiety and depression among immigrants are likely to be increased, further studies of
this particular subset of pregnant women is mandated.
We chose to use PRIME-MD because of its conformity to DSM-IV criteria, ease of use in large
populations, such as in this study, and the high overall accuracy rate. Translation into Swedish has
been made, with subsequent re-translation into English, without displaying any differences.
However, the instrument has not been validated in Sweden against any other DSM-IV based
instruments, such as the Structured Clinical Interview for DSM-IV, used in the original validation
study (Spitzer et al. 1994). Furthermore, it has not been validated for use among pregnant
47
women. Nevertheless, it seems unlikely that depression and anxiety as diagnoses are different in a
pregnant population compared with a non-pregnant. Also, we regarded the benefits of this
method as clearly overweighing possible disadvantages; not least compared with the different
types of rating scales, which were the alternatives. The major disadvantage with rating scales is
that the result only indicates a possible disorder. Another weakness with these is that they mostly
focus on either depression or anxiety, not on both of them together.
We decided to not assess somatoform disorders or alcohol abuse. Considering that pregnant
women normally have lots of somatic complaints, we did not expect it to be meaningful
evaluating the somatic symptoms by using the CEG. In fact, the risk for overestimation of
somatoform disorders was considered high due to the pregnant state. Reasons for omitting the
questions on alcohol abuse were that we assumed more refusals to participate due to perceived
offense. Also, it is a well-known fact that abusing pregnant women mostly withholds the truth
about their drinking habits, well demonstrated in the medical records in this study, where only
one woman reported drinking alcohol in early pregnancy. In a recent Swedish study, the Alcohol
Use Disorders Identification Test was used on a pregnant population, demonstrating that 6%
consumed alcohol two to four times per month, which is more extensive than earlier presumed
(Goransson et al. 2003). However, providing the alcohol questions in the PQ might have
displayed more veracious information than reported in the medical records, but since assessing
and treating alcohol abuse was not our primary objective, we regarded that the disadvantages in
terms of impaired participation rate overweighed possible benefits.
Providing the PQ before the ultrasound examination might have resulted in more screen-positive
women. In fact, many women spontaneously told us that they would have provided different
answers if the PQ had been filled in after the ultrasound examination, which had generally made
them feel relieved. However, our choice to provide the PQ before the ultrasound examination
probably gave us more work to do, but if we had not done so, we might have missed some
women with psychiatric disorders because of incorrectly positive answers due to the relief of a
normal ultrasound result.
Both maternal and neonatal medical records might contain errors because of subjective
judgments of the caregivers. For example, the diagnosis “small-for-gestational-age” was prevalent
in 1.4% of children, compared to expected rate of 2.3%, which is the national prevalence rate
(The National Board of Health and Welfare). Also, the diagnosis “poor progress in labor” was
48
more frequent at Umeå University Hospital than at Sunderby Central Hospital, probably more
reflective of diagnosis methods than prevalence per se. Nevertheless, we did not reveal any
associations between psychiatric disorders and premature deliveries, and psychiatric disorders
were equally distributed between hospitals.
Finally, the time point for postpartum assessment can be questioned. For postpartum depression,
peak incidence has been noted during the first three months after delivery (Cooper and Murray
1998), meaning that the prevalence of postpartum psychiatric disorders in this selected sample of
women might have been underestimated. Our decision to assess psychiatric disorders three to six
months after delivery was mainly due to practical reasons. A possible benefit of choosing that
time point is that we probably diagnosed women with more lengthy disorders, who were less
likely to spontaneously recover and thus more urgent to treat.
Ethical considerations
The women who had a psychiatric disorder were not treated during pregnancy, with the
exception of those who were demanding help and/or had suicidal thoughts. The main reason was
that we wanted to analyze obstetric and neonatal outcome as functions of the natural course of
depression and anxiety. Secondly, antidepressant medication was considered even more risky for
the unborn child at the time when the study started. However, although we did not offer all
women treatment during pregnancy, probably more of them received treatment than they would
have done if we had not performed the study. Actually, 18 pregnant women were referred to
psychiatrists or other professionals for treatment.
Prevalence of psychiatric disorders
Psychiatric disorders were less prevalent than in previous studies using the same type of test
instrument in obstetric-gynecologic patients where 20% and 30.5% of patients were diagnosed
(Spitzer et al. 2000; Sundstrom et al. 2001). In our material we noted a prevalence of 14.1% for all
psychiatric diagnoses. A possible explanation for this discrepancy is that this population did not
include gynecological patients, and subsequently the findings in the present study probably more
49
correctly reflect mental health among pregnant women. Even higher prevalence of depression
has been found in other studies of pregnant women, with rates as high as 17 – 29% (Bolton et al.
1998; Josefsson et al. 2001). But again, these studies have used the EPDS, which estimates
depressive symptoms, but not depression as a diagnosis. Moreover, the highest rates of
depressive symptoms were noted in a study made on socially disadvantaged women in London
(Bolton et al. 1998) and not a population-based sample. The point prevalence of any mood
disorder in the current study was 11.6% and mood disorders were thus the most common
psychiatric disorders in this population, which is in agreement with studies on other pregnant and
non-pregnant women (Spitzer et al. 2000).
The rate of anxiety disorders in this sample of pregnant women was clearly higher than the figure
given by community-based studies of fertile women, where the point prevalence of anxiety was
2.8% in women of reproductive age (Hagnell et al. 1994) compared to 6.6% in our study.
Actually, we do not have any simple explanation for this discrepancy. One possible explanation is
that the community-based study was assessing anxiety disorders as an entity as well as depression,
meaning that co-morbidity might play a role for diverse results; that is, if the women had a
depression diagnosis, the anxiety diagnosis might have been neglected. Surprisingly, we found a
quite low prevalence of social phobia, 0.4%. The point prevalence of social phobia in women has
earlier been estimated to 17.6% (Furmark et al. 1999). In other studies a lifetime prevalence of
15.5% was noted (Weinstock 1999). One reason for the low rate in our study might be that these
women were afraid to attend ultrasound screening or were among those who dropped out for
various reasons. Other possible explanations might be that women with social phobia are so
disabled that they choose neither to become pregnant nor to have a partner.
Somatic symptoms were significantly more frequent among women with any psychiatric
diagnosis than in those without. Kelly and others made a similar discovery in their study of 186
pregnant women (Kelly et al. 2001). Accordingly, these results concur with previous well-
documented findings that unspecified somatic complaints are associated with psychopathology,
especially in women (Kroenke and Spitzer 1998).
Pronounced fear of the approaching childbirth was twice as common in women with a
psychiatric diagnosis compared to those without any diagnosis. This result emphasizes the
importance of special treatment for women with a fear of childbirth. Cognitive therapy in
combination with intensified obstetric information has been shown to be effective in reducing
50
the rate of cesarean sections due to anxiety or concerns, and in shortening labor (Saisto et al.
2001). A possible explanation for the success of psychotherapy in treating women with a fear of
childbirth might be that they more often suffer from psychiatric disorders, which are more
seldom discovered in the conventional antenatal care program. The association between fear of
childbirth and psychiatric disorders might produce questions regarding if this result is due to
either anxiety or depression. However, an additional sub-analysis displayed that no significant
difference was found, depending on a depressive or anxiety disorder (not in text).
The prevalence of psychiatric disorders in our study was high, at least in the range of severe
somatic pregnancy complications. Since most women with a diagnosis were untreated, it is
plausible that the majority of them were unrecognized previously. A possible explanation is that
women often present with atypical symptoms of depression and/or unspecified somatic
complaints as symptoms of psychiatric disorder. Overall, somatic symptoms are common in
otherwise healthy pregnant women. The two most frequent symptoms in depressed women were
fatigue or loss of energy and diminished interest in daily activities, not depressed mood as one
might have expected, supported by results in another study using the same test instrument
(Sundstrom et al. 2001). Also, previous investigators have found the frequency of unrecognized
diagnosis to be higher at obstetrics-gynecology outpatient care sites compared to at primary care
settings, suggesting that diagnosis is difficult without a test instrument (Spitzer et al. 2000).
Obstetric outcome
The results suggest that antenatal depressive and anxiety disorders are associated with more
negative events during pregnancy and delivery. Severe obstetric complications, on the other hand,
were not affected by antenatal depression and/or anxiety.
More women with a psychiatric diagnosis suffered from nausea and vomiting, a finding
supported by Chou and colleagues, who noticed an association between depression and nausea,
vomiting and fatigue in early pregnancy (Chou et al. 2003). Whether depression preceded or
resulted from the symptoms was considered unclear both in their study, as well as in other
investigations (Munch 2002; Swallow et al. 2004). However, in a Swedish study, frequent nausea
was found to decrease from 51% in gestational week 10-12 to 9% in week 20 (Rodriguez et al.
2001), suggesting that the risk for overestimating psychiatric disorders ought to be a minor
51
problem at the later time point. Among women with major depression seeking help at their
general practitioner, the majority presented with other symptoms or causes for their consultation
(Sundstrom et al. 2001). Presumably, nausea and vomiting could represent one such symptom of
discomfort.
Our results showed that women with antenatal depressive and/or anxiety disorder were on sick
leave earlier in the pregnancy and for a longer time period throughout pregnancy compared to
women without any diagnosis. Although not specifically concerned with a pregnant population,
similar results were obtained in Depression Research in European Study, which was the first pan-
European study on depression in the community (Lepine et al. 1997). In our work, 37% of
women, at some time point during pregnancy, had a sick leave period. Although missing data on
disability days was prevalent in 207 subjects, thus opening up for some degree of uncertainty
regarding in the results, the frequency is similar to what previously has been reported from
Swedish register data. In 2002, 39% of pregnant Swedish women were on sick leave during the
last trimester of pregnancy (The National Social Insurance Board).
Another finding in the Depression Research in European Study (Lepine et al. 1997) was that
sufferers from major depression imposed the greatest demand on healthcare resources, making
almost three times as many visits to their GP or family doctor as non-sufferers. In our study we
also found more doctors visits among women with a diagnosis compared to women without.
Furthermore, consultation due to fear of childbirth was significantly associated with a psychiatric
diagnosis. Supporting data is presented in a study by Sjogren and Thomassen (Sjogren and
Thomassen 1997), where the authors found a higher frequency of psychological problems in
women with severe anxiety over childbirth, compared with controls.
Also, we noted significant associations between antenatal depression and/or anxiety and
consultations due to premature contractions, elective caesarean section, use of epidural analgesia
during labor, and a self-experienced longer time of labor. The higher incidence of caesarian
sections might be explained by a co-variation between depression and/or anxiety and fear of
childbirth, as already mentioned. Sjogren and Thomassen noted in their study that 68% of the
women with severe anxiety over childbirth initially requested caesarean section (Sjogren and
Thomassen 1997). In Sweden, the caesarean delivery rate has increased from 10.6% in 1990, to
16.0% in 2001. Since there are no firm somatic explanations behind this increase, psychological
factors have been suggested to be involved. The increased use of epidural analgesia found among
52
patients with depressive and/or anxiety disorders in our study, has also been found by others
(Chung et al. 2001). This finding together with the experienced longer time of labor might be
associated with more sensations of pain. As previously mentioned, somatic complaints seems to
be associated with depressive and/or anxiety disorders (Bixo et al. 2001) and pain especially has
been noted to complicate the diagnosis of depression (Greden 2003). Likewise, associations have
been noted between chronic pain and mood and anxiety disorders (McWilliams et al. 2003).
Other studies have pointed out associations between antenatal depressive symptoms and adverse
events in pregnancy and/or delivery (Chung et al. 2001; Kurki et al. 2000; Orr et al. 2002), in
terms of increased frequency of operative deliveries, premature deliveries, and preeclampsia. Our
study did not reveal any correlation between antenatal depression and/or anxiety and
complications of pregnancy and delivery such as hypertensive disorder including preeclampsia,
fetal growth retardation/hypoxia, and premature delivery. Operative vaginal deliveries and acute
caesarean deliveries were also similarly distributed between women with a psychiatric diagnosis
and healthy subjects.
The prevalence of psychiatric disorder may have been underestimated since the excluded women
(including the dropouts) did, in fact, differ from the study population in that they had a lower
socioeconomic status. Low socioeconomic status was associated with the presence of a
psychiatric diagnosis and thus, it can be assumed that a number of women with antenatal
depression and/or anxiety have been excluded from the study group. Regarding maternal
sociodemographic and medical factors associated to psychiatric disorders, we chose to test
variables that had been proven as confounders/mediators for psychiatric disorders in other
studies. After completed study, we also found that previous legal abortion was associated with
depression and anxiety during the second trimester of pregnancy. Nevertheless, when testing the
variable retroactively, this negligence did not influence the results in terms of obstetric or
neonatal outcome.
Neonatal outcome
The findings suggest that neonatal outcome is not worsened by maternal antenatal depressive
and/or anxiety disorders. Although our results are contradictory to findings in previous studies,
53
the present study is unique in being based on an unselected population-based sample of women,
using modern DSM-IV criteria for psychiatric diagnosis.
Orr and colleagues (Orr et al. 2002) found a significant relationship between spontaneous
premature deliveries and reported depressive symptoms. A major reason for the divergent results
might be that both aims and diagnostic instruments differed between studies, as Orr and co-
workers, used CES-D Scale for assessment of depressive symptoms, not depression as a clinical
diagnosis. In their study, 117 (8.4%) of the women had a CES-D score in the upper 10th. The
prevalence of depressive disorders, diagnosed with PRIME-MD in our study was 11.6% and
major depression was present in 46 (3.1%) women. Besides the use of different methods, another
possible reason for the diverse results might be that the populations were different and that the
risk of premature birth differs considerably between continents. Premature birth per se is about
twice as common in the United States as in Sweden (Diket and Nolan 1997; Hamilton et al. 2003)
with point prevalence of 12.0% and 5.7%, respectively. Our data on premature birth correspond
well with reported numbers of premature births in Sweden in its entirety. The population in the
study of Orr and colleagues consisted of Afro-American women, already known to be at greater
risk of premature deliveries than white women (Blackmore et al. 1993; Blackmore-Prince et al.
1999). One offered explanation could be that black women in the United States are chronically
exposed to specific stressors that adversely affect the outcomes of their pregnancies and that race
is a marker for that stress but not in itself a risk factor for premature delivery (Blackmore et al.
1993).
Kelly and co-workers (Kelly et al. 2002) found independent associations between maternal
psychiatric and substance abuse diagnoses and low birth weight and premature delivery in an
ethnically heterogeneous population in California. However, one of the study limitations noted
by the authors was that unmeasured confounders, such as maternal smoking, could have biased
the risk estimations. Two studies on a large Danish population found no relationship between
elevated distress scores and fetal growth retardation (Hedegaard et al. 1996a), but revealed a
moderate relationship between elevated scores for distress and premature delivery (Hedegaard et
al. 1996b). Nevertheless, these two studies have not assessed depression and anxiety as clinical
diagnoses, but rather scores for distressed symptoms. Hoffman and Hatch (Hoffman and Hatch
2000) pointed out a possible association between prenatal depressive symptoms at 28 weeks of
gestation and deteriorated fetal growth in 222 lower social class women, raising questions
whether being of a lower social class is a vulnerability factor per se. In line with our study results,
54
Perkin and co-workers (Perkin et al. 1993) did not find maternal anxiety and depression to be
associated with premature delivery in a population of white women.
In our study we found no association between depressive and/or anxiety disorders and
premature delivery or small-for-gestational-age birth. As prevalence rates for premature delivery
are comparably low in Sweden, our study had only power to detect at least a doubling of the rate.
Given the fact that the rate of spontaneous premature delivery was actually lower among women
with any PRIME-MD diagnosis than among healthy subjects, it is unlikely that a larger sample
size would have yielded different results. The choice of dichotomizing the premature variable can
be debated, since other studies have found associations between psychiatric disorders and shorter
gestational length (Ericson et al. 1999; Simon et al. 2002). However, we also did test using it as a
continuous variable and did not gain different results. Nevertheless, it must be emphasized that
our results might not be generalizable to other populations, in particular those with higher rates
of premature birth. Furthermore, in the unadjusted analysis, a borderline significant association
between antenatal depression and birth weight 4000 g or more was evident. This association was
lost in the multivariate analysis, probably because of the adjustment for maternal BMI.
Adjustment was also made for smoking, which is known to deteriorate fetal growth. A reasonable
explanation for the absent associations between depressive disorders and deteriorated birth
weight in the adjusted analyses might be that obesity and smoking have opposite effects on fetal
growth. Although not assessable within the study design, this suggestion implies that the
diagnosis of fetal growth retardation, particularly in obese depressed subjects, might be beyond
our screening interventions, as a number of growth retarded fetuses would be found within the
normal range for fetal growth.
A striking finding in prior studies is that use of psychopharmacological medication is seldom
assessed. The matter of medication might be of interest, as prior research has found associations
between antidepressant therapy, shorter gestational length and lower birth weight (Ericson et al.
1999; Simon et al. 2002). In our study, only two women were noted to use antidepressant
medication during pregnancy. Although these figures might be due to the unwillingness of
women to inform their midwife or obstetrician, the low frequency of psychoactive medication
could also be explained by cultural traditions, implying that women in Sweden and their
physicians try to avoid medication as far as possible during pregnancy and lactation.
55
Depression and anxiety through pregnancy and
postpartum
In our study, fewer cases of depressive and/or anxiety disorders were present three to six months
postpartum than antenatally, but there was a significant shift from a majority of sub-threshold
diagnoses during pregnancy to full DSM-IV diagnoses during the postpartum period. The
decrease of depressive disorders is supported by findings in other studies (Evans et al. 2001;
Fergusson et al. 1996; Gotlib et al. 1989; Josefsson et al. 2001). For example, using the Edinburgh
Postnatal Depression Scale (EPDS), Josefsson and colleagues found that depressive symptoms
were prevalent in 17% of women during late pregnancy, in 17% at the maternity ward, and in
13% six to eight weeks and six months after delivery (Josefsson et al. 2001).
Anxiety disorders through pregnancy and the postpartum period have been less studied. In a
review article of Altshuler and colleagues, they concluded that both panic disorder and obsessive-
compulsive disorder (OCD) tended to be more common postpartum than during pregnancy
(Altshuler et al. 1998). One possible explanation for increased vulnerability to recurrence of panic
symptoms was the sharp fall in progesterone levels postpartum (Altshuler et al. 1998).
Postpartum exacerbation of OCD symptoms was also found in a study of Williams and co-
workers (Williams and Koran 1997). In their study, they found premenstrual worsening of OCD
as well, suggesting changes in gonadal hormones as an influencing factor. Furthermore, they
noted that women with OCD seemed to be at increased risk for postpartum depression (Williams
and Koran 1997).
Our study pointed out significant associations between antenatal and postpartum psychiatric
disorders. The adjusted odds ratio for postpartum depression and anxiety was highest when a
DSM-IV depression was prevalent during the second trimester of pregnancy and second highest
for an anxiety disorder during pregnancy. This might be explained by the findings that major
depressive disorder has a longer duration and is more severe than a minor depression. Parker and
coworkers (Parker et al. 1998) studied a cohort over 15 years, were they found a greater
frequency, severity and duration of depressive mood states among those with a previous major
depression compared to those with a previous minor depression. Also, anxiety disorders are
known to be more chronic in nature. For example, in a three-and-a-half year follow-up study in a
primary care setting, Ormel and colleagues (Ormel et al. 1993) found that only one-third of
56
patients with anxiety disorders were fully recovered. For those who did not fully recover,
functional disability continued and exceeded the disability experienced by patients who suffered
from depression with an absence of anxiety (Ormel et al. 1993).
The women, who were lost for follow-up in our study, differed from the actual study population
as they had a lower socioeconomic status and more frequently had a psychiatric disorder during
the second trimester of pregnancy. This finding corresponds well with other studies on dropouts.
For example, Moser and co-workers (Moser et al. 2000) found in a longitudinal multicenter
clinical trial, that dropouts had higher levels of depression, hostility and overall psychosocial
distress, and had a negative attitude against health care. However, their study was not performed
on exclusively women postpartum, but on parents and other caregivers of infants at risk of
cardiopulmonary arrest.
Previous psychiatric disorder and living single was significantly associated with postpartum
continuation/recurrence of psychiatric disorder and a new-onset depressive and/or anxiety
disorder. Postpartum continuation/recurrence of an antenatal psychiatric disorder was
additionally associated with smoking and obesity. Fear of childbirth, sick leave during the first
trimester of pregnancy, nausea and vomiting, planned caesarean delivery, and shorter gestational
length were significantly more common in these women. Furthermore, labor induction was
significantly less common. In contrast, women with a new-onset psychiatric disorder postpartum
did not differ significantly regarding obstetric or neonatal outcome when compared with healthy
subjects. The finding that some maternal characteristics are associated with depression and
anxiety antenatally but not postpartum suggests different etiologies. Prior studies have also
pointed out that sociodemographic variables seem to differ, depending on whether the
depression is already present during pregnancy or if the disease is new-onset. For example, Gotlib
and colleagues (Gotlib et al. 1989) found that new-onset postpartum depression, in contrast to
antenatal depression, was essentially unrelated to maternal characteristics as age, years of
education, number of children in the household, occupational status, and parity. Also,
Buckwalter and colleagues (Buckwalter et al. 1999) found that different steroid hormones were
associated with mood disturbances during pregnancy compared to postpartum, suggesting
different underlying mechanisms. Josefsson and co-workers found that sick leave during
pregnancy and a high number of visits to the antenatal care clinic were the strongest risk factors
for postpartum depression (Josefsson et al. 2002). However, in their study they did not subdivide
the group of postpartum depressed women depending on antenatal depression or lack thereof.
57
Our study displayed shorter gestational length among women with both antenatal and
postpartum psychiatric disorder, probably explained by more elective caesarean sections, which
are most commonly performed one or two weeks before estimated date of delivery. Fewer labor
inducements might also be explained by more elective caesarean sections.
Postpartum depressive and/or anxiety disorders were significantly more common in antenatally
screen-positive women compared with those who were screen-negative. This finding probably
reflects the association between depressive symptoms and depression as a disorder, noted in
other studies (Parker et al. 1998).
Future perspectives
In the light of our study results, one might expect that diagnosing and treating psychiatric
disorders during pregnancy would improve maternal well being, and also obstetric outcome in
terms of reduced sick leave and health care consumption. Furthermore, the study results suggest
decreased costs to society if antenatal depression and anxiety were treated. However, these
expectations might be questioned; i.e. will diagnosis merely generate more worries in mothers and
more costs to society due to unnecessary and unwanted procedures that might even harm the
offspring? Although prior studies have not pointed out adverse effects in offspring as a result of
maternal treatment with SSRIs, one must consider that long-term studies are sparse. To improve
our knowledge, further studies are demanded, with randomized treatment of depression and
anxiety in pregnant women and subsequent assessment of outcome regarding women and
offspring, the latter both neonatally and over a longer perspective.
58
CONCLUSIONS
Psychiatric disorders are common in pregnant women and accompanied by significantly
more somatic symptoms as well as fear of the approaching childbirth.
Depression and anxiety during pregnancy generates increased costs to society in terms of
more visits to doctors, increasing sick leave and more planned caesarean deliveries.
Maternal antenatal depressive disorders and/or anxiety disorders are not independent risk
factors for deteriorated neonatal outcome, such as premature delivery and small-for-
gestational-age birth, in a country with well developed welfare systems.
Postpartum depression and anxiety is significantly associated with the presence of an
antenatal psychiatric disorder, more so when a full DSM-IV psychiatric disorder is
prevalent during pregnancy.
Maternal characteristics are different in women with a postpartum
continuation/recurrence of an antenatal psychiatric disorder compared to women with a
new-onset disorder, indicating different etiologies.
59
ACKNOWLEDGEMENTS
I wish to express my gratitude to everyone involved in making this thesis a reality, and particulary to:
Marie Bixo, associate professor and main supervisor, for your endless support and enthusiasm
throughout the work. Without your encouragement, I would never have dared to try making
research work.
Inger Sundström-Poromaa, associate professor and co-supervisor, for your skilful guidance into the
world of science. I am most impressed of your heroic persistence in teaching me how to use
statistical software!
Marianne Wulff, my co-supervisor, for invaluable contributions of your enormous knowledge
about everything that concerns antenatal care.
Monica Åström, co-author, for your positive attitude and your ability to teach psychiatry in a way
that makes even a gynecologist to understand some of it.
Yvonne Hoff, midwife and co-worker at the beginning of the study, for your brilliance and humour.
I miss you, but the antenatal care sites in Boden made a real bargain when they acquired you.
Ulf Högberg, former supervisor, for your well thought out advices, always given in a respectful
way.
Anna Pohjanen and Gösta Granberg, director and former director of the Division of Obstetrics and
Gynecology, Sunderby Central Hospital, for your support. If you had not believed in my capacity,
this work had been much harder.
Åsa Lindholm, beloved colleague and friend, for your vitalizing company at work, and in Greece,
Cyprus and Majorca.
60
Bertil Bergman, colleague and former supervisor. I have gained most of my best qualities as a
gynaecologist by imitating you. You have a unique quality: a mind that is both stable and versatile.
All other colleagues and staff at the Division of Obstetrics and Gynecology, Sunderby Central
Hospital: bad jokes, lots of coffee and generous minds provide a great comfort when life or
computers are bad to you.
Colleagues and staff at the Department of Clinical Sciences, Obstetrics and Gynecology, Umeå
University and Umeå Neurosteroid Center: I am most grateful for all support and encouragement
during the time of the study.
Oskar and Alvina, my beloved children, for just being who you are. Life has got another
dimension after I had the luck to know you.
Göran Andersson, my husband, for loving me the way I am.
Susanne Risberg, my younger sister, for being a real friend and for providing me and my family
gourmet meals and accordion music, and last but not least, for showing me your secret
mushroom places.
Märta Andersson and Britt-Marie Lindgren, my grandmother and mother. Without you I would not
have become what I am.
Robert and Fredrik Lindgren, my younger brothers. You have turned bad jokes into a form of art!
Tina Gustavsson, old friend of mine, for your talents in both making posters and therapeutic
cosiness. I love you!
Lena Johansson, a real friend and nowadays also a colleague, for unselfishly providing a place to
stay during your time as a student, and for the stimulating chats regarding relations, girl-power
and heavy metal. You are a real hero!
Erik and Elsie Ahlqvist, former husband and mother-in-law, for unselfish help with computers,
children and lots of other things.
61
REFERENCES
American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fourth edition:
DSM-IV. Washington, DC: American Psychiatric Association, 1994.
The National Board of Health and Welfare, Centre for Epidemiology. (http://www.sos.epc/epceng.htm).
The National Social Insurance Board. (http://www.rfv.se/english/index.htm).
Altshuler LL, Hendrick V, Cohen LS. 1998. Course of mood and anxiety disorders during pregnancy and
the postpartum period. J Clin Psychiatry 59 Suppl 2:29-33.
Angold A, Costello EJ, Worthman CM. 1998. Puberty and depression: the roles of age, pubertal status and
pubertal timing. Psychol Med 28(1):51-61.
Appleby L, Warner R, Whitton A, Faragher B. 1997. A controlled study of fluoxetine and cognitive-
behavioural counselling in the treatment of postnatal depression. Bmj 314(7085):932-6.
Austin MP, Lumley J. 2003. Antenatal screening for postnatal depression: a systematic review. Acta
Psychiatr Scand 107(1):10-7.
Avis NE, Crawford S, Stellato R, Longcope C. 2001. Longitudinal study of hormone levels and depression
among women transitioning through menopause. Climacteric 4(3):243-9.
Backstrom T, Andersson A, Andree L, Birzniece V, Bixo M, Bjorn I, Haage D, Isaksson M, Johansson
IM, Lindblad C and others. 2003. Pathogenesis in menstrual cycle-linked CNS disorders. Ann N
Y Acad Sci 1007:42-53.
Barrett JE, Barrett JA, Oxman TE, Gerber PD. 1988. The prevalence of psychiatric disorders in a primary
care practice. Arch Gen Psychiatry 45(12):1100-6.
Baulieu EE. 1991. Neurosteroids: a new function in the brain. Biol Cell 71(1-2):3-10.
Beck AT, Steer RA. 1984. Internal consistencies of the original and revised Beck Depression Inventory. J
Clin Psychol 40(6):1365-7.
Bennett HA, Einarson A, Taddio A, Koren G, Einarson TR. 2004. Prevalence of depression during
pregnancy: systematic review. Obstet Gynecol 103(4):698-709.
Bixo M, Andersson A, Winblad B, Purdy RH, Backstrom T. 1997. Progesterone, 5alpha-pregnane-3,20-
dione and 3alpha-hydroxy-5alpha-pregnane-20-one in specific regions of the human female brain
in different endocrine states. Brain Res 764(1-2):173-8.
Bixo M, Sundstrom-Poromaa I, Bjorn I, astrom M. 2001. Patients with psychiatric disorders in
gynecologic practice. Am J Obstet Gynecol 185(2):396-402.
Blackmore CA, Ferre CD, Rowley DL, Hogue CJ, Gaiter J, Atrash H. 1993. Is race a risk factor or a risk
marker for preterm delivery? Ethn Dis 3(4):372-7.
Blackmore-Prince C, Kieke B, Jr., Kugaraj KA, Ferre C, Elam-Evans LD, Krulewitch CJ, Gaudino JA,
Overpeck M. 1999. Racial differences in the patterns of singleton preterm delivery in the 1988
National Maternal and Infant Health Survey. Matern Child Health J 3(4):189-97.
62
Bolton HL, Hughes PM, Turton P, Sedgwick P. 1998. Incidence and demographic correlates of depressive
symptoms during pregnancy in an inner London population. J Psychosom Obstet Gynaecol
19(4):202-9.
Bosworth HB, Bastian LA, Kuchibhatla MN, Steffens DC, McBride CM, Skinner CS, Rimer BK, Siegler
IC. 2001. Depressive symptoms, menopausal status, and climacteric symptoms in women at
midlife. Psychosom Med 63(4):603-8.
Breslau N, Schultz L, Peterson E. 1995. Sex differences in depression: a role for preexisting anxiety.
Psychiatry Res 58(1):1-12.
Breslau N, Chilcoat H, Schultz LR. 1998. Anxiety disorders and the emergence of sex differences in major
depression. J Gend Specif Med 1(3):33-9.
Brown CS. 2001. Depression and anxiety disorders. Obstet Gynecol Clin North Am 28(2):241-68.
Buckwalter JG, Stanczyk FZ, McCleary CA, Bluestein BW, Buckwalter DK, Rankin KP, Chang L,
Goodwin TM. 1999. Pregnancy, the postpartum, and steroid hormones: effects on cognition and
mood. Psychoneuroendocrinology 24(1):69-84.
Burt VK, Stein K. 2002. Epidemiology of depression throughout the female life cycle. J Clin Psychiatry 63
Suppl 7:9-15.
Charette L, Tate DL, Wilson A. 1990. Alcohol consumption and menstrual distress in women at higher
and lower risk for alcoholism. Alcohol Clin Exp Res 14(2):152-7.
Chou FH, Lin LL, Cooney AT, Walker LO, Riggs MW. 2003. Psychosocial factors related to nausea,
vomiting, and fatigue in early pregnancy. J Nurs Scholarsh 35(2):119-25.
Chung TK, Lau TK, Yip AS, Chiu HF, Lee DT. 2001. Antepartum depressive symptomatology is
associated with adverse obstetric and neonatal outcomes. Psychosom Med 63(5):830-4.
Cloitre M, Yonkers KA, Pearlstein T, Altemus M, Davidson KW, Pigott TA, Shear MK, Pine D, Ross J,
Howell H and others. 2004. Women and anxiety disorders: implications for diagnosis and
treatment. CNS Spectr 9(9 Suppl 8):1-16.
Cooper PJ, Murray L. 1995. Course and recurrence of postnatal depression. Evidence for the specificity of
the diagnostic concept. Br J Psychiatry 166(2):191-5.
Cooper PJ, Murray L. 1998. Postnatal depression. Bmj 316(7148):1884-6.
Cox JL, Holden JM, Sagovsky R. 1987. Detection of postnatal depression. Development of the 10-item
Edinburgh Postnatal Depression Scale. Br J Psychiatry 150:782-6.
Cox JL, Murray D, Chapman G. 1993. A controlled study of the onset, duration and prevalence of
postnatal depression. Br J Psychiatry 163:27-31.
Cullberg J. 1972. Mood changes and menstrual symptoms with different gestagen/estrogen combinations.
A double blind comparison with a placebo. Acta Psychiatr Scand Suppl 236:1-86.
Davidson JR, Meltzer-Brody SE. 1999. The underrecognition and undertreatment of depression: what is
the breadth and depth of the problem? J Clin Psychiatry 60 Suppl 7:4-9; discussion 10-1.
Diket AL, Nolan TE. 1997. Anxiety and depression. Diagnosis and treatment during pregnancy. Obstet
Gynecol Clin North Am 24(3):535-58.
63
Dole N, Savitz DA, Hertz-Picciotto I, Siega-Riz AM, McMahon MJ, Buekens P. 2003. Maternal stress and
preterm birth. Am J Epidemiol 157(1):14-24.
Dong C, Sanchez LE, Price RA. 2004. Relationship of obesity to depression: a family-based study. Int J
Obes Relat Metab Disord 28(6):790-5.
Ellis MJ, Livesey JH, Inder WJ, Prickett TC, Reid R. 2002. Plasma corticotropin-releasing hormone and
unconjugated estriol in human pregnancy: gestational patterns and ability to predict preterm
delivery. Am J Obstet Gynecol 186(1):94-9.
Epperson CN, Terman M, Terman JS, Hanusa BH, Oren DA, Peindl KS, Wisner KL. 2004. Randomized
clinical trial of bright light therapy for antepartum depression: preliminary findings. J Clin
Psychiatry 65(3):421-5.
Ericson A, Kallen B, Wiholm B. 1999. Delivery outcome after the use of antidepressants in early
pregnancy. Eur J Clin Pharmacol 55(7):503-8.
Evans J, Heron J, Francomb H, Oke S, Golding J. 2001. Cohort study of depressed mood during
pregnancy and after childbirth. Bmj 323(7307):257-60.
Fergusson DM, Horwood LJ, Thorpe K. 1996. Changes in depression during and following pregnancy.
ALSPAC Study Team. Study of Pregnancy and Children. Paediatr Perinat Epidemiol 10(3):279-
93.
Freeman EW, Sammel MD, Liu L, Gracia CR, Nelson DB, Hollander L. 2004. Hormones and
menopausal status as predictors of depression in women in transition to menopause. Arch Gen
Psychiatry 61(1):62-70.
Furmark T, Tillfors M, Everz P, Marteinsdottir I, Gefvert O, Fredrikson M. 1999. Social phobia in the
general population: prevalence and sociodemographic profile. Soc Psychiatry Psychiatr Epidemiol
34(8):416-24.
Gasior M, Carter RB, Goldberg SR, Witkin JM. 1997. Anticonvulsant and behavioral effects of
neuroactive steroids alone and in conjunction with diazepam. J Pharmacol Exp Ther 282(2):543-
53.
Goransson M, Magnusson A, Bergman H, Rydberg U, Heilig M. 2003. Fetus at risk: prevalence of alcohol
consumption during pregnancy estimated with a simple screening method in Swedish antenatal
clinics. Addiction 98(11):1513-20.
Gotlib IH, Whiffen VE, Mount JH, Milne K, Cordy NI. 1989. Prevalence rates and demographic
characteristics associated with depression in pregnancy and the postpartum. J Consult Clin
Psychol 57(2):269-74.
Greden JF. 2003. Physical symptoms of depression: unmet needs. J Clin Psychiatry 64 Suppl 7:5-11.
Gregoire AJ, Kumar R, Everitt B, Henderson AF, Studd JW. 1996. Transdermal oestrogen for treatment
of severe postnatal depression. Lancet 347(9006):930-3.
Hagnell O, Ojesjo L, Otterbeck L, Rorsman B. 1994. Prevalence of mental disorders, personality traits and
mental complaints in the Lundby Study. A point prevalence study of the 1957 Lundby cohort of
64
2,612 inhabitants of a geographically defined area who were re-examined in 1972 regardless of
domicile. Scand J Soc Med Suppl 50:1-77.
Hamilton BE, Martin JA, Sutton PD. 2003. Births: preliminary data for 2002. Natl Vital Stat Rep 51(11):1-
20.
Harris B. 1993. A hormonal component to postnatal depression. Br J Psychiatry 163:403-5.
Hayward C, Gotlib IH, Schraedley PK, Litt IF. 1999. Ethnic differences in the association between
pubertal status and symptoms of depression in adolescent girls. J Adolesc Health 25(2):143-9.
Hedegaard M, Henriksen TB, Sabroe S, Secher NJ. 1996a. The relationship between psychological distress
during pregnancy and birth weight for gestational age. Acta Obstet Gynecol Scand 75(1):32-9.
Hedegaard M, Henriksen TB, Secher NJ, Hatch MC, Sabroe S. 1996b. Do stressful life events affect
duration of gestation and risk of preterm delivery? Epidemiology 7(4):339-45.
Heikkinen T, Ekblad U, Kero P, Ekblad S, Laine K. 2002. Citalopram in pregnancy and lactation. Clin
Pharmacol Ther 72(2):184-91.
Heikkinen T, Ekblad U, Palo P, Laine K. 2003. Pharmacokinetics of fluoxetine and norfluoxetine in
pregnancy and lactation. Clin Pharmacol Ther 73(4):330-7.
Hendrick V, Altshuler L, Strouse T, Grosser S. 2000. Postpartum and nonpostpartum depression:
differences in presentation and response to pharmacologic treatment. Depress Anxiety 11(2):66-
72.
Highet N, Drummond P. 2004. A comparative evaluation of community treatments for post-partum
depression: implications for treatment and management practices. Aust N Z J Psychiatry
38(4):212-8.
Hobel CJ, Dunkel-Schetter C, Roesch SC, Castro LC, Arora CP. 1999. Maternal plasma corticotropin-
releasing hormone associated with stress at 20 weeks' gestation in pregnancies ending in preterm
delivery. Am J Obstet Gynecol 180(1 Pt 3):S257-63.
Hoffbrand S, Howard L, Crawley H. 2001. Antidepressant drug treatment for postnatal depression.
Cochrane Database Syst Rev(2):CD002018.
Hoffman S, Hatch MC. 2000. Depressive symptomatology during pregnancy: evidence for an association
with decreased fetal growth in pregnancies of lower social class women. Health Psychol
19(6):535-43.
Josefsson A, Berg G, Nordin C, Sydsjo G. 2001. Prevalence of depressive symptoms in late pregnancy and
postpartum. Acta Obstet Gynecol Scand 80(3):251-5.
Josefsson A, Angelsioo L, Berg G, Ekstrom CM, Gunnervik C, Nordin C, Sydsjo G. 2002. Obstetric,
somatic, and demographic risk factors for postpartum depressive symptoms. Obstet Gynecol
99(2):223-8.
Kelly RH, Russo J, Katon W. 2001. Somatic complaints among pregnant women cared for in obstetrics:
normal pregnancy or depressive and anxiety symptom amplification revisited? Gen Hosp
Psychiatry 23(3):107-13.
65
Kelly RH, Russo J, Holt VL, Danielsen BH, Zatzick DF, Walker E, Katon W. 2002. Psychiatric and
substance use disorders as risk factors for low birth weight and preterm delivery. Obstet Gynecol
100(2):297-304.
Kendler KS, Kessler RC, Walters EE, MacLean C, Neale MC, Heath AC, Eaves LJ. 1995. Stressful life
events, genetic liability, and onset of an episode of major depression in women. Am J Psychiatry
152(6):833-42.
Kendler KS, Gardner CO, Prescott CA. 1999. Clinical characteristics of major depression that predict risk
of depression in relatives. Arch Gen Psychiatry 56(4):322-7.
Kendler KS, Thornton LM, Prescott CA. 2001. Gender differences in the rates of exposure to stressful
life events and sensitivity to their depressogenic effects. Am J Psychiatry 158(4):587-93.
Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB. 1993. Sex and depression in the National
Comorbidity Survey. I: Lifetime prevalence, chronicity and recurrence. J Affect Disord 29(2-
3):85-96.
Kessler RC, Keller MB, Wittchen HU. 2001. The epidemiology of generalized anxiety disorder. Psychiatr
Clin North Am 24(1):19-39.
Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI, Gelenberg AJ, Ryan
CE, Hess AL, Harrison W and others. 2000. Gender differences in chronic major and double
depression. J Affect Disord 60(1):1-11.
Kroenke K, Spitzer RL. 1998. Gender differences in the reporting of physical and somatoform symptoms.
Psychosom Med 60(2):150-5.
Kulin NA, Pastuszak A, Sage SR, Schick-Boschetto B, Spivey G, Feldkamp M, Ormond K, Matsui D,
Stein-Schechman AK, Cook L and others. 1998. Pregnancy outcome following maternal use of
the new selective serotonin reuptake inhibitors: a prospective controlled multicenter study. Jama
279(8):609-10.
Kurki T, Hiilesmaa V, Raitasalo R, Mattila H, Ylikorkala O. 2000. Depression and anxiety in early
pregnancy and risk for preeclampsia. Obstet Gynecol 95(4):487-90.
Lawrie TA, Hofmeyr GJ, De Jager M, Berk M, Paiker J, Viljoen E. 1998. A double-blind randomised
placebo controlled trial of postnatal norethisterone enanthate: the effect on postnatal depression
and serum hormones. Br J Obstet Gynaecol 105(10):1082-90.
Lawrie TA, Herxheimer A, Dalton K. 2000. Oestrogens and progestogens for preventing and treating
postnatal depression. Cochrane Database Syst Rev(2):CD001690.
Leibbrand R, Hiller W, Fichter MM. 1999. Effect of comorbid anxiety, depressive, and personality
disorders on treatment outcome of somatoform disorders. Compr Psychiatry 40(3):203-9.
Lepine JP, Gastpar M, Mendlewicz J, Tylee A. 1997. Depression in the community: the first pan-
European study DEPRES (Depression Research in European Society). Int Clin Psychopharmacol
12(1):19-29.
Magnusson A, Boivin D. 2003. Seasonal affective disorder: an overview. Chronobiol Int 20(2):189-207.
66
Maki P, Veijola J, Rasanen P, Joukamaa M, Valonen P, Jokelainen J, Isohanni M. 2003. Criminality in the
offspring of antenatally depressed mothers: a 33-year follow-up of the Northern Finland 1966
Birth Cohort. J Affect Disord 74(3):273-8.
Mann JJ. 1998. Neurobiological correlates of the antidepressant action of electroconvulsive therapy. J Ect
14(3):172-80.
Marcus SM, Barry KL, Flynn HA, Tandon R, Greden JF. 2001. Treatment guidelines for depression in
pregnancy. Int J Gynaecol Obstet 72(1):61-70.
Mathe AA. 1999. Neuropeptides and electroconvulsive treatment. J Ect 15(1):60-75.
Matza LS, Revicki DA, Davidson JR, Stewart JW. 2003. Depression with atypical features in the National
Comorbidity Survey: classification, description, and consequences. Arch Gen Psychiatry
60(8):817-26.
McEwen BS. 1988. Genomic regulation of sexual behavior. J Steroid Biochem 30(1-6):179-83.
McGrath S, McLean M, Smith D, Bisits A, Giles W, Smith R. 2002. Maternal plasma corticotropin-
releasing hormone trajectories vary depending on the cause of preterm delivery. Am J Obstet
Gynecol 186(2):257-60.
McLeod DR, Foster GV, Hoehn-Saric R, Svikis DS, Hipsley PA. 1994. Family history of alcoholism in
women with generalized anxiety disorder who have premenstrual syndrome: patient reports of
premenstrual alcohol consumption and symptoms of anxiety. Alcohol Clin Exp Res 18(3):664-70.
McWilliams LA, Cox BJ, Enns MW. 2003. Mood and anxiety disorders associated with chronic pain: an
examination in a nationally representative sample. Pain 106(1-2):127-33.
Miranda J, Azocar F, Komaromy M, Golding JM. 1998. Unmet mental health needs of women in public-
sector gynecologic clinics. Am J Obstet Gynecol 178(2):212-7.
Morgan JF, Lacey JH, Sedgwick PM. 1999. Impact of pregnancy on bulimia nervosa. Br J Psychiatry
174:135-40.
Moser DK, Dracup K, Doering LV. 2000. Factors differentiating dropouts from completers in a
longitudinal, multicenter clinical trial. Nurs Res 49(2):109-16.
Munch S. 2002. Chicken or the egg? The biological-psychological controversy surrounding hyperemesis
gravidarum. Soc Sci Med 55(7):1267-78.
Murray CJ, Lopez AD. 1997. Alternative projections of mortality and disability by cause 1990-2020:
Global Burden of Disease Study. Lancet 349(9064):1498-504.
Newman ME, Gur E, Shapira B, Lerer B. 1998. Neurochemical mechanisms of action of ECS: evidence
from in vivo studies. J Ect 14(3):153-71.
Nolen-Hoeksema S. 1987. Sex differences in unipolar depression: evidence and theory. Psychol Bull
101(2):259-82.
Northcott CJ, Stein MB. 1994. Panic disorder in pregnancy. J Clin Psychiatry 55(12):539-42.
Nulman I, Rovet J, Stewart DE, Wolpin J, Gardner HA, Theis JG, Kulin N, Koren G. 1997.
Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med
336(4):258-62.
67
Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, Koren G. 2002. Child
development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: a
prospective, controlled study. Am J Psychiatry 159(11):1889-95.
O'Connor TG, Heron J, Golding J, Beveridge M, Glover V. 2002. Maternal antenatal anxiety and
children's behavioural/emotional problems at 4 years. Report from the Avon Longitudinal Study
of Parents and Children. Br J Psychiatry 180:502-8.
O'Hara MW, Zekoski EM, Philipps LH, Wright EJ. 1990. Controlled prospective study of postpartum
mood disorders: comparison of childbearing and nonchildbearing women. J Abnorm Psychol
99(1):3-15.
O'Hara MW, Stuart S, Gorman LL, Wenzel A. 2000. Efficacy of interpersonal psychotherapy for
postpartum depression. Arch Gen Psychiatry 57(11):1039-45.
Onyike CU, Crum RM, Lee HB, Lyketsos CG, Eaton WW. 2003. Is obesity associated with major
depression? Results from the Third National Health and Nutrition Examination Survey. Am J
Epidemiol 158(12):1139-47.
Oren DA, Wisner KL, Spinelli M, Epperson CN, Peindl KS, Terman JS, Terman M. 2002. An open trial
of morning light therapy for treatment of antepartum depression. Am J Psychiatry 159(4):666-9.
Ormel J, Oldehinkel T, Brilman E, vanden Brink W. 1993. Outcome of depression and anxiety in primary
care. A three-wave 3 1/2-year study of psychopathology and disability. Arch Gen Psychiatry
50(10):759-66.
Orr ST, James SA, Blackmore Prince C. 2002. Maternal prenatal depressive symptoms and spontaneous
preterm births among African-American women in Baltimore, Maryland. Am J Epidemiol
156(9):797-802.
Parker G, Wilhelm K, Asghari A. 1998. Depressed mood states and their inter-relationship with clinical
depression. Soc Psychiatry Psychiatr Epidemiol 33(1):10-5.
Paul SM, Purdy RH. 1992. Neuroactive steroids. Faseb J 6(6):2311-22.
Perkin MR, Bland JM, Peacock JL, Anderson HR. 1993. The effect of anxiety and depression during
pregnancy on obstetric complications. Br J Obstet Gynaecol 100(7):629-34.
Petursson H. 1994. The benzodiazepine withdrawal syndrome. Addiction 89(11):1455-9.
Piyasil V. 1998. Anxiety and depression in teenage mothers: a comparative study. J Med Assoc Thai
81(2):125-9.
Rabheru K. 2001. The use of electroconvulsive therapy in special patient populations. Can J Psychiatry
46(8):710-9.
Rapaport MH, Judd LL, Schettler PJ, Yonkers KA, Thase ME, Kupfer DJ, Frank E, Plewes JM, Tollefson
GD, Rush AJ. 2002. A descriptive analysis of minor depression. Am J Psychiatry 159(4):637-43.
Rasgon NL, Rao RC, Hwang S, Altshuler LL, Elman S, Zuckerbrow-Miller J, Korenman SG. 2003.
Depression in women with polycystic ovary syndrome: clinical and biochemical correlates. J
Affect Disord 74(3):299-304.
68
Rodriguez A, Bohlin G, Lindmark G. 2001. Symptoms across pregnancy in relation to psychosocial and
biomedical factors. Acta Obstet Gynecol Scand 80(3):213-23.
Sackeim HA. 1999. The anticonvulsant hypothesis of the mechanisms of action of ECT: current status. J
Ect 15(1):5-26.
Saisto T, Salmela-Aro K, Nurmi JE, Kononen T, Halmesmaki E. 2001. A randomized controlled trial of
intervention in fear of childbirth. Obstet Gynecol 98(5 Pt 1):820-6.
Sarason IG, Johnson JH, Siegel JM. 1978. Assessing the impact of life changes: development of the Life
Experiences Survey. J Consult Clin Psychol 46(5):932-46.
Schulberg HC, Burns BJ. 1988. Mental disorders in primary care: epidemiologic, diagnostic, and treatment
research directions. Gen Hosp Psychiatry 10(2):79-87.
Shapiro S, Skinner EA, Kessler LG, Von Korff M, German PS, Tischler GL, Leaf PJ, Benham L, Cottler
L, Regier DA. 1984. Utilization of health and mental health services. Three Epidemiologic
Catchment Area sites. Arch Gen Psychiatry 41(10):971-8.
Simon GE, Cunningham ML, Davis RL. 2002. Outcomes of prenatal antidepressant exposure. Am J
Psychiatry 159(12):2055-61.
Sjogren B, Thomassen P. 1997. Obstetric outcome in 100 women with severe anxiety over childbirth.
Acta Obstet Gynecol Scand 76(10):948-52.
Sjostrom K, Thelin T, Valentin L, Marsal K. 1999. Do pre-, early, and mid-pregnancy life events influence
gestational length? J Psychosom Obstet Gynaecol 20(3):170-6.
Smith SS, Gong QH, Hsu FC, Markowitz RS, ffrench-Mullen JM, Li X. 1998. GABA(A) receptor alpha4
subunit suppression prevents withdrawal properties of an endogenous steroid. Nature
392(6679):926-30.
Snyder S, Strain JJ. 1989. Somatoform disorders in the general hospital inpatient setting. Gen Hosp
Psychiatry 11(4):288-93.
Spielberger CD, Gorsuch RL, Lushene P, Vagg PR, Jacobs GA. 1983. Manual for the State Trait
Anxiety Inventory (STAI, Form - Y). Palo Alto, CA: Consulting Psychologist Press.
Spigset O, Hagg S. 2004. [New antidepressive agents during pregnancy and lactation. Drug concentration
should be monitored and the lowest possible dose administered]. Lakartidningen 101(13):1176-81.
Spitzer RL, Williams JB, Kroenke K, Linzer M, deGruy FV, 3rd, Hahn SR, Brody D, Johnson JG. 1994.
Utility of a new procedure for diagnosing mental disorders in primary care. The PRIME-MD
1000 study. Jama 272(22):1749-56.
Spitzer RL, Williams JB, Kroenke K, Hornyak R, McMurray J. 2000. Validity and utility of the PRIME-
MD patient health questionnaire in assessment of 3000 obstetric-gynecologic patients: the
PRIME-MD Patient Health Questionnaire Obstetrics-Gynecology Study. Am J Obstet Gynecol
183(3):759-69.
Steinberg SI, Bellavance F. 1999. Characteristics and treatment of women with antenatal and postpartum
depression. Int J Psychiatry Med 29(2):209-33.
Steiner M. 1992. Female-specific mood disorders. Clin Obstet Gynecol 35(3):599-611.
69
Steiner M, Dunn E, Born L. 2003. Hormones and mood: from menarche to menopause and beyond. J
Affect Disord 74(1):67-83.
Stomati M, Genazzani AD, Petraglia F, Genazzani AR. 1998. Contraception as prevention and therapy:
sex steroids and the brain. Eur J Contracept Reprod Health Care 3(1):21-8.
Stowe ZN, Nemeroff CB. 1995. Women at risk for postpartum-onset major depression. Am J Obstet
Gynecol 173(2):639-45.
Sundstrom I, Spigset O, Andersson A, Appelblad P, Backstrom T. 1999. Lack of influence of menstrual
cycle and premenstrual syndrome diagnosis on pregnanolone pharmacokinetics. Eur J Clin
Pharmacol 55(2):125-30.
Sundstrom IM, Bixo M, Bjorn I, Astrom M. 2001. Prevalence of psychiatric disorders in gynecologic
outpatients. Am J Obstet Gynecol 184(2):8-13.
Swallow BL, Lindow SW, Masson EA, Hay DM. 2004. Psychological health in early pregnancy:
relationship with nausea and vomiting. J Obstet Gynaecol 24(1):28-32.
Troutman BR, Cutrona CE. 1990. Nonpsychotic postpartum depression among adolescent mothers. J
Abnorm Psychol 99(1):69-78.
Weiner CL, Primeau M, Ehrmann DA. 2004. Androgens and mood dysfunction in women: comparison of
women with polycystic ovarian syndrome to healthy controls. Psychosom Med 66(3):356-62.
Weinstock LS. 1999. Gender differences in the presentation and management of social anxiety disorder. J
Clin Psychiatry 60 Suppl 9:9-13.
Weissman MM, Sholomskas D, Pottenger M, Prusoff BA, Locke BZ. 1977. Assessing depressive
symptoms in five psychiatric populations: a validation study. Am J Epidemiol 106(3):203-14.
Weissman MM, John K, Merikangas KR, Prusoff BA, Wickramaratne P, Gammon GD, Angold A,
Warner V. 1986. Depressed parents and their children. General health, social, and psychiatric
problems. Am J Dis Child 140(8):801-5.
Weissman MM, Bland R, Joyce PR, Newman S, Wells JE, Wittchen HU. 1993. Sex differences in rates of
depression: cross-national perspectives. J Affect Disord 29(2-3):77-84.
Weissman MM, Olfson M. 1995. Depression in women: implications for health care research. Science
269(5225):799-801.
Weissman MM, Warner V, Wickramaratne P, Moreau D, Olfson M. 1997. Offspring of depressed parents.
10 Years later. Arch Gen Psychiatry 54(10):932-40.
Wickberg B, Hwang CP. 1997. Screening for postnatal depression in a population-based Swedish sample.
Acta Psychiatr Scand 95(1):62-6.
Wilhelm K, Parker G, Hadzi-Pavlovic D. 1997. Fifteen years on: evolving ideas in researching sex
differences in depression. Psychol Med 27(4):875-83.
Williams KE, Koran LM. 1997. Obsessive-compulsive disorder in pregnancy, the puerperium, and the
premenstruum. J Clin Psychiatry 58(7):330-4; quiz 335-6.
Wisner KL, Peindl K, Hanusa BH. 1993. Relationship of psychiatric illness to childbearing status: a
hospital-based epidemiologic study. J Affect Disord 28(1):39-50.
70
Wittchen HU, Essau CA, von Zerssen D, Krieg JC, Zaudig M. 1992. Lifetime and six-month prevalence
of mental disorders in the Munich Follow-Up Study. Eur Arch Psychiatry Clin Neurosci
241(4):247-58.
Yonkers KA. 1997. The association between premenstrual dysphoric disorder and other mood disorders. J
Clin Psychiatry 58 Suppl 15:19-25.
Zeskind PS, Stephens LE. 2004. Maternal selective serotonin reuptake inhibitor use during pregnancy and
newborn neurobehavior. Obstet Gynecol Surv 59(8):564-6.
Zweifel JE, O'Brien WH. 1997. A meta-analysis of the effect of hormone replacement therapy upon
depressed mood. Psychoneuroendocrinology 22(3):189-212.
71
APPENDIX
1. DSM-IV criteria
Major depressive episode
A. Five (or more) of the following symptoms have been present during the same two-week
period and represent a change from previous functioning; at least one of the symptoms is either
(1) depressed mood or
(2) loss of interest or pleasure.
Note: Do not include symptoms that are clearly due to a general medical condition, or mood-
incongruent delusions or hallucinations.
(1) Depressed mood most of the day, nearly every day, as indicated by either subjective
report (for example, feels sad or empty) or observations made by others (for example,
appears tearful). Note: In children and adolescents, can be irritable mood.
(2) Marked diminished interest or pleasure in all, or almost all, activities most of the day,
nearly every day (as indicated by either subjective account or observation made by
others).
(3) Significant weight loss when not dieting or weight gain (for example, change of more
than 5% of body weight in a month), or decrease or increase in appetite nearly every day.
Note: In children, consider failure to make expected weight gains.
(4) Insomnia or hypersomnia nearly every day.
(5) Psychomotor agitation or retardation nearly every day (observable by others, not merely
subjective feelings of restlessness or being slowed down).
(6) Fatigue or loss of energy nearly every day.
(7) Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional)
nearly every day (not merely self-reproach or guilt about being sick).
(8) Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by
subjective account or as observed by others).
(9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a
specific plan, or a suicide attempt or a specific plan for committing suicide.
B. The symptoms do not meet criteria for a mixed episode.
72
C. The symptoms cause clinically significant distress or impairment in social, occupational, or
other important areas of functioning.
D. The symptoms are not due to the direct physiological effects of a substance (for example, a
drug of abuse, a medication) or a general medical condition (for example, hypothyroidism).
E. The symptoms are not better accounted for by bereavement, that means, after the loss of a
loved one, the symptoms persist for longer than two months or are characterized by marked
functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic
symptoms, or psychomotor retardation.
Dysthymic disorder
A. Depressed mood for most of the day, for more days than not, as indicated either by subjective
account or observation by others, for at least two years. Note: In children and adolescents, mood
can be irritable and duration must be at least one year.
B. Presence, while depressed, of two (or more) of the following:
(1) poor appetite or overeating
(2) insomnia or hypersomnia
(3) low energy or fatigue
(4) low self-esteem
(5) poor concentration or difficulty making decisions
(6) feelings of hopelessness
C. During the two-year period (one year for children or adolescents) of the disturbance, the
person has never been without the symptoms in criteria A and B for more than two months at a
time.
D. No major depressive episode has been present during the first two years of the disturbance
(one year for children and adolescents); i.e., the disturbance is not better accounted for by
chronic major depressive disorders, or major depressive disorder, in partial remission. Note:
There may have been a previous major depressive episode provided there was a full remission
(no significant signs or symptoms for two months) before development of the dysthymic
disorder. In addition, after the initial two years (one year in children or adolescents) of dysthymic
disorder, there may be superimposed episodes of major depressive disorder, in which case both
diagnoses may be given when the criteria are met for a major depressive episode.
E. There has never been a manic episode, a mixed episode, or a hypomanic episode, and criteria
have never been met for cyclothymic disorders.
73
F. The disturbance does not occur exclusively during the course of a chronic psychotic disorder,
such as schizophrenia or delusional disorder.
G. The symptoms are not due to the direct physiological effects of a substance (for example, a
drug of abuse, a medication) or a general medical condition (for example., hypothyroidism).
H. The symptoms cause clinically significant distress or impairment in social, occupational, or
other important areas of functioning.
Generalized anxiety disorder
A. Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at
least six months, about a number of events or activities (such as work or school performance).
B. The person finds it difficult to control the worry.
C. The anxiety and worry are associated with three (or more) of the following six symptoms (with
at least some symptoms present for more days than not for the past six months. Note: Only one
item is required in children.
(1) restlessness or feeling keyed up or on the edge
(2) being easily fatigued
(3) difficult concentrating or mind going blank
(4) irritability
(5) muscle tension
(6) sleep disturbance (difficult falling or staying asleep, or restless unsatisfying sleep)
D. The focus of the anxiety and worry is not confined to features of an axis I disorder, for
example, the anxiety or worry is not about having a panic attack (as in panic disorder), being
embarrassed in public (as in social phobia), being contaminated (as in obsessive-compulsive
disorder), being away from home or close relatives (as in separation anxiety disorder), gaining
weight (as in anorexia nervosa), having multiple physical complaints (as in somatization disorder),
or having a serious illness (as in hypochondriasis), and the anxiety and worry do not occur
exclusively during posttraumatic stress disorder.
E. The anxiety, worry or physical symptoms cause clinically significant distress or impairment in
social, occupational, or other important areas of functioning.
F. The disturbance is not due to the direct physiological effects of a substance (for example, a
drug of abuse, a medication) or a general medical condition (for example, hyperthyroidism) and
do not occur exclusively during a mood disorder, a psychotic disorder, or a pervasive
developmental disorder.
74
Panic disorder without agoraphobia
A. Both (1) and (2):
(1) recurrent unexpected panic attacks
(2) at least one of the attacks has been followed by one month (or more) of one
(or more) of the following:
(a) persistent concern about having additional attacks
(b) worry about the implications of the attack or its consequences
(for example., losing control, having a heart attack, "going crazy")
(c) a significant change in behavior related to the attacks
B. Absence of agoraphobia.
C. The panic attacks are not due to the direct physiological effects of a substance (for example, a
drug of abuse, a medication) or a general medical condition (e.g., hyperthyroidism).
D. The panic attacks are not better accounted for by another mental disorder, such as social
phobia (for example, occurring on exposure to feared social situations), specific phobia (for
example, on exposure to a specific phobic situation), obsessive-compulsive disorder (for example,
on exposure to dirt in someone with an obsession about contamination), posttraumatic stress
disorder (for example, in response to stimuli associated with a severe stressor), or separation
anxiety disorder (for example, in response to being away from home or close relatives).
Obsessive-compulsive disorder
A. Either obsessions or compulsions:
Obsessions as defined by (1), (2), (3), and (4):
(1) recurrent and persistent thoughts, impulses, or images that are experienced, at
some time during the disturbance, as intrusive and inappropriate and that cause
marked anxiety or distress
(2) the thoughts, impulses, or images are not simply excessive worries about real-
life problems
(3) the person attempts to ignore or suppress such thoughts, impulses, or images,
or to neutralize them with some other thought or action
(4) the person recognizes that the obsessional thoughts, impulses, or images are a
product of his or her own mind (not imposed from without as in thought
insertion)
75
Compulsions as defined by (1) and (2):
(1) repetitive behaviors (for example, hand washing, ordering, checking) or mental
acts (for example, praying, counting, repeating words silently) that the person
feels driven to perform in response to an obsession, or according to rules that
must be applied rigidly
(2) the behaviors or mental acts are aimed at preventing or reducing distress or
preventing some dreaded event or situation; however, these behaviors or mental
acts either are not connected in a realistic way with what they are designed to
neutralize or prevent or are clearly excessive
B. At some point during the course of the disorder, the person has recognized that the
obsessions or compulsions are excessive or unreasonable. Note: This does not apply to children.
C. The obsessions or compulsions cause marked distress, are time consuming (take more than
one hour a day), or significantly interfere with the person’s normal routine, occupational (or
academic) functioning, or usual social activities or relationships.
D. If another Axis I disorder is present, the content of the obsessions or compulsions is not
restricted to it (for example, preoccupation with food in the presence of an eating disorder; hair
pulling in the presence of trichotillomania; concern with appearance in the presence of body
dysmorphic disorder; preoccupation with drugs in the presence of a substance use disorder;
preoccupation with having a serious illness in the presence of hypochondriasis; preoccupation
with sexual urges or fantasies in the presence of a paraphilia; or guilty ruminations in the presence
of major depressive disorder).
E. The disturbance is not due to the direct physiological effects of a substance (for example, a
drug of abuse, a medication) or a general medical condition.
Specify if:
With poor insight: if, for most of the time during the current episode the person does not
recognize that the obsessions and compulsions are excessive or unreasonable.
Social phobia
A. A marked and persistent fear of one or more social or performance situations in which the
person is exposed to unfamiliar people or to possible scrutiny by others. The individual fears that
he or she will act in a way (or show anxiety symptoms) that will be humiliating or embarrassing.
Note: In children, there must be evidence of the capacity for age-appropriate social relationships
with familiar people and the anxiety must occur in peer settings, not just in interactions with
adults.
76
B. Exposure to the feared social situation almost invariably provokes anxiety, which may take the
form of a situationally bound or situationally predisposed panic attack. Note: In children, the
anxiety may be expressed by crying, tantrums, freezing, or shrinking from social situations with
unfamiliar people.
C. The person recognizes that the fear is excessive or unreasonable. Note: In children, this
feature may be absent.
D. The feared social or performance situations are avoided or else are endured with intense
anxiety or distress.
E. The avoidance, anxious anticipation, or distress in the feared social or performance situation(s)
interferes significantly with the person's normal routine, occupational (academic) functioning, or
social activities or relationships, or there is marked distress about having the phobia.
F. In individuals under age 18 years, the duration is at least 6 months.
G. The fear or avoidance is not due to the direct physiological effects of a substance (for
example, a drug of abuse, a medication) or a general medical condition and is not better
accounted for by another mental disorder (for example, panic disorder with or without
agoraphobia, separation anxiety disorder, body dysmorphic disorder, a pervasive developmental
disorder, or schizoid personality disorder).
H. If a general medical condition or another mental disorder is present, the fear in criterion A is
unrelated to it; for example, the fear is not of stuttering, trembling in Parkinson’s disease, or
exhibiting abnormal eating behavior in anorexia nervosa or bulimia nervosa.
Specify if: Generalized: if the fears include most social situations (also consider the additional
diagnosis of avoidant personality disorder).
77
78
1. Magont
2. Ryggont
3. Smärta iarmar, benleder (höfter,knän etc)
4. Foglossnings-besvär
5. Smärtor ellerproblem vidsamlag
6. Huvudvärk
7. Smärtor i brösteteller tryck överbröstet
8. Yrsel
9. Svimningar
10. Hjärtklappning
11. Andnöd
12. Förstoppning,lös avföring ellerdiarre
13. Illamående ellerkräkningar
14. Trötthet ellerbristandeenergi
15. Sömnproblem
16. Tappat kontrollenöver ätandet
17. Minskad lust attgöra saker somDu vanligentycker om
18. Att Du har käntDig illa till mods,deprimerad ellerkänt att framtidenser hopplös ut
19. Nervositet,ångest eller oro
20. Ängslan övermånga olika saker
21. Har Du haft enplötslig känsla avångest eller panik?
22. Har Du återkommandeidéer, fantasier ellerimpulser som verkardumma, konstiga,frånstötande ellerhemska?
23. Finns det saker som Dugör om och om igen,eller tankar Du måstetänka upprepade gångerför att känna Dig lugn?
24. Är Du rädd för att bligenerad ellerförödmjukad i socialasituationer ochundviker Du sådanasituationer?
Under senaste månaden
Har Du under den senaste månaden ofta haft......
JA NEJ JA NEJ JA NEJ
FRÅGEFORMULÄR
Namn:
Telefon hemma:
VÄGLEDNING: Det är viktigt att Du fyller i JA eller NEJ på samtliga 25 frågor.
Födelsedata (år, mån, dag):
Telefon arbete:
25. Känner Du uttalad oroeller rädsla inför denstundande för-lossningen?
79
4. Socioeconomic status (SES)
Statistics Sweden has elaborated a socio-economic classification system, “Socioekonomisk
indelning, SEI”. It is intended to be used both by Statistics Sweden and by other bodies in
surveys and studies, primarily in the social field. The system can be used to classify persons as
well as households.
The socioeconomic classification of persons in the labor force is primarily based on their
occupation. Distinctions between self-employed persons and employees, and between employees
with and without subordinates must, however, be based on additional information. In its most
aggregated form the classification consists of six groups:
1. Unskilled and semiskilled workers
2. Skilled workers
3. Assistant non-manual employees
4. Intermediate non-manual employees
5. Employed and self-employed professionals, higher civil servants and executives
6. Self-employed (other than professionals)
In this study, these groups had been further aggregated to two groups. “Laborers” consisted of
the original group one and two and “professional employees” consisted of group three to six.
80