Human Reproduction, Vol.30, No.4 pp.

777 782, 2015

Advanced Access publication on February 5, 2015 doi:10.1093/humrep/dev014

ORIGINAL ARTICLE Early pregnancy

Depression and emotional stress is

highly prevalent among women with
recurrent pregnancy loss
A.M. Kolte 1,*, L.R. Olsen 2, E.M. Mikkelsen3, O.B. Christiansen 1,4, and
H.S. Nielsen 1
1
Recurrent Pregnancy Loss Unit, Fertility Clinic 4071, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark 2Child and
Adolescent Mental Health Center, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark 3Department of Clinical
Epidemiology, Aarhus University Hospital, Aarhus, Denmark 4Department of Obstetrics and Gynaecology, Aalborg Hospital, Aalborg, Denmark

*Correspondence address. Recurrent Pregnancy Loss Unit, Fertility Clinic 4071, University Hospital Copenhagen, Rigshospitalet,
Blegdamsvej 9, 2100 Kbenhavn , Copenhagen, Denmark. Tel: +45-3545-4951. E-mail: astrid.marie.kolte@regionh.dk

Submitted on August 19, 2014; resubmitted on November 5, 2014; accepted on January 13, 2015

study question: Is the prevalence of psychological stress and moderate/severe depression higher for women with recurrent pregnancy
loss (RPL) than pregnancy planners trying to conceive naturally?
summary answer: Both psychological stress and major depression are signicantly more common among women with RPL than in those
trying to conceive naturally.
what is known already: RPL has a signicant emotional impact on couples, especially the woman. Previous studies have shown in-
conclusive results.
study design, size, duration: In this cross-sectional study, we compared the prevalence of stress and depression among 301
women with RPL and 1813 women attempting to conceive naturally. We dened RPL as three or more pregnancy losses before 12 weeks ges-
tation. RPL patients were enrolled from 2010 to 2013 and the comparison group from 2011 to 2014.
participants/materials, setting, methods: RPL patients completed an online questionnaire before their rst consultation
at the Danish RPL Unit. In addition, we included data from a comparison group of 1813 women who participated in the Soon Parents Study (www.
SnartForldre.dk). The Major Depression Index (MDI) was used to assess symptoms of depression, and Cohens Perceived Stress Scale (PSS) was
used to measure stress. Relevant demographic data were also retrieved.
main results and the role of chance: Of the RPL patients, 26 (8.6%) had a score on the MDI corresponding to moderate/
severe depression, as did 40 (2.2%) of the women in Soon Parents Study (adjusted odds ratio (OR) 5.53 (95% condence interval (CI): 2.09;
14.61)). A high stress level, dened as 19 on the PSS scale, was reported by 124 (41.2%) of the patients and 420 (23.2%) in the comparison
group (adjusted OR 1.59 (95% CI 1.03; 2.44)).
limitations, reasons for caution: We used online questionnaires, and have no interview data. We were unaware if any of the
women in the comparison group suffer from RPL.
wider implications of the findings: This study should entail a heightened awareness of mental distress among care providers for
women with RPL.
study funding/competing interest(s): No specic funding was sought for this study. The Soon Parents Study is funded by
National Institute of Child Health and Human Development (R01 HD060680-01A4). No authors have competing interests to declare.
trial registration number: N/A.
Key words: recurrent pregnancy loss / depression / stress / cross-sectional study

& The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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 778
Introduction
The loss of a desired pregnancy is a signicant negative life event asso-
ciated with grief comparable to the grief experienced after a peri- or neo-
natal death (Stirtzinger and Robinson, 1989; Brier, 2008). Recurrent
pregnancy loss (RPL) is a distinct disease entity dened by the repeated,
unintentional demise of pregnancies (Christiansen et al., 2008). It affects
0.5 3% of women seeking to have children (Larsen et al., 2013). In the
Danish Recurrent Pregnancy Loss Unit at Rigshospitalet, Denmark,
RPL is dened as three or more consecutive pregnancy losses in accord-
ance with current European guidelines (Jauniaux et al., 2006; Rai et al.,
2011). Among women referred to a tertiary RPL unit, 1/3 will not
have a live birth afterwards (Lund et al., 2012).
Depression is the leading cause of disability worldwide (Marcus and
Taghi Yasami, 2012), and it is associated with considerable personal
and socio-economic burden. A Danish population-based study with
1205 respondents found a major depression prevalence of 3.3%, as
dened by the Diagnostic and Statistical Manual of Mental Disorders,
4th ed. (DSM-IV) (Olsen et al., 2004). In a subgroup of women aged
20 49 years, the prevalence of major depression was 3.8%. This study
described a signicant relationship between levels of self-reported
stress measured on the Cohen Perceived stress scale (PSS) (Cohen
et al., 1983) and depression measured on the Major Depression Inven-
tory (MDI) (Bech et al., 2001).
Most studies on depression and RPL have been small, using a variety of
scales and lacked an appropriate comparison group (Rowsell et al., 2001;
Craig et al., 2002; Andalib et al., 2006; Kagami et al., 2012; Mevorach-
Zussman et al., 2012; Sugiura-Ogasawara et al., 2013; Toffol et al.,
2013). The reported prevalence of depression varies considerably
across studies, ranging from ,15% (Sugiura-Ogasawara et al., 2013)
to 33% (Craig et al., 2002). Psychological stress and RPL has not been ex-
tensively studied, but one case control study described a signicantly
higher PSS total score among 45 patients with unexplained RPL, com-
pared with 40 controls (median score 20.5 (interquartile range (IQR):
17.0; 25.0) versus 17.0 (IQR: 14.0; 21.0), adjusted odds ratio (OR):
1.13 (1.03; 1.24)) (Li et al., 2012).
Based on a clinical observation of signicant distress among patients
in the Danish RPL Unit, we wanted to investigate the prevalence of
moderate/severe depression according to International Classication
of Disease, version 10 (ICD-10) and prevalence of self-reported
stress. As a relevant comparison group we used baseline data on
women from the Soon Parents Study (www.snartforldre.dk), an
ongoing online cohort study designed to elucidate the impact of life
style factors on fertility. Furthermore, we wanted to investigate if there
was a correlation between scores on the PSS and the MDI.
Materials and Methods
Participants
From June 2010 to June 2013, all women referred to the Danish RPL Unit at
the Fertility Clinic at Rigshospitalet, Denmark, received an email invitation to
participate in the study. Of the invited 438 patients, 302 (69%) completed the
online questionnaire. Patients were offered feedback on their questionnaire
and referral to their general practitioner, but no treatment or counselling for
psychological problems. One respondent was never seen in the Unit and was
therefore excluded.
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Kolte et al.
We dene RPL as three or more consecutive pregnancy losses before 12
weeks gestation (non-visualized pregnancy losses and conrmed intrauter-
ine pregnancy losses), and all patients except nine fullled this criterion.
These nine had two early pregnancy losses and at least one pregnancy loss
after 12 weeks gestation and were kept in the study group. For the
present study we dened a pregnancy loss as the unintentional demise of a
pregnancy, and as such included biochemical pregnancy losses, resolved
and treated pregnancies of unknown location, early and late miscarriages,
stillbirths and conrmed ectopic pregnancies.
For the 136 patients who did not complete the questionnaire, we
extracted information on number of pregnancy losses, live births, country
of origin and daily smoking from their medical charts at the Danish RPL
Unit. Of these, ve never had a consultation at the Unit and were thus
excluded from analysis.
The women in the comparison group are part of the Soon Parents Study
(www.SnartForldre.dk), performed at the Department of Clinical Epidemi-
ology, Aarhus University Hospital. This ongoing study includes males and
females who are actively trying to conceive; in a heterosexual relationship;
not using contraception; and not presently in fertility treatment. The included
women are between 18 and 45 years. The Soon Parents Study was initiated in
August 2011, and participants are recruited by press coverage and advertise-
ments on selected websites popular among couples trying to conceive, e.g.
www.netdoktor.dk and www.minmave.dk.
At the time of data extraction in January 2014, 2226 women had com-
pleted the questionnaire. Of these, we excluded 412 who had not responded
to all questions in the survey. Furthermore, we chose to remove one woman
from the analysis as she reported having experienced 21 pregnancies at the
age of 23 years, leaving 1813 women in the comparison group.
Questionnaires
All participants completed the MDI, a validated self-rating depression scale,
which is used both clinically and in epidemiological studies (Olsen et al., 2004;
Andersen et al., 2009, 2011). The 6-point Likert scale ranges from 0 (no de-
pression) to 50 (extreme depression). The 10 questions in the MDI cover the
10 depressive symptoms described in the ICD-10, which are identical to the
major depression symptoms in the DSM-IV, apart from an additional item of
low self-esteem. The scale enabled us to classify participants in accordance
with the three ICD-10 depression categories: mild (two to three core symp-
toms and two to three additional symptoms); moderate (two core symptoms
and four or more additional symptoms, or three core symptoms and four
additional symptoms); and severe (three core symptoms and ve or more
additional symptoms). Participants who did not full any of these criteria
were classied as no depression. The MDI classication and rating has pre-
viously been described in detail (Olsen et al., 2003).
The participants also completed the PSS, a validated 10-item self-reporting
scale of stress symptoms (Cohen et al., 1983; Cohen and Williamson, 1988).
The 5-point Likert scale ranges from 0 (no stress) to 40 (extreme stress). The
scale was made to evaluate how unpredictable, uncontrollable and over-
loaded respondents nd their lives (Cohen et al., 1983). PSS is not a diagnostic
tool, and allows only for comparisons made between groups in a given study.
Demographics
For both RPL patients and women in the Soon Parents Study, we obtained
information on age; number of previous pregnancies and number of live
born children; education (no education; skilled worker; vocational secondary
schooling; vocational education; and higher education: ,3 years; 3 4 years;
.4 years); and annual household income (,E20 000; 20 000 39 999; 40
000 100 000; .100 000).
Furthermore, the Soon Parents Study participants provided information
on the outcome of their last pregnancy (if previously pregnant), and the
number of months they had been trying to become pregnant presently.
 Depression and stress in recurrent pregnancy loss 779

RPL patients gave information on number of pregnancy losses (early preg-
nancy losses, conrmed ectopic pregnancies, late miscarriages and stillbirths)
before referral; number of months (,3; 3 6; or .6) since their last preg-
nancy loss; perception of own health in the last year; present medication;
daily smoking (non-smokers and smokers); alcohol intake (none; 1 7;
8 14; and .14 units) and country of origin.
income, number of prior pregnancies and number of live born children), we
chose to keep all covariates in the model. We tested for interaction between
all variables. All interaction terms were insignicant and were excluded.
We explored a possible correlation between scores on the PSS scale and
the MDI by Spearmans correlation coefcient test.
All statistical analyses were performed using Statistical Package for Social
Sciences version 19 (SPSS, USA). A P-value ,0.05 was considered signicant.

Statistical analysis
As age, number of previous pregnancies and number of live born children
were not normally distributed in all groups (participating RPL patients, non-
participating RPL patients and Soon Parents Study participants), we used
Mann Whitney U-test. Education and annual household income were com-
pared by the x 2 test for trend.
We analysed results from the MDI in two ways. Firstly, we compared the
median scores using Mann Whitney U-test. Secondly, we graded the results
according to the ICD-10 categories as described (Olsen et al., 2003). We
then dichotomized the results on the MDI scale into no/ mild depression
and moderate/severe depression for logistic modelling. We tested a pos-
sible correlation between time passed since last pregnancy loss in the RPL
group by the x 2 test for trend.
Absolute scores on the PSS in the two groups were compared using Stu-
dents t-test, presented as mean scores and SD. For the logistic regression
analyses, we chose a score of 19 to denote high stress, as 18 was the
75 percentile in the comparison group.
The prevalence (absolute numbers and percentages) of moderate/severe
depression and high stress in the two groups was compared using multiple
logistic regression analysis with results presented as adjusted OR and 95%
condence intervals (95% CI) with the comparison group as the indicator
group. As we only had ve demographic variables (age, education, household
Results
Demographics
As shown in Table I, patients were signicantly older and had signicantly
higher education levels and household income compared with partici-
pants in the Soon Parents Study. The number of pregnancies in the
patient group was also higher. The women in the Soon Parents Study
comparison group had had slightly more live born children (Table I).
Median number of pregnancy losses among the patients was 4 (Range:
3; 12) and 44.4% of the patients had experienced their last pregnancy loss
within the last 6 months. The patients were mostly non-smokers, and all
reported a weekly alcohol consumption of 14 units per week (Table II).
Use of antidepressant medication was reported by four patients, of
which one had an MDI score signifying moderate depression and one a
score corresponding to severe depression. Age, number of live born chil-
dren and pregnancy losses as well as smoking status did not differ signi-
cantly between the participating and non-participating RPL patients
(Supplementary Table SI). Thirty-seven (27%) of the non-respondents
did not have Denmark as their country of origin versus 20 (7%) of the

Table I Demographic data on recurrent pregnancy loss patients (RPL) and comparison group.

RPL patients, n 5 301 Comparison group, N 5 1813 Signicance level

.............................................................................................................................................................................................
Age (years), median (range) 35 (20; 45) 28 (18; 47) P , 0.001
U 104510a
Previous pregnancies, median (range) 4 (3; 13) 1 (0; 12) P , 0.001
U 20709a
Live born children, median (range) 0 (0; 3) 0 (0; 7) P 0.012
U 251764a
Education, n (%)
No education 15 (5) 91 (5.0) P , 0.0001b
Skilled worker 0 3 (0.2)
Vocational secondary schooling 7 (2.3) 35 (1.9)
Vocational education 26 (8.6) 161 (8.9)
Higher education
,3 years 48 (15.9) 204 (11.3)
3 4 years 77 (25.6) 709 (39.1)
.4 years 128 (42.5) 610 (33.6)
Annual household income in E, n (%)
,20 000 9 (3) 54 (3.0) P 0.006b
20 00039 999 24 (8) 275 (15.2)
40 000100 000 66 (21.9) 417 (23.0)
.100 000 202 (67.1) 1067 (58.8)
a
Mann Whitney U-test.
b 2
x test for trend.

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 780 Kolte et al.

depression according to the DSM-IV classication) as did 40 (2.2%) of

Table II RPL patient demographics (N 5 301) in the participants in the Soon Parents Study (unadjusted OR: 4.19 (95%
absolute numbers (%) or as otherwise stated.
CI 2.52; 6.98); adjusted OR: 5.53 (95% CI 2.09; 14.61)) (Table IV).
Pregnancy losses 4 (3; 12)a A high stress level was reported by 124 (41.2%) of the RPL patients and
Perception of own health in the last 12 months
420 (23.2%) of the women in the comparison group (OR 2.34 (95%
CI 1.80; 3.60), adjusted OR: 1.59 (95% CI 1.03; 2.44)).
Very good 77 (25.6)
The RPL patients mean score on the PSS was 16.7 (SD 7.0) and in the
Good 120 (39.9)
comparison group it was 13.97 (SD 6.42), mean difference 2.74 (95%
Intermediate 72 (23.9)
CI 1.94; 3.53) (Table V), while the median score on the MDI was 9.0
Poor 25 (8.3) and 7.0, respectively, a signicant difference (P , 0.001) (Table VI).
Very poor 7 (2.3) There was no correlation between scores on the MDI or PSS and time
Time passed since the patients last pregnancy loss since last pregnancy loss in the RPL group (x 2 for trend: P 0.78).
,3 months 128 (42.5) In both groups, PSS scores and MDI scores were signicantly corre-
3 6 months 126 (41.9) lated, Spearmans rs was 0.657 (P , 0.01) for RPL patients and 0.673
.6 months 47 (15.6) (P , 0.01) in the comparison group.
Daily smoking
Yes 34 (11.3) Discussion
No 267 (88.7)
In this group of 301 well characterized patients with RPL, we found that
Alcohol intake in units per week
the odds of moderate/severe depression was more than ve times
0 6 220 (73)
higher than in a group of 1813 women trying to conceive naturally. We
7 14 16 (5.3)
also found a signicantly higher prevalence of self-reported stress
.14 0 (0) among RPL patients than the comparison group. We consider a depres-
None 65 (21.6) sion prevalence of 8.6% and a high stress level in 42.1% of newly referred
a
Median (Range).
patients with RPL as clinically relevant. The prevalence of moderate/
severe depression in the comparison group is comparable to the preva-
lence in the general Danish population as previously described (Olsen
et al., 2003). In both groups, we conrmed the already described correl-
ation between stress and depression (Olsen et al., 2004).
Table III Comparison group demographics (N 5 1813) We found a lower prevalence of depression among our patients than
in absolute numbers (%) or as otherwise stated. that reported in other studies (Craig et al., 2002; Mevorach-Zussman
et al., 2012; Sugiura-Ogasawara et al., 2013).
Nulligravida 853 (47.0)
The RPL Unit at Copenhagen University Hospital, Rigshospitalet is the
Outcome of last pregnancy
only dedicated RPL Unit in Denmark and we investigate and treat
Live born child 523 (54.5)
patients from the entire country. It has been speculated that women
Stillbirth 13 (1.4) with RPL who are psychologically distraught, are more often referred
Intrauterine pregnancy loss before 22 weeks gestation 244 (25.4) to a specialist centre (Craig et al., 2002). As the Danish RPL Unit is a na-
Abortion 130 (13.6) tional unit, some patients have to undergo investigations and treatment
Ectopic pregnancy 18 (1.9) far from their homes. Furthermore, obtaining a referral to the Unit may
Information not supplied 31 (3.2) require tenacity. This may select for patients who are not mentally
Number of months trying to become pregnant presently 5.4 (8.4)a distressed.
The RPL patients in our study were offered feedback on their stress
a
Mean (SD).
and depression score and therefore, patients with stress or depression
may have been more motivated to enter the study, though treatment
or counselling was not offered. On the other hand, severely stressed
patients who completed the questionnaire (x 2: P , 0.0001) (Supple-
or depressed patients may not have had the energy to complete the
mentary Table SI).
questionnaire.
Of the Soon Parents Study participants, 53% had previously been
The women entering the Soon Parents Study are self-referred, and
pregnant at least once before. In 13 cases (1.4%) the last pregnancy
women with a heightened awareness of psychological problems may
ended in a stillbirth and for 244 (25.4%) women their last pregnancy
be more motivated to participate, however at enrolment they did not
ended as an intrauterine pregnancy loss before 22 weeks gestation.
know they would be asked about stress and depression. In addition, par-
The mean number of months they had tried to become pregnant was
ticipants in the Soon Parents study did not receive feedback on their
5.4 (SD 8.4) (Table III).
questionnaire and did not gain from participating. We noted that a rela-
tively large number of their last pregnancies ended as either a stillbirth or
Stress and depression a miscarriage, both of which may lead to psychological distress. The
Twenty-six of the RPL patients (8.6%) had a score on the MDI scale cor- women in the Soon Parents Study were younger than the Danish
responding to an ICD-10 moderate or severe depression (major average age at rst pregnancy, and the mean number of months they

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 Depression and stress in recurrent pregnancy loss 781

Table IV Prevalence of moderate/severe depression and high stress among RPL patients (n 5 301) and comparison group
(n 5 1813).

RPL patients, n (%) Comparison group, n (%) Unadjusted analysis, Adjusted analysisb,
odds ratio (95% CIa) odds ratio (95% CI)
.............................................................................................................................................................................................
Moderate/severe depression 26 (8.6) 40 (2.2) 4.19 (2.52; 6.98) 5.53 (2.09; 14.61)
c
High stress 124 (41.2) 420 (23.2) 2.34 (1.80; 3.60) 1.59 (1.03; 2.44)
a
CI: condence interval.
b
Adjusted for: Age, education, household income, number of live born children and number of prior pregnancies.
c
High stress: Score of 19 on the Perceived Stress Scale.

Based on the here presented high prevalence of stress and depression

Table V Scores on Cohens Perceived Stress Scale. among women with RPL it would be interesting and relevant also to study
stress and depression among these womens partners, as would
Mean (SD) Range Mean difference
(95% CI)
face-to-face interviews based on the online questionnaires.
........................................................................................ The standard of care for patients with RPL is tender loving care, an
RPL patients 16.71 (7.0) 0 37 2.74 (1.94; 3.53)a approach which usually entails frequent ultrasound examinations in
Comparison group 13.97 (6.42) 0 36 early pregnancy and psychological support, although empirical evidence
a
for the treatment is sparse (Rai et al., 2011). Nevertheless, evaluation of
Students T test
mental distress at referral is not customary in RPL clinics, as far as we
know. Our results indicate that some women with RPL may have a
need for psychological counselling, also when not pregnant.
Table VI Scores on the Major Depression Inventory.

Median Range U
........................................................................................
Conclusions
RPL patients 9.0 0; 58 221944 Symptoms of stress and depression are frequent among women referred
Comparison group 7.0 0; 43 P , 0.001a to the Danish RPL Unit. We hope that the present study will result in a
a
heightened awareness of mental distress among care providers for
Mann Whitney U-test.
women with RPL.

had tried to conceive was relatively high (mean 5.4 months). Unfortu-
nately, we did not have information on country of origin in the compari-
son group, but as the questionnaire is only available in Danish, we assume
that the majority have an ethnically Danish background or have at least
lived in Denmark for a substantial period of time. This is supported by
the signicantly higher proportion of non-native Danish women in the
RPL non-participating group.
It is a key strength in this cross-sectional study that we are able to dir-
ectly compare prevalence of stress and depression as both groups used
the same psychometric scales. We cannot rule out that some of the
women in the Soon Parents Study may suffer from RPL themselves, as
this information was not available to us. If anything, this would lead to
an underestimation of the difference between women with RPL and
other women attempting to have a child.
As the RPL patients are selected a priori by having had at least three
pregnancy losses in their history, it is not surprising that they are older
than the women in the comparison group, of which more than half had
not previously been pregnant. This selection can also reasonably
account for higher household income and higher educational levels.
The women in the two groups may differ on variables that we have not
adjusted for, because they are unknown to us, but they are alike in the
desire to have a child. It is our opinion that the comparison between
the two groups is valid and relevant.
Supplementary data
Supplementary data are available at http://humrep.oxfordjournals.org/.
Acknowledgement
A.M.K. would like to thank Lisbeth Egestad, former nurse at the RPL Unit,
for the idea for the study.
Authors roles
A.M.K. initiated the study of stress and depression among women with
RPL, performed all statistical analyses and wrote the paper. L.R.O. pro-
vided the questionnaires used in the RPL group, contributed to data in-
terpretation and critically revised the manuscript. E.M.M. is the principal
investigator in the Soon Parents Study, provided the base line data on the
women in this cohort, contributed to data interpretation and critically
revised the manuscript. O.B.C. contributed to data interpretation and
critically revised the manuscript. H.S.N. supervised A.M.K. in data
analysis, participated in data interpretation and critically revised the
manuscript.

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 782
Funding
No specic funding was sought for this study. The Soon Parents Study is
funded by National Institute of Child Health and Human Development
(R01 HD060680-01A4).
Conict of interest
None declared.
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