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Hum. Reprod.

Advance Access published May 22, 2009


Human Reproduction, Vol.0, No.0 pp. 1 10, 2009
doi:10.1093/humrep/dep185

ORIGINAL ARTICLE Infertility

Stressful life events are associated with


a poor in-vitro fertilization (IVF)
outcome: a prospective study
S.M.S. Ebbesen 1,3, R. Zachariae 1, M.Y. Mehlsen 1, D. Thomsen 1,
A. Hjgaard 2, L. Ottosen 2, T. Petersen 2, and H.J. Ingerslev 2
1
Department of Psychology, University of Aarhus, Jens Chr. Skous vej 4, 8000 Aarhus, Denmark 2The Fertility Clinic, Aarhus University
Hospital, 8200 Aarhus, Denmark
3
Correspondence address. E-mail: signese@psy.au.dk

background: There is preliminary evidence to suggest an impact of stress on chances of achieving a pregnancy with in-vitro fertilization
(IVF). The majority of the available research has focused on stress related to infertility and going through IVF-treatment, and it is still unclear
whether non-fertility-related, naturally occurring stressors may inuence IVF pregnancy chances. Our aim was to explore the association
between IVF-outcome and negative, i.e. stressful, life-events during the previous 12 months.
methods: Prior to IVF, 809 women (mean age: 31.2 years) completed the List of Recent Events (LRE) and questionnaires measuring
perceived stress and depressive symptoms.
results: Women who became pregnant reported fewer non-fertility-related negative life-events prior to IVF (Mean: 2.5; SD: 2.5) than
women who did not obtain a pregnancy (Mean: 3.0; SD: 3.0) (t(465.28) 2.390, P 0.017). Logistic regression analyses revealed that the
number of negative life-events remained a signicant predictor of pregnancy (OR: 0.889; P 0.02), when controlling for age, total number of
life-events, perceived stress within the previous month, depressive symptoms, and relevant medical factors related to the patient or treat-
ment procedure, including duration of infertility, number of oocytes retrieved and infertility etiology. Mediation analyses indicated that the
association between negative life events and IVF pregnancy was partly mediated by the number of oocytes harvested during oocyte retrieval.
conclusion: A large number of life-events perceived as having a negative impact on quality of life may indicate chronic stress, and the
results of our study indicate that stress may reduce the chances of a successful outcome following IVF, possibly through psychobiological
mechanisms affecting medical end-points such as oocyte retrieval outcome.
Key words: infertility / stress / negative life events / IVF / treatment outcome

private fertility clinics has increased by 83%, from approximately


Introduction 6000 per year to more than 11 000 per year, within the last
Between 10 and 15% of all couples experience fertility problems due 10 years (National Board of Health D, 2006; The Danish Fertility
to a variety of causes (Schmidt et al., 1995; Eugster and Vingerhoets, Society, 2009).
1999; Juul et al., 1999), and infertility is increasing in the industrialized There is evidence to suggest that psychological factors may inu-
countries, possibly due to social and behavioural factors along with ence the chances of obtaining a pregnancy with IVF (Eugster and
environmental exposures (Skakkebaek et al., 2006). Infertility is com- Vingerhoets, 1999; Klonoff-Cohen, 2005; Boivin and Schmidt, 2005).
monly dened as failure to conceive after at least 1 year of attempting A number of studies have shown associations between distress,
to achieve a pregnancy with unprotected intercourse (Schmidt, 2006; mostly anxiety and depression, and IVF-outcome, although a few
Dansk Fertilitetsselskab, 2007). Couples suffering fertility problems studies have been unable to conrm this link (Milad et al., 1998;
frequently turn to articial reproductive technology (ART), and it is Lovely et al., 2003; de Klerk et al., 2008). Such ndings are often
assumed that 50% of all Danish couples experiencing infertility reported as studies on effects of stress on IVF-outcome (Harlow
seek ART treatment (Schmidt et al., 1995). In Denmark, the et al., 1996; Csemiczky et al., 2000; Lovely et al., 2003; Smeenk
number of initiated treatments with in-vitro fertilization (IVF) and et al., 2005). However, the instruments used in these studies are
intra cytoplasmatic sperm injection (ICSI) performed at public and generally measures of various types of distress which may be

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2 Ebbesen et al.

unrelated to external factors. The majority of the available studies has focused on perceived stress in relation to infertility and IVF-
therefore do not qualify as studies of stress. treatment, which may be confounded by the couples knowledge
The term stress is, in fact, often confused with distress, which, about their prognosis, and it is still unclear whether naturally occurring
although considered part of the same process, is a different phenom- stressors, which are unrelated to infertility, may inuence pregnancy
enon. The stress process is generally considered to consist of three chances following IVF. The aim of our study was therefore to investi-
aspects: (1) a stressor, i.e. an environmental demand, e.g. a life gate the possible association between negative life events and preg-
event or a series of life events, followed by (2) a set of appraisals nancy chances in a sample of women in IVF-treatment at a large
and the perception of stress, which then may lead to (3) affective, be- regional university hospital fertility clinic. We hypothesized that an
havioural and/or biological stress responses (i.e. distress) (Cohen increase in the number of negative life events would be associated
et al., 1995). Perception of stress results when the individual nds with reduced chances of obtaining IVF-induced pregnancy. Stress
the environmental demands taxing and/or threatening, and at the may impact fertility possibly by interrupting menstrual cycles
same time feels insufciently able to cope with the demands due to (Chrousos and Gold, 1992; Ferin, 1999) or through a poorer
lack of personal or environmental resources (Cohen et al., 1995). ovarian functional response to IVF-treatment (Klonoff-Cohen and
According to the original conceptualization of a stressor, it is Natarajan, 2004). We therefore planned to explore the possible
dened as that which produces stress (Selye, 1976). role of the number of retrieved oocytes as a possible mediator of
However, there is a challenge in assessing stressors in terms of life this association, if an association between negative life events and
events, as the interpretation of and capacity to handle an experienced pregnancy chances was found.
event both emotionally and practically is highly individual (Cohen et al.,
1995).
For our purpose of examining the possible association between Materials and Methods
stress and reproductive outcomes, stress is dened as events or
environmental demands (i.e. stressors), rated by the individual as
Patients
having had a negative inuence on her quality of life. These events A total of 837 women participated in this study from a cohort of approxi-
will from here on be referred to as negative life events. The psycho- mately 1578 couples undergoing their rst IVF-treatment cycle at the fer-
tility clinic. The selection criteria were: (1) rst IVF-cycle, (2) no previous
biological effects of stress may potentially be long-lasting and persist
attempts with IVF-treatment and (3) ability to read and understand Danish
even after the stressor has ceased to act (Selye, 1976).
well enough to complete the questionnaires. Couples were excluded from
Only very few studies of stress in the strict sense of the term and the study in cases of PGD (Preimplantation Genetic Diagnosis) as the indi-
IVF-outcome have been conducted, focusing primarily on perceived cation for these treatments in the clinic is usually genetic and not infertility.
marital stress and perceived stress caused by infertility and IVF- Another exclusion criterion was unplanned change of treatment type, e.g.
treatment. Infertility can indeed be very stressful for the affected from insemination to IVF due to too many follicles.
couples (Berg et al., 1991; Eugster and Vingerhoets, 1999; Oddens
et al., 1999; Webb and Daniluk, 1999; Peterson et al., 2003, 2006; Procedure
Throsby and Gill, 2004; Schmidt et al., 2005a, b), and two large As a part of a larger study, couples referred to IVF-treatment at the Ferti-
studies conducted with IVF-populations have found some support for lity Clinic, University Hospital, Skejby between October 2001 and
infertility-related stress as a predictor of IVF-outcome (Klonoff-Cohen September 2006 received oral and written information about the study
et al., 2001; Boivin and Schmidt, 2005). Another study, however, and an invitation to participate during their rst treatment cycle.
found the opposite result, i.e. higher infertility-related stress in the Women, who agreed to participate, received a baseline questionnaire
group that subsequently achieved a pregnancy (Cooper et al., 2007). package when presenting themselves at their rst scheduled appointment
One study measured IVF-treatment related stress (Klonoff-Cohen and with a fertility clinic nurse, taking place approximately on the 21th day of
Natarajan, 2004) and found this source of stress to be a predictor of the cycle. At this meeting the patients were also instructed on how to
the number of retrieved and fertilized oocytes. Women who prior to administer hormonal down-regulation with a GnRH-agonist for 2 weeks
followed by 8 days of stimulation with Follicle Stimulating Hormone
treatment had severe concerns about the medical aspects of the pro-
(FSH). The baseline questionnaire was completed at home during this
cedure, about missing work, or about nances, had up to 20% fewer
period and handed in by the patient approximately 2 weeks later when
oocytes retrieved and fertilized, which affected their pregnancy presenting herself for a follicle scan.
chances negatively. The third type of stressor studied in relation to IVF- The physician registered medical and technical details in relation to the
treatment outcome, perceived marital stress, has also been associated oocyte retrieval procedure and results of pregnancy tests were added
with treatment outcome, in that the number of cycles-to-pregnancy was when available. The study was accepted by the Regional Ethics Committee
higher in women reporting high-marital stress compared with women and approved by the Danish Data Protection Agency.
reporting low-marital stress (Boivin and Schmidt, 2005). Preliminary evi-
dence for an association between perceived marital stress and IVF Measurements
outcome has also found partial support in two other studies (Stoleru Independent variables: stress measures
et al., 1997; Verhaak et al., 2001). Finally, two studies (Facchinetti
Negative life events. An adjusted version of The List of Recent Events
et al., 1997; Gallinelli et al., 2001) have provided evidence for an (LRE) (Henderson et al., 1981) was used to measure the presence and
effect of experimentally induced stress on IVF-outcome using the psychological impact of major life events. The original version of the
Stroop Color Word Test (Stroop, 1935). scale consists of an event list of 59 items describing various potentially
Taken together the available evidence is limited, yet suggestive of a stressful environmental events within the following categories: illness,
stress effect on IVF-outcome. The majority of the available research injury and accident, bereavement, pregnancy/children, changes in
Stressful life events and IVF outcome 3

relationships, living conditions, study/schooling, work/employment, In cases of multiple comparisons, Bonferroni adjustments were made in
nances and legal difculties. For each event, the participants are to order to reduce the risk of type-1 error by dividing the alpha level with
answer yes or no to the question Did you within the past 12 months the number of comparisons, resulting in accordingly adjusted p-levels
experience [this event]?. For each event, the participants were asked to (Tabachnick and Fidell, 2007). It has been argued that in large samples,
indicate whether the event had an impact on subjective well-being by normal distribution is not a prerequisite for the t-test (Lumley et al.,
answering the question: Did this event have a negative impact on your 2002), thus in the analyses t-tests are chosen over non-parametric test
life quality with yes or no. The LRE has been shown to adequately in order to retain statistical power.
assess the presence of negative life events in the general population Univariate analyses were conducted, comparing patients who agreed to
(Henderson et al., 1981), and has shown predictive strength in relation participate to the eligible non-participating patients in the cohort. Indepen-
to physical health symptoms (Cohen et al., 1991). In the present study a dent samples t-test was applied in order to explore differences between
shortened 37-item version of the list was used. We excluded events the two groups concerning female age, duration of infertility, total
such as death of spouse, divorce, new partner, giving birth, since these hormone dose before aspiration, number of previous births, number of
events were irrelevant to the sample due to the hospitals admission previous provoked and spontaneous miscarriages, number of previous
criteria for IVF-treatment. Two total scores are derived from the LRE: ectopic pregnancies. x2-analysis was applied to assess differences in preg-
the total number of experienced events, which in the following is nancy outcomes, smoking habits and coffee intake.
termed number of events, and total number of events perceived as Means and standard deviations were calculated for the independent
having had a negative impact on quality of life, from here on termed variables (IVs) BDI, PSS-10 and LRE for women who subsequently did
negative life events. Thus from the total number of events, negative or did not achieve pregnancy following IVF-procedure. A series of inde-
life events refer to the (sum of) events evaluated by the person as pendent samples t-test was carried out to assess differences between
having a negative inuence on her quality of life. these two groups.
If differences in the number of negative life events between IVF-
Perceived stress. Perceived stress within the past month was assessed with successful and non-successful women were found, the data were initially
the Perceived Stress Scale (PSS-10) (Cohen and Williamson, 1988), con- inspected for possible patient- or treatment-related confounders and
sisting of 10 items measuring the present level of self rated stress. The mediators of this association: correlation analyses/linear regression tech-
PSS-10 is a widely used measure that has been shown to be reliable and niques were applied to investigate associations with dependent variables
valid. The internal consistency of the PSS-10 was considered acceptable (DVs): number of oocytes and negative life events, and logistic regression
within this sample (Cronbachs a 0.85). was used for detection of possible associations with pregnancy chances as
a DV. Statistical information is provided for any signicant results.
Next, a series of direct regression analyses were planned in order to
Independent variables: distress measures
examine the main hypothesis of an association between negative life
Depressive symptoms. The Beck Depression Inventory (BDI-II) (Beck et al., events and IVF pregnancy chances, although controlling for relevant bio-
1996) was used to measure depressive symptoms. The BDI consists of 21 logical and medical factors relating to infertility and IVF-treatment pro-
items measuring the severity of both somatic and cognitive-affective cedure. Subsequently, to test the possible mediating role of number of
depressive symptoms. It is a widely used instrument for assessing depress- oocytes for the association between negative life events and IVF preg-
ive symptoms in various populations and has shown good reliability and nancy, we used the method described by Baron and Kenny (Baron and
validity. The internal consistency of the BDI in this sample was acceptable Kenny, 1986). Mediation is proposed to be established when (1) the IV
(a 0.71). signicantly predicts the DV, (2) the IV signicantly predicts the mediator,
(3) the mediator predicts the DV when controlling for the IV and (4)
Dependent variables when controlling for the mediator, the effect of the IV on the DV
ceases (complete mediation) or is reduced (partial mediation) (Baron
Pregnancy. A positive pregnancy test was dened by measurement of a
and Kenny, 1986). Finally, x2 analyses were conducted for each
serum HCG-level of .20 IU 2 weeks following embryo transfer. Pregnant
possible life event on the LRE in order to explore whether some
patients were scanned routinely 5 weeks after embryo transfer. Clinical
types of events posed a higher risk for an adverse IVF-outcome than
pregnancy was dened as a live intrauterine pregnancy detected by ultra-
others.
sound. Where nothing else is specied, pregnancy and IVF-outcome refers
to clinical pregnancy.

Additional measures Missing values


The number of oocytes retrieved at oocyte retrieval, the cause of infertility For all psychometric scales (excl. LRE), the proportion of missing values
(male, tubal, endometriosis, ovulation factor, idiopathic) and the type of was computed, and missing values were substituted with the mean
treatment (ICSI or IVF) were registered by the physician. In case of values for the remaining scale items. In cases where more than 50% of
more than one cause of infertility, the most clinically signicant cause items in the respective scales were unanswered, the case was omitted
was recorded as the primary cause. In the following, cause of infertility from the analysis. Substituting missing values with the mean for the remain-
refers to the primary cause of infertility. Medical and treatment-related ing scale items is recommended, provided that the internal reliability of the
information and information on life style factors was extracted from the scales is high (i.e. a . 0.70) (Schafer and Graham, 2002).
hospital register database and used for comparison between sample and Some variables from the hospital register contained a proportion of
non-participants in the cohort. BMI was calculated from self-reported unubstituted missing data, and are primarily used for comparative analyses
weight and height data. Basal FSH was measured on cycle day 2 4. between participants and non-participants. N is reported for these ana-
lyses. In addition, exploratory analyses were conducted on the basis of
Statistical analyses hospital register data with FSH, BMI, coffee, smoking and duration of
The statistical analyses were conducted with the Statistics Package for the infertility. All other analyses are based on data collected as a part of this
Social Sciences (SPSS) version 15.0. study.
4 Ebbesen et al.

Results No differences were found between patients who agreed to partici-


pate and the 522 eligible non-participating patients in the cohort (total
Study sample n 1359) with respect to age (n 1359), duration of infertility (n
1259) and daily amount of smoking (n 1001), number of previous
Of the 837 couples, 18 cases had not completed questionnaires at
abortions (spontaneous or provoked), number of previous ectopic
baseline and were excluded from the data analyses. Another 10
pregnancies and number of previous births (n 729). Also, there
cases were excluded for various reasons (puncture of cysts, spon-
was no statistically signicant difference between the study group
taneous pregnancy, ovulation prior to oocyte retrieval, treatment can-
and the rest of the cohort as to pregnancy outcome from the rst
cellation or moving away). This resulted in a total of 809 couples in the
treatment cycle (n 336) (data not shown).
nal sample. Sociodemographic and reproductive characteristics of the
The group of study participants represented a larger proportion of
sample can be seen in Table I.
male factor infertility cases (46% male factor, 33% female factor and
Minor inconsistencies between numbers given in Table I and in the
21% idiopathic) compared with the non-participants (37% male factor,
following comparative analyses between sample and non-participants
31% female factor and 32% idiopathic) who, in return represented
are due to data being drawn from two different sources, i.e. study ques-
slightly more cases of idiopathic infertility (x2 (2) 20.193, P
tionnaires and hospital register. Study questionnaire data are used to
0.0005) (n 1359). In accordance, study participants represented a
describe sample characteristics, as these data are more detailed.
larger proportion of patients receiving ICSI treatment for male factor
infertility (40% ICSI, 60% IVF) than the rest of the cohort (23% ICSI,
Table I Socio-demographic and reproductive 77% IVF) (x2(1) 39.220, P 0.0005) (n 1359). Study participants
characteristics of study participants received a higher total hormone dose before aspiration (MEAN:
1650.60 IU, SD: 1592.36 IU) compared with the rest of the cohort
Characteristic n Mean (SD) Range sample (MEAN: 1252.03 IU, SD: 1795.29 IU) (t(1358) 24.272,
or %
........................................................................................ P 0.0005) (n 1358). Total hormone dose before aspiration
Age, mean (SD) 796 31.2 (3.9) [21, 40] showed a moderately skewed distribution. Among study participants
Marriage/Living together 804 4 6 years [2, 8] there was a larger coffee intake compared with the non-participants in
(2 years) the cohort (x2(3) 9.082, P 0.028) (n 986). When correcting
Education (ISCED-based, (UNESCO, 2009)) for multiple comparisons, using a Bonferroni adjustment of the alpha
Lower secondary general (7 years) 4 0.5% level (0.05/13 0.004), differences between participants and non-
Lower secondary general (8 46 5.7% participants coffee habits ceased to be signicant.
10 years)
Upper secondary (11 13 years) 245 30.3% Comparing pregnant and non-pregnant
Tertiary , master degree (14 366 45.2% women
17 years)
Means and standard deviations for women who subsequently did or
Tertiary master degree 137 16.9%
did not achieve pregnancy following the IVF-procedure on the IVs
(18 years)
BDI, PSS-10 and LRE are shown in Table II. The BDI and negative
Missing data 11 1.4%
life events showed moderately skewed distributions. A series of inde-
Duration of infertility in months 668 31.5 (22.9) [0 228]
pendent samples t-tests showed no signicant differences between
Type of procedure successful and unsuccessful IVF-patients for depressive symptoms,
ICSI long down-regulation 284 35.1% perceived stress and total number of life events (with an adjusted
IVF long down-regulation 385 47.6% (0.05/3) alpha level of 0.02) (data not shown).
IVF/ICSI mild hormone stimulation 51 6.3% Initial testing of the main hypothesis showed that women who
Missing data 89 11% obtained a clinical pregnancy following the IVF-procedure reported a
Cause of infertility statistically signicantly smaller proportion of negative life events
Ovulation factor 26 3.2% than women who did not obtain pregnancy. These results are
Tubal 135 16.7% shown in Table II.
Endometriosis 79 9.8%
Male 351 43.4% Correlations with reproductive outcomes
Idiopathic 145 17.9% The number of oocytes retrieved during oocyte retrieval showed a
Missing data 73 9% small, but statistically signicant negative correlation with number of
IVF-treatment outcome negative life events (r 20.10, n 772, P , 0.01 (2-tailed)), and
was also a statistically signicant univariate predictor of pregnancy
Positive pregnancy test 280 34.6%
(OR 1.072, n 733, P 0.0005). FSH is an indicator of potential
Clinical pregnancy 217 26.8%
ovarian response and the ovarian response is a predictor of
Missing data 14 1.7%
IVF-outcome (Yih et al., 2005). Although FSH was a statistically signi-
Number of oocytes retrieved 776 6.93 (4.4) [0 25]
cant univariate predictor of number of oocytes (b 20.197, n
Missing data 33 4% 495, P 0.0005), we found no association between FSH and preg-
nancy, or between negative life events and FSH (no data shown).
Stressful life events and IVF outcome 5

Table II Differences between pregnant and non-pregnant women

Measures Pregnant Non-pregnant T P


Mean (SD) Mean (SD)
.............................................................................................................................................................................................
Perceived stress 14.8 (6.0) 14.4 (6.0) ns
Depressive symptoms 7.2 (6.1) 7.2 (6.5) ns
Total number of life events 5.4 (3.0) 5.9 (3.4) ns
Negative life events 2.5 (2.5) 3.0 (3.0) T(465.28) 2.390 P 0.017

We were therefore unable to establish FSH as a possible mediator, confounded by the persons current level of perceived stress and
either of the association between negative life events and the depressive symptoms, and since the correlations were not sufciently
number of oocytes or the association between negative life events large to suggest problems related to multicollinearity (Tabachnick and
and pregnancy. Similarly, although age was shown to be signicantly Fidell, 2007), these two factors were included in the regression model.
associated with pregnancy (OR 0.948, n 783, P 0.01), this vari- The models provided an acceptable t to the data as indicated by
able was unrelated to negative life events (no data shown), and can the omnibus test of model coefcients (Positive pregnancy test:
thus likewise be excluded as a possible mediator. There were no sig- x2(5) 17.03, P 0.004, n 764, Clinical pregnancy: x2(5)
nicant differences in the number of oocytes retrieved as a function of 16.35), P 0.006, n 764) explaining 23% of the variance in preg-
treatment type (IVF or ICSI) (no data shown). BMI (n 651), daily nancy rate (pseudo R 2-statistics). The IV, negative life events,
smoking habits (n 521), and daily coffee intake (n 518) were remained a statistically signicant predictor of a positive pregnancy
unrelated to clinical pregnancy (data not shown). test following IVF, when controlling for depressive symptoms,
perceived stress, age and total number of events experienced (OR:
0.909, P 0.018). Concerning clinical pregnancy, there was a trend
Effects of negative life events on pregnancy toward negative life events being a predictor IVF-outcome when con-
chances trolling for the same variables (OR: 0.922, P 0.063).
To test whether negative life events predicted the likelihood of obtain- When using pregnancy as a DV, it is important to control for
ing a positive IVF-treatment outcome, a series of logistic regression selected medical factors related to the IVF-patient and the treatment.
analyses were carried out with pregnancy versus no pregnancy as We therefore conducted a second logistic regression analysis,
the DV and negative life events as the predictor, while controlling additionally controlling for number of oocytes, duration of infertility
for total number of life events experienced, current perceived in months and cause of infertility, categorized into female, male or
stress, depressive symptoms, and age. idiopathic factor. Female factor was used as a simple contrast (refer-
Moderate to strong positive correlations were seen between the ence group) in the analysis. The results are presented in Table III.
number of negative life events (LRE) and depressive symptoms (BDI), Negative life events continued to be a predictor of clinical pregnancy
and between negative life events and perceived stress within the last chances when controlling for number of oocytes, cause of infertility
month (PSS-10). Whether life events are negatively evaluated may be and duration of infertility in the model (OR: 0.889, P 0.02). The

Table III Effects of stress measures on IVF outcome, when controlling for medical variables

Measures Coefcient (B) S.E. Wald d.f. Odds Ratio 95% CI P


.............................................................................................................................................................................................
Negative life eventsa 20.118 0.050 5.423 1 0.889 [0.805, 0.982] 0.02
Number of eventsb 0.009 0.040 0.058 1 1.010 [0.934, 1.091] 0.81
Depressive symptoms 0.005 0.020 0.070 1 1.005 [0.967, 1.045] 0.79
Perceived stress 0.032 0.022 2.181 1 1.032 [0.990, 1.077] 0.14
Age 20.074 0.026 8.349 1 0.928 [0.882, 0.976] 0.00
Number of oocytes 0.061 0.022 7.839 1 1.063 [1.018, 1.109] 0.01
Female cause of infertility 1.586 2 0.45
Male cause of infertility 20.269 0.215 1.570 1 0.764 [0.501, 1.164] 0.21
Idiopathic infertility 20.179 0.269 0.444 1 0.836 [0.493, 1.417] 0.50
Duration of infertility 0.004 0.004 0.936 1 1.004 [0.996, 1.012] 0.33

All variables used in the analysis are shown.


N 588 (Missing cases: 221). Pseudo R 2-statistics: Cox and Snell, R 2 0.048, Nagelkerke R 2 0.069.
a
LRE, events rated as having had negative impact on quality of life.
b
LRE, number of events.
6 Ebbesen et al.

results indicated that for every negative life event a patient had experi- among close relatives. A larger proportion of the women who
enced within the past 12 months, there was approximately a 10% reported having had a parent with serious illness did not achieve IVF-
decrease in the chances of obtaining a clinical pregnancy. pregnancy (21% pregnant) in the year following this event compared
Age and the number of oocytes retrieved were both signicantly with those who did not report this type of event (29% pregnant)
associated with chances of obtaining a clinical pregnancy, even when (X2(1) 3.691, P , 0.055, total n 795) (Bonferroni adjusted
controlling for other medical factors related to the patient or the IVF- p-level of 0.001 (0.05/37)).
treatment. Duration of infertility in months and cause of infertility did
not predict clinical pregnancy. As in the previous analyses, perceived
recent stress and depressive symptoms did not emerge as signicant Discussion
independent predictors of the DV. Our results showed that women who became pregnant following IVF-
treatment reported fewer negative life events than women who did
Mediation analysis not obtain pregnancy. The data in this study indicate that the lower
As a small correlation was observed between the number of negative pregnancy rate associated with negative life events is partly mediated
life events and number of oocytes retrieved, we further examined by a lower number of oocytes harvested. Our results thus extend pre-
whether the association between number of negative life events and vious ndings linking the presence of infertility and relationship stress
pregnancy rates could possibly be mediated by number of oocytes with impaired chances of achieving pregnancy with an IVF-procedure
harvested during oocyte retrieval. (Facchinetti et al., 1997; Stoleru et al., 1997; Gallinelli et al., 2001;
A series of linear regression analyses showed that the number of Klonoff-Cohen et al., 2001; Verhaak et al., 2001; Boivin and
negative life events signicantly predicted both IVF-outcome and Schmidt, 2005).
number of oocytes harvested during the oocyte retrieval procedure.
Furthermore, when controlling for negative life events, the number Effects of negative life events
of oocytes harvested predicted pregnancy. When controlling for on IVF-outcome
oocytes harvested, the rst association between negative life events
Our results are in line with two of the three other studies exploring
and pregnancy ceased to be signicant. The results of the mediation
associations between environmental stressors and reduced chances
analysis are shown in Table IV. Applying the criteria for mediation
of pregnancy following IVF-treatment. In a 12-month prospective
(Baron and Kenny, 1986), the analysis showed the number of
study by Boivin and Schmidt (2005) of a cohort of 818 Danish
oocytes harvested during oocyte retrieval to be a partial mediator
couples in IVF-treatment, an association was found between baseline
of the association between negative life events and pregnancy.
perceived infertility-related stress and pregnancy obtained within the
following 12 months of treatment. Among couples reporting that fer-
Impact of specic types of life events tility problems had disrupted their lives, were difcult to cope with, or
Finally, analyses were conducted to explore whether failure to obtain a had caused severe strain on their physical and mental health, fewer
pregnancy was associated with specic life events. x2-tests revealed a conceived within the subsequent 12 months of treatment when com-
trend as to whether the woman reported having experienced violence pared with couples not reporting such stressors. The authors also
or threats of violence within the past 12 months or not: 16 women explored another potential environmental stressor, marital problems,
reported experiences of violence or threats of violence and none of and found that the number of cycles-to pregnancy was signicantly
these women achieved a viable pregnancy following their rst cycle higher in women reporting high perceived marital stress compared
of IVF (X2(1) 6.130, P , 0.009 (Fishers Exact Test), total n with women reporting low levels of this stressor. Women who
795). Furthermore, a trend was seen with respect to whether reported that infertility had caused a crisis in their relationship, given
couples had experienced prolonged or serious incidents of illness rise to thoughts of divorce, or placed great strain on their sexual
relationship thus had reduced chances of a successful IVF-outcome
(Boivin and Schmidt, 2005). The preliminary evidence for an associ-
Table IV Mediation analysis
ation between perceived marital stress and IVF-outcome has also
Testing for mediation of the association between number of found support in one other study (Stoleru et al., 1997). One study,
negative life events and IVF outcome however, has reported the opposite result (Cooper et al., 2007),
........................................................................................
but this study was potentially confounded by access to psychological
Step Coeff. (B) P
........................................................................................ counselling offered by the fertility clinic, which was not controlled
1: Negative life events predict IVF-outcome 20.012 0.028 for statistically. Together with our results, the limited available evi-
2: Negative life events predict number of 20.154 0.005 dence is suggestive of an association between stress and fertility,
oocytes with stress having a detrimental impact on chances of achieving a
3: Number of oocytes predict IVF-outcome, 0.014 0.000 viable pregnancy through IVF-treatment.
controlling for negative life events Depression and perceived stress within the past month were not
4: Negative life eventsIVF-outcome 20.010 0.072 (ns) signicant predictors of IVF-outcome in multivariate analysis. This is
association reduced, when controlling for not an uncommon nding, and previous studies have shown low pre-
the number of oocytes
dictive quality of the particular measures used (BDI and PSS-10) con-
N 791 (step 1), 772 (step 2, 4), 773 (step 3). cerning IVF-outcomes (Klonoff-Cohen et al., 2001; Smeenk et al.,
2001). The BDI may be too exclusively designed for populations of
Stressful life events and IVF outcome 7

clinically depressed individuals, failing to capture ongoing mood shifts of negative life events as well as for implementing alternative health
in psychologically healthy samples, and several studies have stated behaviours. If the effect is unrelated to health behaviour, interventions
that IVF-patients are not clinically depressed (Greil, 1997; Eugster targeted at conscious processing of psychological consequences of
and Vingerhoets, 1999). experiencing negative life events may alleviate psychobiological stress
The PSS-10 measures current experiences of stress in that the time- reactions and thereby possibly optimize pregnancy chances following
frame is limited to feelings of stress during the past month, and we IVF through a reduction of stress-related HPA-axis activity.
suggest that the uctuations in current stress captured by the
PSS-10 may not be potent enough to harm the reproductive Mediating mechanisms
system. Consistent with this, perceived stress did not emerge as a sig-
Stress (Facchinetti et al., 1997; Klonoff-Cohen et al., 2001; Gallinelli
nicant predictor of IVF-outcome. In contrast to the lack of effect of
et al., 2001) and distress (Sanders and Bruce, 1999; Smeenk et al.,
perceived current stress, we did nd an effect of having experienced
2001) have been found to be associated with a poorer ovarian func-
traumatic or negative life events within the past 12 months on preg-
tional response to IVF-treatment, and reduced fertilization, implan-
nancy chances. Major life stressors may be viewed as a more
tation and live birth rates. It has been suggested that stress may
chronic source of stress. The fact that the effect of negative life
impact fertility by interrupting menstrual cycles (Demyttenaere et al.,
events on IVF-outcome was independent of effects of distress, i.e.
1992) or by interacting with aspects of the IVF-treatment (Boivin
depression and of perceived stress, warrants further discussion.
and Takefman, 1995); our study has provided preliminary evidence
Negative life events may exert inuence on the female reproductive
for the latter.
system in two ways, either directly or indirectly (i.e. through life style
The number of oocytes retrieved during oocyte retrieval is a critical
behaviours). It is possible that the experience of negative life events
characteristic of the ovarian response to IVF-treatment. The quality of
may result in a subtle stress reaction, that may only be partially per-
the ovarian response is a potent predictor of IVF-outcome and has
ceived (or even suppressed) by the individual. Although thus not
been shown to predict increased clinical pregnancy rates relatively
necessarily being considered by the individual as a source of daily (per-
independent of other factors such as maternal age (Yih et al., 2005).
ceived) stress, the negative life events or series of negative life events
It has been reported that the biological response of the ovaries
may over time lead to an increase in maladaptive coping strategies and
during IVF-treatment (e.g. number of follicles and number of
life style behaviours (i.e. diet, drinking, smoking habits etc.) and thus
oocytes) can be predicted by psychological variables (Lancastle and
indirectly impact pregnancy chances. The experience of highly stressful
Boivin, 2005). This suggests a possible association between stress,
life events is generally known to be associated with behavioural health
number of oocytes, and pregnancy. Wishing to gain a more detailed
problems (i.e. maladaptive life style behaviours in terms of eating
knowledge about the mechanisms at work, we used mediation analysis
behaviours, alcohol and cigarette use) (Veenstra et al., 2007;
to explore oocytes as a potential link in the stress-fertility association,
Bacharach et al., 2008; Hooper et al., 2008; Ogden et al., 2009),
and found that the number of oocytes retrieved was a partial mediator
and behavioural health problems are known to be associated with
between negative life events and IVF-pregnancy.
reduced fertilization chances (Klonoff-Cohen, 2005). Specically, in
Evidence for a link between stress and number of oocytes has been
one study the authors investigated female alcohol consumption and
reported in a study by Klonoff-Cohen and colleagues, who prospectively
found this related to pregnancy chances (Klonoff-Cohen et al., 2003).
studied infertility-related stress and IVF-treatment-related stress in 151
This possibility is however in need of further testing, as our study
female IVF-patients (Klonoff-Cohen et al., 2001; Klonoff-Cohen and
only used relatively simple measures of life-style behaviours and had
Natarajan, 2004). Although they did not nd infertility-related stress
no appropriate measure of alcohol consumption, which may be an
to be a signicant predictor of pregnancy, trends were found for this
important life-style variable in this context. BMI was unrelated to
source of stress as a predictor of number of oocytes retrieved (Klonoff-
probability of a clinical pregnancy. However, as BMI was based upon
Cohen et al., 2001). Concerning treatment-related stress, it appeared
self-reported measures, this may have given rise to bias.
that women who prior to treatment had severe concerns about the
A direct effect of negative life events on the female reproductive
medical aspects of the procedure, about missing work, or about
system may take place through release of stress hormones such as
nances, had up to 20% fewer oocytes retrieved and fertilized (Klonoff-
cortisol, which may cause estradiol inhibition indicated by impaired
Cohen and Natarajan, 2004).
granulosa cell function and possibly compromised follicular maturation
Together with our ndings, the results by Klonoff-Cohen et al. thus
and lower number of oocytes to be harvested (Lancastle and Boivin,
suggest a detrimental effect of stress on the number of oocytes that
2005). The more severe the stress, the more cycle disturbance is
can be retrieved during procedure. Our results pointed to further con-
likely to be produced, with stress responses inhibiting the reproductive
sequences in terms of a reduction in pregnancy chances.
system through activation of the hypothalamic-pituitary-adrenal (HPA)
axis (Chrousos and Gold, 1992).
In terms of psychological interventions, it seems premature to put Impact of specic types of life events
forth suggestions, before direct and/or indirect pathways of a stress Psychological stress refers to an individuals psychological reaction
effect on pregnancy chances have been claried. Should further when faced with challenges (stressors) exceeding his or her personal
research point to mediating effects of maladaptive coping strategies resources, i.e. coping abilities (Lazarus and Folkman, 1984). The
and life style behaviours (i.e. diet, drinking, smoking habits etc.) in total amount of psychological stress experienced is known to be inu-
the association between stress and IVF-outcome, cognitive- enced by the level of subjective control over the situation, which again
behavioural interventions could provide a useful tool for addressing is closely related to perceived coping possibilities. According to the
these maladaptive ways of handling the psychological consequences theoretical and empirical works on stress, it is especially the prolonged
8 Ebbesen et al.

exposure to an environmental stressor and/or uncontrollable situ- between negative life events and IVF-outcome. Participants and non-
ations that lead to human psychological and psychobiological stress participants were also generally similar with respect to age as well as
with potentially adverse consequences for health (Bloom and Lazer- life style factors, medical variables, and reproductive history, suggesting
son, 1988). Trends were found in our study that long lasting illness that our results can be considered relatively generalizable.
within the nearest family and experiences with violence were more Use of variables from the hospital register meant acceptance of an
highly related to IVF-outcome than other stressors. Long lasting appreciable proportion of missing values on some variables, thus
illness in the family and experienced violence are highly uncontrollable results from these analyses must be interpreted with some caution,
and therefore likely to produce a very high amount of psychological e.g. comparisons between participants and non-participants. In the
stress, which, without proper resolution, may also be of a long analyses, we were unable to investigate any effects of alcohol con-
lasting character. Due to the relatively small number of participants sumption as we did not have an appropriate measure of this potential
having experienced such life events, these results must however be confounder. Future studies should include measures of alcohol con-
considered preliminary, and more studies are needed to conrm sumption in order to assess this factor as a possible mediator of
this nding. stress-infertility associations. Concerning the non-appearance of a stat-
istically signicant association of FSH, BMI and other life style habits
with IVF-outcome, we cannot exclude lack of statistical power as a
Strengths and limitations possible explanation.
This is the rst study to examine a possible association between
IVF-outcome and stress following negative life experiences, even
though taking into account procedural stress related to the immediate Conclusion
treatment situation. Investigating life events within the year before Our results indicate that the number of negative life events inuences
commencing treatment provides knowledge about stressors of poten- IVF outcome, an effect that is partly mediated by number of oocytes
tial damage to the reproductive system that take place at a very early harvested during treatment. A large number of negative life-events
point in time, compared with the time frame set in the existing studies may indicate chronic stress, which may only be partially acknowledged
on stress and IVF-outcome. This study also includes a sufciently large by the individual, and which could reduce the chances of a successful
sample to explore mechanisms while at the same time controlling for IVF-outcome through a detrimental impact on the number of oocytes
relevant demographic, clinical and treatment-related factors. Existing retrieved. Ovarian response is one of the most important predictors
studies exploring psychological factors in IVF-treatment rarely of pregnancy and may prove to be an important link in the association
include more than 100 participants, and most studies include less between psychological factors, e.g. stress, and pregnancy. More
than 50 participants (e.g. Demyttenaere et al., 1991; Boivin and Takef- studies are needed, focusing specically on stress and preferably
man, 1995; Facchinetti et al., 1997; Csemiczky et al., 2000; Lovely including physiological measures, in order to properly clarify the mech-
et al., 2003), which limits the number of IVs in the statistical analyses anisms behind the stress-fertility association, both in terms of (1) indir-
and enhances the risk of type-2 error (Tabachnick and Fidell, 2007). ect pathways of this association, i.e. health problem behaviour, and (2)
However, our study is not without limitations. We had no precise direct effects in terms of psychoneuroendocrine mechanisms.
monitoring of non-response per se as questionnaires unfortunately
were handed out at the clinic without complete registration of those
who chose to participate and those who declined. Therefore a detailed Acknowledgements
non-responder analysis was not possible as some of the women may not
The authors gratefully thank all the couples who willingly participated
have been offered participation. The problem was addressed by careful
in our study as well as the co-workers of Aarhus University Hospital.
comparison between participants and non-participants in the cohort on
Special thanks are extended to the nurses at the hospital for taking
the basis of hospital registry data on relevant variables. Comparisons of
great interest in our study and for providing invaluable help in
participants with non-participating women in the same cohort showed
handing out/distributing the questionnaires to all the couples. Also,
that participants included more cases of male factor infertility and ICSI
the authors would like to thank Sren Christensen for valuable statisti-
treatment than non-participants, whereas the latter group consisted
cal assistance.
of more cases of idiopathic infertility. Treatment modality and infertility
etiology were however unrelated to pregnancy in our study, and general
differences for these two parameters are therefore less likely to affect
the external validity of our ndings concerning stress and IVF-outcome.
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