Does psychological stress affect the outcome of in vitro fertilization?

L. Anderheim1,3, H. Holter1, C. Bergh1 and A. Möller2

1 Reproductive Medicine, Department of Obstetrics and Gynaecology, Institution of Women’s and Children’s Health, Sahlgrenska University Hospital, Göteborg University, SE-413 45 Göteborg, and 2 Nordic School of Public Health, Box 12133, SE-402 42 Göteborg, Sweden

3 To whom correspondence should be addressed. E-mail: lisbeth.anderheim-soderqvist{at}vgregion.se


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Measures
 Statistics
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: The aim of the study was to investigate the effect of psychological stress before and during IVF treatment on the outcome of IVF, controlling for known physiological predictors. METHODS: This is a prospective, longitudinal study. A total of 166 women were studied during their first IVF treatment. They answered questionnaires concerning psychological and social factors on two occasions. Psychological well-being was measured by the Psychological General Well-Being (PGWB) index and psychological effects of infertility were assessed by 14 items. RESULTS: In the analysis of the psychological variables, no differences were found between pregnant and non-pregnant women. The total number of good quality embryos, the number of good quality embryos transferred, and the number of embryos transferred were significantly higher in the pregnant than in the non-pregnant group. In a multivariate analysis, the number of good quality embryos transferred was the only variable that was independently associated with pregnancy. CONCLUSIONS: We found no evidence that psychological stress had any influence on the outcome of IVF treatment. When counselling infertile couples, it might be possible to reduce the stress they experience during the treatment procedure by informing them of these findings.

Key words: counselling/in vitro fertilization/outcome/psychology/stress/well-being


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Measures
 Statistics
 Results
 Discussion
 Acknowledgements
 References
 
For most couples unable to conceive, childlessness is a source of stress. Both the condition of infertility and its treatment cause stress, and it is well known that infertility can induce psychological disturbances (Möller and Fällström, 1991Go; Lalos, 1999Go). Infertility has been ranked as one of the greatest sources of stress in a person’s life, comparable to a somatic disease such as cancer (Domar et al., 1993Go). The stress of infertility treatment was ranked second to that involving the death of a family member or divorce by couples undergoing this treatment (Freeman et al., 1985Go; Baram et al., 1988Go).

The concept of stress can be defined and described in different ways. In the present study, stress refers to reactions (psychological or physiological) to the differences between the woman’s experience of demands, both internal and external, and how she perceives her capacity to cope with these demands.

Several authors have discussed the concept of stress as an aetiological factor related to infertility (Seibel and Taymor, 1982Go; Harrison, 1983Go; Harrison et al., 1986Go, 1987Go; Edelman and Golombok, 1989; Reading et al., 1989Go; Domar et al., 1990Go; Strauss et al., 1992Go; Wasser et al., 1993Go; Christie, 1994Go; Vartiainen et al., 1994Go; Domar, 1996Go). The mechanisms in this interaction are not yet known, but different ways in which psychological stress reactions might influence reproduction have been suggested (Reading et al., 1989Go). These are: (i) by disturbing the secretion of gonadotropin; (ii) by local effects of catecholamines on the uterus and on the functions of the fallopian tubes; (iii) by immunological processes that can disturb implantation; and (iv) by influencing behaviour, e.g. drug addiction and sexual problems. In addition, an association between psychological stress and sperm quality has been observed in some studies (Harrison et al., 1987Go; Ragni and Caccamo, 1992Go), while others have found that the effect of psychological stress on sperm quality is small or non-existent (Hjollund et al., 2004Go). The stress caused by infertility itself might also further diminish the chances of having a child irrespective of the primary cause of the infertility.

However, whether psychological factors have any independent influence on the outcome of in vitro fertilization is still under discussion. Several researchers have demonstrated that the treatment procedure can cause women to experience great psychological stress (Newton et al., 1990Go; Litt et al., 1992Go; Mahlstedt, 1994Go), but whether psychological stress has any effect on treatment outcome is unclear. It seems, however, that variables such as age of the woman, embryo quality, infertility diagnosis, IVF technique and number of earlier trials do not totally explain the variation in the results of IVF treatment.

Harlow and co-workers (Harlow et al., 1996Go) found no evidence that psychological stress has any influence on the outcome of IVF. The groups conceiving and not conceiving had similar levels of state and trait anxiety. In another study, high levels of anxiety and stress did not predict an adverse pregnancy outcome (Milad et al., 1998Go).

In contrast, other studies found an association between psychological stress and the results of in vitro fertilization. In these studies, the dependent variable was the outcome of IVF, either as pregnancies or births. The independent variables were anxiety (Demyttenaere et al., 1989Go, 1992Go, 1994Go; Merari et al., 1992Go, 1996Go; Boivin and Takefman, 1995Go; Csemiczky et al., 2000Go; Smeenk et al., 2001Go; Lancastle and Boivin, 2005Go), depression (Reading, 1992Go; Merari et al., 1992Go, 1996Go; Smeenk et al., 2001Go), coping patterns or coping resources (Demyttenaere et al., 1992Go; Merari et al., 1992Go, 1996Go; Boivin and Takefman, 1995Go), psychosocial interventions ( Boivin, 2003Go), baseline and procedural stress (Klonoff-Cohen et al., 2001Go), marital satisfaction (Boivin and Takefman, 1995Go; Merari et al., 1996Go), personality (Kemeter, 1988Go), intensity of the child-wish (Stoleru et al., 1996Go), sperm quality related to psychological stress (Harrison et al., 1987Go; Ragni and Caccamo, 1992Go), participation in psychotherapy (Brandt and Zech, 1991Go), and vulnerability to psychological stress (Facchinetti et al., 1997Go).

However, support for a causal relationship between psychological stress and results of IVF is often weak. Few studies indicating an association between psychological stress and IVF outcome have tried to control for known confounders. In addition, the number of women included has often been low.

Thus, several studies have shown certain physiological markers such as age, duration of infertility, number of earlier failed IVF cycles, tubal indication for infertility, previous pregnancies, number of good quality embryos transferred and number of oocytes to be independent predictors of IVF outcome (Stolwijk et al., 1996Go; Templeton et al., 1996Go; Strandell et al., 2000Go).

The aim of the present study was to investigate the effect of psychological stress before and during IVF treatment on the outcome of IVF, controlling for known physiological predictors. The hypothesis was that psychological stress may have a negative influence on the results of IVF. Psychological stress is expressed here as a low level of general psychological well-being including experienced negative psychological effects of infertility, negative effects of infertility on the woman’s relationship with her partner, high intensity of the child-wish, experiencing infertility as a threat to a positive self-picture, experiencing life as meaningless and feeling little affinity with others, and a major difference between an ideal life situation and the way the woman experiences the life she is living.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Measures
 Statistics
 Results
 Discussion
 Acknowledgements
 References
 
Design
This is a prospective, longitudinal study of women during their first IVF cycle at Sahlgrenska University Hospital, Göteborg, Sweden. The women were recruited between March 1999 and June 2002 from the Reproductive Unit, Department of Obstetrics and Gynaecology. They answered questionnaires concerning psychological and social factors on two occasions during the IVF treatment. The study was approved by the ethics committee at Göteborg University.

Subjects
Two hundred women planning to start their first IVF/ICSI treatment were invited to participate in the study. Before their first visit to the clinic, the women received a letter with information about the study. Following an information meeting at the clinic, the women were asked if they were interested in participating. The exclusion criteria were inadequate knowledge of the Swedish language and participation in other studies. A total of 166 women agreed to participate in the study. The main reasons for not participating in the study were lack of interest, considering the treatment too demanding, and not wanting any more obligations. The mean age of those who declined to participate in the study was 32.3 years and did not differ significantly from that of participants. The pregnancy rate per started cycle among women not participating in the study was 38.2%, which did not differ significantly from the rate of those who participated (34.9%).

The demographic data for all women who received embryo transfer, obtained from the women’s medical records, are presented in Table I.


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Table I. Background variables for pregnant and non-pregnant women in patients receiving embryo transfer

 

The mean age of the women was 32.1 years. The majority (89.9%) were working, 37.4% had a university/college level education, and 68.3% lived in urban areas. Among the women, 13% were smokers. The cause of infertility was male factors in 41.7%, while the remaining cases involved female factors, unknown factors and mixed factors. Five women had a psychiatric history such as earlier depression, psychosis, anxiety or anorexia. Somatic diseases such as diabetes, asthma, epilepsy, gastro-intestinal disorders and gynaecological diseases such as endometriosis were observed frequently.

IVF treatment
All women were treated using a stimulation procedure including down-regulation with a GnRH agonist according to a long protocol starting either in the follicular phase or the luteal phase (1.2 mg/day nasally or 1.0 mg/day as a subcutaneous injection; Suprecur or Suprefact; Hoechst, Frankfurt, Germany). Down-regulation was followed by stimulation with recombinant FSH (Gonal-F, Serono, Geneva, Switzerland or Puregon, Organon, Oss, Netherlands). Monitoring was carried out by vaginal ultrasound scans and serum estradiol measurements. When adequate stimulation was achieved (≥3 follicles of ≥18 mm diameter), 10,000 IU HCG (Profasi, Serono) was administered.

Fertilization was performed by conventional IVF or by ICSI following standard techniques. In general, two embryos were transferred two or three days after oocyte retrieval using a Wallace or a Frydman catheter. Luteal support was given either with s.c. HCG or with progesterone (i.m. or vaginally). Additional embryos of good quality were cryopreserved and replaced later. Pregnancy was defined as a positive HCG test in urine on day 19 post-transfer. Clinical pregnancy was defined as ultrasound verified pregnancy 5 weeks after embryo transfer.


    Measures
 Top
 Abstract
 Introduction
 Materials and methods
 Measures
 Statistics
 Results
 Discussion
 Acknowledgements
 References
 
The women answered extensive questionnaires concerning psychological factors. The first questionnaire was filled in directly after the information meeting one month before onset of down-regulation, and the second questionnaire one hour before oocyte retrieval. The questionnaires included the following.

First occasion of measurement
Psychological well-being
General psychological well-being during recent weeks was measured by the Psychological General Well-Being (PGWB) index (Dupuy, 1984Go). PGWB contains 22 items with six response alternatives (1–6). The higher the value, the better the well-being. In addition to a total score for the index, there are sub-scores for anxiety, depressed mood, positive well-being, self-control, general health and vitality. In the current study, we focused on the total score and two sub-scores—depressed mood and anxiety. The scale has been translated into Swedish and tested on Swedish patients (Dimenäs et al., 1996Go). PGWB has shown satisfactory reliability and validity (Dupuy, 1984Go; Naughton and Wiklund, 1993Go).

In addition to the well-evaluated PGWB, psychological effects of infertility were measured by 14 items (guilt, success, anger, contentment, frustration, happiness, isolation, confidence, anxiety, satisfaction, depression, powerlessness, competence and control). These items were devised for the present study and seek to capture aspects of experiences often expressed by infertility patients. The items were formulated as questions like ‘How much of the following feelings do you experience during the present days: guilt, success, etc?’. The items were analysed separately.

Each item was graded from 1 to 5. Low figures indicate well-being.

Relationship with her partner
The effects of infertility on the woman’s relationship with her partner were estimated by two questions: (i) do you feel that infertility has caused problems in your marriage? and (ii) do you find it harder to talk to each other now than before? These items were also graded from 1 to 5 (1 = not at all, 5 = very much).

Intensity of the child-wish
The strength of the child-wish was estimated by seven questions [visual analogue scale (VAS)] covering perceptions of the woman’s own wishes (six questions) and of the expectations of others (one question).

Meaning of reproduction
The meaning of reproduction was estimated by six items (VAS) covering aspects of self-picture, meaningfulness and affinity (Möller and Fällström, 1991Go).

Difference between the ideal and the real-life situation
Seven items were formulated concerning the woman’s perceptions of the correspondence between how she wanted her life to be and how she thought it was. The answers were given on a VAS. The items covered work, leisure time, social contacts with friends and relatives, relation with her partner, sexual life, and life in general.

Optimism versus pessimism
Optimism/pessimism was captured by two questions: (i) what do you think about the results of the treatment you are about to start? And (ii) how do you describe yourself, as an optimist or a pessimist? The answers were given on a VAS.

Second occasion of measurement
The same 14 items regarding psychological effects of infertility were assessed as at the first measurement occasion. The same two questions regarding the relationship were asked as at the first measurement occasion.

Subgroups
The following subgroups were analysed in relation to pregnant versus non-pregnant:

  1. those with scores on the PGWB in the lowest quartile, i.e. those who experienced the poorest psychological well-being (n = 39);
  2. those with scores for psychological effects of infertility in the highest quartile at the second measurement occasion, i.e. those who experienced the most negative effects of infertility (n = 35);
  3. those who answered ‘no’ to the question as to whether they could consider an alternative to IVF (n = 36);
  4. a combination of groups 1–3 (n = 8).


    Statistics
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 Abstract
 Introduction
 Materials and methods
 Measures
 Statistics
 Results
 Discussion
 Acknowledgements
 References
 
Means, standard deviations, medians and ranges are descriptive statistics. Continuous and ordered variables were compared by the Mann–Whitney U-test, dichotomous variables by Fisher’s exact test and the Mantel–Haenszel {chi}2 test for the variable number of previous IVF cycles. A stepwise forward logistic regression analysis was performed for the dependent variable clinical pregnancy. Variables with P < 0.1 in the univariate analysis were included in the model. All significance tests were two-sided and performed at a significance level of 0.05.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Measures
 Statistics
 Results
 Discussion
 Acknowledgements
 References
 
Demographic and treatment variables for the pregnant and non-pregnant groups are shown in Tables I and II. No differences between pregnant and non-pregnant women were found regarding age, length of infertility or number of previous pregnancies/previous births. The total number of good quality embryos, the number of good quality embryos transferred, and the number of embryos transferred were significantly higher in the pregnant than in the non-pregnant group (Table II).


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Table II. Treatment variables for pregnant and non-pregnant women in patients receiving embryo transfer

 

All 166 women answered the first questionnaire and 151 women answered the second questionnaire. In seven patients, the IVF cycle was cancelled before oocyte aspiration due to poor ovarian response. Embryo transfer was performed in 139 (83.7%) out of 166 patients. Reasons for not reaching embryo transfer were: risk of ovarian stimulation syndrome (n = 3); fertilization failure (n = 3); bad quality embryos (n = 12); and freezing of all embryos due to myoma uteri or intrauterine polyps that had not been detected earlier (n = 2).

First measurement occasion
Psychological well-being
PGWB results did not differ between pregnant and non-pregnant women. In general, PGWB values were comparable with Swedish reference values (Dimenäs et al., 1996Go) reflecting that the women starting IVF treatment were in good psychological health.

When analysing each of the 14 items in the questionnaire concerning the psychological effects of infertility, no significant difference was found. The mean scores for each of the 14 items were mainly in the middle of the scale (Table III). However, there was considerable variation between individual women.


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Table III. Psychological variables for pregnant and non-pregnant women in patients receiving embryo transfer

 

There were no differences between women who got pregnant and those who did not with regard to the relationship with her partner, intensity of the child-wish, meaning of reproduction, difference between ideal and real-life situations, and optimism versus pessimism. For problems in the marriage, we found a mean of 1.5 (SD 0.8) (range 1–4) in the pregnant group versus a mean of 1.6 (SD 0.8) (range 1–4 ) in the non-pregnant group. Regarding intensity of the child-wish (the sum of six items), the pregnant women scored a mean of 35.7 (SD 10.0) (range 14.6–54.9) compared with 34.9 (SD 10.2) (range 13.6–58.3) in the non-pregnant group.

Second measurement occasion
The results of the 14 items covering psychological effects of infertility and the two questions covering the woman’s relationship with her partner did not differ between the women who got pregnant and those who did not. In the pregnant group, frustration measured a mean of 2.5 (SD 1.2) (range 1.0–5.0) versus 2.8 (SD 1.4) (range 1.0–5.0) in the non-pregnant group. The item anxiety scored a mean of 2.8 (SD 1.1) (range 1.0–5.0) by the pregnant women and a mean of 2.9 (SD 1.2) (range 1.0–5.0) by the non-pregnant.

When analysing the subgroups, scores on the PGWB in the lowest quartile (n = 39), scores for psychological effects of infertility in the highest quartile (n = 35), those who could not consider an alternative to IVF (n = 36) and a combination of these groups (n = 8), no statistically significant differences were found between the women who got pregnant and those who did not [PGWB group (P = 0.70), effects of infertility (P = 0.32), those who could not consider an alternative (P = 0.85) and a combination of the three subgroups (P = 0.46)].

Selected psychological variables in the univariate analysis are presented in Table III.

A stepwise forward logistic regression analysis was performed for variables that showed a difference at P < 0.1 in the univariate analysis (number of good quality embryos transferred, total number of good quality embryos, number of embryos transferred, number of previous IVF cycles, number of women with current somatic disease). The only variable that was significantly associated with pregnancy was the number of good quality embryos transferred.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Measures
 Statistics
 Results
 Discussion
 Acknowledgements
 References
 
During IVF treatment, patients frequently ask about the relationship between psychological stress and IVF outcome. They often express worries that their own stress might have a negative influence on the outcome. The results of the present prospective study do not indicate any relationship between perceived psychological stress or perceived psychological well-being before or during the first IVF treatment and outcome of IVF. These results can be regarded as reassuring and can help to decrease the stress experienced by patients.

Our findings are in accordance with some earlier studies (Harlow et al., 1996Go; Slade et al., 1997Go, Ardenti et al., 1999Go). However, we had expected to find such a relationship regarding at least some of the variables or for the group of women who scored in the lowest quartile on the PGWB index and in the highest quartile for the questions on psychological effects of infertility. A recent study from the Netherlands (Smeenk et al., 2001Go) showed that psychological factors were independently related to treatment outcome. Differences in population and choice of questionnaires may explain these differences. In our study, a relatively large number of patients were included, several different psychological measurements were used, and the design was prospective. Even when analysing the subgroup of patients with very high scores for stress, the results changed only marginally and no significant differences between pregnant and non-pregnant women were noted.

Analysing all data including those patients not achieving embryo transfer did not change the overall results
According to the PGWB results and those for other questions, the women in this study, as a group, expressed surprisingly good psychological well-being prior to the IVF treatment, although there were large inter-individual differences. This finding was somewhat unexpected and did not correspond with our earlier clinical impression. One possible reason for this could be that patients’ answers were more positive than what they actually experienced, and that they kept their worries and anxiety to themselves because they had great expectations regarding both themselves and the anticipated treatment. Perhaps they also wanted to show how well they felt and that they could handle the treatment. It has been reported that infertility patients suppress their feelings of stress because they want to show the clinic that they are functioning well both socially and psychologically (Demyttenaere et al., 1998Go).

Time points for questionnaires could, of course, always be discussed. The choice of the first measurement was because we wished to study the psychological status before any appointments at the clinic apart from the information meeting. The second measurement was chosen based on our clinical experience that patients often express feelings of anxiety and stress just before the oocyte retrieval. The day of embryo transfer is certainly also a distressing moment for the patients and perhaps it could have been valuable to measure on that occasion.

One of the chosen instruments, PGWB, has proven good reliability and validity. It is also sensitive to changes (Dimenäs et al., 1996Go). The other instruments have been devised for the present study and have not been psychometrically evaluated. The instruments were chosen in order to capture aspects of stress seen in the literature and expressed by infertility patients. One cannot exclude, however, that the failure to find an association between psychological stress and outcome of IVF is due to a lack of sensitivity of the instruments used.

Another aspect, at least in Sweden, is the observation that patients tend to express negative emotions and psychological strain in verbal interviews rather than in questionnaires (Sjögren, 1989Go; Forsberg-Wärleby et al., 2002). It could be regarded as more ‘definitive’ and ‘dangerous’ to put experiences of negative feelings in writing rather than expressing these feelings verbally in an interview. The tendency to level out one’s responses is more pronounced when filling in questionnaires.

However, it is also true that when IVF treatment is imminent, women have great hope for success. Couples have waited for this possibility for years and their view is that ‘at last’ something concrete and hopeful is going to happen. If this study had been performed after failed IVF treatments, the results might have been different.

In conclusion, this study could not demonstrate an association between psychological stress and IVF outcome. This information should be reassuring and should help to reduce women’s stress and worry during infertility treatment.


    Acknowledgements
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 Abstract
 Introduction
 Materials and methods
 Measures
 Statistics
 Results
 Discussion
 Acknowledgements
 References
 
We would like to thank Nils-Gunnar Pehrsson and Mattias Molin for statistical assistance. The study was supported by grants from the Vardal Foundation and Sahlgrenska Academy.


    References
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 Abstract
 Introduction
 Materials and methods
 Measures
 Statistics
 Results
 Discussion
 Acknowledgements
 References
 
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Submitted on April 29, 2005; resubmitted on June 17, 2005; accepted on July 4, 2005.





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