Hum. Reprod. Advance Access originally published online on November 25, 2005
Human Reproduction 2006 21(3):721-727; doi:10.1093/humrep/dei395
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The psychological impact of mild ovarian stimulation combined with single embryo transfer compared with conventional IVF
1 Department of Medical Psychology and Psychotherapy, 2 Department of Obstetrics and Gynaecology, Erasmus MC, 3015 GD Rotterdam and 3 Department of Reproductive Medicine, University Medical Center, 3584 CX Utrecht, The Netherlands
4 To whom correspondence should be addressed. E-mail: c.deklerk{at}erasmusmc.nl
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Abstract |
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BACKGROUND: The objective of this study was to assess the psychological implications of mild ovarian stimulation combined with single embryo transfer (SET) during a first IVF cycle. METHODS: We conducted a randomized controlled two-centre trial. Three hundred and ninety-one couples were randomized to undergo either mild ovarian stimulation with GnRH antagonist co-treatment and SET (n = 199) or conventional GnRH agonist long protocol ovarian stimulation with double embryo transfer (DET) (n = 192). Women completed the Hospital Anxiety and Depression Scale, the Hopkins Symptom Checklist and the Subjective Sleep Quality Scale at baseline, on the first day of ovarian stimulation and following embryo transfer. Affect was assessed daily with the Daily Record Keeping Chart from the first day of ovarian stimulation until the day treatment outcome became known. RESULTS: The conventional IVF group experienced elevated levels of physical and depressive symptoms during pituitary downregulation. At oocyte retrieval, this group experienced more positive affect and less negative affect than the mild IVF group. In the conventional IVF group, cycle cancellation was associated with less positive and more negative affect. CONCLUSIONS: During the first IVF treatment cycle, mild ovarian stimulation and SET does not lead to more psychological complaints than conventional IVF.
Key words: affect/GnRH antagonist/IVF/psychology/single embryo transfer
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Introduction |
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Ovarian stimulation for IVF with the use of GnRH agonist co-treatment is not without health risks. Between 0.1 and 0.5% of women receiving ovarian stimulation will develop ovarian hyperstimulation syndrome (OHSS; Delvigne and Rozenberg, 2003
). Furthermore, IVF combined with multiple embryo transfer is associated with a high incidence of multiple pregnancy (Fauser et al., 2005). In 2001, 
26% of IVF deliveries in Europe were multiples (Nyboe Andersen et al., 2005). As compared with IVF singleton pregnancies, IVF twin pregnancies are associated with a higher incidence of pre-eclampsia, lower birth weight and gestational age and higher frequency of sick leave and hospitalization (Pinborg et al., 2004).
Apart from health risks, standard IVF treatment can be an emotional burden to patients. According to a study by Olivius et al. (2004), psychological distress is the main reason why many patients drop out of IVF treatment before they have received all reimbursed treatment cycles. The authors reported a cumulative drop-out rate of 54% after two free cycles. Many couples have to face treatment failure, which seems to be related to an increased prevalence of subclinical anxiety and depression in women (Verhaak et al., 2005). Furthermore, IVF treatment itself, with its daily injections, scans and invasive procedures, such as oocyte retrieval, might be a cause of psychological distress in patients. There is some evidence that ovarian suppression with the use of GnRH agonists can cause symptoms of depression, anxiety (Eyal et al., 1996) and headache (Amir et al., 2005) in patients. Multiple pregnancy may also be associated with emotional distress in parents. In a recent study, mothers with IVF multiples seemed to experience more parenting stress than mothers with either naturally conceived or IVF singletons (Glazebrook et al., 2004).
In recent years, the clinical availability of GnRH antagonists has facilitated the development of milder ovarian stimulation protocols for IVF (Fauser and Devroey, 2005). Milder stimulation is likely to be associated with fewer side effects and a lower risk of OHSS than standard ovarian stimulation (Fauser et al., 1999). Moreover, in a recent randomized study, pregnancy rates per started IVF cycle after mild ovarian stimulation with GnRH antagonist co-treatment were similar to a standard long GnRH agonist protocol (Hohmann et al., 2003). Single embryo transfer (SET) offers the most efficient means of reducing the incidence of multiple pregnancy. Although a slightly reduced pregnancy rate per cycle may occur, similar overall pregnancy rates have been reported when the transfer of cryopreserved embryos is included (Thurin et al., 2004). However, little is known regarding the psychological disadvantages or benefits of the use of mild stimulation protocols and SET. To date, there has been one study addressing patients’ satisfaction with minimal stimulation protocols (Højgaard et al., 2001). In this study, patients receiving minimal stimulation (unstimulated cycle or clomiphene citrate) reported fewer side effects and stress related to hormone treatment and cycle cancellation compared with conventional stimulation. Among the minimal stimulation group, however, non-pregnant patients were less likely to prefer the same treatment protocol for future ovarian stimulation than pregnant patients. This suggests that patients who fail to conceive with minimal stimulation IVF start to question the effectiveness of low stimulation protocols. Likewise, most IVF couples seem to be more concerned about the possible higher risk of treatment failure associated with SET than about potential maternal, fetal and neonatal complications related to multiple embryo transfer (Murray et al., 2004). Many infertile couples actually consider multiple birth to be a favourable treatment outcome (Child et al., 2004). Also, IVF patients are concerned about possible psychological and physical effects of increased length of treatment associated with SET (Porter and Bhattacharya, 2005). Since the duration of GnRH antagonist co-treatment is shorter compared with treatment with GnRH agonists, the use of mild ovarian stimulation protocols might facilitate the acceptability of SET (Macklon and Fauser, 2003).
In this randomized controlled trial, potential psychological implications of mild ovarian stimulation in combination with SET were assessed. Self-reported physical and psychological complaints of women undergoing mild ovarian stimulation using GnRH antagonist co-treatment combined with SET were compared with those of women undergoing conventional IVF treatment [GnRH agonist long protocol with double embryo transfer (DET)]. We aimed to ascertain whether the combination of mild ovarian stimulation and SET reduces physical and psychological complaints related to medical procedures or whether this mild approach leads to more psychological complaints related to doubts about the effectiveness of treatment. In this study, the results of the first treatment cycle are presented.
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Materials and methods |
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Subjects
Between February 2002 and February 2004, women admitted to an IVF programme at the Erasmus MC (Rotterdam, The Netherlands) and the University Medical Center (Utrecht, The Netherlands) were invited to participate in this study. To exclude women for whom either mild stimulation or SET would not be suitable, the study was limited to women aged <38, with a regular menstrual cycle (25–35 days) and a body mass index between 18 and 28 kg/m2 (Lintsen et al., 2005
). Only couples with no previous unsuccessful IVF treatment were included. Since women had to be able to read and write Dutch to complete the questionnaires, only women who spoke Dutch were selected. Three hundred and eighty-eight women agreed to participate in the study.
Conventional stimulation with DET
In the conventional, GnRH agonist long protocol, DET group, standard ovarian stimulation was performed. After daily administration of GnRH agonist s.c. (leuproline, Lucrin®, Abbott BV, Amstelveen, The Netherlands, 0.2 mg/day; or triptoreline, Decapeptyl®, Ferring BV, Hoofddorp, The Netherlands, 0.1 mg/day) for 2 weeks from the mid-luteal phase of the pre-treatment cycle onwards, ovarian stimulation was started with a starting dose between 112.5 and 150 IU/day recombinant FSH (recFSH) s.c. (Gonal-F®, Serono Benelux BV, Amsterdam, The Netherlands; or Puregon®, NV Organon, Oss, The Netherlands). HCG (Profasi®, Serono Benelux BV; or Pregnyl®, NV Organon) 10 000 IU s.c. was administered to induce final oocyte maturation, when the largest follicle had reached at least 18 mm in diameter and at least one additional follicle >15 mm had been observed. Oocyte retrieval and fertilization in vitro was performed according to standard procedures as described previously (Kastrop et al., 1999; Huisman et al., 2000). A maximum of two (best quality) embryos was transferred (van de Pas et al., 2003). Luteal phase supplementation with progesterone, 600 mg/day, intravaginally (Progestan®, NV Organon) was started on the evening of the oocyte retrieval and continued for 12 days.
Mild stimulation with SET
In the mild, GnRH antagonist co-treatment, SET group, mild ovarian stimulation was performed with a fixed starting dose of 150 IU recFSH s.c. per day, initiated on the fifth cycle day. GnRH antagonist (ganirelix, Orgalutran®, NV Organon, 0.25 mg/day; or cetrorelix, Cetrotide®, Serono Benelux, 0.25 mg/day) was administered s.c. when at least one follicle 
14 mm was observed (Hohmann et al., 2003). Similar criteria applied for HCG, oocyte retrieval, fertilization and luteal phase support procedures as in the conventional IVF group. Only the best quality embryo was transferred (van de Pas et al., 2003).
Demographics
Information on women’s demographics and infertility history was gathered from medical records and patient questionnaires.
Daily Record Keeping Chart (DRK)
Infertility-specific distress was measured with the DRK (Boivin and Takefman, 1996; Boivin, 1997). The DRK consists of 21 items that represent emotional reactions common to women undergoing infertility treatment. Each item is rated on a 4-point Likert scale (‘none’ to ‘severe’). Scores on four subscales (range 0–12) can be obtained: depression/anger; uncertainty; anxiety; and positive affect. The depression/anger, uncertainty and anxiety subscales can be combined into one negative affect scale (range 0–36). The DRK has shown good criterion-related validity and good convergent validity with other conceptually related scales, such as the Spielberger State Anxiety Inventory. The DRK has shown good internal consistency: Cronbach coefficient alphas varied from 0.76 to 0.88 for the individual subscales, while the coefficient alpha for the negative affect scale was 0.87 (Boivin, 1997). The original items of the DRK were translated into Dutch in a previous study (de Klerk et al., 2005).
Hospital Anxiety and Depression Scale (HADS)
The HADS (Zigmond and Snaith, 1983) was developed as a screening tool to detect anxiety and depression in medical patients. This questionnaire does not include physical symptoms of anxiety and depression, such as insomnia and weight loss, to avoid bias as a result of co-existing medical conditions. Each of the two subscales (range 0–21) of the HADS consists of seven items, which are scored on a 4-point Likert scale from 0 to 3. Subjects were asked how they had felt during the last week. The Dutch version of the HADS (Spinhoven et al., 1997) has shown good test–retest reliability, homogeneity and internal consistency. Cronbach alphas for the total scale and both subscales ranged from 0.71 to 0.90.
Hopkins Symptom Checklist (HSCL)
To gain insight into possible physical side effects related to IVF treatment, self-reported physical complaints were measured with the somatic subscale of the HSCL (Derogatis et al., 1974). Individuals were asked to score how they had felt during the past week on eight items, which were rated on a 4-point Likert scale from 0 (‘not at all’) to 3 (‘extreme’). The Dutch version of the HSCL has shown adequate to good test–retest reliability, internal consistency and validity (Luteijn et al., 1984). Cronbach alphas from 0.68 to 0.78 were found for this subscale, while test–retest correlation coefficients ranged from 0.71 to 0.86.
Subjective Sleep Quality Scale (SSQS)
Subjective sleep quality was assessed with the SSQS, a Dutch questionnaire (De Diana, 1976) that consists of 10 dichotomous (‘yes’ and ‘no’) items on various aspects of sleep (e.g. ‘I easily fall asleep’, ‘I often wake up several times during the night’). Subjects were asked to rate their sleeping problems during the past week. The SSQS has shown high reliability and homogeneity: Cronbach alphas varied between 0.84 and 0.87, while the item homogeneity coefficients (Loevingers H) ranged from 0.48 to 0.50.
Study design
This psychological study is part of a randomized controlled trial, which encompasses the medical, economical and psychological evaluation of mild ovarian stimulation combined with SET.
Four hundred and one couples were randomized according to a computer-generated random numbers table into either the mild IVF arm (n = 205) or the conventional IVF arm (n = 196) by one of the researchers. Block randomization, stratified by clinic, was applied to achieve balance between the two groups within each hospital. For this psychological study, women who spoke Dutch were selected (n = 388). Women completed the HADS, the HSCL and the SSQS after they had received their stimulation schedule (baseline), on the first day of ovarian stimulation and again some days (range: 0–15) following embryo transfer. In addition, women’s affect was measured daily with the DRK during 1 week at baseline and again from the first day of ovarian stimulation until the day treatment outcome became known.
Procedure
This study was reviewed and approved by the Ethical Review Boards of both participating clinics. Couples were verbally informed about the study during information evenings for couples about to start their first IVF cycle. During these meetings, all couples received written information with regard to the study. In Rotterdam, patients who met the eligibility criteria were invited to participate in the study by their fertility physician during the IVF planning consultation. In Utrecht, couples received an invitation from one of the medical researchers either on the day of their first medical appointment or during the information evening. After the objectives of the study were discussed, both partners signed an informed consent form. Randomization was carried out using sealed envelopes. Envelopes were opened by the fertility physician or one of the researchers. Women received a booklet containing the psychological questionnaires. At the time of this study, three IVF treatment cycles were covered by health insurances in The Netherlands. Couples in the mild IVF group received an additional reimbursed treatment cycle to compensate for the possible lower birth rate associated with mild ovarian stimulation combined with SET.
Statistical analyses
Demographic data were analysed using Student’s t-test for continuous variables and 
2-test for categorical variables. Analyses of covariance (ANCOVAs) were performed for the HADS scores, the HSCL scores and the SSQS scores, while controlling for the baseline scores. For the analysis of the DRK scores, a distinction was made between seven individual IVF treatment stages: baseline, ovarian stimulation, oocyte retrieval, fertilization, embryo transfer, waiting period and pregnancy test. Stage scores for both positive and negative affect were calculated by averaging daily scores on the DRK within each treatment stage. ANCOVAs were conducted for group comparisons of both positive and negative affect during each individual treatment stage, adjusting for baseline affect scores. Analyses for the day of the pregnancy test were also statistically controlled for pregnancy outcome.
To determine changes in affect over treatment for all subjects, including women whose first IVF cycle was cancelled, random effects regression analysis was conducted. Random effects regression allows for missing observations, assessments at different end-points, time-independent co-variables and time-dependent co-variables. Individual time trend curves are based on the available data from a specific individual and data from all other subjects: intercepts represent estimated baseline functioning, while slopes characterize change in functioning over time. Since affect is strongly related to treatment outcome, the first treatment cycle was divided into periods: the period before treatment outcome was known (from baseline until the waiting days) and the day that treatment outcome became known.
In the random effects regression analyses for stage scores from baseline until the waiting period, both dependent variables (negative affect and positive affect) were modelled on the basis of a random intercept term, a random effect representing time (stage) in treatment, and fixed effects representing treatment (mild IVF versus conventional IVF) and cancellation (yes versus no). In a second series of random effects regression analyses, both dependent variables were modelled on the basis of a random intercept term, a random effect representing time (before versus after treatment outcome) in treatment, and fixed effects representing treatment (mild IVF versus conventional IVF), pregnancy (no versus yes) and cancellation (no versus yes). Interaction terms were entered into the models if it made sense both clinically and statistically. All models were adjusted for the time-independent co-variable hospital (Rotterdam versus Utrecht) and were fitted using restricted maximum likelihood measures. The covariance matrix was specified as unstructured (general covariance). All analyses were performed using the Statistical Package for the Social Sciences (SPSS version 10.1), while random effects regression models were implemented with the PROC MIXED procedure of the SAS System (version 8.2). Significance testing on all outcome measures was done at the 0.05 level of significance (two-tailed). Effect sizes were measured using Cohen’s d (Cohen, 1988). The SD of the conventional IVF group was used as the denominator of Cohen’s d.
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Results |
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Demographics
Of the 388 couples that were recruited, 29 did not receive their allocated intervention (see Figure 1).
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Table I shows the demographic characteristics for the remaining women in both the mild and the conventional IVF group. No significant differences were found for any of the demographic variables between groups. Twenty-six women failed to return their psychological questionnaires. Drop-outs did not differ from participants on most demographics, with the exception of the number of previous children. Of the drop-outs, 25.5% (12 out of 47) had one or more children of their own at the time they started treatment, while 13.3% (37 out of 278) of the participants were parents.
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Psychological and physical complaints related to pituitary downregulation
Table II shows the adjusted means and 95% confidence intervals (CIs) of the scores on the HADS, the HSCL and the SSQS for both the mild and the conventional IVF group at three points during the first IVF treatment cycle. To assess the possible physical and psychological complaints related to downregulation, group comparisons (ANCOVA) were made for all scores on the first day of ovarian stimulation. Women in the conventional IVF group reported more depressive symptoms (P < 0.01, two-tailed) and more physical discomfort (P < 0.01, two-tailed) in the week before the first day of ovarian stimulation (last week of downregulation) than women in the mild IVF group (no downregulation). In that week, women undergoing pituitary downregulation reported more frequent headache, lower back pain and muscle pain than women in the control group. Effect sizes of these differences were small (Cohen’s d = 0.43) and medium (Cohen’s d = 0.57), respectively. Exploratory analyses showed that 5.2% (eight out of 154) of women in the conventional IVF group scored above the cut-off score for probable depressive disorder against 2.4% (four out of 170) of women in the control group.
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Psychological and physical complaints during each individual IVF stage
In Table III, the adjusted means and 95% CIs of the DRK scores are shown for both groups for each individual treatment stage. ANCOVA showed that the mild and the conventional IVF groups did not differ significantly on positive or negative affect for most individual treatment stages, with the exception of the day of oocyte retrieval. On this day, women in the mild IVF group scored higher on negative affect (P = 0.03, two-tailed) and lower on positive affect (P = 0.01, two-tailed) than women in the conventional IVF group. However, the effect sizes of these differences were small (Cohen’s d = –0.28 and Cohen’s d = 0.32, respectively). No group differences were found on HADS, HSCL and SSQS scores during the waiting days.
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Positive and negative affect over time (first IVF cycle)
The results of the random effects regression analyses evaluating changes in positive and negative affect from baseline until the waiting period are presented in Table IV. For positive affect, a significant effect for treatment by cancellation was found (P < 0.01). Women in the conventional IVF group whose first treatment cycle was cancelled experienced less positive affect during treatment than women in the mild IVF group with a cancelled first cycle. Significant effects for time were found for both positive and negative affect. The day of oocyte retrieval was associated with more negative and less positive affect than other treatment stages.
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In Table V, the results are presented of the random effects regression analyses evaluating changes in positive and negative affect from the period before treatment outcome to the day that treatment outcome became known. For positive affect, a significant effect for treatment by cancellation was found (P < 0.01). Women in the conventional IVF group with a cancelled first cycle experienced less positive affect on the day their treatment was cancelled than women undergoing mild IVF. For negative affect, a significant effect for time by treatment was found (P < 0.01). Women undergoing conventional IVF experienced more negative affect on the day treatment outcome became known than the mild IVF group. Significant effects were found for time and time by pregnancy for both positive and negative affect. Women experienced more negative and less positive affect on the day treatment outcome became known than during treatment, especially women who were not pregnant.
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Discussion |
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The objective of this study was to investigate whether mild ovarian stimulation in combination with SET represents a more patient-friendly alternative for conventional IVF treatment. In this study, pituitary downregulation with GnRH agonist was associated with elevated levels of physical discomfort. Women who were undergoing pituitary downregulation more frequently reported symptoms such as headache, abdominal pain and sore muscles in the week before the start of ovarian stimulation compared with the control group. During subsequent treatment stages, however, no differences were found with regard to physical discomfort between the two study groups. This suggests that mild ovarian stimulation might not be milder in terms of experience for the patient. Since the average cycle duration is shorter for mild stimulation protocols, patients suffer from physical complaints for a shorter period of time.
In line with previous research (Eyal et al., 1996), pituitary downregulation with GnRH agonist was associated with elevated levels of symptoms of depression in the current study. However, average depression scores did not reach the cut-off score defining clinical depression in either group. Furthermore, the percentage of women that showed probable depression disorder was just a little higher in the conventional IVF group than in the control group. During most corresponding treatment stages, women in the mild IVF group did not differ from the conventional IVF group in terms of self-reported psychological symptoms. At oocyte retrieval, however, the mild IVF group showed significantly more negative and less positive affect than women undergoing conventional IVF. It must be noted that the clinical relevance of this finding might be limited, since effect sizes of these differences were small. Nonetheless, there might be a change of attitude needed in the way fertility physicians view the mild IVF approach. Since some of the fertility physicians were a little sceptical about the mild stimulation protocol, it is possible that these physicians were more inclined to show negative reactions towards mild IVF patients at oocyte pick-up. Furthermore, patients receiving mild IVF might have compared their results with the results of patients who were treated with standard IVF treatment which might also have influenced how patients in the mild IVF group perceived their chance of success. In future, information provision about expected results throughout treatment might reduce concerns about effectiveness in patients.
Consistent with the findings of Højgaard et al. (2001), the results of this study suggest that cycle cancellation is associated with a less positive and a more negative mood in women undergoing conventional IVF than in women who undergo mild IVF. When cycle cancellation occurs, women undergoing mild IVF have usually been through a few days of ovarian stimulation only. Women in the conventional IVF group, on the other hand, have already invested much more in their treatment at that time. Aside from a few days of ovarian stimulation, they have also been through 1–2 weeks of medication in order to achieve pituitary downregulation. Another explanation for this finding could be the fact that women undergoing mild stimulation were offered a maximum of four instead of three reimbursed cycles in conventional IVF.
The attrition rate of the study was just 14.2% (55 out of 388). After randomization, seven couples in the conventional IVF group preferred SET to DET. None of the couples that were randomized into the mild IVF group changed their minds about having SET before treatment had started. Only 26 women failed to return their booklet with questionnaires. Not all women who did return their booklet provided scores on all time points, probably because of the complexity and the frequency of the measurements. This might have led to an underestimation of symptoms, since one could hypothesize that filling in questionnaires would have been a greater burden to women who were experiencing more symptoms.
Another limitation of this study is that no records were kept on non-respondents. It is therefore not entirely clear how representative the study group is for all patients that are eligible for mild ovarian stimulation combined with SET. Based on the average number of couples who undergo IVF treatment annually in the two participating hospitals and who would qualify for the study (n = 300), the estimated response rate is 64.7% (388 out of 600). This estimated number of patients who were willing to undergo SET is relatively high in comparison with other studies on patient attitudes towards SET. In a study by Pinborg et al. (2003), for example, only 25% of 870 interviewed IVF mothers would agree to SET. However, 25% of these women would reconsider accepting SET, if offered more than the usual number of covered treatment cycles. In the present study, women in the mild IVF group were offered four reimbursed treatment cycles instead of the usual three, which may have been an incentive to participate.
One could expect that psychological complaints in women undergoing mild IVF would only emerge after a negative treatment outcome. In the study by Højgaard et al. (2001), patients undergoing minimal ovarian stimulation were less likely to prefer the same treatment protocol for future ovarian stimulation after treatment failure. In the current study, women in the mild IVF group actually experienced less negative affect on the day of pregnancy test than women in the conventional IVF group, although this difference was only marginally significant. Future research is needed to study psychological consequences of mild IVF during later cycles. What if overall treatment fails? Maybe then women will start wondering whether or not they chose the best treatment protocol available.
In conclusion, these first results suggest that mild stimulation in combination with SET represents a patient-friendly alternative for conventional IVF. Mild stimulation protocols circumvent the need for pituitary downregulation, which is associated with symptoms of depression, headache, lower back pain and muscle pain. Possible concerns with regard to the effectiveness that may arise during treatment (especially around the day of oocyte retrieval) might be reduced if objective information concerning treatment and expected results is provided during all stages of treatment.
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The authors would like to thank all couples for participation in this study. We would also like to thank the personnel of the IVF department at the Erasmus MC (Rotterdam, The Netherlands) and the University Medical Centre Utrecht (Utrecht, The Netherlands). This study (no. 945-12-010) was funded by ZonMw (The Netherlands).
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References |
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Amir BY, Yaacov B, Guy B, Gad P, Itzhak W and Gal I (2005) Headaches in women undergoing in vitro fertilization and embryo-transfer treatment. Headache 45,215–219.[CrossRef][Medline]
Boivin J (1997) The Daily Record Keeping Chart: reliability and validity. Paper presented at the British Psychological Society Special Group in Health Psychology Annual Conference.
Boivin J and Takefman JE (1996) Impact of the in-vitro fertilization process on emotional, physical and relational variables. Hum Reprod 11,903–907.
Child TJ, Henderson AM and Tan SL (2004) The desire for multiple pregnancy in male and female infertility patients. Hum Reprod 19,558–561.
Cohen J (1988) Statistical Power Analysis for the Behavioural Sciences, 2nd edn. Lawrence Erlbaum Associates, New Jersey.
De Diana IPF (1976) Two stochastic sleep quality scales for self-rating of subjects’ sleep. Sleep Qual 5,101.
de Klerk C, Hunfeld JA, Duivenvoorden HJ, den Outer MA, Fauser BC, Passchier J and Macklon NS (2005) Effectiveness of a psychosocial counselling intervention for first-time IVF couples: a randomized controlled trial. Hum Reprod 20,1333–1338.
Delvigne A and Rozenberg S (2003) Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS). Hum Reprod Update 9,77–96.
Derogatis LR, Lipman RS, Rickels K, Uhlenhuth EH and Covi L (1974) The Hopkins Symptom Checklist (HSCL): a self-report symptom inventory. Behav Sci 19,1–15.[Web of Science][Medline]
Eyal S, Weizman A, Toren P, Dor Y, Mester R and Rehavi M (1996) Chronic GnRH agonist administration down-regulates platelet serotonin transporter in women undergoing assisted reproductive treatment. Psychopharmacology 125,141–145.[CrossRef][Medline]
Fauser BC and Devroey P (2005) Why is the clinical acceptance of gonadotropin-releasing hormone antagonist cotreatment during ovarian hyperstimulation for in vitro fertilization so slow? Fertil Steril, in press.
Fauser BC, Devroey P, Yen SS, Gosden R, Crowley WF Jr, Baird DT and Bouchard P (1999) Minimal ovarian stimulation for IVF: appraisal of potential benefits and drawbacks. Hum Reprod 14,2681–2686.
Fauser BCJM, Devroey P and Macklon NS (2005) Multiple birth resulting from ovarian stimulation for subfertility treatment. Lancet, in press.
Glazebrook C, Sheard C, Cox S, Oates M and Ndukwe G (2004) Parenting stress in first-time mothers of twins and triplets conceived after in vitro fertilization. Fertil Steril 81,505–511.[CrossRef][Web of Science][Medline]
Hohmann FP, Macklon NS and Fauser BCJM (2003) A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol. J Clin Endocrinol Metab 88,166–173.
Højgaard A, Ingerslev HJ and Dinesen J (2001) Friendly IVF: patient opinions. Hum Reprod 16,1391–1396.
Huisman GJ, Fauser BC, Eijkemans MJ and Pieters MH (2000) Implantation rates after in vitro fertilization and transfer of a maximum of two embryos that have undergone three to five days of culture. Fertil Steril 73,117–122.[CrossRef][Web of Science][Medline]
Kastrop PM, Weima SM, Van Kooij RJ and Te Velde ER (1999) Comparison between intracytoplasmic sperm injection and in-vitro fertilization (IVF) with high insemination concentration after total fertilization failure in a previous IVF attempt. Hum Reprod 14,65–69.
Lintsen AM, Pasker-de Jong PC, de Boer EJ, Burger CW, Jansen CA, Braat DD and van Leeuwen FE (2005) Effects of subfertility cause, smoking and body weight on the success rate of IVF. Hum Reprod 20,1867–1875.
Lukassen HG, D DB, Wetzels AM, Zielhuis GA, Adang EM, Scheenjes E and Kremer JA (2005) Two cycles with single embryo transfer versus one cycle with double embryo transfer: a randomized controlled trial. Hum Reprod 20,702–708.
Luteijn F, Hamel LF, Bouwman TK and Kok AR (1984) Hopkins Symptom Checklist. Swets & Zeitlinger, Lisse.
Macklon NS and Fauser BC (2003) Mild stimulation in in vitro fertilization. Ann NY Acad Sci 997,105–111.[CrossRef][Web of Science][Medline]
Murray S, Shetty A, Rattray A, Taylor V and Bhattacharya S (2004) A randomized comparison of alternative methods of information provision on the acceptability of elective single embryo transfer. Hum Reprod 19,911–916.
Nyboe Andersen A, Gianaroli L, Felberbaum R, de Mouzon J and Nygren KG (2005) Assisted reproductive technology in Europe, 2001. Results generated from European registers by ESHRE. Hum Reprod 20,in press.
Olivius C, Friden B, Borg G and Bergh C (2004) Why do couples discontinue in vitro fertilization treatment? A cohort study. Fertil Steril 81,258–261.[CrossRef][Web of Science][Medline]
Pinborg A, Loft A, Schmidt L and Andersen AN (2003) Attitudes of IVF/ICSI-twin mothers towards twins and single embryo transfer. Hum Reprod 18,621–627.
Pinborg A, Loft A, Schmidt L, Langhoff-Roos J and Andersen AN (2004) Maternal risks and perinatal outcome in a Danish national cohort of 1005 twin pregnancies: the role of in vitro fertilization. Acta Obstet Gynecol Scand 83,75–84.[CrossRef][Web of Science][Medline]
Porter M and Bhattacharya S (2005) Investigation of staff and patients’ opinions of a proposed trial of elective single embryo transfer. Hum Reprod 20,in press.
Spinhoven PH, Ormel J, Sloekers PPA and Kempen G (1997) A validation study of the Hospital Anxiety and Depression scale (HADS) in different groups of Dutch subjects. Psychol Med 27,363–370.[CrossRef][Web of Science][Medline]
Thurin A, Hausken J, Hillensjo T, Jablonowska B, Pinborg A, Strandell A and Bergh C (2004) Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization. N Engl J Med 351,2392–2402.
van de Pas MM, Weima S, Looman CW and Broekmans FJ (2003) The use of fixed distance embryo transfer after IVF/ICSI equalizes the success rates among physicians. Hum Reprod 18,774–780.
Verhaak CM, Smeenk JM, van Minnen A, Kremer JA and Kraaimaat FW (2005) A longitudinal, prospective study on emotional adjustment before, during and after consecutive fertility treatment cycles. Hum Reprod 20,in press.
Zigmond AS and Snaith RP (1983) The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 67,361–370.[Web of Science][Medline]
Submitted on July 18, 2005; resubmitted on October 18, 2005; accepted on October 27, 2005.
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  P. Devroey, M. Aboulghar, J. Garcia-Velasco, G. Griesinger, P. Humaidan, E. Kolibianakis, W. Ledger, C. Tomas, and B. C.J.M. Fauser Improving the patient's experience of IVF/ICSI: a proposal for an ovarian stimulation protocol with GnRH antagonist co-treatment Hum. Reprod., April 1, 2009; 24(4): 764 - 774. [Abstract] [Full Text] [PDF]
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M.F.G. Verberg, B.C. Fauser, and N.S. Macklon Reply: Why do couples drop out from IVF treatment? Hum. Reprod., March 1, 2009; 24(3): 759 - 759. [Full Text] [PDF]
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 M.F.G. Verberg, N.S. Macklon, G. Nargund, R. Frydman, P. Devroey, F.J. Broekmans, and B.C.J.M. Fauser Mild ovarian stimulation for IVF Hum. Reprod. Update, January 1, 2009; 15(1): 13 - 29. [Abstract] [Full Text] [PDF]
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M.F.G. Verberg, M.J.C. Eijkemans, E.M.E.W. Heijnen, F.J. Broekmans, C. de Klerk, B.C.J.M. Fauser, and N.S. Macklon Why do couples drop-out from IVF treatment? A prospective cohort study Hum. Reprod., September 1, 2008; 23(9): 2050 - 2055. [Abstract] [Full Text] [PDF]
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 I. Kosmas, J. Van der Elst, P. Devroey, and H. Tournaye Elective single embryo transfer Obstet Gynaecol (Lond), July 1, 2008; 10(3): 163 - 169. [Abstract] [Full Text] [PDF]
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C. de Klerk, J.A.M. Hunfeld, E.M.E.W. Heijnen, M.J.C. Eijkemans, B.C.J.M. Fauser, J. Passchier, and N.S. Macklon Low negative affect prior to treatment is associated with a decreased chance of live birth from a first IVF cycle Hum. Reprod., January 1, 2008; 23(1): 112 - 116. [Abstract] [Full Text] [PDF]
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C. de Klerk, N.S. Macklon, E.M.E.W. Heijnen, M.J.C. Eijkemans, B.C.J.M. Fauser, J. Passchier, and J.A.M. Hunfeld The psychological impact of IVF failure after two or more cycles of IVF with a mild versus standard treatment strategy Hum. Reprod., September 1, 2007; 22(9): 2554 - 2558. [Abstract] [Full Text] [PDF]
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G. Pennings and W. Ombelet Coming soon to your clinic: patient-friendly ART Hum. Reprod., August 1, 2007; 22(8): 2075 - 2079. [Abstract] [Full Text] [PDF]
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