Prospective study of a Swedish infertile cohort : population characteristics, treatments and pregnancy rates

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1 Family Practice, 2014, Vol. 31, No. 3, doi: /fampra/cmu003 Advance Access publication 3 March 2014 Prospective study of a Swedish infertile cohort : population characteristics, treatments and pregnancy rates Arthur Aanesen a, * and Margareta Westerbotn b a IVF-Unit, Sophiahemmet Hospital and b Sophiahemmet University, Stockholm, Sweden *Correspondence to Arthur Aanesen, IVF Unit, Sophiahemmet Hospital, Box 5605, Valhallavägen 91 A, Stockholm , Sweden; arthur.aanesen@telia.com Received May ; revised January ; Accepted January Abstract Background. We here report on results from a prospective study comprising 380 infertile couples undergoing infertility work-up and various treatments for infertility in our clinic. The aim was to investigate the overall birth rate as a result of different treatments, as well as spontaneous pregnancies. Methods. Three hundred and eighty couples were consecutively included between December 2005 and May All couples underwent a fertility work-up, including hysterosalpingogram, hormonal characterization, clinical examination, screening for infectious diseases and semen analysis. The mean age of the women at the time of inclusion was 33.2 years. The mean duration of infertility prior to inclusion was 1.8 years. And 46.6% (n = 177) of the women had been pregnant prior to their first visit to the clinic and 30.0% (n = 114) had been pregnant earlier in their present relationship. Results. As of November 2010, 57.3% (n = 218) of the women had given birth to a child when they were lost to follow up by the study. Spontaneous conception was observed in 11.3% (n = 43) of the women, 14.5% (n = 64) conceived after intrauterine insemination (IUI), 4.2% (n = 16) conceived after ovarian hyperstimulation and ovulation induction (OH/OI) and 28.4% (n = 113) after in vitro fertilization. There were 280 pregnancies and 58 spontaneous abortions (22.3%) in the group. Mean anti-mullerian hormone significantly correlated with antral follicle count and age and was significantly higher in the subgroup that became pregnant after IUI. Conclusions. Spontaneous pregnancies and IUI + OH/OI contributed significantly to the pregnancies observed in the total population. Predictive factors for pregnancy were anti-mullerian hormone in the group undergoing IUI treatment and in the age group 38 duration of infertility. Previous pregnancies, body mass index, estradiol, follicle stimulating hormone or having given birth prior to the infertility period were not predictive of pregnancy for the infertile couples in this study. Key words: Infertility work-up, IUI, IVF, long-term outcome, ovarian hyperstimulation, spontaneous pregnancies, unexplained infertility. Introduction Research reports on success rates in infertility treatment often focus on pregnancy rates per treatment cycle and the take home baby rate. The patient perspective in relation to success rates and pregnancy rates per couple is more difficult to grasp, and discrepancies between the statistical success of different infertility clinics and the couples experiences of success have been a matter of concern (1). Infertility treatments cause emotional distress (2) and several factors influence the psychological The Author Published by Oxford University Press. All rights reserved. For permissions, please journals.permissions@oup.com. 290

2 Prospective study of a Swedish infertile cohort 291 trauma that many couples experience. Reports on coping and psychological stress related to in vitro fertilization (IVF) have indicated that loss of control is an important contributing factor (3). Alongside the development of novel treatment options and new insights in reproductive biology, we observe more women delaying child-bearing into their 30s and even 40s, and an increasing number of these women experience fertility problems. Causes of infertility can be categorized according to several diagnostic groups: Male infertility, tubal infertility, ovulation disorders, endometriosis, endocrine disorders and unexplained/mixed causes. Unexplained infertility is a commonly used term to describe as many as 30 40% of infertile couples (4). The increased age of the infertile cohort may also increase the proportion of unexplained infertility, as initial stages of ovarian ageing may not be clinically apparent. Our present study from Stockholm, Sweden, represents a prospective study of an infertile cohort from the start of their infertility investigation and treatment in one single clinic. Couples already investigated and diagnosed at other centres were excluded from the study, as well as couples admitted directly to the clinic for IVF treatment. Following the process of investigation and testing, different treatment options were discussed with the couples when this was applicable. Treatment strategies were chosen depending on test results, age and personal preferences; in many couples this led to treatment cycles with intrauterine insemination (IUI) or ovarian hyperstimulation and ovulation induction (OH/OI) prior to IVF. Several other authors have addressed cumulative pregnancy rates in infertile cohorts, showing that the relative contribution of IVF to the total number of pregnancies in subfertile cohorts varies. Brandes et al. (5) reported that IVF contributed to 21.2% of the pregnancies in a large study on subfertile couples in the Netherlands, and a Danish study of cumulative 5-year delivery rates by Pinborg et al. (6) showed that the contribution of IVF to the total number of deliveries was 52.8%. Donckers et al. (7) reported that no treatment/expectant management contributed to 50% of the live births in an infertile cohort and IVF contributed to 50% in the same cohort. Large differences exist between regions in terms of population characteristics and approaches to both infertility work-up and treatments. For each region, knowledge about treatment results and prognosis is important for proper counselling. Our aim is to give an overview of the causes, work-up results, treatment results and pregnancy outcomes of couples seeking help for infertility problems at an infertility clinic in Northern Europe. Material and methods Population and design A prospective cohort study was initiated in December 2005, which included infertile couples at our fertility unit at Sophiahemmet Hospital, Stockholm, Sweden. The unit annually performs more than 700 IVF/intra-cytoplasmatic sperm injection (ICSI) cycles, 600 IUI cycles and 150 OH/OI cycles. Couples were included consecutively, and the infertility work-up included a routine gynaecological investigation, investigation for tubal patency (hysterosalpingogram or hydrosonosalpingography), a routine hormonal work-up including follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol in early follicular phase [Cycle Day (CD) 2 4], prolactin, thyroid stimulating hormone (TSH) and free thyroxin. Anti-Müllerian hormone (AMH) was analysed separately in a research laboratory, and tests for AMH were analysed regardless of CD. Following the initial infertility work-up, couples were informed about diagnostic findings (Table 1) and were offered the opportunity to begin a treatment period if this was indicated by test results (Table 2). Treatment options were discussed with the couples, and decisions regarding choice of treatment were made in consensus where possible (Table 3). Treatment cycles with IUI or OI were not required prior to IVF treatments. IVF was performed both at private centres and at centres where IVF treatments are reimbursed by the social security system. Only couples going through a primary infertility work-up at the clinic were included. Couples who were referred to the clinic directly for IVF were excluded as their investigation had been completed at other centres. Women <42 years were allowed to enter the study, but initial counselling prior to the first visit advised women older than 40 years to primarily enter an IVF programme. Couples who finished their investigation and treatment period at the clinic were contacted for follow-up 2 3 years after their first visit. The final follow-up calls were carried out during November Ethics The Regional Committee for Medical and Health Research Ethics (2006/ ) approved the study. Intrauterine insemination Patients with unexplained or mild male factor infertility were offered insemination. Being 42 years of age or younger was not a contraindication for IUI, but when a female partner was Table 1. Diagnosis and live births in 380 infertile couples in an infertility clinic, Stockholm, Sweden Diagnostic findings Patiens (%) Live births (%) Unexplained and mixed causes 214 (56.3) 122 (57.0) Ovulation disorder 61 (16.1) 36 (59.0) Male factor 51 (13.4) 24 (47.1) Tubal factor 7 (1.8) 2 (28.6) Endometriosis 5 (1.3) 3 (60) Other causes 42 (11.1) 31 (73.8)

3 292 Family Practice, 2014, Vol. 31, No. 3 Table 2. Patient characteristics in 380 infertile couples in an infertility clinic, Stockholm, Sweden All couples Pregnant Not pregnant t-test BMI 22.6 ± 3.5 ( ) 22.2 ± 3.5 ( ) 22.8 ± 3.3 ( ) P > 0.05; ns FSH (IU/l) 6.4 ± 2.6 ( ) 6.4 ± 2.1 ( ) 6.6 ± 1.9 ( ) P > 0.05; ns CD 2 4 Estradiol (pmol/l) 186 ± 121 (3 1570) 195 ± 158 ( ) 180 ± 83 ( ) P > 0.05; ns CD 2 4 AMH (pg/ml) 4.1 ± 3.9 ( ) 4.4 ± 4.2 ( ) 3.8 ± 3.5 ( ) P > 0.05; ns AFC (n) 7.8 ± 3 (0 20) 7.8 ± 3.1 (0 20) 7.7 ± 3.7 (2 20) P > 0.05; ns Total sperm count (million) 235 ± 177 ( ) 202 ± 183 ( ) 213 ± 168 ( ) P > 0.05; ns Progressive sperm (%) 54 ± 16 (3 98) 54 ± 16 (6 95) 53 ± 16 (3 98) P > 0.05; ns Table 3. Treatment options Expectancy OH/OI IUI IVF HMG, human menopausal gonadotropin; rfsh, recombinant FSH. >40 years of age couples were advised to choose IVF as a preferred treatment option. IUI was performed following ovarian stimulation with clomiphene citrate or rfsh. Cycles were routinely monitored with ultrasound examinations. More than two follicles 15 mm on the planned day for ovulation induction led to cancellation of the cycle. Ovulation induction [5000 IU human chorionic gonadotropin (HCG)] was administered subcutaneously hours prior to IUI with 0.5 ml highly motile sperm. Ovarian hyperstimulation and ovulation induction Ovarian hyperstimulation and ovulation induction was offered to patients with ovulation disorder. Routine stimulation with low dose recombinant FSH was followed by ovulation induction (5000 IU HCG) on the day the leading follicle reached 18 mm. Cycles were routinely monitored with ultrasound examinations. More than two follicles 15 mm on the planned day for ovulation induction led to cancellation of the cycle. Couples were advised to have intercourse the day after HCG administration. In vitro fertilization Following the initial infertility work-up, IVF was offered either as a first line of treatment or following treatment with IUI or Including correction of hypothyroidism, weight loss, counseling and surgical procedures such as hysteroscopy Controlled ovarian stimulation with clomiphene citrate, HMG or rfsh and consecutively ovulation induction with HCG Controlled ovarian stimulation with clomiphene citrate, HMG or rfsh and consecutively ovulation induction with HCG. IUI with motile sperm (swim-up preparation) hours following HCG injection Standard IVF or ICSI, ovarian stimulation with clomiphene citrate, HMG or rfsh. Sperm from ejaculated samples prepared with swim-up procedure OH/OI that had failed. ICSI was performed when indicated. Both gonadotropin releasing hormone agonist and antagonist protocols were applied. Single embryo transfer was increasingly applied during the course of the study, and a maximum of two embryos were transferred. Results Patient characteristics and hormonal analysis The mean age of patients included in the study was 33.2± years. Column statistics for the patients reaching a pregnancy versus the patients who did not become pregnant are shown in Table 2. AMH decreased and FSH increased with increasing age (Fig. 1A and B). The pregnancy rate for patients with previous pregnancies (n = 177) was 45.8%; this was not significantly different from the pregnancy rate in the group with no previous pregnancy (n = 203), which was 46.3%. The mean age of women becoming pregnant during the observation period of the study was 34.0 ± 3.9 years. The mean age at inclusion was not significantly different between the group that became pregnant and the group that did not achieve pregnancy (Fig. 2B). The proportion of women achieving a pregnancy in the group <38 years was 58% [53 64, 95% confidence interval (CI)] and the proportion of women achieving a pregnancy in the group 38 years was 50% (37 63, 95% CI). Miscarriage rates increased in the older age groups, reaching a maximum of

4 Prospective study of a Swedish infertile cohort % in women 40 years (Fig. 2C). Laboratory characteristics and demographic data of the study population are presented in Tables 2 and 4. The mean serum FSH was 6.4 IU/l, and mean serum AMH was 4.1 pg/ml. AMH and FSH inversely correlated with each other, and both significantly correlated with age (Fig. 1). AMH correlated with antral follicle count (AFC) but was not predictive of pregnancy in the total population of women included in the study. Body mass index (BMI), FSH, estradiol and AFC were not significantly different between women who had a live birth and those who were still trying to achieve a pregnancy at the end of the follow-up period. Total sperm count and number of progressive sperm was not significantly different between the groups. Overall results in terms of pregnancies are presented in Table 5. By the end of the follow- up period, 218 of the women had given birth to a child, and there were a total of a b 50 Figure 1. Age, AMH and FSH in a Swedish infertile cohort. (A) Correlation between AMH and age in an infertile cohort undergoing investigation for infertility, r 2 = 0.1, P < ; (B) Correlation between FSH and age in an infertile cohort undergoing investigation for infertility, r 2 = 0.03, P < pregnancies in the group and 58 spontaneous abortions (22.3%). Spontaneous pregnancies Thirty-three spontaneous pregnancies were carried to term. One of the spontaneous deliveries occurred in a couple with a previous successful IVF treatment that also had led to delivery. All spontaneous pregnancies resulted in singletons. Ovarian hyperstimulation and ovulation induction Fifty-one couples completed one or more OH/OI cycles, with a total of 121 cycles performed. The treatment cycles resulted in 16 pregnancies and 14 deliveries. One pregnancy was a twin pregnancy (7.1% duplex/live birth) that went to term, and two pregnancies resulted in miscarriage (12.5%). The average number of treatment cycles per couple was 2.4 ± 1.8 [1 11] (mean ± SD, range). Overall, OH/OI treatments resulted in a 27.5% take home baby rate/couple. Intrauterine insemination Two hundred and forty-five couples underwent one or more IUI cycles. Sixty-four pregnancies were carried to term following IUI (26.1% take home baby rate/couple). The number of treatments per couple ranged from one to seven, with a mean of 2.2 IUI per couple. In total, 542 IUI cycles were performed. There were 13 miscarriages in the group (16.8%), of which five of the couples who experienced an initial miscarriage repeated IUI and subsequently became pregnant, while three couples went on to IVF after the miscarriage. IUI resulted in three twin pregnancies (4.7%) that continued to term. AMH was significantly higher in the IUI treatment group that became pregnant compared with the non-pregnant group (5.6 versus 3.8 pg/ml), P < Sperm count after preparation in the IUI cycles did not differ between the pregnant and the non-pregnant groups (15.4 and 12.1 million, respectively, ns, P > 0.05). The mean age of women starting IUI treatments was 34 ± 3.5 years (24 42) and the mean age for women achieving a pregnancy following IUI treatment was 33 ± 3.7 years (24 40). In vitro fertilization and intra-cytoplasmatic sperm injection Couples proceeded to IVF either as a first treatment choice following the infertility work-up, or following OH/OI or IUI. One hundred and fourteen women (30.0% of the total population) had become pregnant and experienced a pregnancy/delivery following IVF treatment by the end of the follow-up period.

5 294 Family Practice, 2014, Vol. 31, No. 3 a 40 The live birth rate for women going through IVF was 42.0% per couple. b c Discussion Fertility treatments are stressful and demanding for infertile couples. Data from couples undergoing IVF treatments indicate that many couples terminate further treatment attempts for psychological reasons, in spite of fully financed additional IVF cycles (8,9) Cultural factors, the local panorama of causes for infertility, as well as how infertility treatment is financed, are important factors behind a couple s strategies for coping with their situation. The current study describes a situation in Stockholm where the average maternal age at birth of the first child has risen from 27.2 years in 1980 to 30.6 years in 2010 (10). Information about treatment options, their efficacy and prognosis is necessary to assist couples in making family planning choices. Although much attention is given to improving tools for predicting fertility, we are also in need of a reliable test or combination of tests that enable us to advise our patients with full confidence: What is the best treatment option? Or even more important: should we choose not to treat some patients? During the observational period, 57.4% of the women had at least one child, either spontaneously or as a result of different treatments. Other per-patient-based studies have reported pregnancy rates that range from 19% to 52% (11) while a recent Danish population-based study reported a delivery rate of 69.9% at a 5-year follow-up (6). The analysis of our cohort was performed only 2.5 years following the inclusion of the last patients; hence a further increase in the number of cumulative pregnancies might be expected. During the course of the study, 102 women (26.8%) conceived and gave birth to a child spontaneously or as a result OH/ OI or IUI. The contribution of IVF to the final pregnancy rate may not reflect the situation for an unselected infertile population, as couples from other infertility centres referred direct to the clinic for IVF treatment were not included in the study. However, the results do indicate that a large proportion of infertile couples might benefit from a less aggressive approach to infertility treatment than IVF as the first-line choice. The most recent Cochrane Report on IUI, comparing it with timed intercourse, indicates that IUI improves the odds of becoming pregnant for couples with unexplained subfertility when the treatment is combined with fertility drugs to induce ovulation (12). Figure 2. Age distribution, pregnancy rates and spontaneous abortions in a Swedish infertile cohort. (A) Frequency distribution of women s age at the couple s first visit at the infertility clinic (n = 380). (B) Age-related take home baby rates of women (n = 218) during the follow-up period for 380 infertile couples undergoing investigation and treatment for infertility. The pregnancies illustrated in the figure originated from different treatment modalities, some of which were tailored to patients age: OH/OI, IUI, IVF and spontaneous pregnancies. (C) Agerelated miscarriage rates of women (n = 218) during the follow-up period for 380 infertile couples undergoing investigation and treatment for infertility.

6 Prospective study of a Swedish infertile cohort 295 Table 4. Demographic data in 380 infertile couples in an infertility clinic, Stockholm, Sweden All couples (n = 380) Pregnant (n = 218) Not pregnant (n = 162) t-test Mean ± SD Age at inclusion (years) 33.2 ± ± ± 4 P > 0.05; ns Duration of infertility previous to inclusion (years) 1.8 (1.2) 1.7 ± ± 1.3 P > 0.05; ns n (%) (95% CI) Ever pregnant previous to inclusion, n (%) 177 (46.6) 95 (43.6) [ ] 82 (50.6) [ ] Legal abortions previous to inclusion, n (%) 76 (20.0) 36 (16.5) [ ] 40 (24.7) [ ] Spontaneous abortions previous to inclusion, n (%) 74 (19.5) 40 (18,3) [ ] 34 (21,0) [ ] Children previous to inclusion 86 (22.6) 42 (20.5) [ ] 40 (24,7) [ ] Pregnancies in the couple previous to inclusion, n (%) 114 (30) 63 (28,9) [ ] 51 (31,5) [ ] Table 5. Live births in 380 couples attending a Swedish urban infertility clinic Treatment A recent randomized study from the Netherlands reports no additional effect from IUI during the first 6 months following randomization to either IUI with OH or expectant management (13). A less aggressive approach in terms of a delayed start of treatment for young couples with unexplained infertility might be indicated. Diagnostic findings Live births No treatment (spontaneous) 33 (11.8) IUI 61 (15,0) OH/OI 14 (3.9) IVF 114 (30,0) Total number of couples with live 218 (57,4) a birth to one or more children Data are n (%) unless otherwise specified. a Four couples belong to two different treatment groups because of more than one child. The distribution of diagnosis (Table 1) may reflect the fact that couples referred directly to IVF were not included in the study. Isolated tubal pathology represented only 1.8% of the cases and male factor in 13.4%. Previous prospective studies on cumulative delivery rates in infertile cohorts have reported tubal pathology at 18% and male factor infertility at 29.9% (6). A majority of the patients in our study ended up in the diagnostic group unexplained and mixed causes (56.3%). This illustrates the complexity of the situation following the initial infertility workup: often multiple factors contribute to the couples infertility and age does not appear to be a diagnostic category. The low number of registered isolated tubal pathology might, however, also indicates a low frequency of sexually transmitted diseases in the studied population. Biochemical markers The panel of analysis for each of the women enrolled in the study included several markers of ovarian function and possible predictors for pregnancy (FSH, LH, Estradiol and AMH). Several tests (FSH, Estradiol and AMH) correlated significantly with age (Fig. 1); however, our data showed that no parameter was significantly different in the group that became pregnant compared with the non-pregnant group (Table 4). An isolated analysis of pregnancies in the subgroup undergoing IUI indicated that analysis of AMH might be a valuable parameter to consider when counselling couples o their treatment options. As patients in this study were not randomized into treatment categories (spontaneous, OH/OI, IUI or IVF), several patients were subject to different treatments during the course of the study. IVF was the final step following other treatments for several of the couples in this study. A subdivision of prognostic markers in treatment categories would have introduced a selection bias and was not applicable in the analysis of data. The role of AMH as a predictor of pregnancy has been debated, but as a marker of ovarian capacity it may be a valuable tool for the clinician (14). The limitation of AMH as an isolated predictor can be partially explained by the fact that it measures ovarian capacity, but not oocyte quality. Recently published data indicate that AMH in combination with age and ovulatory menstrual cycles might be predictive of live birth in couples with unexplained infertility or male infertility (15). A tendency towards decreasing pregnancy rates was observed in the age group >39 years when they started their infertility work-up (Fig. 2). Possibly due to the limited sample size (54 women 38 years at the time for enrolment in the study), no significant differences were observed between the groups with regard to FSH, LH, Estradiol, AMH, AFC or BMI. AMH. Age Fecundability (probability of conception during a single menstrual cycle with unprotected intercourse) is doubtlessly reduced

7 296 Family Practice, 2014, Vol. 31, No. 3 with increasing age. Improved timing and frequency of intercourse are behavioural factors that might partially mask agerelated decline in fecundibility. The negative effect of increasing age has, however, been demonstrated by numerous studies. Studies on natural fertility rates have revealed that younger women have higher fecundity rates and therefore conceive sooner than older women (16,17). The age effect on fecundity has previously been shown to be modest in parous women until 37 years of age, but spontaneous fertility rates in the whole population can be expected to decrease by 50% at the age of 40 compared with women younger than 25 (17,18). The present study demonstrated a drop in birth rates after 39 years but failed to confirm a drop in birth rates for the age groups up to 39 (Fig. 2B). No differences were observed between parous women and nulliparas in this material. Previous reports demonstrating higher birth rates in parous women have been based on spontaneous conceptions in population studies rather than results from infertility treatment groups (16,18). The duration of infertility as a prognostic factor was also studied in relation to age. In patients >39 years of age, a significant difference was observed between the pregnant and the non-pregnant group with regard to duration of infertility duration (1.4 ± 0.6 versus 2.3 ± 1.8 years (mean ± SD), P = 0.02). This might reflect the increased aneuploidy rates known to occur with advanced maternal age. Earlier studies have detected increased chromosomal abnormalities in live births (19) with increased maternal age, as well as increased aneuploidy rates from oocytes and fertilized embryos (20). Reports on human oocytes from IVF cycles have demonstrated that the overall aneuploidy frequency increases from 45% in the age group up to 34 years to 80% in the age group of 43 years and older (21). In the process of pre-conception counselling, the age-related increase in miscarriage rates should be a matter of concern. Data from Denmark indicated a miscarriage rate after natural conception of 9.2% in a female age group of years, 12.0% at age 30 34, 19.7% at age 35 39, 40.1% at age and 74.7% at age 45 (22). The age-related miscarriage rate in the present study is shown in Fig. 2c and in the age group the overall miscarriage rate was 21.9%. Treatment strategies It has been argued that IUI followed by IVF is less cost-effective than IVF as the primary treatment alternative for unexplained and mild male factor infertility (23). An additional study of couples with good prognosis and unexplained infertility found that expectancy for up to 6 months compared with IUI gives comparable pregnancy rates (24). In our study, women older than 40 years were advised to enter the IVF program as the primary treatment option. This recommendation was based on a recently published literature (25). In the group younger than 40 years and with unexplained/mixed causes of infertility, IUI was offered as a primary treatment option. According to recent data, several of the patients achieving a pregnancy following IUI could have benefited from expectant management for at least 6 months (26). The decision to treat, rather than expect, must, in our opinion, be based on a dialogue with the couple, where individual requests and psychological factors must be taken into account. Important factors in this counselling process are age, duration of infertility and a continuous dialogue with the couple as infertility work-up and treatments proceed. The search for a single test, or a panel of tests, to guide us in the decision to choose a certain treatment option is highly desirable, but neither this study nor previous studies have provided us with the final answer. Several published studies have focused on emotional stress and fertility treatment. High dropout rates from couples in infertility clinics are often explained by emotional distress and poor prognosis (5). An approach where the couple has the freedom to choose a less effective alternative as a first-line treatment may, in our opinion, increase patient autonomy and motivation to continue treatment if medically motivated. Acknowledgements The authors wish to express their gratitude to Midwife Cecilia von Segebaden at the Fertility Unit, Sophiahemmet, for her enthusiastic cooperation in enrolling patients, Laboratory Technician Eva Andersson, for her excellent work with AMH analysis, and Lars Nylund and Claes Gottlieb, for critically reading the manuscript. Declaration Funding: Sophiahemmet Research Council. Ethical approval: local ethical committee (2006/ ). Conflict of interest: none. References 1. Peters K, Jackson D, Rudge T. Failures of reproduction: problematising success in assisted reproductive technology. Nurs Inq 2007; 14: Verhaak CM, Smeenk JM, Evers AW et al. 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