Are repeated assisted reproductive technology treatments and an unsuccessful outcome risk factors for unipolar depression in infertile women?

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1 A C TA Obstetricia et Gynecologica AOGS ORIGINAL RESEARCH ARTICLE Are repeated assisted reproductive technology treatments and an unsuccessful outcome risk factors for unipolar depression in infertile women? CAMILLA S. SEJBAEK 1, ANJA PINBORG 2, IDA HAGEMAN 3, JULIE L. FORMAN 4, CHARLOTTE Ø. HOUGAARD 1 & LONE SCHMIDT 1 1 Section of Social Medicine, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2 Department of Obstetrics and Gynecology, Copenhagen University Hospital, Hvidovre Hospital, Hvidovre, 3 Psychiatric Center Copenhagen, Copenhagen University Hospital, Rigshopitalet University Hospital, Copenhagen, and 4 Section of Biostatistics, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Key words Assisted reproductive technology treatment, cohort study, depression, live birth, registerbased study, women Correspondence Camilla S. Sejbaek, Section of Social Medicine, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen,Oester Farimagsgade 5, Post Box 2099, 1014 Copenhagen K, Denmark. case@sund.ku.dk Conflict of interest Camilla S. Sejbaek was funded by research grants received by Lone Schmidt from the Danish Health Insurance Foundation (J.nr. 2008B105) and Merck, Sharpe & Dohme (MSD). The sponsors had no influence on how data were retrieved and analyzed, or on the conclusions of the study. Anja Pinborg, Ida Hageman, Julie L. Forman and Charlotte Ø. Hougaard declare that they have no conflicts of interest in connection with this article. Please cite this article as: Sejbaek CS, Pinborg A, Hageman I, Forman JL, Hougaard CØ, Schmidt L. Are repeated assisted reproductive technology treatments and unsuccessful outcome risk factors for unipolar depression in infertile women? Acta Obstet Gynecol Scand 2015; 94: Abstract Introduction. Previous studies have shown conflicting results as to whether unsuccessful medically assisted reproduction is a risk factor for depression among women. This study therefore investigated if women with no live birth after assisted reproductive technology (ART) treatment had a higher risk of unipolar depression compared with women with a live birth after ART treatment. Material and methods. The Danish National ART-Couple (DANAC) Cohort is a national register-based cohort study that consists of women who received ART treatment from 1 January 1994 to 30 September 2009, in Denmark (n = ). Information on unipolar depression was obtained from the Danish Psychiatric Central Research Register. The analyses were conducted in Cox regression analysis. Results. During the person-years of follow up, 552 women were diagnosed with unipolar depression. A Cox proportional hazards model showed that women in ART treatment, with no live birth yet, had a lower risk of unipolar depression compared with women with a live birth. Women had the highest risk of unipolar depression 0 42 days after a live birth (adjusted hazard ratio 5.08, 95% CI ) compared with women with no live birth. A lower, but still increased, risk of unipolar depression, was found in women 43 days to 1 year and >1 year after a live birth compared with women with no live birth yet. Conclusions. Motherhood is an important trigger of unipolar depression in women conceiving after ART treatment. Abbreviations: ART, assisted reproductive technology; CI, confidence interval; DANAC, the Danish National ART-Couple Cohort; FET, frozen/thawed embryo transfer cycle; HR, hazard ratio; ICD, International Classification of Diseases; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization. Received: 8 January 2015 Accepted: 23 June 2015 DOI: /aogs ª 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015)

2 C.S. Sejbaek et al. Depression, ART treatment, no live birth Introduction Worldwide, more than 5 million children have been born after assisted reproductive technology (ART) treatment. Currently about 8% of the Danish birth cohort are children conceived after fertility treatment, and about 50% of these children are born after ART methods [i.e. in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), frozen thawed embryo transfer cycle (FET) or oocyte donation] (1). Infertility is a severe stressor, which could be a risk factor for depression among women. Studies investigating associations between ART, live birth and depression vary considerably in the design and mode by which depression was measured, from smaller studies using self-reported assessment of depressive symptoms to larger register-based studies using a clinical depression diagnosis. Studies based on self-reported depressive symptoms suggested that women with unsuccessful fertility treatment had a higher risk of depressive symptoms compared with women achieving a live birth (2,3). Childless women, who had undergone unsuccessful fertility treatment years earlier, reported more self-reported depressive symptoms compared with women who had children (4). According to a review by Ross et al. (5) women conceiving after ART treatment had a similar risk of postpartum depression compared with women giving birth after spontaneous conception. All studies included in the review used self-reported data of depressive symptoms and most studies included fewer than 150 participants. Similarly, one Finnish register-based study showed that women undergoing unsuccessful fertility treatment had a higher risk of depression (6). However, a Danish register-based study showed that women evaluated for infertility who did not achieve a live birth had an increased risk of mental disorder, overall [hazard ratio (HR) 1.17, 95% CI ] but had a lower risk of depression (HR 0.87, 95% CI ) compared with women achieving a live birth (7). Contrary to most previous studies we investigated ART, live birth, and clinically diagnosed depression in a large national study population. The aims of the study were to investigate if repeated ART treatment cycles were a risk factor of a clinical diagnosis of unipolar depression and to investigate if unsuccessful ART treatment was a risk factor of unipolar depression in a cohort of female ART patients. Material and methods In Denmark, fertility treatment is offered in the public healthcare system to couples (heterosexual/lesbians) where the woman is <40 years of age and with no children in common; and to single women <40 years of age without children. Patients can be reimbursed for a maximum of three IVF or ICSI cycles with transfer of fresh embryos. Fertility treatment is allowed until the woman s 45th birthday in the private sector, where women/couples have full self-payment. Around 50% of all fertility treatments are performed at public fertility clinics. This study was part of the Copenhagen Multi-Centre Psychosocial Infertility (COMPI) Research Program (8) and was a register-based, national cohort study. Population-based registers are linkable through the unique personal identification number given to all residents in Denmark. The Danish National ART-Couple (DANAC) Cohort includes all women registered in the Danish IVF register with at least one ART treatment from 1 January 1994 to 30 September 2009 (n = , Figure 1). The Danish IVF register is compulsory for all clinics to report to, public as well as private. The register includes all records on ART treatment, i.e., IVF, ICSI, FET, and oocyte recipient cycles (9,10). The register is cycle-based with information about the type of treatment given. Information about deliveries was obtained from the Danish Medical Birth Register (11) and we have obtained information about deliveries from 1994 onwards. Only the first live birth of each woman was included in the analyses (single/multiple births). Live birth was dichotomized into yes or no, where yes included all deliveries; both deliveries after ART conception as well as deliveries after non-art deliveries. Non-ART deliveries were a combination of spontaneous conceptions and conceptions after medically assisted reproduction treatments other than ART; the registers do not allow any distinction between these two types of conception. The psychiatric diagnoses were obtained from the Danish Psychiatric Central Research Register where data on all psychiatric hospital admissions from 1969, and all outpatient treatments and emergency room contacts from 1995, are recorded (12). The register does not include general practitioner contact information. The following codes from the International Classification of Diseases (ICD) were used: Depression ICD-8 (296.0, 296.2) and ICD-10 (F32, F33); schizophrenia ICD-8 ( , , Key Message Women having received assisted reproductive technology treatment and with no live birth yet were at lower risk of unipolar depression compared with women with a live birth. Risk of unipolar depression among mothers was highest within 6 weeks after birth. ª 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015)

3 Depression, ART treatment, no live birth C.S. Sejbaek et al. Total ART treatments women Exclusions Born before 1 January 1946 or born after 31 December 1990 and missing info on first and/or last ART treatment date 79 ART treatments 32 women First depression diagnosis prior to ART treatment (childhood and adulthood) 919 ART treatments 386 women Diagnosed with schizophrenia or bipolar affective disorder prior to ART treatment or initiated treatment after 30 September ART treatments 162 women Missing information on education 3045 ART treatments 1285 women Lost ART treatments due to censoring (Cox regression analysis) 478 ART treatments 0 women Final cohort ART treatments women Figure 1. Flow diagram, women included from Danish National ART-Couple (DANAC) Cohort, Denmark, ART, assisted reproductive technology , 297.9, , , 299.0) and ICD-10 (F20 F29); and bipolar affective disorder ICD-8 (296.1, 296.3, 296.8, 296.9) and ICD-10 (F30, F31). The date for the first admission or first outpatient contact was used as the psychiatric diagnosis date. The diagnoses of schizophrenia and bipolar affective disorder were identified to exclude or censor these women. All the psychiatric diagnoses were dichotomized (yes/no). Information about age, educational level, and emigration were obtained from the national sociodemographic registers (established in 1995). The highest obtained educational level at the time of the woman s first ART treatment was used in the analyses. For women with their first ART treatment in 1994 the educational level from 1995 was used. Educational level was categorized in accordance with the International Standard Classification of Education (ISCED) system: Low I (up to 10 years education), Medium II (upper secondary education, vocational education and academy profession), High III (professional bachelor programs), and Highest IV (bachelor and master s programs and PhD). Information on death is registered in the Danish Register of Causes of Death according to the ICD-10 classification. The DANAC cohort is outlined in detail elsewhere (13). In total, 1865 women were excluded due to the following criteria: (i) women born before 1 January 1946 or after 31 December 1990 and women with missing information about the date of first/last ART treatment, (ii) women diagnosed with depression before ART treatment, (iii) women diagnosed with schizophrenia or bipolar 1050 ª 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015)

4 C.S. Sejbaek et al. Depression, ART treatment, no live birth affective disorder before their ART treatment, as the focus of this study solely was unipolar depression, (iv) women who initiated ART treatment after 30 September 2009, or (v) women with missing information on educational level. The final study population included n = women, who had all received at least one ART treatment. Figure 1 presents a flow diagram of the study population. Approvals for the research project were obtained from the Danish Data Protection Agency (J.nr ), the National Board of Health (J.nr /1), the Danish Medical Agency, and Statistics Denmark (J.nr ). The project follows the Helsinki II Declaration. According to the Danish law, register-based studies do not require approval from the ethics committee system. Statistical analysis The statistical analyses were conducted in SAS version 9.3 (SAS Institute Inc., Cary, NC, USA). To compare women in ART treatment with a live birth to women in ART treatment with no live birth chi-squared tests (educational level, number of ART treatments, type of treatment) and t tests (mean age at first ART treatment, mean age at unipolar depression) were used in the descriptive analyses. In all the Cox regression analyses age was used as the underlying time scale. First, in the initial Cox regression analysis women in ART treatment with no live birth yet were compared with women with a live birth (reference group) for the diagnosis of unipolar depression to address the aim of the study. However, a result of these findings the further Cox regression analyses were reversed and conducted using the women in ART treatment with no live birth yet as the reference group; this change was done to elaborate on the time after the live birth and the risk of a unipolar depression. Second, the additional Cox regression analyses for risk of unipolar depression were conducted for the two exposures: (i) Number of ART treatment cycles [time dependent; 1 (reference group), 2,...6 or more], and (ii) Time after a live birth [time dependent; no live birth yet (reference group), 0 42, 43 days to 1 year and >1 year after a live birth]. Age at first ART treatment was used as entry date. In the Cox regression analyses the women were followed until diagnosis with unipolar depression, schizophrenia or bipolar affective disorder, emigration, death, or study termination 30 September 2009, whichever came first. Three different models were tested in the additional analyses and as a minimum they were all controlled for the woman s age and the year of ART treatment. In model 1, analyses were conducted including either number of ART treatment cycles or time after live birth, age and the year of ART treatment. In model 2, educational level was added in the two separate analyses for the two exposures (number of ART treatment cycles and time after live birth). In model 3, both of the exposures were additionally included. Sensitivity analyses were conducted by stratification of the women with and without a child before ART to investigate if their risk of unipolar depression differed. A Cox regression analysis was performed to test if an increasing number of unsuccessful ART treatments was a risk factor for unipolar depression. To test this, women were censored at delivery and thereby only women with continued unsuccessful ART treatment were kept in the analysis. To investigate if missing information about births before 1994 (i.e. before ART treatment) influenced the results of the analyses, we also conducted sensitivity analyses excluding women initiating ART treatment in 1994, , , and so on for the whole cohort and for all of their subsequent treatments, analyzed by one calendar year at a time. Results In this study 552 (1.3%) women were registered with a unipolar depression after receiving at least one ART treatment cycle; 355 (64.3%) women with a live birth and 197 (35.7%) women with no live birth received a unipolar depression diagnosis (ICD-8: 296.0, 296.2; ICD-10: F32, F33) (Table 1). The mean age at first ART treatment for women with and without a live birth differed by 2.0 years, women with no live birth being the oldest (p < 0.001). Women in ART treatment with no live birth had a lower educational level compared with women with a live birth (p < 0.001). Furthermore, women with a live birth received fewer ART treatment cycles compared with women with no live birth (p < 0.001; Table 1). In total, 65.8% of all children were born after ART treatment. The majority of the treatment cycles were IVF/ICSI treatments with fresh embryo transfer. Women with a live birth received significantly more FET cycles compared with women with no live birth yet (14.5% vs. 11.8%; p < 0.001; data not shown). Women with no live birth yet had a lower risk of a unipolar depression diagnosis after ART compared with women with a live birth (p < 0.001). Hence, the results are shown for women with a live birth compared with women with no live birth yet as the reference group. Women with a live birth had an increased risk of a unipolar depression diagnosis compared with women with no live birth yet (data not shown; adjusted analysis, HR 1.36, 95% CI ; p < 0.001). Table 2 presents the risk of unipolar depression by number of ART treatment cycles and by time after live birth. In model 1, adjusted for age and year of ART treatment, no significant association was found between ª 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015)

5 Depression, ART treatment, no live birth C.S. Sejbaek et al. Table 1. Characteristics of women with and without a live birth from the Danish National ART-Couple (DANAC) Cohort, Denmark, Women with a live birth Women with no live birth p value Women, n (%) NA Person-years of follow-up Unipolar depression, n (%) NA Censoring or end of study, n (%) End of study <0.001 Migration Schizophrenia Bipolar affective disorder Deceased Mean age at first ART treatment, mean (SD) 32.3 (4.2) 34.3 (4.8) <0.001 Mean age at depression diagnosis, mean (SD) 37.4 (5.2) 39.4 (6.3) <0.001 ISCED, n (%) 1. Low < Middle High Highest Total ART treatments received per women, n (%) < or more ART, assisted reproductive technology; ISCED, International Standard Classification of Education System; NA, not applicable; SD, standard deviation. Table 2. Hazard ratios by number of assisted reproductive technology treatment and time after first live birth for unipolar depression among women from Danish National ART-Couple (DANAC) Cohort, Denmark Model 1 a Model 2 b Model 3 c No of cases HR 95% CI p value HR 95% CI p value HR 95% CI p value Unipolar depression by number of ART treatments Reference Reference Reference or more Unipolar depression by time since first delivery No child Reference < Reference < Reference < days days to 1 year >1 year ART, assisted reproductive technology; CI, confidence interval; HR, hazard ratio. a Model 1 included repeated ART treatment or time after live birth adjusted for age and ART treatment year. b Model 2 included repeated ART treatment or time after live birth adjusted for age, ART treatment year and educational level. c Model 3 included repeated ART treatment and time after live birth adjusted for age, ART treatment year and educational level. number of ART treatments and risk of a unipolar depression although the risk seemed to decrease with increasing number of ART treatments. The risk of a unipolar depression in women with a live birth was highest in the period 0 42 days after the live birth (HR 4.82, 95% CI ) compared with women with no live birth yet. The risk of unipolar depression was increased for 43 days to 1 year after a live birth (HR 1.77, 95% CI ) 1052 ª 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015)

6 C.S. Sejbaek et al. Depression, ART treatment, no live birth and >1 year after a live birth (HR 1.24, 95% CI ) compared with women with no live birth yet. In model 2, the educational level did not change the risk of unipolar depression by number of ART treatment cycles. The estimated risk of a unipolar depression diagnosis after a live birth was still increased and the risk was highest 0 42 days after a live birth (HR 5.22, 95% CI ). For model 3 the risk of unipolar depression by the number of ART treatment cycles did not change compared to the first model. The time after a live birth and unipolar depression remained significant (p < 0.001) with a more than five-fold increased risk of a unipolar depression diagnosis for women 0 42 days after a live birth compared with women with no live birth yet (HR 5.08, 95% CI ). An increased risk of developing a unipolar depression was still present both 43 days to 1 year after a live birth and >1 year after a live birth compared with women with no live birth yet. The results from the sensitivity analyses did not differ from the results of the main analyses. Discussion Contrary to our hypothesis, we found that women having received ART treatment who achieved a live birth were at higher risk of a unipolar depression diagnosis compared with women who had not yet given birth to a child. However, repeated ART treatments did not seem to increase the risk of a subsequent unipolar depression diagnosis compared with women with only one treatment cycle. This finding contrasts with a previous Finnish registerbased study showing that women undergoing unsuccessful fertility treatment had a higher risk of a unipolar depression diagnosis compared with women with successful fertility treatment (6). A Danish register-based study using clinical diagnoses for psychiatric disorders in a psychiatric hospital setting reported differences between women from the IVF register with a biological child and childless women from the IVF register with regard to psychiatric disorders in general or affective disorders specifically (14). However, in that study unipolar depression was not investigated as a separate diagnosis. Our study showed that women who underwent ART and achieved a live birth had a higher risk of a unipolar depression compared with women with no live birth yet. This finding is in line with two other Danish register-based studies showing that women evaluated for infertility and not giving birth had a decreased risk of unipolar depression treated at the psychiatric hospitals (7). Women giving birth after ART also had an increased risk of any type of psychiatric disorder compared with women with no delivery (15). Studies based on self-reported measurements of depressive symptoms suggested that women who remain childless after fertility treatment had a higher level of depressive symptoms compared to women, who gave birth (4) and further, that childless women who retained a wish for motherhood had higher levels of depressive symptoms compared to childless women with new life goals (16). These studies indicate that women with repeated unsuccessful fertility treatments and who remain childless may suffer from mild or moderate depressive symptoms; however, mild or moderate symptoms of depression do generally not require referral to psychiatric hospitals. Our findings showed that women in previous ART treatment had the highest risk of a unipolar depression within the first 6 weeks after a live birth compared to women not having achieved a live birth yet. The registers did not allow us to compare this result to women with ART treatment, who achieved a live birth after spontaneous conception as it is not possible to distinguish between deliveries obtained after other fertility treatments than ART and deliveries obtained after spontaneous conception. In the review by Ross et al. (5) it was found that women conceiving after ART treatment had a similar risk of self-reported depressive symptoms as women giving birth after spontaneous conception. However, Ross et al. (5) stressed that the seven reviewed studies were of low quality and that women in ART treatment differed from other childbearing women by being older and by a higher socio-economic status; both are a lower risk of depression after a birth. McMahon et al. (17) compared first-time mothers conceiving by ART to women conceiving spontaneously and found no increased prevalence of major depressive disorders in the first 4 months after birth among older ( 37 years) first-time ART mothers. Munk-Olsen and colleagues found that in the general population women giving birth had an increased risk of a hospital admission and an outpatient contact for any mental disorder up to 2 months after a childbirth compared to women who remained childless (18). In line with these findings, our study showed that the highest risk for a unipolar depression diagnosis was during the first 6 weeks after a live birth compared to women with no live birth yet. In contrast, no increase in mental disorder was found after 2 months by Munk-Olsen et al. (18) but they included women with all mental disorders in the analyses while we focused on unipolar depression. In general, pregnant women and mothers are in close contact with the health care system. One could speculate that mothers, who have a unipolar depression after a childbirth are more likely to be diagnosed and treated at the psychiatric hospitals, because of their close contact to the health care system. ª 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015)

7 Depression, ART treatment, no live birth C.S. Sejbaek et al. Beutel et al. (19) reported that self-reported depressive symptom scores increased from two treatment cycles to three or more treatment cycles among women having unsuccessful fertility treatment. Our sensitivity analyses censoring women at live birth confirmed our main finding that the number of ART treatment was not associated with unipolar depression among women undergoing ART treatment. Women undergoing several ART treatments may not be comparable to the general population without children, which is partly supported by the findings from a study among all adult women in Denmark (20). That study found that women with a severe mental disorder, who were admitted to a psychiatric hospital, had lower fertility rates compared to women who had never had a psychiatric admission. This indicates a healthy patient selection bias in our cohort in that women choosing to have ART treatment might be more mentally robust than infertile women not choosing to initiate fertility treatment. This is supported by an overall prevalence of 2.6% of the women in the DANAC cohort were diagnosed with unipolar depression (21), which is lower compared to the depression point prevalence of 3 5% in the background Danish female population (22,23). The strengths in our study are that the validity of the national registers is acceptable (12,24); the analyses were based on a large national population and include longitudinal data; the women were followed for an average of 7.5 years (range: ). Depression was diagnosed by a psychiatrist in a clinical setting in comparison to most other studies using self-administered questionnaires as a diagnostic tool for depression. Furthermore, several sensitivity analyses were conducted to validate our findings. Limitations of the study include the register-based design, which only makes it possible to include women with a depression treated in a hospital setting; i.e., the most severe cases of depression. Women with milder depression/ depressive symptoms are most often treated at their general practitioner, at a private psychiatrist/psychologist outpatient clinic, or may remain untreated. None of these health care professionals reports diagnoses to the Psychiatric Central Research Register. No information on possible confounders such as time-to-pregnancy, overweight, smoking status, and the level of stress the women experienced were available. These factors could be associated with the number of ART treatment cycles the women initiate and/or the outcome of ART treatment. Only ART treatments were included in the IVF register in the period investigated in this study. In general, couples with unexplained, anovulatory or minor to moderate male infertility receive other medically assisted reproduction treatments before ART treatment. Therefore, a certain proportion of the women in our cohort will have tried other fertility treatments before inclusion. The DANAC cohort does not fully represent infertile women as it is restricted to women in ART treatment, thus, caution should be taken when generalizing our findings to the total infertile population. In conclusion, this study showed that unsuccessful ART treatment is not associated with an increased risk of major depression compared with successful ART treatment. On the contrary, becoming a mother is an important trigger of a unipolar depression after a childbirth among women in ART treatment even though the child is long-awaited. Acknowledgments This study is part of the Copenhagen Multi-Centre Psychosocial Infertility (COMPI) Research Programme initiated by Dr. L. Schmidt, University of Copenhagen, The authors wish to thank Gurli Pilgaard Perto, the Danish Psychiatric Central Research Register; Jørn Korsbø Petersen, Statistics Denmark; and Steen Rasmussen, previously at the National Board of Health for their efforts in extracting and linking register data for this project. Funding This work was supported by the Danish Health Insurance Foundation (J.nr. 2008B105) and Merck Sharpe & Dohme (MSD). The sponsors had no influence on how data were retrieved and analyzed or on the conclusions of the study. References 1. Lemmen F, Erb K [Internet]. Annuel report Denmark: Danish Fertility Society, Available online at: option=com_content&view=article&id=230&itemid=156 (accessed January 7, 2015). 2. Verhaak CM, Smeenk JM, Evers AW, Kremer JA, Kraaimaat FW, Braat DD. Women s emotional adjustment to IVF: a systematic review of 25 years of research. Hum Reprod Update. 2007;13: Pasch LA, Gregorich SE, Katz PK, Millstein SG, Nachtigall RD, Bleil ME, et al. 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