The cost of mental disorders: a systematic review.

AIMS: To identify and synthesise the literature on the cost of mental disorders. METHODS: Systematic literature searches were conducted in the databases PubMed, EMBASE, Web of Science, EconLit, NHS York Database and PsychInfo using key terms for cost and mental disorders. Searches were restricted to January 1980-May 2019. The inclusion criteria were: (1) cost-of-illness studies or cost-analyses; (2) diagnosis of at least one mental disorder; (3) study population based on the general population; (4) outcome in monetary units. The systematic review was preregistered on PROSPERO (ID: CRD42019127783). RESULTS: In total, 13 579 potential titles and abstracts were screened and 439 full-text articles were evaluated by two independent reviewers. Of these, 112 articles were included from the systematic searches and 31 additional articles from snowball searching, resulting in 143 included articles. Data were available from 48 countries and categorised according to nine mental disorder groups. The quality of the studies varied widely and there was a lack of studies from low- and middle-income countries and for certain types of mental disorders (e.g. intellectual disabilities and eating disorders). Our study showed that certain groups of mental disorders are more costly than others and that these rankings are relatively stable between countries. An interactive data visualisation site can be found here: https://nbepi.com/econ. CONCLUSIONS: This is the first study to provide a comprehensive overview of the cost of mental disorders worldwide.

Comorbidity within mental disorders: a comprehensive analysis based on 145 990 survey respondents from 27 countries.

AIMS: Epidemiological studies indicate that individuals with one type of mental disorder have an increased risk of subsequently developing other types of mental disorders. This study aimed to undertake a comprehensive analysis of pair-wise lifetime comorbidity across a range of common mental disorders based on a diverse range of population-based surveys. METHODS: The WHO World Mental Health (WMH) surveys assessed 145 990 adult respondents from 27 countries. Based on retrospectively-reported age-of-onset for 24 DSM-IV mental disorders, associations were examined between all 548 logically possible temporally-ordered disorder pairs. Overall and time-dependent hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Absolute risks were estimated using the product-limit method. Estimates were generated separately for men and women. RESULTS: Each prior lifetime mental disorder was associated with an increased risk of subsequent first onset of each other disorder. The median HR was 12.1 (mean = 14.4; range 5.2-110.8, interquartile range = 6.0-19.4). The HRs were most prominent between closely-related mental disorder types and in the first 1-2 years after the onset of the prior disorder. Although HRs declined with time since prior disorder, significantly elevated risk of subsequent comorbidity persisted for at least 15 years. Appreciable absolute risks of secondary disorders were found over time for many pairs. CONCLUSIONS: Survey data from a range of sites confirms that comorbidity between mental disorders is common. Understanding the risks of temporally secondary disorders may help design practical programs for primary prevention of secondary disorders.

Postpartum psychiatric disorders and subsequent live birth: a population-based cohort study in Denmark.

STUDY QUESTION: Are women with a history of first-onset postpartum psychiatric disorders after their first liveborn delivery less likely to have a subsequent live birth? SUMMARY ANSWER: Women with incident postpartum psychiatric disorders are less likely to go on to have further children. WHAT IS KNOWN ALREADY: Women are particularly vulnerable to psychiatric disorders in the postpartum period. The potential effects of postpartum psychiatric disorders on the mother's future chances of live birth are so far under-researched. STUDY DESIGN, SIZE, DURATION: A population-based cohort study consisted of 414 571 women who had their first live birth during 1997-2015. We followed the women for a maximum of 19.5 years from the date of the first liveborn delivery until the next conception leading to a live birth, emigration, death, their 45th birthday or 30 June 2016, whichever occurred first. PARTICIPANTS/MATERIALS, SETTING, METHODS: Postpartum psychiatric disorders were defined as filling a prescription for psychotropic medications or hospital contact for psychiatric disorders for the first time within 6 months postpartum. The outcome of interest was time to the next conception leading to live birth after the first liveborn delivery. Records on the death of a child were obtained through the Danish Register of Causes of Death. Cox regression was used to estimate the hazard ratios (HRs), stratified by the survival status of the first child. MAIN RESULTS AND THE ROLE OF CHANCE: Altogether, 4327 (1.0%) women experienced postpartum psychiatric disorders after their first liveborn delivery. The probability of having a subsequent live birth was 69.1% (95% CI: 67.4-70.7%) among women with, and 82.3% (95% CI: 82.1-82.4%) among those without, postpartum psychiatric disorders. Women with postpartum psychiatric disorders had a 33% reduction in the rate of having second live birth (HR = 0.67, 95% CI: 0.64-0.69), compared to women without postpartum psychiatric disorders. The association disappeared if the first child died (HR = 1.01, 95% CI: 0.85-1.20). If postpartum psychiatric disorders required hospitalisations, this was associated with a more pronounced reduction in live birth rate, irrespective of the survival status of the first child (HR = 0.54, 95% CI: 0.47-0.61 if the first child survived, and HR = 0.49, 95% CI: 0.23-1.04 if the first child died). LIMITATIONS, REASONS FOR CAUTION: The use of population-based registers allows for the inclusion of a representative cohort with almost complete follow-up. The large sample size enables us to perform detailed analyses, accounting for the survival status of the child. However, we did not have accurate information on stillbirths and miscarriages, and only pregnancies that led to live birth were included. WIDE IMPLICATIONS OF THE FINDINGS: Our study is the first study to investigate subsequent live birth after postpartum psychiatric disorders in a large representative population. The current study indicates that postpartum psychiatric disorders have a significant impact on subsequent live birth, as women experiencing these disorders have a decreased likelihood of having more children. However, the variations in subsequent live birth rate are influenced by both the severity of the disorders and the survival status of the first-born child, indicating that both personal choices and decreased fertility may have a role in the reduced subsequent live birth rate among women with postpartum psychiatric disorders. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Danish Council for Independent Research (DFF-5053-00156B), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 837180, AUFF NOVA (AUFF-E 2016-9-25), iPSYCH, the Lundbeck Foundation Initiative for Integrative Psychiatric Research (R155-2014-1724), Niels Bohr Professorship Grant from the Danish National Research Foundation and the Stanley Medical Research Institute, the National Institute of Mental Health (NIMH) (R01MH104468) and Fabrikant Vilhelm Pedersen og Hustrus Legat. The authors do not declare any conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Reproduction after the loss of a child: a population-based matched cohort study.

STUDY QUESTION: Is the death of a child associated with higher subsequent fertility? SUMMARY ANSWER: Women who had lost a child had higher fertility both shortly after the loss and throughout the entire follow-up, independent of the child's age at the time of death. WHAT IS KNOWN ALREADY: Women who lose a child in the perinatal period often have another child shortly after. However, to our knowledge no previous study has investigated if the death of an older child affects reproductive behavior. STUDY DESIGN, SIZE, DURATION: The source population for this matched cohort study consisted of all women who gave birth in Denmark from 1978 to 2004 and in Sweden from 1973 to 2002 (N = 1 979 958). Women were followed through to the end of 2008 in Denmark and the end of 2006 in Sweden. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who had lost a child before the age of 45 years during the study period (exposed group; n = 36 511) were matched with up to five women who were from the same country and of similar age and family characteristics and had not lost a child at the time of matching (unexposed group; n = 182 522). MAIN RESULTS AND THE ROLE OF CHANCE: During follow-up, 74% of exposed and 46% of unexposed women had another birth (live- or stillbirth) after a gestation of 28 weeks or more. Compared with unexposed women, exposed women had a shorter interpregnancy interval and, consequently, a higher rate of conception leading to a birth (HR = 5.5 [95% CI: 5.4-5.6]). Rates for exposed women were higher from the first month following the child's death, but the largest difference was between 2 and 3 months after the event. This pattern was independent of the age of the deceased child. Exposed women had more subsequent children than unexposed, leading to a comparable number of living children at the end of follow-up. LIMITATIONS, REASONS FOR CAUTION: The use of population-based registers allows for the inclusion of virtually all eligible women and nearly complete follow-up; the potential for selection bias is thus negligible. However, only pregnancies that led to a live birth or a stillbirth could be identified, thus fetal losses occurring before week 28 of gestation were missing. WIDER IMPLICATIONS OF THE FINDINGS: Our findings corroborate the previous evidence suggesting that women try to conceive again shortly after a perinatal death, and many succeed. In addition, this is the first study to investigate the reproductive trajectory after losing an older child. The current study indicates that most women who lose a child between the ages of 6 months and 5 years conceive shortly after the loss, and they have a comparable number of living children at the end of the follow-up compared to those who do not lose a child. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Grant ERC-2010-StG-260242 from the European Research Council, 176673 and 186200 from the Nordic Cancer Union, DFF-6110-00019 from the Danish Council for Independent Research, 904414 and 15199 from TrygFonden, Karen Elise Jensens Fond (2016), and the Program for Clinical Research Infrastructure (PROCRIN) established by the Lundbeck Foundation and the Novo Nordisk Foundation. The authors do not declare any conflicts of interests. TRIAL REGISTRATION NUMBER: N/A.

Reproductive life in women with celiac disease; a nationwide, population-based matched cohort study.

STUDY QUESTION: How does celiac disease (CD) influence women's reproductive life, both prior to and after the diagnosis? SUMMARY ANSWER: Prior to the diagnosis of CD, an increased risk of adverse pregnancy outcomes was seen, whereas after the diagnosis, no influence on reproductive outcomes was found. WHAT IS KNOWN ALREADY: CD has been associated with several conditions influencing female reproduction and pregnancy outcomes including spontaneous abortion and stillbirth. STUDY DESIGN, SIZE, DURATION: A nationwide matched cohort study following 6319 women diagnosed with CD and 63166 comparison women and identifying reproductive events between the ages of 15 and 50 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Through linkage of several Danish national health registers, we identified all women diagnosed with CD between 1977 and 2016. We identified an age- and sex-matched comparison cohort and obtained data on reproductive outcomes for both cohorts. Adjusted stratified Cox and logistic regression models were used to estimate differences in reproductive outcomes between women with and without CD. MAIN RESULTS AND THE ROLE OF CHANCE: Comparing women with diagnosed CD with the non-CD women, the chance of pregnancy, live birth and risk of stillbirth, molar and ectopic pregnancy, spontaneous abortion and abortion due to foetal disease was the same. However, prior to being diagnosed, CD women had an excess risk of spontaneous abortion equal to 11 extra spontaneous abortions per 1000 pregnancies (adjusted odds ratio (OR) = 1.12, 95% CI: 1.03, 1.22) and 1.62 extra stillbirths per 1000 pregnancies (adjusted OR = 1.57, 95% CI: 1.05, 2.33) compared with the non-CD women. In the period 0-2 years prior to diagnosis fewer pregnancies occurred in the undiagnosed CD group, equal to 25 (95% CI: 20-31) fewer pregnancies per 1000 pregnancies compared to the non-CD group and in addition, fewer undiagnosed CD women initiated ART-treatment in this period, corresponding to 4.8 (95% CI: 0.9, 8.7) fewer per 1000 women compared to non-CD women. LIMITATIONS, REASONS FOR CAUTION: Validity of the diagnoses in the registers was not confirmed, but reporting to the registers is mandatory for all hospitals in Denmark. Not all spontaneous abortions will come to attention and be registered, whereas live- and stillbirths, ectopic and molar pregnancies and abortion due to foetal disease are unlikely not to be registered. We adjusted for several confounding factors but residual confounding cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS: These findings suggest that undiagnosed CD can affect female reproduction and the focus should be on early detection of CD in risk groups. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Health Research Fund of Central Denmark Region and The Hede Nielsens Foundation, Denmark. The authors report no conflicts of interest in this work.

Maternal stress before and during pregnancy and subsequent infertility in daughters: a nationwide population-based cohort study.

STUDY QUESTION: Is maternal stress following the death of a close relative before or during pregnancy associated with the risk of infertility in daughters? SUMMARY ANSWER: Compared with unexposed women, women whose mothers had experienced bereavement stress during, or in the year before, pregnancy had a similar risk of infertility overall, but those exposed to maternal bereavement during the first trimester had a higher risk of infertility. WHAT IS KNOWN ALREADY: Animal studies have shown that prenatal maternal stress results in reduced offspring fertility. In humans, there is evidence that girls who have been prenatally exposed to stress have a more masculine behaviour and a slight delay in having their first child. STUDY DESIGN, SIZE AND DURATION: This population-based cohort study, included 660 099 females born in Denmark between 1 January 1973 and 31 December 1993 to mothers of Danish origin and with at least one living relative in the exposure window, and followed the women through 31 December 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 13 334 women (2.0%) were considered prenatally exposed to stress because their mother had lost a spouse/partner, a child, a parent, or a sibling during pregnancy or in the year before conception. Infertility was defined as any record of infertility treatment or diagnosis of female infertility. We considered the date of onset as the date of the first appearance of any such record. The association between exposure and outcome was examined using hazard ratios (HR) with 95% confidence intervals (CI). MAIN RESULTS AND THE ROLE OF CHANCE: Based on our definition, 40 052 (6.5%) women were infertile in the follow-up period (median age at the end of follow-up: 26.7 years, maximum age: 39 years). Overall, prenatal exposure to maternal stress was not associated with risk of infertility (adjusted HR = 1.04 [CI: 0.95-1.14]). However, women prenatally exposed during the first trimester had a higher estimated risk (adjusted HR = 1.40 [CI: 1.05-1.86]). These findings were consistent in subgroups defined by the relationship of the mother to the deceased and in several sensitivity analyses, including a sibling-matched analysis, and in analyses restricted to women who were married or cohabitating with a man, or to women born at term. LIMITATIONS, REASONS FOR CAUTION: We did not have a direct measure of stress, but bereavement due to death of a close relative is likely to be very stressful. We based the timing of exposure on the date of the death of the family member, although the stress may well have started earlier. Infertility was also defined indirectly, and many women in the cohort were too young at the end of the follow-up to have been diagnosed. However, misclassification of the outcome was most likely non-differential, and the similar results from all sensitivity analyses suggest that it is unlikely that the effect observed in first trimester exposure would be due to chance. WIDER IMPLICATIONS OF THE FINDINGS: Prenatal exposure to maternal stress in the first trimester may affect the later fecundity of daughters. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a grant from the European Research Council (ERC-2010-StG-260242-PROGEURO) to the ProgEuro project (http://progeuro.au.dk). O.P.-R. is partly supported by a fellowship from Aarhus University and a travel grant from Oticon Fonden. The authors report no conflict of interests.