Risk of psychiatric disorders among the surviving twins after a co-twin loss

The death of a close relative has been linked to a variety of adverse health consequences among bereaved family members. An excess risk of morbidity and mortality was observed among individuals who experienced the loss of a spouse (Prior et al., 2018; Brenn and Ytterstad, 2016), parent (Bylund Grenklo et al., 2013; Rostila et al., 2016), or child (Hendrickson, 2009; Li et al., 2003). Nevertheless, although the sibling tie represents one of the most enduring kin relations across the life course (Bedford, 2012), sibling loss has received relatively scant attention in the scientific literature. A recent Danish population-based study compared the relative weight of the different types of bereavement (loss of child, spouse, sibling, and parents) with regard to the subsequent risk of suicide, deliberate self-harm and psychiatric illness (Guldin et al., 2017). The results revealed that, although loss of a sibling led to less obvious short-term rate elevations (compared to the loss of a child or spouse), sibling bereavement was associated with the greatest long-term risk elevations of the studied adverse psychiatric consequences.

By virtue of being born at the same time, both monozygotic and dizygotic twins tend to have more in common (e.g., early life experiences) and report stronger emotional bond than other sibling-pairs (Bank and Kahn, 1997; Neyer, 2002). Moreover, the 100% genetic share between monozygotic twins may contribute to even closer emotional ties between them than dizygotic twins (Neyer, 2002; Cassell, 2011; Fortuna et al., 2010). Consequently, losing a co-twin by death may be a particularly devastating life stressor with considerable health implications for the surviving twins (Segal and Bouchard, 1993). Nevertheless, scientific studies on this topic are relatively rare. With regard to psychiatric reactions to a co-twin death, only a handful of descriptive studies with small sample sizes have been conducted, mainly using self-reported measures of grief (i.e. sorrow or general sadness) as an outcome (Segal et al., 1995; Segal and Ream, 1998; Rosendahl and Björklund, 2013). Evidence on a potential rise in rates of clinically diagnosed psychiatric disorders associated with the loss of a co-twin is, however, totally lacking. Moreover, given the shared genetic background of twins, the psychiatric consequences after a co-twin loss need to be estimated with caution (Segal, 2009; Pompili et al., 2006), ideally using family comparison with additional vigorous control of previous psychiatric morbidities and the causes of the co-twin’s death.

Due to the sharp rise of medically assisted reproduction and delayed childbearing, the twinning rate, particularly the rate for dizygotic twins, has increased dramatically in all developed countries since 1970 s (Pison et al., 2015) which calls for a vigorous documentation of the potential health consequences suffered by surviving twins after a co-twin loss. Therefore, taking advantage of nationwide health registers in Sweden and the unique Swedish Twin Registry, we conducted a nationwide population- and sibling-matched cohort study to estimate the short- and long-term association between loss of a co-twin and subsequent risk of first-recorded psychiatric disorders.

Here, we included all Swedish-born twins that lost a co-twin by death between 1973 and 2013 (exposed twins), their full siblings, together with a group of age- and sex-matched unexposed twins who were randomly selected from the twin population and did not experience such a loss. While comparing twins exposed to a co-twin loss to twins without such an experience allowed control for pregnancy-, birth- and some psychosocial aspects of being a twin (the matched twin cohort), the comparison of exposed twins with their full siblings within the same family enabled a direct comparison between two types of stressors, that is loss of a co-twin and loss of a full sibling, while controlling for familial factors (the twin-sibling family cohort). See details in ‘Materials and methods’, and Figure 1 and Supplementary file 1-Table 1.

Figure 1

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In total, the matched twin cohort (i.e., 4528 exposed twins and 22,640 matched unexposed twins) accrued 263,215 person-years, with an approximately 8 year average duration of follow-up. The median age at co-twin loss was 59 years and around 50% of the exposed twins were males (Table 1). While there were only small differences in family income, educational level, and marital status, exposed and unexposed twins differed somewhat with respect to history of severe somatic diseases and family history of psychiatric disorders (19.7% vs 11.8%, 49.9% vs 37.3%, respectively). As expected, owing to the shared familial background, we observed more similarities between exposed twins and their full siblings on all studied characteristics (the ‘twin-sibling cohort’, Table 1).

During the follow-up, we identified 2047 twins with first-recorded psychiatric disorders in the matched twin cohort, including 526 among the exposed and 1521 among the unexposed twins, with a crude incidence rate (IR) of 12.29 and 6.90 per 1000 person-years, respectively (Table 2). The corresponding age- and sex-adjusted hazard ratio (HR) was 1.80 (95% confidence interval ①CI] 1.63–2.00), and decreased to 1.65 (95% CI 1.48–1.83) after further adjustment for socioeconomic factors, history of severe somatic disease, and family history of psychiatric disorders. Notably, the association was considerably stronger within the first month after a co-twin loss (HR = 7.16, 95% CI 3.07–16.70) than thereafter. The HR was 1.59 (95% CI 1.31–1.92) for the period 10 years and onwards. The twin-sibling cohort (i.e. exposed twins compared to their full siblings who also experienced a full sibling loss) yielded similar results, with a fully adjusted HR of 1.55 (95% CI 1.31–1.82) (Table 2).

Subgroup analyses, in both the matched twin and the twin-sibling cohorts, indicated that the association between loss of a co-twin and subsequent risk of psychiatric disorders did not differ by sex and family history of psychiatric disorders (Supplementary file 1-Table 2). Of note, although higher HRs were observed after loss of a co-twin due to unnatural death (e.g., death with any external cause), loss of a co-twin due to natural causes was also associated with a significantly increased risk of first-recorded psychiatric disorders among the surviving twins (e.g. HR = 1.49, 95% CI 1.32–1.69, based on analyses of matched twin cohort). In addition, an age-dependent risk pattern was found, suggesting that after age of 40, there was a decline in HR with increasing age at the index date (Figure 2 and Supplementary file 1-Table 2).

Figure 2

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Figure 2—source data 1

Summary data for Figure 2.

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To explore potential differences in relative risks by type of sibling loss, we did sub-analyses by zygosity (78% of included twins had such information). Compared to unexposed monozygotic twins, twins who lost a monozygotic co-twin were at a subsequently increased risk of psychiatric disorders (HR = 1.86, 95% CI 1.40–2.47), which was significantly higher than the risk elevation related to loss of a dizygotic co-twin among dizygotic twins (HR = 1.33, 95% CI 1.15–1.54, P for difference = 0.0395, Table 3). The analyses of twin-sibling cohort conveyed similar information, indicating a hierarchy of psychiatric disorder risk ―the HR for ‘loss of a monozygotic twin’, ‘loss of a dizygotic twin’, and ‘loss of a full sibling’ was 2.45, 1.29, and 1.00, respectively (Table 3). In addition, we observed increasing HRs with larger age gaps between twins and non-twin full siblings held as reference (P for trend <0.001, Supplementary file 1-Table 2).

Based on the matched twin cohort, we separately estimated HRs for six subtypes of psychiatric disorders (Figure 3). The association between loss of a co-twin and risk of psychiatric disorders was noted for all subtypes of psychiatric disorders, with the highest HRs observed for psychotic disorders (HR 3.30, 95% CI 2.02–5.38) and stress-related disorders (HR 2.17, 95% CI 1.65–2.84) during the entire follow-up period, and for stress-related disorders (HR 5.36, 95% CI 2.31–12.40) and mood disorders (HR 2.63, 95% CI 1.32–5.24) during the first year after loss.

Figure 3

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With slightly lower crude IRs, sensitivity analyses where the ascertainment of psychiatric disorders was merely based on the primary diagnoses in the National Patient Register (NPR) or the diagnoses from inpatient care in NPR revealed largely similar estimates (Supplementary file 1-Table 3).

To our knowledge, this is the first nationwide population-based and sibling-matched cohort study testing the association between loss of a co-twin and the subsequent risk of psychiatric disorders. Compared to twins without such loss experience or full siblings of the bereaved twins (who also experienced a loss of a full sibling), twins exposed to a co-twin loss were at considerably elevated risk of psychiatric disorders, especially during the first month after loss and particularly when the loss occurred before the age of 40. The excess risk was most pronounced after loss of a monozygotic co-twin and was higher for loss of a dizygotic co-twin than loss of a full sibling. In addition, we observed evident risk elevation after co-twin loss through either natural or unnatural deaths.

The twin bond has been suggested to be the closest and most enduring human social relationship (Segal et al., 1995; Segal, 2000). Besides the genetic relatedness, the unique relationship between twins is characterized by distinct intimacy and ambiguous identity boundaries. The genetic relatedness, shared early life experiences, and attachment have been suggested to contribute to the development of the shared twin identity (Schave, 1983; Macdonald, 2002). Consequently, when exposed to a co-twin death, both the grief (i.e., emotional reactions) and confusion of identity may contribute to a profound and long-lasting vulnerability of surviving twins. Indeed, in line with previous literature describing intense grief of surviving twins after co-twin loss (Segal and Ream, 1998; Rosendahl and Björklund, 2013), in the present study, we showed that the subsequent risk of developing first-diagnosed psychiatric disorders increased by 55–65% in the twin population, after carefully controlling for familial factors. Of note, such risk elevation was most obvious during the first month (7-fold), but persistently existed more than 10 years after the loss. In addition to the aforementioned factors (i.e., grief and identity confusion) which might underlie both the short- and long-term rise in the risk of psychiatric disorders, the long-term mental health decline among the surviving twins could also be attributable to the impairment of beneficial social support due to the co-twin loss and possible life-style changes, such as substance abuse or sleep problems (Sinha, 2001).

Moreover, consistent with prior theories that twin attachment changes across developmental stages, we found particularly strong risk increases of first-recorded psychiatric disorders when twins were exposed to co-twin loss in childhood and early adulthood (Neyer, 2002; Segal and Bouchard, 1993). Indeed, young people seem more vulnerable to various health consequences of trauma. We have previously reported higher excess risk of life-threatening infections and cardiovascular disease among individuals with stress-related disorders after trauma at an earlier age (Song et al., 2019; Song et al., 2018). Long-lasting biological interruptions, for example promoted inflammatory reactions (Danese et al., 2011) and neuropsychological/cognitive impairment (De Bellis and Zisk, 2014; Kennedy et al., 2018), have been associated with childhood exposure to trauma.

Without any comparable data, our finding that individuals suffering the loss of a monozygotic co-twin were at higher risk of psychiatric disorders compared to individuals suffering loss of co-dizygotic twin gains support from previous reports indicating a greater grief intensity (Segal and Bouchard, 1993), together with a less grief reduction (Segal and Ream, 1998), after loss of a monozygotic co-twin relative to loss of a dizygotic co-twin. Interpretations for this phenomenon include evolutionary theories linking more intense grief after the bereavement to greater genetic relatedness to the deceased (Neyer, 2002; Segal and Ream, 1998; Parkes, 1993). Alternatively, monozygotic twins have been reported to be emotionally closer and more dependent on their co-twin than dizygotic twins (Fortuna et al., 2010; Penninkilampi-Kerola et al., 2005). Thus, it is plausible that losing a monozygotic co-twin can result in more severe psychiatric consequences, compared to losing a dizygotic co-twin.

The abovementioned explanations may also apply to our next finding indicating that the loss of a full sibling is associated with lower risk of psychiatric disorder compared to loss of a co-twin. Particularly, with respect to dizygotic twins, the twin pair shares equal genetic relatedness as a twin-sibling pair. Therefore, even with an extreme assumption that the increase in the risk of psychiatric disorders after loss of a monozygotic co-twin than loss of a dizygotic co-twin was solely due to genetic factors, the 29% increased rate of psychiatric disorders observed after loss of a dizygotic co-twin than loss of a full sibling should be largely attributable to bereavement. Furthermore, the stronger associations observed with larger age gaps between twins and non-twin siblings supports the notion that siblings closer in age who share more life experiences are more likely have a closer relationship (Conger and Little, 2010) and hence might experience more difficult bereavement after a sibling loss. Similarly, other studies have also suggested a 15–20% excess risk of psychiatric disorders among individuals exposed to loss of a full sibling, as compared to the general population (Guldin et al., 2017; Rostila et al., 2019).

While we attempted to evaluate the influence of co-twin loss on the potential rise in psychiatric disorders, genetic confounding, namely the genetic susceptibility to psychiatric disorders and premature death shared within a twin pair, especially the monozygotic twins, is a concern in the present study. We made every effort to address this issue in the design of our study (e.g. excluding twins with past history of psychiatric disorders, controlling for family history of psychiatric disorders, and comparisons with full siblings) as well as in our analytic strategies (e.g. disentangling natural from unnatural deaths and performing a time-trend analysis). Although we cannot completely exclude the possibility of residual confounding, the results of the abovementioned analyses do argue against a pure explanation by genetic factors. Also, the time-trend analyses demonstrated – above and beyond possible genetic confounding - a distinct bereavement-response pattern, illustrated by the dramatic risk rise of first onset psychiatric disorders during the first months after the loss of a co-twin. Since we had limited information on prenatal/neonatal factors and behavior-related factors (e.g., smoking and alcohol consumption), residual confounding due to these factors remains another concern. Further research with detailed data on birth characteristics and lifestyle is warranted to clarify the role of such factors on the reported associations. Additionally, the absence of data from primary care as well as late inclusion of outpatient specialist care records in the NPR might have led to an underestimated number of individuals with milder forms of psychiatric disorders.

The major merit of our study is the use of population-based cohort design, including 4528 surviving twins with a complete follow-up of up to 40 years, and the between twin-full sibling comparison which enabled a direct comparison between two types of stressors, that is loss of a co-twin and loss of a full sibling, while controlling for potential familial confounders (e.g., genetic background was fully controlled for monozygotic twins, and partially controlled for dizygotic twins). As the largest cohort study on co-twin loss so far, we had sufficient statistical power to perform all planned subgroup analyses. Information bias was minimized since the registration and diagnosis of exposure and outcome was compiled prospectively and independently. Furthermore, the availability of rich information on sociodemographic and medical factors enabled considerations of a wide range of important confounding factors.

In conclusion, in the Swedish population, death of a co-twin was associated with a subsequently elevated rate of first-recorded psychiatric disorders among the surviving twins, particularly among monozygotic twins but also dizygotic twins as compared to their non-twin full siblings. Given that dizygotic twins share equal genetic relatedness to the twin-sibling pairs, this dose-response pattern suggests that both genetic relatedness and early life attachment may contribute to the subsequent risk of psychiatric disorders among surviving twins after co-twin loss.

From the Total Population Register, we identified all individuals born in Sweden between 1932 and 2013. We then linked these individuals to other registers in Sweden, including the Multi-Generation Register, the Causes of Death Register, the Swedish Twin Registry, and the National Patient Register (NPR), utilizing the personal identification numbers that are uniquely assigned to all Swedish residents.

From the Multi-Generation Register which includes almost complete familial link for all individuals born in Sweden since 1932, we identified all twin pairs as full siblings (i.e., with the same biological father and mother) that were born on the same day (+ / - 1 day), after excluding multiple births (more than two babies), and defined individuals with same biological father and mother but born on different dates as normal full siblings.

Two source data files have been provided. Original data is held by Swedish National Board of Health and Welfare, Statistics Sweden and the Swedish Twin Registry. Due to Swedish law on data protection and the ethical approval of the current study, we cannot make the data publicly available. However, any researcher can access the data by obtaining an ethical approval from a regional ethical review board and thereafter request the original data from the Swedish National Board of Health and Welfare, Statistics Sweden, and the Swedish Twin Register. Detailed information on data application can be found at https://www.registerforskning.se/en/ and https://ki.se/en/research/the-swedish-twin-registry.

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Author details

1. Huan Song

   1. West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China
   2. Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland
   3. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Methodology, Writing - original draft, Writing - review and editing

   For correspondence

   songhuan@wchscu.cn

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3845-8079

2. Henrik Larsson

   1. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
   2. School of Medical Sciences, Örebro University, Örebro, Sweden

   Contribution

   Resources, Data curation, Writing - review and editing

   Competing interests

   No competing interests declared

3. Fang Fang

   Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

   Contribution

   Conceptualization, Supervision, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

4. Catarina Almqvist

   1. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
   2. Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden

   Contribution

   Supervision, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

5. Nancy L Pedersen

   1. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
   2. Department of Psychology, University of Southern California, Los Angeles, United States

   Contribution

   Supervision, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

6. Patrik KE Magnusson

   Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

   Contribution

   Conceptualization, Resources, Data curation, Supervision, Writing - review and editing

   Competing interests

   No competing interests declared

7. Unnur A Valdimarsdóttir

   1. Center of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland
   2. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
   3. Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, United States

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Funding acquisition, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5382-946X

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