Introduction
Among the most prevalent medical conditions within the first year after delivery are postpartum psychiatric disorders and autoimmune thyroid disorders (AITDs). Both conditions are well known to have a de novo onset particularly in the first few months after childbirth compared with other time points (Andersen et al. Reference Andersen, Olsen, Carle and Laurberg2015, Reference Andersen, Carle, Olsen and Laurberg2016; Munk-Olsen et al. Reference Munk-Olsen, Maegbaek, Johannsen, Liu, Howard, di Florio, Bergink and Meltzer-Brody2016).
The postpartum period aggravates thyroid autoimmunity, which can lead to a spectrum of AITDs (Muller et al. Reference Muller, Drexhage and Berghout2001; Weetman, Reference Weetman2010). AITDs include hyperthyroid Graves disease, hypothyroid autoimmune thyroiditis (Hashimoto thyroiditis, postpartum thyroiditis) as well as a combination of these. Symptoms of hyperthyroidism (also called thyrotoxicosis) include heat intolerance, insomnia, palpitations, anxiety/irritability, weight loss and fatigue; symptoms of hypothyroidism include fatigue, weight gain, constipation, dry skin, depression and poor exercise tolerance. The specific characteristics of postpartum thyroiditis is a period of hyperthyroidism followed by a period of hypothyroidism, which can be either transient or permanent (Lazarus et al. Reference Lazarus, Parkes and Premawardhana2002; Stagnaro-Green, Reference Stagnaro-Green2004; Alexander et al. Reference Alexander, Pearce, Brent, Brown, Chen, Dosiou, Grobman, Laurberg, Lazarus, Mandel, Peeters and Sullivan2017).
In contrast to AITDs, a prototypical organ-specific autoimmune disease, the etiology of postpartum psychiatric disorders is largely unknown. The relative risk of severe psychiatric episodes (e.g. psychosis, mania and severe depression) is highly increased during the early postpartum period (Munk-Olsen et al. Reference Munk-Olsen, Maegbaek, Johannsen, Liu, Howard, di Florio, Bergink and Meltzer-Brody2016). Researchers have named autoimmunity as well as sensitivity of the brain for changes in sex steroids as potential etiologic contributors for these severe episodes (Bergink et al. Reference Bergink, Burgerhout, Weigelt, Pop, de Wit, Drexhage, Kushner and Drexhage2013; Schiller et al. Reference Schiller, Meltzer-Brody and Rubinow2015). In comparison, mild and moderate psychiatric episodes (including depressive, anxiety and adjustment disorders) usually have a later onset compared with more severe episodes, and psychosocial and psychological factors are known to play a major role (Stewart & Vigod, Reference Stewart and Vigod2016). High co-occurrence of AITDs and postpartum depression and psychosis has been described in case series and cohort studies (Pop et al. Reference Pop, de Rooy, Vader, van der Heide, van Son, Komproe, Essed and de Geus1991; Bergink et al. Reference Bergink, Kushner, Pop, Kuijpens, Lambregtse-van den Berg, Drexhage, Wiersinga, Nolen and Drexhage2011). However, the interpretation of these results are hampered since psychiatric disorders and AITDs are both highly prevalent postpartum, and consequently their concomitant occurrence could also be due to chance.
We conducted a register-based cohort study and examined the complex bidirectional association between first-onset autoimmune thyroid disorders and first-onset psychiatric disorders postpartum. Specifically, we investigated the risk of first onset of postpartum psychiatric disorders among women with first onset of postpartum AITDs and vice versa the risk of first-onset postpartum AITDs among women with first-onset psychiatric disorders. Furthermore, we explored the co-existence between these two disorders using a comorbidity index (Laursen et al. Reference Laursen, Agerbo and Pedersen2009), summarizing the extent to which the two disorders co-occur.
Methods
Study population
A population-based cohort study using the Danish national registers was conducted. In Denmark, all Danish citizens are assigned a unique Civil Personal Register number, which permits linkage of individual-level data within and between registers. We identified 383 205 women who gave birth to their first child during 1997–2010 from the Danish Medical Birth Registry (Knudsen & Olsen, Reference Knudsen and Olsen1998). To ensure that the recorded AITDs and psychiatric disorders diagnosed within 2 years after the delivery were first-onset ever, several exclusion criteria were employed (Fig. 1). These included: (1) previous psychiatric disorders (ICD-8 codes 290–315; and ICD-10 codes F00–F99); (2) previous redeemed prescription of psychotropic drugs (Anatomical Therapeutic Chemical Classification System (ATC) codes N05–N06); (3) previous thyroid disorders (ICD-8 codes 240–246; and ICD-10 codes E00–E07); or (4) previous prescription redeemed for therapy of AITDs (ATC code H03) before the index delivery. We further excluded 171 women who emigrated before the index delivery, and in total 312 779 women contributed to the final analyses (Fig. 1).
Fig. 1. Flowchart illustrating the identification of the study population.
Assessment of AITDs
For the present study, we defined AITDs as (1) a diagnosis of AITDs and at least one prescription for AITD therapy; or (2) two or more redeemed prescriptions for AITD therapy. The timing of first-onset AITDs was defined as the day of the first prescription redeemed for thyroid function therapy or first diagnosis of AITDs, whichever came first.
Diagnosis of AITDs
Information on the diagnosis of AITDs was obtained from the Danish National Patient Register (Andersen et al. Reference Andersen, Madsen, Jorgensen, Mellemkjoer and Olsen1999). The register holds information on all inpatient treatment during 1977–1994 and also on outpatient treatment from 1995 onwards. In- and outpatient treatment for AITDs within 2 years after the delivery were identified. The following ICD-10 codes were used to determine the diagnosis of thyroid disorders, including both hypothyroidism and hyperthyroidism: E01–E03, E05, E06, and E07.9. We excluded thyroid disorders not autoimmune in nature: All congenital thyroid disorders, thyroid disorders due to medicaments and other exogenous substances, non-toxic goitre and thyrotoxicosis factitia (E03.0, E03.1, E03.2, E05.4, and E06.4).
Drug prescription for AITD therapy
Information on a prescription for AITD therapy within 2 years after the delivery was retrieved from the Danish National Prescription Registry (Kildemoes et al. Reference Kildemoes, Sorensen and Hallas2011). This register covers all prescriptions dispensed in Denmark since 1995. Information on the drugs is recorded as ATC codes, and the ATC code for AITD therapy is H03. Specifically, this includes H03A thyroid hormones (e.g. levothyroxine, liothyronine, or combinations), H03B antithyroid preparations (e.g. thiouracils, carbimazole, thiamazole, or combinations) and H03C iodine therapy.
Assessment of psychiatric disorders
Information on psychiatric disorders was retrieved from the Danish Psychiatric Central Research Register (Mors et al. Reference Mors, Perto and Mortensen2011). The register holds information on inpatient treatments at psychiatric hospitals and psychiatric wards in general hospitals from 1969 onwards and includes outpatient treatments since 1995. From 1977 to 1993 the ICD-8 codes were used and ICD-10 codes from 1994 onwards. Women were classified as having psychiatric disorders if they had at least one in- or outpatient treatment for psychiatric disorders excluding mental retardation and substance abuse within 2 years after the delivery. Women diagnosed and treated solely in primary care were not included. The ICD-10 codes for psychiatric disorders were F00–F09, F20–F69, and F80–F99.
Study design
We followed women from delivery to 2 years after the index delivery. The underlying rationale for the 2-year follow-up is a clinically observed delay in the diagnosis and treatment for AITDs. Moreover, it is well known that postpartum thyroid dysfunction can be transient in the first months after delivery, but these women are at high risk of developing permanent hypothyroidisms within the first years postpartum (Lazarus et al. Reference Lazarus, Parkes and Premawardhana2002; Stagnaro-Green, Reference Stagnaro-Green2004; Alexander et al. Reference Alexander, Pearce, Brent, Brown, Chen, Dosiou, Grobman, Laurberg, Lazarus, Mandel, Peeters and Sullivan2017). Using this approach enabled us to include all registered cases with postpartum onset.
The study design comprised three parts:
1) first-onset postpartum AITDs as a risk factor for first-onset postpartum psychiatric disorders
2) first-onset postpartum psychiatric disorders as a risk factor for first-onset postpartum AITDs
3) comorbidity of postpartum AITDs and psychiatric disorders.
Details of the design are described below:
(1) AITDs as a risk factor for psychiatric disorders. We treated the first-onset AITDs as a time-dependent variable. All women were in the non-AITD group until they received a diagnosis of AITDs after which they were included in the AITD group. We examined the incidence rate ratio (IRR) of first onset of postpartum psychiatric disorders in the AITD group, compared with that of the non-AITD group. The time-at-risk for psychiatric disorders was defined as the years from the delivery until the first diagnosis of psychiatric disorders, emigration, death, 2 years after the delivery, or 31 December 2012, whichever came first. The total person-years was the sum of time-at-risk in years contributed by all subjects.
(2) Psychiatric disorders as a risk factor for AITDs. We treated the first-onset postpartum psychiatric disorders as a time-dependent variable. All women were in the non-psychiatric disorder group until they received a diagnosis of psychiatric disorders. From this time point, they were included in the psychiatric disorder group. We examined the IRR of first-onset AITDs in the psychiatric disorder group, compared with the non-psychiatric disorder group. The time-at-risk for AITDs was defined as years from the delivery until the first diagnosis of AITDs, emigration, death, 2 years after the delivery, or 31 December 2012, whichever came first. The total person-years were the sum of time-at-risk in years contributed by all subjects.
(3) Comorbidity of psychiatric and AITDs (Comorbidity Index). The comorbidity index describes whether a woman with one disorder of interest (e.g. AITDs) has a larger risk of being diagnosed with the other disorder of interest (e.g. psychiatric disorders) than a woman from the general population, irrespective of which disorder comes first. We calculated the probability of (1) psychiatric disorders, (2) AITDs, and (3) psychiatric disorders and AITDs. Then, we computed the comorbidity index to describe the overlap between first onset of postpartum AITDs and psychiatric disorders.
Statistical analysis
Statistical analyses were performed in Stata 13.1 (StataCorp, College Station, TX, USA). The incidence rate of AITDs was calculated as the number of women with first-onset AITDs divided by the total person-years at risk. We subsequently calculated the incidence rate of AITDs in each 1-month interval from delivery to 2 years postpartum. We likewise estimated the incidence rate of psychiatric disorders in the study period.
We calculated IRRs of psychiatric disorders and AITDs with 95% confidence intervals (CIs) using log-linear Poisson regression models. A p value of <0.05 (two-sided test) was considered statistically significant. We adjusted for age (<25, 25–34, or ⩾35 years), smoking (yes/no), marital status (married or cohabiting/single, divorced or widowed), income status (lowest quartile/above lowest quartile), calendar year at delivery (each year as a category), parental history of AITDs (yes/no), and parental history of psychiatric disorders (yes/no) in the models. Parental history of AITDs and parental history of psychiatric disorders were treated as time-dependent variables in the models. The remaining covariates were treated as fixed (time-independent) variables and information on these variables was obtained at the time of delivery. Information on smoking was only available during pregnancy, we therefore adjusted for smoking during pregnancy in the models as a proxy for smoking status during the study period.
The probability of (1) psychiatric disorders, (2) AITDs, and (3) psychiatric disorders and AITDs was estimated using the command ‘stcompet’ by Coviello & Boggess (Reference Coviello and Boggess2004). This method accounts for competing risk from emigration and death. We used the comorbidity index developed by Laursen et al. (Reference Laursen, Agerbo and Pedersen2009) to measure the overlap between psychiatric disorders and AITDs. If psychiatric disorders and AITDs are independent disorders, the probability of having both disorders is the product of the probability of psychiatric disorder and the probability of AITDs, i.e., P(psychiatric disorders and AITDs) = P(psychiatric disorders) × P(AITDs). If psychiatric disorders and AITDs are dependent, there should be a certain dependency between these two disorders. The degree of dependency between psychiatric disorders and AITDs can be measured by the comorbidity index, defined as the fraction between the right side and the left side of this equation: P (psychiatric disorders and AITDs)/(P(psychiatric disorders) × P(AITDs)). Consider the following as an example: A comorbidity index >1 indicate a dependency between AITDs and psychiatric disorders, while an index of 1 suggests no overlap between these two disorders. Alternatively, a hypothesized comorbidity index of 5 would imply that having AITDs and psychiatric disorders is 5 times as common as if they were independent.
Sensitivity analysis
There were 55 044 (17.6%) women who had another delivery within 2 years after the index delivery. Because the second delivery increased the risk for both AITDs and psychiatric disorders, we repeated our analyses by excluding these women from our study. To determine whether the length of follow-up could influence our results, we repeated our analyses using a 1-year follow-up period. We redefined first-onset psychiatric disorders and AITDs in the postpartum period as the first-ever diagnosis within 1 year after childbirth.
Ethical considerations
The study was approved by the Danish Data Protection Agency. No informed consent is needed for register-based studies based on anonymized data in Denmark.
Results
Incidence rate of AITDs and psychiatric disorders
Figure 2 displays the incidence rate of AITDs and psychiatric disorders in a 1-month interval within 2 years after delivery. |Altogether 2144 (0.69%) women were diagnosed with first onset of AITDs during the study period. The incidence rate of AITDs was 3.46 per 1000 person-years (95% CI: 3.31–3.61), with the highest incidence rate of AITDs observed 5–6 months postpartum (10.55 per 1000 person-years, 95% CI: 9.38–11.88). Overall 3164 (1.01%) women were diagnosed with psychiatric disorders, and the incidence rate of psychiatric disorders was 5.11 per 1000 person-years (95% CI: 4.93–5.29) within 2 years postpartum. The highest incidence rate was observed within 1 month after delivery (11.10 per 1000 person-years, 95% CI: 9.92–12.49).
Fig. 2. Incidence rate of autoimmune thyroid disorders and psychiatric disorders within 2 years after delivery.
First-onset postpartum AITDs as a risk factor for psychiatric disorders
During 617 533 person-years of follow-up, 3164 women were diagnosed with psychiatric disorders. Among them, 24 women were in the AITD group and 3140 in the non-AITD group. Of these 24 women, eight women had mood disorders, 11 neurotic, stress-related and somatoform disorders, and five other disorders. Table 1 shows the IRRs of psychiatric disorders according to AITDs and other covariates. After adjustment for other covariates, AITDs were associated with an increased risk of psychiatric disorders (IRR = 1.88, 95% CI: 1.25–2.81).
Table 1. Incidence rate ratios of psychiatric disorders according to the diagnosis of autoimmune thyroid disorders and covariates
IRRs, incidence rate ratios; CI, confidence interval.
a Adjusted for the calendar year at delivery, and all covariates in the table were mutually adjusted for.
First-onset psychiatric disorders as a risk factor for AITDs
During 618 324 person-years of follow-up, 2144 women were diagnosed with AITDs of whom 25 women were in the psychiatric disorder group and 2119 in the non-psychiatric disorder group. Of these 25 women, 12 women had mood disorders, nine neurotic, stress-related and somatoform disorders, and four other disorders. Table 2 presents the IRRs of AITDs according to psychiatric disorders and other covariates. After adjustment for other covariates, psychiatric disorders were associated with an increased risk of AITDs (IRR = 2.16, 95% CI: 1.45–3.20).
Table 2. Incidence rate ratios of autoimmune thyroid disorders according to the diagnosis of psychiatric disorders and covariates
IRRs, incidence rate ratios; CI, confidence interval.
a Adjusted for the calendar year at delivery, and all covariates in the table were mutually adjusted for.
Comorbidity index of thyroid disorders and psychiatric disorders
At the time of 2 years after delivery, the probability of having AITDs was 0.69%; for psychiatric disorders: 1.01%; and for both AITDs and psychiatric disorders: 0.02%. The comorbidity index was 2.26 (95% CI: 1.61–2.90), indicating that the probability of having AITDs and psychiatric disorders was 2.26 times as common as if they were independent within 2 years postpartum (Table 3).
Table 3. Comorbidity index for autoimmune thyroid disorders and psychiatric disorders from delivery to 2 years after delivery
All numbers have been rounded up.
Sensitivity analysis
We excluded 55 044 women who had another delivery within 2 years after the index delivery. After this, a higher risk of psychiatric disorders was still observed among women with AITDs (IRR = 2.08, 95% CI: 1.38–3.14), compared with those with no AITDs. Women with psychiatric disorders had a higher risk of AITDs (IRR = 2.25, 95% CI: 1.49–3.41), in comparison with those with no psychiatric disorders. The comorbidity index at the time of 2 years after delivery was 2.42 (95% CI: 1.71–3.14). When we redefined the length of follow-up as 1 year after the delivery of the first child, similar results were obtained. Specifically, the IRR of psychiatric disorders was 2.20 (95% CI: 1.14–4.24) among women with first-onset AITDs v. women with no AITDs. The IRR of AITDs was 3.11 (95% CI: 1.87–5.19) among women with first-onset psychiatric disorders v. those with no psychiatric disorders. The comorbidity index was 2.88 (95% CI: 1.71–4.06).
Discussion
In this population-based study, we described incidence rates of AITDs and postpartum psychiatric disorders in 312 779 women with follow-up until 2 years after delivery. For both disorders, there is a possible delay between first symptoms and diagnosis. This means that any temporal order of events from first symptoms to time of diagnoses can be uncertain when relying on the available dates of diagnoses in the registers. For this reason and to capture the bidirectional association, our main outcome of interest was the comorbidity index between AITDs and postpartum psychiatric disorders. The comorbidity index we observed was 2.26, which implies that having the first episode of postpartum AITDs and the first episode of postpartum psychiatric disorders is 2.26 times as common as if these were independent events. This high co-occurrence is an important consideration, both regarding the pathophysiological understanding and clinical management.
Pathophysiology
Symptoms related to malfunctioning of the thyroid sometimes mimic symptoms of psychiatric disorders. This is most obvious for hypothyroidism and depression and hyperthyroidism and (hypo) mania (Bocchetta et al. Reference Bocchetta, Traccis, Mosca, Serra, Tamburini and Loviselli2016). Consequently, there is a risk of misclassification, leading to high rates of ‘double diagnosis’. We do think that in some cases the comorbidity actually represents initial misdiagnosis, but there are also arguments in favor of a joint underlying biology. AITDs are complex multifactorial diseases, and both genetic and environmental factors contribute to the pathogenesis (Wiersinga, Reference Wiersinga2016). Postpartum AITDs are conceptualized as an acute phase of autoimmune thyroid destruction in the context of a preexisting process of thyroid autosensitization (Muller et al. Reference Muller, Drexhage and Berghout2001). This preexisting process of thyroid sensitization is linked to a genetic susceptibility (Yoo & Chung, Reference Yoo and Chung2016). In addition to major histocompatibility complex (MHC) class I and II genes, t cell related genes (CTLA4, CD40, CD25, FoxP3) and the cytokine regulatory genes have all been identified as contributors in AITDs (Yoo & Chung, Reference Yoo and Chung2016). The acute phase might be triggered by the rebound of the immune system in the postpartum period after the relative immune suppression of pregnancy (Muller et al. Reference Muller, Drexhage and Berghout2001; Luppi, Reference Luppi2003; Jorgensen et al. Reference Jorgensen, Pedersen, Nielsen, Jacobsen and Frisch2012). The ‘normal’ postpartum period is a time of robust immune system activation, and the T cell system is broadly activated across multiple T-cell subtypes, including T regulatory cells (Wegienka et al. Reference Wegienka, Havstad, Bobbitt, Woodcroft, Zoratti, Ownby and Cole Johnson2011). Regulatory T cells control immune responses, prevent excessive inflammations, and these cells have been described as dysfunctional in AITDs (Shi et al. Reference Shi, Li, Li, Guan, Fan, Teng, Ouyang, Shan and Teng2009; Glick et al. Reference Glick, Wodzinski, Fu, Levine and Wald2013). Together, the postpartum occurrence of AITDs in genetically vulnerable women could be linked to a dysbalance between inflammatory and anti-inflammatory T cell forces (T effector cells and T regulatory cells).
Postpartum psychiatric disorders may be governed by a similar immune mechanism as AITDs (Gleicher, Reference Gleicher2007; Jorgensen et al. Reference Jorgensen, Pedersen, Nielsen, Jacobsen and Frisch2012; Osborne & Monk, Reference Osborne and Monk2013). We previously described an immune-mediated developmental two-hit model for postpartum psychiatric disorders. In genetically susceptible individuals environmental influences lead to developmental brain abnormalities (a ‘vulnerable brain’), the second hit occurs after delivery, leading to activated immune cells in the brain and thus abnormalities of the neuronal circuitry and psychiatric symptoms (Bergink et al. Reference Bergink, Gibney and Drexhage2014). Given the overlap between AITDs and postpartum psychiatric disorders, future research in postpartum psychiatric disorders could include measurements of AITDs related genes and focus on T cell abnormalities with a special focus on the T regulatory cells.
Methodological considerations
The strength of our study is the representative study population and large sample size.
Our study also has several limitations. We defined AITDs on the basis of diagnosis or drug prescription for the treatment of thyroid dysfunction, while we had no data on autoimmune parameters such as thyroid peroxidase antibodies. Therefore we might have missed women at high risk for later AITDs. In general for AITDs the delay between first symptoms and diagnosis can be years (Mohandas & Gupta, Reference Mohandas and Gupta2003). Moreover, our incidence rates for both conditions are relatively low (Stagnaro-Green, Reference Stagnaro-Green2004; Gavin et al. Reference Gavin, Gaynes, Lohr, Meltzer-Brody, Gartlehner and Swinson2005; Banti et al. Reference Banti, Mauri, Oppo, Borri, Rambelli, Ramacciotti, Montagnani, Camilleri, Cortopassi, Rucci and Cassano2011). This is largely explained by the exclusion of women in the current study who had previous psychiatric disorders or AITDs before delivery. It is well known that a previous episode of a psychiatric disorder and of AITD is one of the most important predictors of (another) episode, this time triggered by giving birth. Moreover, we were especially interested in women with psychiatric diseases (severe enough for a referral to a psychiatry department) rather than the large group of women of the general population with postpartum mental illness symptoms.
Information on smoking during pregnancy was used as a proxy measure of smoking during the defined study period. If women changed their smoking habit over time, our results might be biased by residual confounding from smoking.
Clinical considerations
From a clinical point of view, it is evident that early diagnosis and treatment of both AITDs and psychiatric disorders are important. The loss of thyroid function is a gradual process (Yoo & Chung, Reference Yoo and Chung2016) and detection of the first clinical symptoms of AITDs is especially difficult in the postpartum period. The months after delivery are characterized by major physical and psychological changes and symptoms such as fatigue, sleep loss, weight changes, and irritability are generally regarded as being part of the normal physiological spectrum.
Psychiatric symptoms during the postpartum period can easily be overlooked because they are either fluctuating or hidden, and therefore assessment at multiple postpartum time points or referral to a mental health professional could be considered. In case of a positive psychiatric disorder, thyroid-stimulating Hormone (TSH) should be assessed. If TSH is abnormal, free thyroxine (fT4) levels and thyroid peroxidase antibodies (TPO Abs) should be determined. In case of a hyperthyroid phase, which can belong to the thyrotoxic phase of postpartum thyroiditis, symptomatic women may be treated with beta-blockers while antithyroid drugs are not recommended (guidelines, recommendation 86 and 87). If women show a symptomatic hypothyroid phase, either due to the hypothyroid phase of postpartum thyroiditis or due to a first manifestation of AITDs, levothyroxine should be considered with a regular check-up of thyroid function every 4–8 weeks (recommendation 89) (Alexander et al. Reference Alexander, Pearce, Brent, Brown, Chen, Dosiou, Grobman, Laurberg, Lazarus, Mandel, Peeters and Sullivan2017).
Conclusion
We showed high co-occurrence of first-onset AITDs and psychiatric disorders in the postpartum period, which is relevant for patient care. Psychiatric comorbidity is an important diagnostic consideration for women with AITDs. Vice versa, measurement of thyroid function is an essential part of diagnostic evaluations in women with postpartum psychiatric episodes. The co-occurrence of AITDs and psychiatric disorders has further relevance to studies on the etiologies of these disorders and why childbirth in particular triggers the onset.
Acknowledgements
We thank Hemmo Drexhage for his edits of the section: ‘pathophysiology’ and Wilmar Wiersinga for his help with the selection of the ICD codes for AITDs. VB is supported by the Netherlands Organisation for Scientific Research (NWO, VENI and clinical fellow). EA, PRN and TM have received funding from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (R155-2014-1724), iPSYCH, Denmark. EA is also supported by Niels Bohr Professorship Grant from the Danish National Research Foundation and the Stanley Medical Research Institute. TM is also supported by the National Institute of Mental Health (NIMH) (R01MH104468). XL is funded by the Danish Council for Independent Research (Project No. DFF-5053-00156B). The other authors report no financial relationships.
Declaration of Interest
None.
