HIGH RATES OF ANXIETY DETECTED IN MOTHERS OF CHILDREN WITH INCONCLUSIVE CYSTIC FIBROSIS SCREENING RESULTS

Abstract

Objective

The purpose was to assess postpartum depression, anxiety, and depression in mothers of children with an inconclusive diagnosis after a positive cystic fibrosis (CF) newborn screening (NBS), known as cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) or CF screen positive, inconclusive diagnosis (CFSPID). There is limited information on the prognosis and on the impact of this designation on maternal mental health.

Methods

Mothers of children with CRMS/CFSPID and CF identified by NBS were recruited from two centers in California. Maternal mental health was assessed using measures of depression, anxiety, and a scripted interview. Descriptive statistics and multivariate logistic regression were applied for data reporting.

Results

A total of 109 mothers were recruited: CF: 51, CRMS/CFSPID: 58. Mothers from both groups showed higher rates of depression and anxiety symptoms than women in the general population. CRMS/CFSPID and CF mothers had no significant difference on their self-reported symptoms of anxiety and depression after adjusting for potential confounders. Mothers equally reported that their child’s diagnosis had a negative impact, and that genetic counseling had a positive impact on their emotional health.

Conclusions

CF and CRMS/CFSPID diagnoses impact maternal mental health similarly. Uncertain prognosis of CRMS/CFSPID likely contributed to the negative mental health impact. Providers should consider conducting mental health screening for every mother of a child with CRMS/CFSPID, in addition to the recommended mental health screening for mothers of children with CF. Genetic counseling has potential to mitigate emotional stress on these families.

Introduction

Newborn screening (NBS) for cystic fibrosis (CF) is a successful public health strategy for early recognition of affected infants, facilitating proactive treatment and prevention.¹ As expanded and increasingly sensitive NBS for CF detects CF transmembrane conductance regulator (CFTR) gene mutations of unknown clinical significance, it has increased the number of infants receiving an inconclusive diagnosis.^2,3 These infants have been designated cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) in the US and CF screen positive, inconclusive diagnosis (CFSPID) in other countries. The frequency of CRMS/CFSPID detection increases for protocols that uses DNA analysis and it surpasses the detection of CF in protocols adding gene sequencing.³ Currently there is limited guidance to families about the likelihood that affected infants will reclassify to CF or when they may show symptoms.⁴

There is an increased incidence of anxiety and depression in patients and families when a child is diagnosed with a chronic life-limiting disease.⁵ In a large study called the “The International Depression Epidemiological Study,” in which over 6,000 individuals with CF and over 4,000 caregivers of children with CF were screened, patients and their caregivers were found to have symptoms of anxiety and depression that were two to three times higher than the general population.⁶ Despite the fact that CRMS/CFSPID children are asymptomatic, the diagnosis carries significant ambiguity that could precipitate emotional distress for families. Intolerance of Uncertainty, or fear of the unknown and negative beliefs about uncertainty and its implications, has been linked as a transdiagnostic feature that contributes to both depression and anxiety symptoms.^7,8

To our knowledge, the mental health impact on parents of CRMS/CFSPID children has not been assessed in the US. Evidence suggests that genetic counseling improves caregivers’ knowledge of genetic information and has potential to mitigate caregiver distress, though the direct impact of counseling provided by trained professionals in the CF and CRMS/CFSPID population has not been thoroughly studied. ^9,10

The aim of this study was to assess the relationship between the CRMS/CFPSID designation and maternal mental health. Postpartum depression in mothers of infants and anxiety and depression in mothers of older CRMS/CFSPID children were assessed. We hypothesize that mothers of CRMS/CFSPID children have higher rates of anxiety and depression compared to adult women in the general population and similar to those of CF mothers.

Methods

Participants

Participants were recruited from two urban medical centers during their routine clinic visit or by phone. One-hundred and nine mother-child dyads were recruited based on NBS for CRMS/CFSPID and CF. All activities and procedures were approved by the Institutional Review Board of Children’s Hospital Los Angeles (CHLA) and Kaiser Permanente Los Angeles Medical Center (KP).

Procedures

Mental health screening questionnaires and scripted interview were completed in person or via telehealth using a HIPAA compliant platform or telephone. Of the total 58 CRMS/CFSPID participants, 13 were recruited from a lost-to-follow-up pool. We collected data through cross-sectional, self-administered questionnaires based on the age of the child, as suggested by the U.S. Cystic Fibrosis Foundation (www.cff.org). The scripted interview was administered verbally.

All mothers received psychoeducation at the time of the interview, which included a packet that contained information about postpartum depression, anxiety, depression, treatment options, and Mental Health Hotline. As this was an observational trial no mental health intervention was provided as a part of the study. For mothers who had elevated scores on the mental health screeners, a trained social worker or a psychologist met with the mother to conduct further assessment and provide resources as indicated.

Measures

Data collected from the medical records included demographics, genotype, birth weight, and immunoreactive trypsinogen (IRT).

Postpartum Depression:

The Edinburgh Postpartum Depression Scale (EPDS), a 10-item self-report survey that measures depressive symptoms in postnatal populations, was used to assess for depression in mothers of infants.⁹ A total score of less than 10 indicates low risk; 10–12 moderate risk; and greater than 13 suggests major risk of depression. EPDS has a sensitivity of 68–86%, specificity of 78–96%, and good to excellent internal consistency reliability.¹¹

Depression:

The Patient Health Questionnaire – 8 (PHQ-8), an 8-item questionnaire used to measure depressive symptoms, was administered to mothers of children over 12 months old.¹² The PHQ-8 provides a continuous score of depressive symptoms, with cut-off scores of 5, 10, and 15 indicating mild, moderate, and severe depression, respectively. The PHQ-8 is a psychometrically sound measure with a sensitivity of 70% and specificity of 98% for any depressive disorder, and a sensitivity of 100% and specificity of 95% for major depressive disorder.¹² The PHQ-8 has been found to have good to excellent internal consistency reliability.¹²

Anxiety:

The Generalized Anxiety Disorder – 7 (GAD-7), a 7-item, self-report questionnaire used to measure anxiety symptoms, was administered to mothers of children over 12 months old.¹³ Answers are added to yield a total score, with thresholds of 5, 10, and 15 indicating mild, moderate, and severe anxiety, respectively. The GAD-7 is a psychometrically sound measure, with excellent internal consistency reliability.¹³ Using a threshold of 10, the GAD-7 sensitivity is 89% and specificity is 82% for generalized anxiety disorder, with sensitivity decreasing at higher thresholds (48% sensitivity at the cut-off of 15).¹³

The Scripted Semi-Structured Interview:

A semi-structured interview assessed four categories: 1. Demographics and socioeconomic factors: race/ethnicity, type of insurance, household income, maternal education level, and number of residents living in the household; 2. Mental health history: personal/family history, traumatic events, chronic illness, and current stressors, such as restrictions from the COVID-19 pandemic; 3. Influence of the diagnosis on mental health measures and emotional health; and 4. Impact of genetic counseling. The scripted interview was created for the purpose of this study and was administered by mental health professionals and trained medical doctors. (Supplemental Table 1)

Statistical Analysis

Data from the scripted interview and mental health assessments are described in mean and standard deviation or median and range for continuous variables, and frequency and percentage for categorical variables. The differences in demographics and mental health assessment and history distribution between site and diagnosis were examined using contingency table analysis. The mental health association with diagnosis, mental health history, and demographic characteristics was assessed univariately by Firth logistic regression model to reduce bias due to the small number of patients from KP. Multivariate Firth logistic regression model further assessed the association between mental health measurements and diagnosis adjusting for site and patient characteristics. Whether the association between maternal mental health and child’s diagnosis is moderated by age was examined by including interaction term into the model. The final model included variables that were statistically significant in the univariate analysis and based on expert opinion. Results are described in odds ratio with its associated 95% confidence interval, and p value after multiple testing adjustment using Simes false discovery rate. Statistical tests were two-sided with Type I error of p< 0.05. All statistical computations were performed in Stata 17 (StataCorp, College Station, TX).

Results

A total of 109 subjects were recruited for this study from February 2019 until July 2021. This included 51 subjects with CF and 58 with CRMS/CFSPID. Of those, 91 were recruited at CHLA, and 18 were recruited at KP. About 90% of families who were approached, participated in the study. There was a similar distribution of gender and birth weight. The children were younger in the CRMS/CFSPID group. (Table 1)

Table 1:

Demographics by Diagnosis

	n (%) of participants
	Total (n = 109)	CF (n = 51)	CRMS/CFSPID (n = 58)	P
Age Group
Infancy	26 (24.85%)	13 (25.49%)	13 (22.41%)	0.001 a
Toddler	8 (7.34%)	5 (9.80%)	3 (5.17%)
Early childhood	32 (29.36%)	7 (13.73%)	25 (43.10%)
Middle childhood	37 (33.9%)	20 (39.22%)	17 (29.31%)
Early adolescence	6 (5.50%)	6 (11.76%)	0 (0%)
Sex				0.55 b
Female	56 (51.38%)	28 (54.90%)	28 (48.28%)
Male	52 (47.71%)	23 (45.10%)	29 (50%)
Missing	1 (0.92%)	0 (0%)	1 (1.72%)
Ethnicity				0.32 a
White	33 (30.28%)	13 (25.49%)	20 (34.48%)
Hispanic	23 (21.10%)	14 (27.45%)	9 (15.52%)
Hispanic White	43 (39.45%)	18 (35.29%)	25 (43.10%)
Other	10 (9.17%)	6 (11.76%)	4 (6.90%)
IRT (ng/mL), median [range]	101 [50, 370]	123 [51, 370]	86 [50, 174]	<0.0001 c
Birth weight (g), mean ± SD	3306 ± 429	3230 ± 428	3375 ± 423	0.08 d

^aFisher’s exact test

^bChi-square test

^cWilcoxon rank-sum test

^dTwo sample t-test Age groups were defined as follows: Infancy is 28 days to 1 year; Toddler is 1 to 2 years old; Early childhood is 2 to 5 years old; Middle Childhood is 6 to11 years old; Early adolescence is 12 to 18 years old.

Population characteristics were compared between the two sites. Besides household income, there were no differences in other socio-economic and mental health assessment results between sites (all p>0.05). Therefore, stratification by site was not necessary.

A total of 26 mothers completed EPDS, 83 completed both GAD-7 and PHQ-8, and all 109 completed the scripted interview. There was no significant difference between CF and CRMS/CFSPID groups on any of the mental health assessments. (Table 2) Mothers from both groups showed high levels of depression and anxiety symptoms: 49% of CF and 38% of CRMS/CFSPID mothers had a positive mental health screen, for any positive screen among the three tests. Results from CF and CRMS/CFSPID mothers were as follows: postpartum depression: 31% and 15%, anxiety: 40% and 40%, and depression: 37% and 27%, respectively.

Table 2.

Mental Health Assessment by Diagnosis

Measure	n (%) of participants
	Total	CF	CRMS/CFSPID	p
EPDS1				0.39 a
High risk (≥ 13)	3 (11.54%)	3 (23.08%)	0 (0%)
Moderate risk (10 – 12)	3 (11.54%)	1 (7.69%)	2 (15.38%)
Low risk (0 – 9)	17 (65.38%)	8 (61.54%)	9 (69.23%)
Not collected	3 (11.54%)	1 (7.69%)	2 (15.38%)
GAD-72				0.81 a
Severe (≥ 15)	1 (1.20%)	0 (0%)	1 (2.22%)
Moderate (10 – 14)	11 (13.25%)	4 (10.53%)	7 (15.56%)
Mild (5 – 9)	21 (25.30%)	11 (28.95%)	10 (22.22%)
Negative (< 5)	49 (59.04%)	23 (60.53%)	26 (57.78%)
Missing	1 (1.20%)	0 (0%)	1 (2.22%)
PHQ-82				0.71 a
Moderate (10 – 14)	6 (7%)	3 (8%)	3 (7%)
Mild (5 – 9)	20 (24%)	11 (29%)	9 (20%)
None (0 – 4)	56 (67%)	24 (63%)	32 (71%)
Missing	1 (1%)	0 (0%)	1 (2%)

¹Total n=26, CF=13, CRMS/CFSPID=13

²Total n=83, CF=38, CRMS/CFSPID=45

^aFisher’s exact test

When asked if the diagnosis of CF or CRMS/CFSPID influenced their responses on postpartum depression, depression, and anxiety measures there was no significant difference between CF and CRMS/CFSPID mothers, as follows. With postpartum depression, 69% of CF and 31% of CRMS/CFSPID mothers said their child’s diagnosis impacted their responses on the EPDS (p=0.053). Regarding depression, 63% of CF and 56% of CRMS/CFSPID mothers said their child’s diagnosis impacted their responses on the PHQ-8 (p=0.52). With anxiety, 74% of CF and 69% of CRMS/CFSPID mothers said their child’s diagnosis impacted their responses on the GAD-7 (p=0.61). Regardless of answers on mental health measures, 78% of CF and 79% of CRMS/CFSPID mothers said their child’s diagnosis impacts their emotional health.

In this sample, 76% of CF mothers received genetic counseling, compared to 98% of CRMS/CFSPID mothers. Of the mothers who received genetic counseling, 68% indicated that genetic counseling had a positive or very positive impact on their emotional health (Figure 1). The impact of genetic counseling on emotional health was not significantly different between CF and CRMS/CFSPID (p=0.65). Genetic counseling provider was significantly different between CF and CRMS/CFSPID (p=0.008): 41% of CF and 71% of CRMS/CFSPID mothers received genetic counseling from a certified genetic counselor, while all others who received genetic counseling received it from a CF physician.

Figure 1.

Mother’s ratings of the impact of genetic counseling on their emotional health is shown by diagnosis. Most mothers indicated that genetic counseling had a positive or very positive impact on their emotional health.

Univariate analysis showed that personal and family history of mental health disorders were associated with a positive screen for anxiety, but not depression. (Supplemental Table 2)

In the multivariate Firth logistic regression model, CRMS/CFSPID and CF mothers had no significant difference in anxiety and depression (Table 3 and 4). Positive family and personal mental health history were no longer significantly associated with positive anxiety or depression screens after multiple test adjustment. Age did not influence the associations between diagnosis and depression (interaction p=0.54) or anxiety (interaction p=0.27).

Table 3.

Multivariate Firth Logistic Regression Model of Anxiety

Anxiety (GAD-7)	OR	95% CI	p value *
Diagnosis (Ref = CF)
CRMS/CFSPID	0.54	(0.18, 1.66)	0.524
Personal mental health history (Ref = No)
Yes	3.71	(1.24, 11.08)	0.114
Family mental health history (Ref = No)
Yes	3.43	(1.11, 10.61)	0.114
Site (Ref = CHLA)
KP	0.46	(0.10, 2.01)	0.524
Age group (Ref = Toddler)
Early childhood	1.22	(0.21, 7.24)	0.824
Middle childhood	0.53	(0.10, 2.96)	0.643
Early adolescence	0.50	(0.05, 4.88)	0.643

Ref = Reference category

^*p value adjusted for multiple testing

Table 4.

Multivariate Firth Logistic Regression Model on Depression

Depression (PHQ-8)	OR	95% CI	p value *
Diagnosis (Ref = CF)
CRMS/CFSPID	0.36	(0.11, 1.20)	0.273
Personal mental health history (Ref = No)
Yes	2.03	(0.64, 6.41)	0.338
Family mental health history (Ref = No)
Yes	2.54	(0.79,8.15)	0.273
Site (Ref = CHLA)
KP	0.06	(0.003, 1.15)	0.273
Age group (Ref = Toddler)
Early childhood	3.20	(0.46, 22.37)	0.338
Middle childhood	1.48	(0.24, 8.98)	0.781
Early adolescence	1.19	(0.12, 11.87)	0.881

Ref = Reference Category

^*p value adjusted for multiple testing

Discussion

Results support the hypothesis that mothers of children with CRMS/CFSPID have higher rates of postpartum depression (15%), anxiety (40%), depression, and anxiety (27%) compared to adult women in the general population and similar rates as mothers of children with CF. Among adult women in the general population, the prevalence of postpartum depression is 11%, anxiety is 19%, and depression is 22%,14–16 while mothers of children with CF reflect rates of postpartum depression (31%), anxiety (40%), and depression (37%). Mothers of children with CRMS/CFSPID reported that their child’s diagnosis influenced their scores on all three screening tools no differently than CF mothers. Most mothers of children with CF and CRMS/CFSPID reported the diagnosis influenced their emotional health, regardless of their mental health scores, with no difference between the two groups. Most mothers reported a “positive” or “very positive” impact of genetic counseling on their emotional health, with no difference between mothers from the two groups. The present study represents the first assessment of the relations between the CRMS/CFSPID designation and maternal mental health in the United States.

The current results reflecting high rates of anxiety and depression in mothers of children diagnosed with CF and CRMS/CFSPID are similar to those seen in studies conducted internationally. In Italy, the level of anxiety is greater in parents of children with CF compared to CRMS/CFSPID, but long-term emotional distress is similar between the two groups and is higher than in those of healthy children.¹⁷ Studies in Canada and England identified a negative psychological impact in caregivers upon their child receiving a CRMS/CFSPID diagnosis due to difficulties understanding the diagnosis, uncertainty about the diagnostic meaning and what to expect, and how to manage their child’s needs.¹⁸ Diagnostic ambiguity likely contributed to higher mental health scores observed in our study.

Differences were not observed between CF and CRMS/CFSPID after adjusting for factors that may have influenced their assessments. Personal and family history were significantly associated with positive mental health screens in the univariate analysis; however, proven not to be significantly associated after multiple test adjustment. Nevertheless, this finding coincides with previous research, where many psychiatric conditions are moderately inheritable, can recur across the lifespan, and that a history of mental health concerns increases the risk of mental health challenges in the future.^{19, 20} Genetic, biological, and behavioral/learned predispositions combined with the stress of having a child diagnosed with a chronic illness may have contributed to increased anxiety.²¹ In the current study, most mothers indicated this life stress influenced their reported depression and anxiety symptoms. Future research should examine specific vulnerabilities and other stressors that may contribute to heightened mental health symptoms.

Given that children with CRMS/CFSPID are asymptomatic by definition, the authors anticipated that caregivers would naturally reduce their initial symptoms of anxiety and depression after overcoming the shock of the diagnosis at infancy by watching their child grow older and healthy. However, contrary to expectations, age of the child did not have an impact on mental health assessment scores. Future studies should continue to look at vital covariates, such as age, response to a new diagnosis, and impact of genetic counseling, to determine the natural history and developmental trajectory of caregiver’s emotional health status.

Genetic counseling may play an important role in alleviating caregiver distress by providing education, information, and emotional support. Well-informed parents have shown less anxiety and depression when receiving a positive NBS result for CF.²² The high percentage of mothers who indicated that genetic counseling had a “positive” or “very positive” impact on their emotional health supports the notion that genetic counseling has potential to mitigate emotional stress on families. Genetic counselors provide support to families beginning with prenatal care through adulthood and family planning for the patient. They provide medical information necessary for decision making and emotional and psychological support.¹⁰ There are multiple barriers to having sufficient genetic counseling, including funding, logistics, and numbers of genetic counselors trained in CF that results in a general shortage that cannot meet the clinical needs of CF centers. Further challenges include variability in billing and reimbursement, as well as credentialing and state licensure.¹⁰ In the present study only 41% of CF and 71% of CRMS/CFSPID families received counseling from a certified and CF-trained genetic counselor. Increasing access of trained genetic counselors for the CF and CRMS/CFSPID population is of paramount importance.^{10, 23}

CF centers in California experience a lost-to-follow-up rate of 45% in the CRMS/CFSPID population.²⁴ Both sites had a high lost-to-follow-up rate (51% at CHLA and 34% at KP), potentially introducing selection bias. We attempted to address this by specifically recruiting from this population; 13 of the 58 (22%) subjects in the CRMS/CFSPID group were recruited from a lost-to-follow-up pool. There were no statistically significant differences between mothers of CRMS/CFSPID children who were lost-to-follow-up versus those who stayed in care based on demographics and mental health outcomes. (Supplemental Table 3)

In general, the association between caregiver and child mental health has been shown to negatively impact medical adherence.^6,25 Although we did not find differences in mental health outcomes between mothers of patients with CRMS/CFSPID who were lost-to-follow-up versus those who were medically adherent, this was a modest sample. Programs in California still face ~50% lost-to-follow-up rates, which is very concerning. The ambiguous diagnosis in an otherwise “healthy-looking” child may contribute to a caregiver’s choice not to return to CF clinic. Beliefs about the necessity of preventive care and caregiver perceptions of their child’s health can adversely impact follow-up care.²⁶ Similarly, the lost-to-follow-up rate may be influenced by maternal mental health, which can adversely influence healthcare utilization and health behaviors.²⁷ While caregivers with anxiety who fear medicalization may avoid or deny illness and not seek routine care, others may cope by seeking control through not only attending medical follow-ups but developing an over-protective and over-vigilant behavior towards the child.²⁸ Relatedly, the purpose of NBS is early disease detection and intervention to reduce morbidity and mortality. Annual follow-up visits are recommended by both European and US guidelines.^{4, 29} It is critical that general pediatricians are made aware not only of this diagnosis, but also of potential CF signs and symptoms between annual visits and re-refer if a patient is lost to follow-up. Pediatricians should also be aware of the impact the ambiguity of this diagnosis can have on caregiver mental health to ensure adherence to recommended guidelines. As accurate testing can only be performed at an accredited CF center, children who do reclassify to CF benefit most from early diagnosis and intervention. Reclassification rates have been reported from 6% to 48% therefore it is vital that a reclassification diagnosis be made early.^30–32

Although this is the largest known cohort of CRMS/CFSPID patients to be studied in the United States, there were limitations. The small sample is powered to statistically detect only large differences between CF and CRMS/CFSPID mothers for the outcomes measured. However, given the paucity of data from this population, this is a relatively large and unique sample, which we use to raise awareness on the potential impact of the CRMS/CFSPID designation on maternal mental health. Recruitment was limited by families concerns to come to clinic during the COVID-19 pandemic, so telehealth options were offered. The high lost-to-follow-up rate may have introduced selection bias, which was mitigated by attempting to recruit patients from this pool. The study sample entirely reflected mothers; therefore, future studies should consider assessing all caregivers. Additionally, genetic counseling was not consistently delivered by a certified genetic counselor due to limited availability, therefore the measured impact may be influenced by who delivered the counseling and different stylistic approaches. This study was expanded from a single site to a multicenter study for further generalizability.

Providers should consider conducting a mental health screening for every mother of a child with CRMS/CFSPID, in addition to the recommended mental health screening for mothers of children with CF. Given the known adverse impact chronic and/or untreated caregiver psychological distress can have on child development in various domains, our findings further necessitate the importance of addressing caregiver emotional health.³³ Routine early universal screening for mental health concerns and resiliency with these caregivers could lead to greater medical adherence, and ultimately to greater education, use of resources, and improved health outcomes for both patients and their families. Considering the current findings and the significant impact of the CRMS/CFSPID designation on maternal emotional health, an effort should also be made to optimize CF newborn screening algorithms to minimize the burden of identification of high numbers of CRMS/CFSPID and to continue to invest in guidelines for monitoring this population.

Conclusion

Mothers of children with CRMS/CFSPID have an increased rate of anxiety, depression, and postpartum depression compared to adult women in the general population, and comparable to that detected in mothers of children with CF. Regardless of caregiver’s self-reported symptoms, most mothers reported an impact of the diagnosis on their emotional health. Pediatricians and CF specialists alike might consider screening mothers of children with an inconclusive NBS diagnosis for anxiety and depression to ensure they are being adequately supported and referred to a mental health specialist when indicated. The mental health impact of the CRMS/CFSPID diagnosis can lead some families to avoid care in a CF center, and therefore pediatricians will play a critical role in referring these children back to a CF specialist or, at minimum, monitoring them for signs and symptoms concerning for reclassification to CF.

Highlights.

• Mothers of CRMS/CFSPID children had high rates of anxiety and depression

• Diagnosis had a negative impact while genetic counseling supported emotional health

• Mental health screening is recommended to mothers of CFSPID children

Abbreviations:

CF

cystic fibrosis

CFSPID

cystic fibrosis screen positive, inconclusive diagnosis

CFTR

cystic fibrosis transmembrane conductance regulator

CHLA

Children’s Hospital Los Angeles

CRMS

cystic fibrosis transmembrane conductance regulator-related metabolic syndrome

EPDS

Edinburgh Postpartum Depression Scale

GAD – 7

Generalized Anxiety Disorder – 7

HIPAA

Health Insurance Portability and Accountability Act

HMO

Health Maintenance Organization

IRT

immunoreactive trypsinogen

NBS

newborn screening

PHQ – 8

Patient Health Questionnaire – 8