BACKGROUND:

Objective measures on parental distress after a child’s cancer diagnosis are sparse. We examined the risk for first prescription of psychotropic medicine among parents of children with cancer compared with parents of children who were cancer free. In addition, we examined if sociodemographic and clinical characteristics are associated with risk of first prescription of psychotropic medication in parents of children with cancer.

METHODS:

We followed all parents of children with cancer (N = 6744) from the Danish Cancer Registry (1998–2014) using parents of matched children who were cancer free (N = 65 747) as a comparison. To identify vulnerable subgroups among parents of children with cancer, we followed all parents of children with cancer from the Childhood Cancer Registry (2003–2015; N = 3290 parents). In Cox proportional hazard models, we estimated hazard ratios (HRs) for a first prescription of psychotropic medication according to cancer status of the child and sociodemographic and clinical risk factors.

RESULTS:

Parents of children with cancer were at increased risk for a first prescription of psychotropic medication compared with parents of children who were cancer free up to 2 years after the diagnosis, the risk being highest in the first year (HR, 1.83 [95% confidence interval (CI), 1.66–2.01]). Parents of children with cancer, especially parents who lost their child, had an increased risk for a first prescription of hypnotics (HR, 6.91; 95% CI, 3.50–13.66) and anxiolytics (HR, 4.55, 95% CI, 1.57–13.17) in the first year after diagnosis.

CONCLUSIONS:

Efforts should be made to ensure that medical teams are adequately educated to address stress responses in the parents.

What’s Known on This Subject:

Parents of children with cancer experience long-term psychological distress, even years after successful treatments. However, objective measures on parental distress after a child’s cancer diagnosis are sparse.

What This Study Adds:

In this article, we provide new knowledge to health professionals about how and when parents of children with cancer experience psychological distress that is severe enough to seek medical treatment.

Childhood cancer is a heterogeneous group of diseases1 affecting >380 000 children worldwide.2 Despite the overall survival rate of >80%,2 parents may struggle emotionally with the shadowing threat of the death of their child. Stress reactions to a life-threatening disease such as childhood cancer may precipitate mental health problems, including insomnia, anxiety, and depression,3 even several years after the child’s diagnosis.4 Support is not systematically available to families of children with cancer,5 and the 2 most recent review studies differ in terms of the long-term adverse psychological impact on the parents: authors of a study from the United States reported that distress levels decreased to normal in most parents 6 months after diagnosis, whereas authors of a Swedish study reported that up to 44% of the parents experience depression, anxiety, or posttraumatic stress symptoms up to 5 years after diagnosis.5,6 Inconsistencies in findings may be related to a lack of comparison groups, differences in support available to parents, or different measurements of self-reported distress. This may be resolved through large population-based studies that follow parents long-term, which are essential for preventing longer-term psychiatric morbidity. In Denmark, psychotropic medication is available only through prescription by a medical doctor; thus, it provides an objective measure of psychological distress that is severe enough to warrant medical treatment and circumvents the biases of self-reported distress. Using nationwide Danish health registries,7 we conducted a population-based retrospective cohort study on the risk of psychotropic medication (antidepressants, anxiolytics, or hypnotics) in parents of children with cancer. The primary indication for prescribing antidepressants is moderate-to-severe depression,8 whereas the primary indications for anxiolytics and hypnotics include sleep disorders, severe anxiety, and acute stress–related anxiety.9 

First, using data from the nationwide Danish Cancer Registry (DCR), with registration of all cancers in adults since 1943 and children since 1975,10 we examined the risk of a first prescription of psychotropic medication in a cohort of parents of all children with cancer diagnosed between January 1, 1998, and December 31, 2014, compared with a matched cohort of parents of children who were cancer free (Supplemental Fig 2). However, no treatment and prognostic information is available in the DCR. Thus, to identify vulnerable subgroups of parents according to sociodemographic and clinical risk factors for prescription of psychotropic medication, we obtained information on a separate cohort of parents of children diagnosed with cancer between January 1, 2003, and December 31, 2015, according to the Childhood Cancer Registry11 (Supplemental Fig 3). This allowed us to include information on cancer type in 3 main diagnostic groups (hematologic cancer, central nervous system [CNS] tumors, and other solid tumors), relapse (yes versus no), and death (yes versus no). Information on biological parents was obtained from the Central Population Registry.7 

We obtained information on all redeemed prescriptions for psychotropic medication since the start of the Danish National Prescription Registry12 in 1995, using the codes N06A for antidepressants, N05BA and N05CD for anxiolytics, and N05CF for hypnotics, according to the Anatomical Therapeutic Chemical classification system.

From the Civil Registration System,7 we obtained information on characteristics of the parents at the time of cancer diagnosis or index date for parents of children who were cancer free: sex, date of birth, migration, and death. Information on highest attained education (basic [up to 9 years], vocational school [10–12 years], higher education [>12 years], or unknown) was obtained from the Danish education registries,7 and annual family income (in quartiles of 5) was obtained from the income statistics registry13 both 1 year before cancer diagnosis or index date.

We identified 7821 biological parents (3853 fathers and 3968 mothers) >18 years of age in the Central Population Registry7 of all children and adolescents <20 years of age who resided in Denmark and were diagnosed with cancer according to the DCR10 between January 1, 1998, and December 31, 2014. Because previous psychiatric disorder is a strong predictor of distress, we excluded 1056 parents (14%) with a prescription for psychotropic medication in the years 1 to 3 before the date of diagnosis or index date. Parents who received prescriptions in the year before diagnosis were not excluded because it is possible that their children had symptoms of undiagnosed cancer that were causing distress in the parents. This resulted in a final study sample of 6744 parents of children with cancer. For each child with cancer, we randomly selected 10 children who were cancer free individually matched on year of birth from the Central Population Registry. The comparison cohort comprised parents of these children who, at the index date, were aged >18 years, had resided in Denmark for at least 3 years, and had no prescriptions for psychotropic medication in the 1 to 3 years before the index date. Again, parents who had prescriptions in the year before the index date were not excluded. We identified 65 747 parents (33 416 fathers and 32 331 mothers) and excluded 347 parents because of missing information on either family size, age, education, or income and 9304 (14%) parents who had had a prescription for a psychotropic medication 1 to 3 years before the date of diagnosis or index date, resulting in 65 747 parents of children who were cancer free (33 416 fathers and 32 331 mothers).

To study the impact of socioeconomic and disease characteristics, which is not available in the DCR, we identified 3364 parents of children <15 years of age who resided in Denmark and were diagnosed with cancer according to the Childhood Cancer Registry between January 1, 2003, to June 30, 2015, with no prescription for a psychotropic medication 1 to 3 years before the date of diagnosis. Excluding 74 parents with missing information resulted in a final cohort of 3290 parents of children with cancer.

Risk for First Prescription of Psychotropic Medication According to Cancer Status in a Child

Parents were followed from the date of diagnosis or the index date until first redeemed prescription, death, emigration, or June 30, 2015 (end of study), whichever came first. To illustrate the development of risk by time since diagnosis, we estimated the cause-specific hazard for a first prescription of psychotropic medication (combined and separately as antidepressants, anxiolytics, and hypnotics) according to the child’s cancer status nonparametrically using a kernel smoother. To investigate the absolute difference in first prescription of psychotropic medication (combined) between parents of children with cancer and parents of children who were cancer free, cumulative incidence proportion of 3 years after cancer diagnosis or index date was estimated.

We used Cox proportional hazard models to estimate whether having a child with cancer was associated with an increased risk for a first prescription for any psychotropic medication or for the 3 types of medication separately. The assumption of proportional hazards was assessed graphically by the observed standardized empirical score process. If proportionality did not hold, the variable was included in the baseline hazard when it was not the main exposure of interest. Otherwise, an interaction with time since diagnosis (0–1, 1–2, 2–3, and ≥3 years) was included in the model, leading to different exposure effects according to time period since diagnosis. Models were adjusted for age at entry (18–33, 34–38, 39–42, 43–47, and ≥48 years) and calendar period at entry (1998–2001, 2002–2005, 2006–2009, and 2010–2013).

Risk Factors for First Prescription of Psychotropic Medication Among Parents of Children With Cancer

Parents were followed from the date of cancer diagnosis in the child until first redeemed prescription, death, emigration, or June 30, 2015, whichever came first. We used Cox proportional hazard models to examine whether sociodemographic factors (education and income obtained 1 year before diagnosis) and disease characteristics (cancer type obtained at diagnosis, relapse, and death as a time-dependent covariate) were associated with an increased risk for a first prescription of any psychotropic medication or for each of the 3 types of medication (antidepressants, anxiolytics, and hypnotics) among parents of children diagnosed with cancer. The assumption of proportional hazards was assessed graphically by the observed standardized empirical score process. If proportionality did not hold, an interaction between time since diagnosis (0–1, 1–2, 2–3, and ≥3 years) was included in the model, leading to different exposure effects according to time period since diagnosis. Models were adjusted for calendar period at entry (1998–2001, 2002–2005, 2006–2009, and 2010–2013), and time since diagnoses was used as the underlying time scale. In addition, individual confounders (education, income, cancer type, and relapse) were included depending on the exposure considered.

For both analyses, risk estimates were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). Because parents within a couple cannot be considered independent, the variance was estimated with adjustment for within-cluster correlation.14 All analyses were conducted in Stata version 14.15 The study was approved by the Danish Data protection Agency (2014-41-3405). Research based solely on registry data is exempt from ethical approval as well as from informed consent according to Danish law.16 

We followed 72 165 parents until first prescription of any psychotropic medication (n = 15 233), death (n = 471), emigration (n = 1037), cancer in a comparison child (n = 52), or end of follow-up (n = 55 372). Parents were followed up for 0 to 16 years, with a median of 5.6 years. Only small differences were seen between parents of children with cancer (N = 6744) and parents of children who were cancer free (N = 65 421; Table 1). The cumulative incidence of risk of first prescription of psychotropic medication after 3 years for parents of children with cancer was 14% (95% CI, 13.6–15.3), compared with 10% for parents of children who were cancer free (Supplemental Fig 4).

TABLE 1

Characteristics of the 6744 Parents of Children With Cancer and the 65 421 Parents of Children Who Were Cancer Free

Parents of Children With CancerParents of Children Who Were Cancer Free
n%n%
Parent     
 Father 3406 51 33 185 51 
 Mother 3338 49 32 236 49 
Family size     
 1 1022 15 9699 15 
 2 3215 48 30 591 47 
 3 1768 26 17 411 26 
 ≥4 739 11 7720 12 
Age at entry, y     
 18–33 1325 20 12 847 20 
 34–38 1312 19 13 209 20 
 39–42 1263 19 12 063 18 
 43–47 1483 22 14 218 22 
 ≥48 1361 20 13 084 20 
Period of entry     
 1998–2001 1649 25 16 109 25 
 2002–2005 1587 23 15 379 23 
 2006–2009 1682 25 16 233 25 
 2010–2013 1826 27 17 700 27 
Education     
 Basic 1098 16 10 578 16 
 Vocational 3361 50 32 802 50 
 High 2160 32 20 704 32 
 Unknown 125 1337 
Income quintile     
 1 1027 15 10 294 16 
 2 1396 21 13 120 20 
 3 1524 23 14 406 22 
 4 1504 22 14 733 22 
 5 1293 19 12 868 20 
Family type     
 1 biological parent with a partner 535 5455 
 2 biological parents 5263 78 51 692 79 
 Single parent 946 14 8274 13 
N 6744 — 65 421 — 
Parents of Children With CancerParents of Children Who Were Cancer Free
n%n%
Parent     
 Father 3406 51 33 185 51 
 Mother 3338 49 32 236 49 
Family size     
 1 1022 15 9699 15 
 2 3215 48 30 591 47 
 3 1768 26 17 411 26 
 ≥4 739 11 7720 12 
Age at entry, y     
 18–33 1325 20 12 847 20 
 34–38 1312 19 13 209 20 
 39–42 1263 19 12 063 18 
 43–47 1483 22 14 218 22 
 ≥48 1361 20 13 084 20 
Period of entry     
 1998–2001 1649 25 16 109 25 
 2002–2005 1587 23 15 379 23 
 2006–2009 1682 25 16 233 25 
 2010–2013 1826 27 17 700 27 
Education     
 Basic 1098 16 10 578 16 
 Vocational 3361 50 32 802 50 
 High 2160 32 20 704 32 
 Unknown 125 1337 
Income quintile     
 1 1027 15 10 294 16 
 2 1396 21 13 120 20 
 3 1524 23 14 406 22 
 4 1504 22 14 733 22 
 5 1293 19 12 868 20 
Family type     
 1 biological parent with a partner 535 5455 
 2 biological parents 5263 78 51 692 79 
 Single parent 946 14 8274 13 
N 6744 — 65 421 — 

—, not applicable.

During the first year after diagnosis, parents of children with cancer had an increased risk for a first prescription of any psychotropic medication (HR, 1.83; 95% CI, 1.66–2.01; Table 2). Significantly increased risks were seen in the first year for anxiolytics (HR, 2.99; 95% CI, 2.54–3.52) and hypnotics (HR, 2.64; 95% CI, 2.26–3.09) but not for antidepressants (HR, 1.02; 95% CI, 0.87–1.20; Table 2, Fig 1).

TABLE 2

Adjusted HRs and 95% CIs for the Risk of 6744 Parents of Children With Cancer for Redeeming a First Prescription for Psychotropic Medication When Compared With a Cohort of 65 421 Parents of Children Without Cancer

Cancer Status in a ChildTime Since Diagnosis, yPerson-y at RiskAll PrescriptionsAntidepressantsAnxiolyticsHypnotics
No. EventsHR (95% CI)No. EventsHR (95% CI)No. EventsHR (95% CI)No. EventsHR (95% CI)
Yes 0–1 6165 536 1.83 (1.66–2.01)a 164 1.02 (0.87–1.20) 192 2.99 (2.54–3.52)a 212 2.64 (2.26–3.09)a 
No 0–1 61 547 2923 1 (reference) 1593 1 (reference) 643 1 (reference) 798 — 
Yes 1–2 5446 251 1.31 (1.15–1.50) 106 1.15 (0.94–1.41) 80 1.76 (1.38–2.24)a 77 1.32 (1.03–1.68) 
No 1–2 54 982 1933 1 (reference) 933 1 (reference) 461 1 (reference) 592 — 
Yes 2–3 4772 181 1.16 (0.99–1.35) 91 1.20 (0.97–1.50) 42 1.10 (0.80–1.51) 54 1.12 (0.84–1.49) 
No 2–3 48 572 1594 1 (reference) 768 1 (reference) 390 1 (reference) 492 — 
Yes ≥3 25 011 681 0.98 (0.91–1.06) 322 0.94 (0.84–1.06) 150 1 0.01 (0.85–1.19) 232 1.03 (0.90–1.18) 
No ≥3 256 958 7134 1 (reference) 3501 1 (reference) 1534 1 (reference) 2319 — 
Cancer Status in a ChildTime Since Diagnosis, yPerson-y at RiskAll PrescriptionsAntidepressantsAnxiolyticsHypnotics
No. EventsHR (95% CI)No. EventsHR (95% CI)No. EventsHR (95% CI)No. EventsHR (95% CI)
Yes 0–1 6165 536 1.83 (1.66–2.01)a 164 1.02 (0.87–1.20) 192 2.99 (2.54–3.52)a 212 2.64 (2.26–3.09)a 
No 0–1 61 547 2923 1 (reference) 1593 1 (reference) 643 1 (reference) 798 — 
Yes 1–2 5446 251 1.31 (1.15–1.50) 106 1.15 (0.94–1.41) 80 1.76 (1.38–2.24)a 77 1.32 (1.03–1.68) 
No 1–2 54 982 1933 1 (reference) 933 1 (reference) 461 1 (reference) 592 — 
Yes 2–3 4772 181 1.16 (0.99–1.35) 91 1.20 (0.97–1.50) 42 1.10 (0.80–1.51) 54 1.12 (0.84–1.49) 
No 2–3 48 572 1594 1 (reference) 768 1 (reference) 390 1 (reference) 492 — 
Yes ≥3 25 011 681 0.98 (0.91–1.06) 322 0.94 (0.84–1.06) 150 1 0.01 (0.85–1.19) 232 1.03 (0.90–1.18) 
No ≥3 256 958 7134 1 (reference) 3501 1 (reference) 1534 1 (reference) 2319 — 

All analyses were adjusted for age group and calendar year at entry. —, not applicable.

a

P < .01.

FIGURE 1

Cause-specific hazards for first prescription of antidepressants, anxiolytics, or hypnotics and for any psychotropic medication according to cancer status of the child.

FIGURE 1

Cause-specific hazards for first prescription of antidepressants, anxiolytics, or hypnotics and for any psychotropic medication according to cancer status of the child.

Close modal

Examining subgroups of vulnerable parents of children with cancer, we followed 3290 parents of children with cancer until first prescription (n = 952), death (n = 9), emigration (n = 27), or end of follow-up (n = 2728). Parents were followed up for 0 to 12.4 years, with a median of 4.4 years. A total of 656 parents (20%) received a first prescription of psychotropic medication during the study period. The only differences across cancer types were seen for age (a larger proportion of younger parents of children with solid tumors than of parents of children with other cancer types; Table 3). Of the 656 parents who received a prescription, 89 parents experienced a first prescription after relapse in their child, and 94 after death of their child (Table 4).

TABLE 3

Characteristics of 3290 Parents of Children With Cancer According to 3 Main Diagnostic Groups of Cancer

HematologicaCNS TumorsbSolid Tumors and OthercTotal
n%n%n%n%
Parent         
 Father 757 50 380 50 515 51 1652 50 
 Mother 754 50 382 50 502 49 1638 40 
 Total 1511 100 762 100 1017 100 3290 100 
No. children         
 1 271 18 133 17 240 23 644 19 
 2 729 48 363 48 443 44 1535 47 
 3 380 25 192 25 236 23 808 25 
 >4 131 74 10 98 10 303 
 Total 1511 100 762 100 1017 100 3290 100 
Age of parent at entry, y         
 18–32 347 23 146 19 283 28 776 24 
 33–35 277 18 126 16 167 16 570 17 
 36–38 266 18 120 16 160 16 546 16 
 39–42 298 20 185 24 205 20 688 21 
 >43 323 21 185 24 202 20 710 21 
 Total 1511 100 762 100 1017 100 3290 100 
Education         
 Basic 261 17 140 18 173 17 574 17 
 Vocational 683 45 347 46 473 46 1503 46 
 High 567 38 275 36 371 37 1213 37 
 Total 1511 100 762 100 1017 100 3290 100 
Income quantile         
 1 217 14 98 13 152 15 467 14 
 2 322 21 172 23 213 21 707 22 
 3 314 21 168 22 241 24 723 22 
 4 350 23 168 22 214 21 732 22 
 5 308 21 156 20 197 19 661 20 
 Total 1511 100 762 100 1017 100 3290 100 
Family type         
 1 biological parent with a partner 72 30 39 141 
 2 biological parents 1276 84 648 85 843 83 2767 84 
 Single parent 163 11 84 11 135 13 382 12 
 Total 1511 100 762 100 1017 100 3290 100 
HematologicaCNS TumorsbSolid Tumors and OthercTotal
n%n%n%n%
Parent         
 Father 757 50 380 50 515 51 1652 50 
 Mother 754 50 382 50 502 49 1638 40 
 Total 1511 100 762 100 1017 100 3290 100 
No. children         
 1 271 18 133 17 240 23 644 19 
 2 729 48 363 48 443 44 1535 47 
 3 380 25 192 25 236 23 808 25 
 >4 131 74 10 98 10 303 
 Total 1511 100 762 100 1017 100 3290 100 
Age of parent at entry, y         
 18–32 347 23 146 19 283 28 776 24 
 33–35 277 18 126 16 167 16 570 17 
 36–38 266 18 120 16 160 16 546 16 
 39–42 298 20 185 24 205 20 688 21 
 >43 323 21 185 24 202 20 710 21 
 Total 1511 100 762 100 1017 100 3290 100 
Education         
 Basic 261 17 140 18 173 17 574 17 
 Vocational 683 45 347 46 473 46 1503 46 
 High 567 38 275 36 371 37 1213 37 
 Total 1511 100 762 100 1017 100 3290 100 
Income quantile         
 1 217 14 98 13 152 15 467 14 
 2 322 21 172 23 213 21 707 22 
 3 314 21 168 22 241 24 723 22 
 4 350 23 168 22 214 21 732 22 
 5 308 21 156 20 197 19 661 20 
 Total 1511 100 762 100 1017 100 3290 100 
Family type         
 1 biological parent with a partner 72 30 39 141 
 2 biological parents 1276 84 648 85 843 83 2767 84 
 Single parent 163 11 84 11 135 13 382 12 
 Total 1511 100 762 100 1017 100 3290 100 
a

Leukemia and lymphoma.

b

CNS tumors and miscellaneous intracranial and intraspinal neoplasms.

c

Neuroblastoma and other peripheral nervous cell tumors; retinoblastoma; renal tumors; hepatic tumors; malignant bone tumors; soft-tissue sarcomas; germ-cell, trophoblastic, and other gonadal tumors; other malignant epithelial neoplasms and malignant melanomas; and lastly, other and unspecified malignant neoplasms.

TABLE 4

Adjusted HRs and 95% CIs for a First Prescription for Psychotropic Medication According to Sociodemographic and Clinical Characteristics in 3290 Parents of Children With Cancer

Person-y at RiskTotalAntidepressantsAnxiolyticsHypnotics
No. EventsHR (95% CI)No. EventsHR (95% CI)No. EventsHR (95% CI)No. EventsHR (95% CI)
Cancer type, totala 17 713 656  322  133  230  
 Hematologic 8159 302 0.97 (0.81–1.16) 150 1.04 (0.80–1.34) 59 0.87 (0.58–1.29) 104 0.89 (0.66–1.19) 
 CNS tumors 3914 143 0.96 (0.77–1.20) 73 1.05 (0.77–1.43) 28 0.87 (0.53–1.42) 47 0.84 (0.58–1.22) 
 Solid and other tumors 5640 211 1 (reference) 99 1 (reference) 46 1 (reference) 79 1 (reference) 
 Test for no effect of cancer type, P — — .9188 — .9476 — .7548 — .5988 
Relapse, total 17 713 656 — 322 — 133 — 230 — 
 Yesb 2316 89 1.49 (1.16–1.90)c 37 1.13 (0.79–1.60) 20 2.30 (1.39–3.79)c 35 1.91 (1.25–2.92)c 
 No 15 397 567 1 (reference) 285 1 (reference) 113 1 (reference) 195 1 (reference) 
 Test for no effect of relapse, P — — .0015 — .5129 — .0012 — .0029 
Relapse, time since diagnosis, y          
 Yes, 0–1 79 1.10 (0.40–3.05) <3 1.18 (0.28–4.91) <3 1.03 (0.14–7.75) <3 0.99 (0.13–7.25) 
 No, 0–1 2974 229 1 (reference) 97d 1 (reference) 59d 1 (reference) 94d 1 (reference) 
 Yes, 1–2 275 24 2.22 (1.42–3.47)c 1.38 (0.61–3.13) 2.06 (0.90–4.74)c 12 4.04 (1.93–8.44)c 
 No, 1–2 2446 99 1 (reference) 49 1 (reference) 29 1 (reference) 26 1 (reference) 
 Yes, 2–3 331 15 1.75 (0.96–3.18)c 1 0.42 (0.593–0.48) 4.41 (1.32–14.67)c 2.30 (0.77–6.85)c 
 No, 2–3 2047 54 1 (reference) 29 1 (reference) 1 (reference) 18 1 (reference) 
 Yes, 3+ 1632 46 1.23 (0.88–1.73) 21 0.98 (0.63–1 0.55) 2.38 (1.03–5.51)c 16 1.32 (0.75–2.31) 
 No, 3+ 7929 185 1 (reference) — 1 (reference) 19 1 (reference) 58 1 (reference) 
Death, totale 1902 94 1.75 (1.34–2.29) 34 1.17 (0.80–1.71) 21 2.28 (1.24–4.17) 41 2.51 (1.65–3.83) 
 No death 15 811 562 1 (reference) 288 1 (reference) 112 1 (reference) 189 1 (reference) 
 Test for no effect of death, P — — <.0001 — .4198 — .0077 — <.0001 
Death, time since diagnosis, y          
 Yes, 0–1 98 20 3.65 (2.15–6.21)c 1.40 (0.50–3.88) 4.55 (1.57–13.17)c 11 6.91 (3.50–13.66)c 
 No, 0–1 2954 213 1 (reference) 93 1 (reference) 53 1 (reference) 83 1 (reference) 
 Yes, 1–2 209 20 2.13 (1.29–3.52) 0.83 (0.30–2.25) 2.13 (0.84–5.36)c 10 3.52 (1.63–7.58)c 
 No, 1–2 2512 103 1 (reference) 53 1 (reference) 29 1 (reference) 28 1 (reference) 
 Yes, 2–3 256 12 1.58 (0.82–3.06) 1.85 (0.78–4.36) 4.13 (1.15–14.76)c 1.06 (0.23–4.96) 
 No, 2–3 2123 57 1 (reference) 29 1 (reference) 1 (reference) 21 1 (reference) 
 Yes, 3+ 1339 42 1.22 (0.86–1.73) 20 1.10 (0.66–1.82) 1.00 (0.38–2.64) 17 1.50 (0.85–2.64) 
 No, 3+ 8222 189 1 (reference) 113 1 (reference) 23 1 (reference) 57 1 (reference) 
Educationf          
 Basic 2834 171 2.25 (1.81–2.79)c 97 3.02 (2.23–4.10)c 36 2.65 (1.62–4.34)c 44 1.19 (0.82–1.74) 
 Vocational 8356 314 1.44 (1.20–1.74) 152 1.65 (1.25–2 0.17) 67 1.76 (1.15–2 0.71) 104 0.99 (0.74–1.33) 
 High 6524 171 1 (reference) 73 1 (reference) 30 1 (reference) 82 1 (reference) 
 Test for no effect of education, P — — <.0001 — <.0001 — .0005 — .5772 
Incomeg          
 1 2414 138 1.40 (1.09–1.79) 70 1.46 (1.02–2.09) 31 1.81 (1.01–3.24)c 43 1.09 (0.72–1.65) 
 2 3668 165 1.16 (0.92–1.47) 95 1.38 (0.98–1.93) 32 1.33 (0.75–2.37) 47 0.81 (0.55–1.21) 
 3 4119 110 0.74 (0.57–0.96) 50 0.69 (0.47–1.01) 25 1.01 (0.55–1.85) 37 0.60 (0.39–0.91) 
 4 4003 122 0.89 (0.69–1.15) 51 0.79 (0.54–1.16) 25 1.11 (0.61–2.02) 48 0.79 (0.53–1.16) 
 5 3509 121 1 (reference) 56 1 (reference) 20 1 (reference) 55 1 (reference) 
 Test for no effect of income, P — — <.0001 — <.0001 — .1654 — .0601 
Person-y at RiskTotalAntidepressantsAnxiolyticsHypnotics
No. EventsHR (95% CI)No. EventsHR (95% CI)No. EventsHR (95% CI)No. EventsHR (95% CI)
Cancer type, totala 17 713 656  322  133  230  
 Hematologic 8159 302 0.97 (0.81–1.16) 150 1.04 (0.80–1.34) 59 0.87 (0.58–1.29) 104 0.89 (0.66–1.19) 
 CNS tumors 3914 143 0.96 (0.77–1.20) 73 1.05 (0.77–1.43) 28 0.87 (0.53–1.42) 47 0.84 (0.58–1.22) 
 Solid and other tumors 5640 211 1 (reference) 99 1 (reference) 46 1 (reference) 79 1 (reference) 
 Test for no effect of cancer type, P — — .9188 — .9476 — .7548 — .5988 
Relapse, total 17 713 656 — 322 — 133 — 230 — 
 Yesb 2316 89 1.49 (1.16–1.90)c 37 1.13 (0.79–1.60) 20 2.30 (1.39–3.79)c 35 1.91 (1.25–2.92)c 
 No 15 397 567 1 (reference) 285 1 (reference) 113 1 (reference) 195 1 (reference) 
 Test for no effect of relapse, P — — .0015 — .5129 — .0012 — .0029 
Relapse, time since diagnosis, y          
 Yes, 0–1 79 1.10 (0.40–3.05) <3 1.18 (0.28–4.91) <3 1.03 (0.14–7.75) <3 0.99 (0.13–7.25) 
 No, 0–1 2974 229 1 (reference) 97d 1 (reference) 59d 1 (reference) 94d 1 (reference) 
 Yes, 1–2 275 24 2.22 (1.42–3.47)c 1.38 (0.61–3.13) 2.06 (0.90–4.74)c 12 4.04 (1.93–8.44)c 
 No, 1–2 2446 99 1 (reference) 49 1 (reference) 29 1 (reference) 26 1 (reference) 
 Yes, 2–3 331 15 1.75 (0.96–3.18)c 1 0.42 (0.593–0.48) 4.41 (1.32–14.67)c 2.30 (0.77–6.85)c 
 No, 2–3 2047 54 1 (reference) 29 1 (reference) 1 (reference) 18 1 (reference) 
 Yes, 3+ 1632 46 1.23 (0.88–1.73) 21 0.98 (0.63–1 0.55) 2.38 (1.03–5.51)c 16 1.32 (0.75–2.31) 
 No, 3+ 7929 185 1 (reference) — 1 (reference) 19 1 (reference) 58 1 (reference) 
Death, totale 1902 94 1.75 (1.34–2.29) 34 1.17 (0.80–1.71) 21 2.28 (1.24–4.17) 41 2.51 (1.65–3.83) 
 No death 15 811 562 1 (reference) 288 1 (reference) 112 1 (reference) 189 1 (reference) 
 Test for no effect of death, P — — <.0001 — .4198 — .0077 — <.0001 
Death, time since diagnosis, y          
 Yes, 0–1 98 20 3.65 (2.15–6.21)c 1.40 (0.50–3.88) 4.55 (1.57–13.17)c 11 6.91 (3.50–13.66)c 
 No, 0–1 2954 213 1 (reference) 93 1 (reference) 53 1 (reference) 83 1 (reference) 
 Yes, 1–2 209 20 2.13 (1.29–3.52) 0.83 (0.30–2.25) 2.13 (0.84–5.36)c 10 3.52 (1.63–7.58)c 
 No, 1–2 2512 103 1 (reference) 53 1 (reference) 29 1 (reference) 28 1 (reference) 
 Yes, 2–3 256 12 1.58 (0.82–3.06) 1.85 (0.78–4.36) 4.13 (1.15–14.76)c 1.06 (0.23–4.96) 
 No, 2–3 2123 57 1 (reference) 29 1 (reference) 1 (reference) 21 1 (reference) 
 Yes, 3+ 1339 42 1.22 (0.86–1.73) 20 1.10 (0.66–1.82) 1.00 (0.38–2.64) 17 1.50 (0.85–2.64) 
 No, 3+ 8222 189 1 (reference) 113 1 (reference) 23 1 (reference) 57 1 (reference) 
Educationf          
 Basic 2834 171 2.25 (1.81–2.79)c 97 3.02 (2.23–4.10)c 36 2.65 (1.62–4.34)c 44 1.19 (0.82–1.74) 
 Vocational 8356 314 1.44 (1.20–1.74) 152 1.65 (1.25–2 0.17) 67 1.76 (1.15–2 0.71) 104 0.99 (0.74–1.33) 
 High 6524 171 1 (reference) 73 1 (reference) 30 1 (reference) 82 1 (reference) 
 Test for no effect of education, P — — <.0001 — <.0001 — .0005 — .5772 
Incomeg          
 1 2414 138 1.40 (1.09–1.79) 70 1.46 (1.02–2.09) 31 1.81 (1.01–3.24)c 43 1.09 (0.72–1.65) 
 2 3668 165 1.16 (0.92–1.47) 95 1.38 (0.98–1.93) 32 1.33 (0.75–2.37) 47 0.81 (0.55–1.21) 
 3 4119 110 0.74 (0.57–0.96) 50 0.69 (0.47–1.01) 25 1.01 (0.55–1.85) 37 0.60 (0.39–0.91) 
 4 4003 122 0.89 (0.69–1.15) 51 0.79 (0.54–1.16) 25 1.11 (0.61–2.02) 48 0.79 (0.53–1.16) 
 5 3509 121 1 (reference) 56 1 (reference) 20 1 (reference) 55 1 (reference) 
 Test for no effect of income, P — — <.0001 — <.0001 — .1654 — .0601 

All analyses were adjusted for calendar period of cancer diagnosis at entry. —, not applicable.

a

Adjusted for income and education 1 year before cancer diagnosis or index date.

b

Adjusted for cancer type at diagnosis, income, and education 1 year before cancer diagnosis or index date.

c

P < .01.

d

Total number of events for 0–1 y since cancer diagnosis in the child.

e

Adjusted for relapse (time-dependent covariate), cancer type at cancer diagnosis, income, and education 1 year before cancer diagnosis or index date.

f

Adjusted for age group at cancer diagnosis of the child.

g

Adjusted for age group at cancer diagnosis of the child and education.

No statistically significant difference was seen for risk of psychotropic medication according to cancer type (Table 4). For the time-dependent covariates of relapse and death, we did observe a difference in effect according to time since diagnosis. Parents who experienced relapse in the child had an increased risk for first prescription of hypnotics in the second year (year 1–2: HR, 4.04; 95% CI, 1.93–8.44) after diagnosis. Parents who experienced the death of a child had an increased risk of a first prescription of anxiolytics in the first year (year 0–1: HR, 4.55; 95% CI, 1.57–13.17) and third year (year 2–3: HR, 4.13; 95% CI, 1.15–14.76) after diagnosis and of hypnotics in the first year (year 0–1: HR, 6.91; 95% CI, 3.50–13.66) and second year (year 1–2: HR, 3.52; 95% CI, 1.63–7.58). Parents with basic education (up to 9 years) had a significantly increased risk of a first prescription of antidepressants (HR, 3.02; 95% CI, 2.23–4.10) and anxiolytics (HR, 2.65; 95% CI, 1.62–4.34) but not hypnotics. Finally, parents with the lowest income had an increased risk of psychotropic medication, especially of hypnotics (HR, 1.81; 95% CI, 1.01–3.24) and antidepressants (HR, 1.46; 95% CI, 1.02–2.09).

To our knowledge, this study is the first registry-based study to document that parents of children with cancer are at increased risk of having psychotropic medication prescribed compared with parents of children who are cancer free. We found an increased risk of use of psychotropic medication, especially for first prescriptions of hypnotics and anxiolytics, potentially indicating psychological reactions of anxiety and sleep disturbances. The primary indication for prescribing antidepressants is moderate-to-severe depression,8 whereas the primary indications for anxiolytics and hypnotics include sleep disorders, severe anxiety, and acute stress–related anxiety.9 

Only 9 of 190 previous studies on the risk of psychological distress in parents of children with cancer had a moderate sample (N > 100) and a control group of parents of children who were cancer free, and only 2 of these studies included follow-up of at least 5 years. In the first study, which included 474 parents of childhood cancer survivors and 176 parents of children who were cancer free, the authors found elevated anxiety and depression symptoms 2.5 years after the diagnosis, and up to 12% of these parents had posttraumatic stress symptoms 5 years after diagnosis.17 In contrast, the authors of the second study, which included 305 parents of children with cancer and 231 parents of children who were cancer free, did not find elevated posttraumatic stress in parents of children with cancer 5 years after diagnosis.18 Our results are supportive of previous studies suggesting elevated psychological distress, anxiety, and depression in parents of children with cancer, especially in the first 2 years after diagnosis.19 The mechanisms underlying the results could imply that the parents may experience intrusive disease-related thoughts, ultimately with increased avoidance and worry that disrupts sleep,20 potentially resulting in symptoms of acute or posttraumatic stress symptoms,21 depression, anxiety, and sleep disturbances6 that are clinically significant enough to warrant intervention. We are not able to determine the mechanisms, but one may speculate if medication management of anxiety and sleep disturbances may have prevented further development of depressive symptoms. The pathogenesis and how symptoms of depression, anxiety, and insomnia develop in co-occurrence in the stress-reaction management phase needs further examination.17 

No clear consensus has been reached on who are the most vulnerable parents of children with cancer. Thirty-two studies investigated distress among parents of children with cancer (N >100), and many were limited by their use of self-report measures of psychological symptoms22,24 and by potential recall and selection bias because, often, only the most resourceful parents are able to participate.25 The studies suggest that parents of children with cancer are especially vulnerable if the child dies26 and if the family only has basic education and a single mother.23 Among parents of children with cancer, we found that parents who experienced relapse or death of a child as well as families with basic-level education and low income had the greatest risk of having psychotropic medications prescribed. We had expected differences across cancer types (eg, because of the variation in length of cancer treatment,1,27 in the care burden,28 and in life-expectancy1). The lack of variation may suggest that the distress may be less influenced by the care burden than expected; however, further studies should explore this. As expected, we observed an increased risk of hypnotics and anxiolytics in parents of children who relapsed or died. This is in line with a recent study that revealed an increased risk of prescription of antidepressants and anxiolytics in parents 1 year after the death of their child26 as well as several investigations demonstrating the long-term psychological challenges that parents face after the death of their child to cancer.29 Finally, in line with a previous study,23 our findings suggest that parents with higher education and income may have a lower risk of psychotropic medication because of a higher health literacy, enabling them to establish social support from friends and family, attend counseling, and learn how to cope with their child’s cancer and the changes in their everyday life.

The strengths of this study include identification of all parents of children with cancer in the comprehensive Danish registries and a matched population-based comparison cohort of parents who had not been exposed to cancer in their children. This also gave us a unique opportunity to examine psychotropic medication use established independently of the hypothesis under study. In Denmark, the health care system is free of charge, and the cost of medication is subsidized, making medication affordable to all residents. In addition, mainly general practitioners evaluate the need for prescription of psychotropic medication using validated screening instruments for depression. Together, these conditions minimize selection and reporting biases.

The main limitation is the use of prescriptions for psychotropic medication as an indicator of psychological distress because we may only capture severe psychiatric morbidity and not unrecognized, mild distress, which may be managed through psychotherapy or remain unmanaged. Also, parents of children with cancer may not have the time nor energy during their child’s cancer treatment to pursue long psychotherapeutic treatment, whereas anxiolytics and hypnotics may offer fast symptom relief.9 For bereaved parents, this may additionally reflect challenges with confronting the pain of their loss through talk therapy. Thus, we cannot exclude bias related to treatment choices, and we expect to underestimate the number of parents in need of support because we excluded previous use of psychotropic medication. Also, we cannot exclude potential surveillance bias because the parents of children with cancer might receive more attention from pediatric teams perhaps urging them to attend their general practitioner. Lastly, because prescriptions for psychotropic medications have been registered only since 1995, we were unable to take into account lifetime previous use of psychotropic medication, only use within the last 3 years.

Parents of children with cancer are at increased risk of a first prescription of anxiolytics and hypnotics, which may point to increased risk of anxiety symptoms and sleep dysfunction severe enough to seek medical treatment, compared with parents of children who are cancer free. Parents of children with a poor prognosis as well as parents with basic education or low income are especially at risk. Further research is needed to identify parents with unmet need for support and on developing family interventions. Efforts should be made to ensure that medical teams are adequately educated to address stress responses in the whole family.

Ms Salem, Dr Andersen, and Ms Bidstrup contributed to the study concepts, study design, data analysis and interpretation, and manuscript preparation, editing, and review; Ms Dalton, Mr Schmiegelow, Ms Winther, Ms Lichtenthal, and Mr Johansen contributed to data interpretation, critically reviewed the manuscript for important intellectual content, and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: Supported by the Danish Childhood Cancer Foundation (grant 2015- 35).

     
  • CI

    confidence interval

  •  
  • CNS

    central nervous system

  •  
  • DCR

    Danish Cancer Registry

  •  
  • HR

    hazard ratio

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data