Zoledronate Increases Bone Mineral Density in Nonambulant Children With Cerebral Palsy: A Randomized Controlled Trial.

CONTEXT: Zoledronate appears to reduce fracture rates in children with cerebral palsy (CP), but no previous randomized, controlled trial has been performed to compare the effect of zoledronate to placebo in children with CP. OBJECTIVE: To investigate the effect of zoledronate on bone mineral density (BMD) Z-scores in children with nonambulant CP in a randomized, controlled, double-blind trial. METHODS: Nonambulant children with CP (5 to 16 years of age) were randomized 1:1 to receive 2 doses of zoledronate or placebo at a 6-month interval. BMD Z-score changes at the lumbar spine and the lateral distal femur (LDF) were calculated from dual-energy x-ray absorptiometry scans. Monitoring included weight, bone age, pubertal staging, knee-heel length, adverse events, biochemical markers, and questionnaires. RESULTS: Twenty-four participants were randomized and all completed the study. Fourteen were assigned to zoledronate. The mean lumbar spine BMD Z-score increased 0.8 SD (95% CI: 0.4; 1.2) in the zoledronate group, which was significant when compared to 0.0 SD (95% CI: -0.3; 0.3) in the placebo group. Similarly, the LDF BMD Z-scores increased more in the zoledronate group. Severe acute phase symptoms affected 50% of the patients in the zoledronate group but were reported exclusively after the first dose. Growth parameters were similar in both groups. CONCLUSION: Zoledronate for 12 months increased BMD Z-scores significantly without affecting growth, but first-dose side effects were common and considerable. Studies into lower first doses and long-term outcomes are needed.

Suspicion of child maltreatment: Knowledge and experiences with mandatory reports to social services among general practitioners in Denmark in 2019-20.

BACKGROUND: Child maltreatment has many consequences through the lifespan. The general practitioners (GPs) are in longitudinal contact with the family and can play an important role in identifying children in danger and reporting to the social services. OBJECTIVE: To explore how GPs manage suspicions of child maltreatment and to investigate potential demographic and geographic differences in reporting practices among Danish GPs. PARTICIPANTS AND SETTING: All registered GPs in Denmark retrieved from Medcom, a state-financed non-profit organization. METHODS: We mailed a questionnaire to all registered GPs with demographics, experiences, knowledge, and attitudes in the context of child maltreatment. RESULTS: We received 1252 completed questionnaires (response rate: 38 %). Most of the participants had suspected child maltreatment during their professional life (90 %) and had made a mandatory report (85 %). More than half had received feedback after the report (56 %) and said that their report led to action (56 %). Most GPs reported feeling confident in dealing with child maltreatment (79 %) and being willing to get involved in case of suspicion (8.9 on a 0-10 scale). We observed no geographical differences in reporting neither across the Danish regions nor among rural and urban practices, but GPs working in single practices made fewer reports to the social services. CONCLUSIONS: Participant GPs in this study are aware of their role in child protection, have experiences with mandatory reports, and are willing to get involved. Possible areas for attention include collaboration and support between different settings, especially between GP practice, hospitals, justice sector, and social services.

Cerebral palsy and bisphosphonates - and what can be learned from other types of secondary osteoporosis in children: A scoping review.

AIM: We aimed to improve bone health management of children with cerebral palsy (CP) by reviewing studies investigating bisphosphonate therapy in children with CP and other types of secondary osteoporosis. METHODS: We included trials on bisphosphonate treatment reporting any direct bone measurement or fracture outcome. All studies of patients with CP were included. We also included all controlled trials of children with secondary bone fragility as well as observational studies with ≥20 participants or at least 3 years of follow-up. Studies were assessed according to PRISMA guidelines using the RoB2-tool and the Newcastle-Ottawa Scale. RESULTS: We reviewed 1104 studies and found 37 eligible. Some studies were sufficiently homogeneous to include in a meta-analysis, and we found a 1-year effect on lumbar spine bone mineral density (BMD) Z-score of +0.65 after oral and + 1.21 after intravenous bisphosphonates in children with secondary osteoporosis. Further, data on adverse events and post-treatment follow-up were reviewed. Limitations were heterogeneity and small size of the included studies. CONCLUSION: Meta-analysis consistently showed significant BMD increases with bisphosphonates in children with secondary osteoporosis. Direct evidence of the effect of bisphosphonates on reducing fractures is lacking. We found no reports of long-term adverse events yet longer studies are needed.

Fracture Rates in Children with Cerebral Palsy: A Danish, Nationwide Register-Based Study.

Background: In children with cerebral palsy (CP), fracture rates have been reported to be higher than in the general population but age-specific fracture rates have not been directly compared and the effect of comorbid epilepsy needs elucidation. This impairs decision-making regarding bone health interventions. Aim: We aimed to establish the age-specific fracture rates in children with CP with and without epilepsy in Denmark. Materials and Methods: Data from Danish registers were combined to establish cohorts of children with and without CP born in Denmark from 1997 to 2007. Fracture rates were calculated for 1997-2016. Results: We identified 1,451 children with CP and 787,159 without CP. Female/male fracture rates per 1,000 person-years were 23/27 with CP and 23/29 without CP. Male sex, epilepsy and anti-seizure medication, but not the diagnosis of CP or GMFCS-level, were associated with higher fracture rates. Relatively more lower extremity fractures occurred in non-ambulant children with CP. Interpretation/Conclusion: We found no increased fracture rates in children with CP when compared to peers; however, fracture locations suggested bone fragility in non-ambulant children. All children with epilepsy and on anti-seizure medication had increased fracture rates. We suggest bone health optimization in these groups.

Center differences in diabetes treatment outcomes among children with type 1 diabetes: A nationwide study of 3866 Danish children.

OBJECTIVE: Mean differences in HbA1c across centers are well established, but less well understood. The aim was to assess whether differences in patient case-mix can explain the variation in mean HbA1c between pediatric diabetes centers in Denmark. The association between HbA1c , frequency of blood glucose monitoring (BGM), treatment modality, and center visits was investigated. RESEARCH DESIGN AND METHODS: This longitudinal nationwide study included 3866 Danish children with type 1 diabetes from 2013 to 2017 (n = 12,708 child-year observations) from 16 different pediatric diabetes centers. Mean HbA1c , proportion of children reaching HbA1c treatment target (HbA1c  ≤ 58 mmol/mol [7.5%]) were compared across centers using linear regression models. This was done with and without adjustment for socioeconomic characteristics (patient case-mix). RESULTS: The mean difference in HbA1c during follow-up was 11.6 mmol/mol (95% CI 7.9, 15.3) (1.1% [95% CI 0.7, 1.4]) when comparing the centers with the lowest versus highest mean HbA1c . The difference was attenuated and remained significant after adjustment for the patient case-mix (difference: 10.5 mmol/mol [95% CI 6.8, 14.2] (1.0% [95% CI 0.6, 1.3])). Overall, 6.8% of the differences in mean HbA1c across centers were explained by differences in the patient case-mix. Across centers, more frequent BGM was associated with lower HbA1c . The proportion of insulin pump users and number of visits was not associated with HbA1c . CONCLUSION: In a setting of universal health care, large differences in HbA1c across centers were found, and could not be explained by patient background, number of visits or use of technology. Only BGM was associated with center HbA1c .

Lethal abusive head trauma in infancy in Denmark from 2000 to 2011.

INTRODUCTION: We aimed to estimate the incidence of lethal abusive head trauma (AHT) in infancy in Denmark from 2000 through 2011 and to describe autopsy findings and information from police reports on lethal AHT cases. METHODS: This was a nationwide retrospective study. We identified AHT cases in the National Cause of Death Register (CODR) and in forensic archives and compared data from the two sources. Moreover, we collected data on medical history, witness statements and conviction reports from police files and the Director of Public Prosecutions. RESULTS: We identified eight cases of lethal infant AHT (incidence: 1.04 per 100,000 person years). Three AHT cases from autopsy reports were not registered correctly in the CODR. The median age of the victims was 46.5 days. They all had recent subdural and/or subarachnoid haemorrhage. We also found a high prevalence of retinal haemorrhage and fractures. Seven perpetrators were identified, all male relatives, and all were convicted. We moreover identified a surprisingly large number of infants with unspecific cause of death and missing information on whether an autopsy had been performed in the CODR (n = 56). CONCLUSIONS: The incidence of lethal infant AHT found in this study is lower than findings from most other countries. Data from the CODR are inadequate for identifying all lethal AHTs. Further studies including non-fatal cases of AHT are needed to determine the real incidence of AHT in Denmark. FUNDING: none. TRIAL REGISTRATION: not relevant.

Developmental Coordination Disorder in Children with a History of Infantile Colic.

OBJECTIVE: To investigate whether children with a history of infantile colic showed impaired motor development at age 7 years compared with unaffected peers. STUDY DESIGN: We studied 27,940 children from the Danish National Birth Cohort (1997-2002), including 1879 (6.8%) with a history of infantile colic. Infantile colic was defined according to the modified Wessel criteria as crying for more than 3 hours per day and more than 3 days per week. We compared the parental Developmental Coordination Disorder Questionnaire 2007 (DCDQ'07) scores in children with and without infantile colic after adjustment for intrauterine exposures, feeding type, parity, maternal age, socioeconomic status, Apgar score, gestational age, and birth weight. RESULTS: Children with a history of infantile colic had an elevated risk of scoring above the predefined cutoff limit of possible or suspected developmental coordination disorder (OR, 1.3; 95% CI, 1.0-1.7; P = .034). The mean total DCDQ'07 score was -0.4 point (95% CI, -0.8 to 0) lower in children with a history of infantile colic. Moreover, they were at higher risk for a low total score (OR for a 10-point decrease, 1.1; 95% CI, 1.0-1.1; P = .006) and a low general coordination score (OR, 1.3; 95% CI, 1.1-1.5, P = .000) in the DCDQ'07. All associations appeared to be stronger among boys, but no statistically significant effect measure modification between infantile colic and sex was found. CONCLUSION: We found no evidence of a strong association between infantile colic and developmental coordination disorder in this large Danish cohort.

Gestational age, small for gestational age, and infantile colic.

BACKGROUND: Preterm and growth restricted infants may have developmental delays and deviations from normal organ function related to the gastrointestinal tract and the central nervous system. Since both organ systems are hypothesised to be involved in the pathogenesis of infantile colic, a condition characterised by excessive crying during the first months of life, impaired fetal growth and preterm birth may be risk factors for infantile colic. METHODS: A total of 62,761 liveborn singletons from the Danish National Birth Cohort (1996 to 2002) were studied. Infantile colic was defined according to Wessel's modified criteria based on maternal interview conducted at 6 months post-partum. RESULTS: A total of 2605 (4.2%) infants were born preterm, 54,441 (86.7%) at term, and 5715 (9.1%) post-term. A total of 4964 (7.9%) infants fulfilled Wessel's modified criteria for infantile colic. The risk for infantile colic increased with decreasing gestational age after adjustment for covariates. The highest odds [odds ratio (95% confidence interval)] was observed for infants born before 32 completed gestational weeks (1.5 [95% CI 1.0, 2.2], reference: 40 gestational weeks). Small for gestational age infants (birthweight below 10th percentile) had an increased odds of infantile colic (1.2 [95% CI 1.1, 1.3]) in all gestational age groups. CONCLUSIONS: We observed an increased risk of infantile colic in preterm and small for gestational age infants in a large cohort. Our results suggest that the aetiology of infantile colic may be found in the prenatal, perinatal, and neonatal period.

Nicotine replacement therapy during pregnancy and infantile colic in the offspring.

OBJECTIVE: To investigate the associations between use of nicotine replacement therapy (NRT) and smoking during pregnancy and infantile colic in the offspring. METHODS: We used data from maternal interviews (from pregnancy and at 6 months post partum) from the Danish National Birth Cohort (1996-2002). We included 63 128 live-born singletons with complete information on nicotine exposure during pregnancy and infantile colic symptoms as recorded at 6 months of age. RESULTS: A total of 46 660 infants (73.9%) were unexposed to nicotine during pregnancy; 207 (0.3%) were exposed to NRT, 15 016 (23.8%) were exposed to smoking, and 1245 (2.0%) to both. A total of 4974 (7.9%) infants fulfilled Wessel's modified criteria for infantile colic. Prenatal nicotine exposure was associated with elevated risk for infantile colic in the offspring. Compared with the unexposed, NRT users had an adjusted odds ratio (OR) (95% confidence interval) of 1.6 (1.0-2.5; P = .03), smokers had OR = 1.3 (1.2-1.4), and women who both smoked and used NRT had OR = 1.6 (1.3-1.9). Partners' smoking was not associated with infantile colic after adjustment for maternal smoking. CONCLUSIONS: We corroborated the association between smoking and infantile colic after adjustment for several possible confounders in a large cohort study. Moreover, we found that infants exposed to NRT prenatally had an increased risk for infantile colic of the same magnitude as those exposed to tobacco smoke. Thus, nicotine may play a role in the pathogenesis of infantile colic.

Normal Levels of Plasma Free Carnitine and Acylcarnitines in Follow-Up Samples from a Presymptomatic Case of Carnitine Palmitoyl Transferase 1 (CPT1) Deficiency Detected Through Newborn Screening in Denmark.

Carnitine palmitoyl transferase (CPT) 1 A deficiency is a rare disorder of hepatic long-chain fatty acid oxidation. CPT1 deficiency is included in newborn screening programs in a number of countries to allow presymptomatic detection and early treatment of affected patients.We present a case of presymptomatic CPT1A deficiency detected through newborn screening in Denmark with diagnostic levels of carnitine and acylcarnitines in the initial dried blood spot. Levels of plasma-free carnitine and acylcarnitines in follow-up samples were normal, but reverted to diagnostic levels when the patient developed clinical symptoms at the age of 8 months. At that time, a diagnosis of CPT1A deficiency was confirmed by sequence analysis of the CPT1A gene revealing homozygosity for a novel c.167C>T variation in exon 3. Enzyme activity measurements showed a relatively mild enzyme defect with a decreased residual enzyme activity of 17-25%. We conclude that CPT1A gene testing and/or enzyme assay is mandatory to confirm an abnormal newborn screen suggesting CPT1A deficiency to avoid delayed diagnoses.

[Mowat-Wilson syndrome: a report of three Danish cases]. / Mowat-Wilson-syndrom hos tre danske børn.

Mowat-Wilson syndrome (MWS) is an autosomal dominant intellectual disability syndrome characterised by unique facial features and congenital anomalies such as Hirschsprung disease, congenital heart defects, corpus callosum agenesis and urinary tract anomalies. Some cases also present epilepsy, growth retardation and microcephaly. The syndrome is caused by mutations or deletions of the ZEB2 gene at chromosome 2q22-q23. MWS was first described in 1998 and until now approximately 180 cases have been reported worldwide. We report the first three molecularly confirmed Danish cases with MWS.

A medical record review for functional somatic symptoms in children.

OBJECTIVE: The objectives of this study were to develop and test a systematic medical record review for functional somatic symptoms (FSSs) in paediatric patients and to estimate the inter-rater reliability of paediatricians' recognition of FSSs and their associated impairments while using this method. METHODS: We developed the Medical Record Review for Functional Somatic Symptoms in Children (MRFC) for retrospective medical record review. Described symptoms were categorised as probably, definitely, or not FSSs. FSS-associated impairment was also determined. Three paediatricians performed the MRFC on the medical records of 54 children with a diagnosed, well-defined physical disease and 59 with 'symptom' diagnoses. The inter-rater reliabilities of the recognition and associated impairment of FSSs were tested on 20 of these records. RESULTS: The MRFC allowed identification of subgroups of children with multisymptomatic FSSs, long-term FSSs, and/or impairing FSSs. The FSS inter-rater reliability was good (combined kappa=0.69) but only fair as far as associated impairment was concerned (combined kappa=0.29). CONCLUSIONS: In the hands of skilled paediatricians, the MRFC is a reliable method for identifying paediatric patients with diverse types of FSSs for clinical research. However, additional information is needed for reliable judgement of impairment. The method may also prove useful in clinical practice.

The Soma Assessment Interview: new parent interview on functional somatic symptoms in children.

OBJECTIVE: Medically unexplained or functional somatic symptoms (FSS) in children constitute a major clinical problem. Epidemiological studies of this phenomenon are, however, hampered by a lack of good standardized measures. The objective of this study was therefore to (1) develop a parent-report measure of FSS in children aged 5-10 years and (2) perform an initial validation. METHODS: A parent interview, the Soma Assessment Interview (SAI), for FSS detection in young children was developed for lay interviewers with subsequent clinical assessment. A preliminary validation was based on interview tests of the parents of 54 children with well-defined physical disease, 59 with likely functional disorder and 105 from the community. Independent measures of the somatic complaints were completed before the interview, and children from the clinical samples were also assigned independent FSS diagnoses based on medical record review. RESULTS: The Kappa value for two clinical assessors' agreement on FSS recognition was 0.86. Good discrimination was obtained between a community sample and a clinical sample with an expected high prevalence of FSS. In the former convergent validity with independent measures of somatic complaints was found. In the latter substantial agreement (89%) appeared between a medical record diagnosis of FSS and SAI detection of FSS. CONCLUSION: The SAI offers comprehensive description of FSS in young children in population-based studies and may also prove useful in clinical settings. It is readily accepted and relatively quickly completed, and preliminary assessment of its validity is promising.

Socioeconomic factors and risk of hospitalization with infectious diseases in 0- to 2-year-old Danish children.

Although the association between low socioeconomic status and illness in childhood is well known, the impact of socioeconomic factors on risk and frequency of hospitalizations for infectious diseases, the most frequent disease category, during the first 2 years of life has scarcely been studied. Through linkage of records drawn from public administrative and health registries, we conducted a population-based cohort study of 5024 Danish children born in 1997 to examine the frequency of hospitalization for infectious diseases in very young children. The main exposure variables, adjusted for potential confounding factors, were mother's education level, household income, and cohabitation status. The outcome was number of hospital admissions (0, 1-2, or 3+) for infectious diseases. A total of 737 children (14.7%) were admitted to hospital 1-2 times, and 83 (1.6%) were admitted 3-10 times. The risk of hospitalization was increased in children of mothers with a low level of education compared with vocational education (1-2 admissions: adjusted odds ratio (OR) 1.3 (95% confidence interval [CI]: 1.1-1.6). Children from low-income families had an increased risk of 3 or more admissions (low cf middle income: adjusted OR 2.0 [95% CI: 0.6-6.0]). Children of single mothers had an increased risk of hospitalization (1-2 admissions: adjusted OR 1.7 [95% CI: 1.1-2.6]. We found the highest risk of hospitalization for infectious diseases in children of mothers with only basic schooling, and particularly among those coming from single parent homes with a low income.