Short developmental milestone risk assessment tool to identify Duchenne muscular dystrophy in primary care.

BACKGROUND: In patients without a family history, Duchenne muscular dystrophy (DMD) is typically diagnosed at around 4-5 years of age. It is important to diagnose DMD during infancy or toddler stage in order to have timely access to treatment, opportunities for reproductive options, prevention of potential fatal reactions to inhaled anesthetics, awareness of a child's abilities needed for good parenting, and opportunities for enrolment in clinical trials. METHOD: We aimed to develop a short risk assessment tool based on developmental milestones that may contribute to the early detection of boys with DMD in primary care. As part of the case-control 4D-DMD study (Detection by Developmental Delay in Dutch boys with DMD), data on developmental milestones, symptoms and therapies for 76 boys with DMD and 12,414 boys from a control group were extracted from the health records of youth health care services and questionnaires. Multiple imputation, diagnostic validity and pooled backward logistic regression analyses with DMD (yes/no) as the dependent variable and attainment of 26 milestones until 36 months of age (yes/no) as the independent variable were performed. Descriptive statistics on symptoms and therapies were provided. RESULTS: A tool with seven milestones assessed at specific ages between 12 and 36 months resulted in a sensitivity of 79% (95CI:67-88%), a specificity of 95.8% (95%CI:95.3-96.2), and a positive predictive value of 1:268 boys. Boys with DMD often had symptoms (e.g. 43% had calf muscle pseudohypertrophy) and were referred to therapy (e.g. 59% for physical therapy) before diagnosis. DISCUSSION: This tool followed by the examination of other DMD-related symptoms could be used by youth health care professionals during day-to-day health assessments in the general population to flag children who require further action. CONCLUSIONS: The majority of boys (79%) with DMD can be identified between 12 and 36 months of age with this tool. It increases the initial a priori risk of DMD from 1 in 5,000 to approximately 1 in 268 boys. We expect that other neuromuscular disorders and disabilities can also be found with this tool.

Health status and public health needs in a Togolese child health care centre modelled after the Dutch system.

BACKGROUND: The charity foundation Association Soutien Enfants Togo started a child health care (CHC) centre in Togo that was modelled after the Dutch high-quality CHC system to improve child health. AIM: To describe health care data of children who visited the centre. SUBJECTS AND METHODS: Data were routinely collected between October 2010-July 2017. Outcomes were completed vaccinations, growth, development, lifestyle, physical examination, and laboratory testing results. RESULTS: In total, 8,809 children aged 0-24 years were available. Half (47.5%) of children aged 0-4 years did not receive all eligible free vaccinations from the government. The proportions of stunted children (all) or with a developmental delay (0-4 years) were 10.1% and 9.5%, respectively. In total, 40-50% of all children did not wash their hands with soap after toilet or before eating, or did not use clean drinking water. Furthermore, 5.1-6.6% had insufficient vision, high eye pressure or hearing loss. Sickle cell disease was detected in 5.3%. CONCLUSION: A large group of children in need of prevention and early treatment were detected, informed and treated by the centre. Further research is needed to confirm if this strategy can improve children's health in Sub-Saharan Africa. Our data are available for further research.

Birth weight discordance in very and extremely preterm twins and the risk of neonatal hearing loss.

OBJECTIVE: Birth weight (BW) discordant twins have an increased risk of mortality and morbidity. We aimed to study the effect of BW discordance on the risk of neonatal hearing loss (NHL) in very and extremely preterm twins. STUDY DESIGN: Results of the nationwide newborn hearing screening program in Dutch Neonatal Intensive Care Units and diagnostic examination were centrally registered between 2003 and 2021 and included in this study. We selected twins and singletons with a gestational age (GA) 24- < 32 weeks. Logistic regression analyses were applied to study the effect of BW discordance on the risk of NHL adjusted for BW, GA and sex. Singletons and concordant twins, defined as a BW discordance of ≤20 %, were used as two reference groups. BW discordance was further categorized as medium (>20-30 %) and high (>30 %). RESULTS: In total, 3430 twins (2694 concordant, 428 medium and 308 high BW discordant), and 23,114 singletons were available. Smaller newborns of high BW discordant twins showed an increased risk of NHL compared to singletons (adjusted odds ratio with 95 % confidence interval was 3.56 (2.26-5.60)). Also, smaller newborns of medium and high BW discordant twins showed an increased risk of NHL compared to concordant twins (adjusted odds ratio with 95 % confidence interval were 1.97 (1.13-3.44) and 4.17 (2.56-6.82), respectively). No other statistically significant differences were found. CONCLUSION: BW discordance increased the risk of NHL in the smaller of the twin born very or extremely preterm. This risk increased as the weight difference increased.

Key developmental milestones helped to identify children with special educational needs and disabilities at an early stage.

AIM: Responding to developmental delay promptly is important, as it helps children to reach their full potential. This study investigated how developmental milestones predicted primary school children with special educational needs and disabilities (SEND) at an early stage. METHODS: We obtained data about 36 milestones between 12 and 45 months using the Dutch Development Instrument. Development, primary school classification and background characteristics were collected from the Dutch Preventive Child Healthcare system in Utrecht from 2008 to 2016. We investigated SEND classifications and the primary schools that the children attended at 4-12 years of age. The findings include area under the curve (AUC) data. RESULTS: Data on 30 579 children in mainstream schools and 1055 children with SEND were available. Different milestones predicted SEND classifications. Fourteen milestones and parental education predicted attendance at special needs schools with smaller classes (AUC 0.913). Nine milestones, sex, migration background and parental education predicted attendance at schools for severe communication problems (AUC 0.963). Ten milestones and parental education predicted attendance at schools for severe learning difficulties (AUC 0.995). Milestones did not accurately predict attendance at schools for severe behavioural or psychiatric problems. CONCLUSION: Milestones at 12-45 months predicted most SEND classifications at primary school age, except severe behavioural or psychiatric problems.

Exploring the Effects of Environmental Factors on the Development of 0-4-Year Old Children in The Netherlands.

Air pollution, noise, and green space are important environmental exposures, having been linked to a variety of specific health outcomes. However, there are few studies addressing overall early life development. To assess their effects, associations between developmental milestones for a large population of 0-4-year old children in The Netherlands and environmental exposures were explored. Developmental milestones and background characteristics were provided by Preventive Child Health Care (PCHC) and supplemented with data from Statistics Netherlands. Milestones were summarized and standardized into an aggregate score measuring global development. Four age groups were selected. Environmental exposures were assigned to geocoded addresses using publicly available maps for PM2.5, PM10, PMcoarse, NO2, EC, road traffic noise, and green space. Associations were investigated using single and multiple-exposure logistic regression models. 43,916 PCHC visits by 29,524 children were available. No consistent associations were found for air pollution and road traffic noise. Green space was positively associated in single and multiple-exposure models although it was not significant in all age groups (OR 1.01 (0.95; 1.08) (1 year) to 1.07 (1.01; 1.14) (2 years)). No consistent associations were found between air pollution, road traffic noise, and global child development. A positive association of green space was indicated.

Health-Related Quality of Life in Patients With Early-Detected Central Congenital Hypothyroidism.

CONTEXT: Central congenital hypothyroidism (CH) requires lifelong medical treatment. The majority of children with central CH have multiple pituitary hormone deficiencies (MPHD), but in some cases central CH is isolated. Most pituitary hormone deficiencies are associated with impaired health-related quality of life (HRQoL). However, studies on HRQoL in central CH are lacking. OBJECTIVE: To evaluate HRQoL and fatigue in children and young adults with central CH, as well as parent perspectives. DESIGN: Nationwide cross-sectional study comparing HRQoL between early-detected central CH patients and unaffected siblings with the Pediatric Quality of Life inventory (PedsQL™) and PedsQL Multidimensional Fatigue Scale. Participants ≥ 8 years old filled in self-reports; parents of participants aged 3 to 18 years filled in parent reports. Isolated central CH patients, MPHD patients, and siblings were compared using a linear mixed model and Tukey's post hoc test. RESULTS: Eighty-eight patients and 52 siblings participated, yielding 98 self-reports and 115 parent reports. Isolated central CH patients (n = 35) and siblings showed similar scores on all subscales, both in the self-reports and parent reports. For MPHD patients (n = 53), self-reported scores were similar to those of siblings. Parent reported total HRQoL and fatigue scores were significantly poorer in MPHD patients compared with siblings (mean differences -10.2 and -9.4 points; P < 0.01), as were scores for physical functioning, social functioning and general fatigue. CONCLUSION: Self-reported HRQoL scores in isolated central CH and MPHD patients were similar to siblings. However, parents reported significantly lower HRQoL and fatigue scores for MPHD patients, suggesting a difference in perceived limitations between MPHD patients and their parents.

Cognitive and Motor Outcome in Patients with Early-Detected Central Congenital Hypothyroidism Compared with Siblings.

CONTEXT: Early treatment of primary congenital hypothyroidism (CH) prevents irreversible brain damage. Contrary to primary CH, outcome studies on central CH are scarce. Most patients with central CH have multiple pituitary hormone deficiencies (MPHD); these patients are also at risk for neonatal hypoglycemia. OBJECTIVE: To assess cognitive and motor outcome in patients with early-treated central CH detected by the Dutch neonatal screening. METHODS: In this cross-sectional study, primary outcome full-scale intelligence quotient (FSIQ) was measured in patients with MPHD and patients with isolated central CH born between January 1, 1995, and January 1, 2015, with siblings as controls. Secondary outcomes were intelligence test subscales and motor function. Linear mixed models were used to compare both patient groups and siblings, followed by post hoc tests in case of significant differences. RESULTS: Eighty-seven patients (52 MPHD; 35 isolated central CH) and 52 siblings were included. Estimated marginal means for FSIQ were 90.7 (95% CI 86.4-95.0) in patients with MPHD and 98.2 (95% CI 93.0-103.5) in patients with isolated central CH. While patients with MPHD scored lower FSIQs than siblings (mean difference -7.9 points, 95% CI -13.4 to -2.5; P = .002), patients with isolated central CH did not. Processing speed was lower in both patient groups than in siblings (mean differences -10.5 and -10.3 points). Motor difficulties occurred significantly more often in patients (33%) versus siblings (5%; P = .004). CONCLUSION: In early-treated central CH, FSIQ is comparable with siblings in patients with isolated central CH, while patients with MPHD have a significantly lower FSIQ. This may be explained by disease-specific consequences of MPHD, such as neonatal hypoglycemia and more severe hypothyroidism.

Costs and effects of conventional vision screening and photoscreening in the Dutch preventive child health care system.

BACKGROUND: Little is known about costs and effects of vision screening strategies to detect amblyopia. Aim of this study was to compare costs and effects of conventional (optotype) vision screening, photoscreening or a combination in children aged 3-6 years. METHODS: Population-based, cross-sectional study in preventive child health care in The Hague. Children aged 3 years (3y), 3 years and 9 months (3y9m) or 5-6 years (5/6y) received the conventional chart vision screening and a test with a photoscreener (Plusoptix S12C). Costs were based on test duration and additional costs for devices and diagnostic work-up. RESULTS: Two thousand, one hundred and forty-four children were included. The estimated costs per child screened were €17.44, €20.37 and €6.90 for conventional vision screening at 3y, 3y9m and 5/6y, respectively. For photoscreening, these estimates were €6.61, €7.52 and €9.40 and for photoscreening followed by vision screening if the result was unclear (combination) €9.32 (3y) and €9.33 (3y9m). The number of children detected with amblyopia by age were 9, 14 and 5 (conventional screening), 6, 13 and 3 (photoscreening) and 10 (3y) and 15 (3y9m) (combination), respectively. The estimated costs per child diagnosed with amblyopia were €1500, €1050 and €860 for conventional vision screening, €860, €420 and €1940 for photoscreening and €730 (3y) and €450 (3y9m) for the combination. CONCLUSIONS: Combining photoscreening with vision screening seems promising to detect amblyopia in children aged 3y/3y9m, whereas conventional screening seems preferable at 5/6y. As the number of study children with amblyopia is small, further research on the effects of these screening alternatives in detecting children with amblyopia is recommended.

Maturation of the auditory system in normal-hearing newborns with a very or extremely premature birth.

BACKGROUND: Literature shows that lower gestational age leads to greater delays in the auditory conduction, which suggests atypical maturation of the brainstem in normal-hearing premature newborns. Our aim is to investigate if there is a difference between the extrauterine and intrauterine maturation of the auditory system in normal-hearing newborns with a very premature (28-31 weeks) or extremely premature (<28 weeks) birth. METHODS: Results of the Automated Auditory Brainstem Response Newborn Hearing Screening Program in Dutch Neonatal Intensive Care Units and diagnostic examinations were centrally registered from 1998 to 2016. Normal-hearing newborns with a gestational age of 25-31 weeks were included. Screening results at 32-45 weeks of postmenstrual age were compared between newborns born with different gestational ages. Multiple imputation was used to predict missing screening results. Small for gestational age was defined as birth weight corrected for gestational age < -1.6 standard deviation. Descriptive and (pooled) logistic regression analyses were performed. RESULTS: 23,964 newborns with 28,754 screening results were eligible. At the same postmenstrual age, pass rates were lower when gestational age was lower in normal-hearing newborns with a very and extremely preterm birth. Pass rates of 80% could be obtained at 34-35, 32-33, and 30-32 weeks' postmenstrual age in newborns with 25, 26-27, 28-31 weeks gestational age, respectively. Small for gestational age had an additional negative effect on pass rates. CONCLUSION: Analysis of hearing screening data suggests that extrauterine maturation of the auditory system is delayed in normal-hearing newborns with a very or extremely premature birth.

Early developmental milestones in Duchenne muscular dystrophy.

AIM: To investigate the differences in attainment of developmental milestones between young males with Duchenne muscular dystrophy (DMD) and young males from the general population. METHOD: As part of the case-control 4D-DMD study (Detection by Developmental Delay in Dutch boys with Duchenne Muscular Dystrophy), data on developmental milestones for 76 young males with DMD and 12 414 young males from a control group were extracted from the health care records of youth health care services. The characteristics of DMD were acquired from questionnaires completed by parents. Logistic regression analyses were performed with milestone attainment (yes/no) as the dependent variable and DMD (yes/no) as the independent variable, with and without adjustment for age at visit. RESULTS: The mean number of available milestones was 43 (standard deviation [SD]=13, range: 1-59) in the DMD group and 40 (SD=15, range: 1-60) in the control group. The presence of developmental delay was evident at 2 to 3 months of age, with a higher proportion of young males with DMD failing to attain milestones of gross/fine motor activity, adaptive behaviour, personal/social behaviour, and communication (range age-adjusted odds ratios [ORs]=2.3-4.0, p<0.01). Between 12 and 36 months of age, differences in the attainment of developmental milestones concerning gross motor activity increased with age (range age-adjusted ORs=10.3-532, p<0.001). We also found differences in developmental milestones concerning fine motor activity, adaptive behaviour, personal/social behaviour, and communication between 12 and 48 months of age (range age-adjusted ORs=2.5-9.7, p<0.01). INTERPRETATION: We found delays in the attainment of motor and non-motor milestones in young males with DMD compared to the control group. Such delays were already evident a few months after birth. Developmental milestones that show a delay in attainment have the potential to aid the earlier diagnosis of DMD.

Predictive validity of developmental milestones for detecting limited intellectual functioning.

Developmental milestones are commonly used in child health care, although from many milestones the predictive validity has not been adequately assessed. We aimed to determine the predictive validity of 75 developmental milestones for detecting limited intellectual functioning that can be obtained before the age of 4 years. We performed a case-control study with 148 children aged 5-10 years with limited intellectual functioning (IQ 50-69), who were in special education (cases) and a random sample of 300 children aged 5-10 years who were in regular elementary education (controls). Developmental milestones scores were retrieved from Child Healthcare files. We calculated sensitivity, specificity, positive likelihood ratios (LR+) and diagnostic odds ratios (DOR) for limited intellectual functioning. The LR+ determines whether a test result changes the probability that a condition exists. Given the prevalence of intellectual disability (1-3%), we considered that an LR+ > 10 would be clinically useful, as it increases the a priori probability of limited intellectual functioning from 2% to a posteriori probability of at least 17%. Out of 75 assessed milestones, 50 were included in the analysis. We found nine milestones to have a significant adjusted (for socio-economic status and prematurity) DOR > 1 and a significant LR+ > 10 (assessment age in months between brackets): 'says "dada-baba‴ (9), 'balances head well while sitting' (9), 'sits on buttocks while legs stretched' (9), 'babbles while playing' (12), 'sits in stable position without support' (12), 'walks well alone' (24), 'says "sentences" of 3 or more words' (36), 'places 3 forms in form-box' (36) and 'copies circle' (48). Sensitivities of these 9 milestones varied from 8-54%, specificities of these 9 milestones varied from 95-100%. Combining these milestones at 9, 12, and 36 months respectively resulted in sensitivities of 27-60% and specificities of 94-99%. These nine developmental milestones have substantial predictive validity for limited intellectual functioning.

Evaluation of the Dutch neonatal screening for congenital adrenal hyperplasia.

BACKGROUND: In 2002, a nationwide screening for congenital adrenal hyperplasia (CAH) was introduced in the Netherlands. The aim of our study is to evaluate the validity of the neonatal screening for CAH and to assess how many newborns with salt-wasting (SW) CAH have already been clinically diagnosed before the screening result was known. METHODS: Retrospective, descriptive study. The following data of patients with positive screening results since implementation of the screening programme were collected (1 January 2002 up until 31 December 2013): gestational age, sex, diagnosis, clinical presentation and contribution of screening to the diagnosis. RESULTS: In the evaluated period, 2 235 931 newborns were screened. 479 children had an abnormal screening result, 133 children were diagnosed with CAH (114 SW, 14 simple virilizing (SV)), five non-classic CAH. During this period, no patients with SW CAH were missed by neonatal screening (sensitivity was 100%). After exclusion of 17 cases with missing information on diagnosis, specificity was 99.98% and positive predictive value was 24.7%. Most false positives (30%) were attributable to prematurity. Of patients with SW CAH, 68% (71/104) patients were detected by neonatal screening and 33 (33/104) were clinically diagnosed. Of girls with SW CAH, 38% (14/37) were detected by neonatal screening and 62% (23/37) were clinically diagnosed. CONCLUSION: The Dutch neonatal screening has an excellent sensitivity and high specificity. Both boys and girls can benefit from neonatal screening.

Cost-effectiveness of newborn screening for severe combined immunodeficiency.

Severe combined immunodeficiency (SCID) is a condition that often results in severe infections and death at young age. Early detection shortly after birth, followed by treatment before infections occur, largely increases the chances of survival. As the incidence of SCID is low, assessing cost-effectiveness of adding screening for SCID to the newborn screening program is relevant for decision making. Lifetime costs and effects of newborn screening for SCID were compared to a situation without screening in the Netherlands in a decision analysis model. Model parameters were based on literature and expert opinions. Sensitivity analyses were performed. Due to earlier detection, the number of deaths due to SCID per 100,000 children was assessed to decrease from 0.57 to 0.23 and a number of 11.7 quality adjusted life-years (QALYs) gained was expected. Total yearly healthcare costs, including costs of screening, diagnostics, and treatment, were €390,800 higher in a situation with screening compared to a situation without screening, resulting in a cost-utility ratio of €33,400 per QALY gained.Conclusion: Newborn screening for SCID might be cost-effective. However, there is still a lot of uncertainty around the cost-effectiveness estimate. Pilot screening projects are warranted to obtain more accurate estimates for the European situation. What is Known: • Severe combined immunodeficiency (SCID) is a condition that often results in severe infections and death at a young age. • As the incidence of SCID is low, assessing cost-effectiveness of adding screening for SCID to the newborn screening program is needed. What is New: • Newborn screening for SCID is expected to reduce mortality from 0.57 to 0.23 per 100,000 children at additional healthcare costs of €390,800. The cost-utility ratio is €33,400 per QALY gained. • Due to large uncertainty around cost-effectiveness estimates, pilot screening projects are warranted for Europe.

Newborn blood spot screening for cystic fibrosis with a four-step screening strategy in the Netherlands.

BACKGROUND: Newborn screening for cystic fibrosis (NBSCF) was introduced in the Dutch NBS program in 2011 with a novel strategy. METHODS: Dutch NBSCF consisted of four steps: immuno-reactive trypsin (IRT), Pancreatitis-associated Protein (PAP), DNA analysis by Inno-LiPa (35 mutations), extended gene analysis (EGA) as fourth step and as safety net. Only samples with two CFTR-variants were considered screen-positive, but samples with one disease-causing variant were considered also screen-positive from April 2013. The first 5 years of NBSCF were evaluated during a follow-up ranging from 2 to 6.8 years for sensitivity, specificity, positive predictive value (PPV), ratio of CF/Cystic Fibrosis Screen Positive infants with an Inconclusive Diagnosis (CFSPID) and median age at diagnosis, and were compared to other novel strategies for NBSCF and European Cystic Fibrosis Society (ECFS) Best Practice Standards of Care. RESULTS: NBSCF achieved a sensitivity of 90% (95% CI 82%-94%), specificity of 99.991% (95% CI 99.989%-99.993%), PPV of 63% (95% CI 55%-69%), CF/CFSPID ratio of 4/1, and median age at diagnosis of 22 days, if samples with two variants as well as samples with one disease-causing variant were considered screen-positive. CONCLUSION: The program achieved the goal to minimize the number of false positives and showed a favourable performance but sensitivity and CF/CFSPID ratio did not meet criteria of EFCS Best Standards of Care. Changed cut-off values for PAP and IRT and classification of R117H-7T/9T to non-pathogenic may improve sensitivity to ≥95% and CF/CFSPID ratio to 10/1. PPV is estimated to be around 60%.

Concise tool based on language milestones identifies children with specific language impairment at 24-45 months of age.

AIM: This study aimed to develop a concise tool with acceptable predictive properties to identify young children with specific language impairment (SLI). METHODS: In this nested case-control study children with SLI attending two special needs schools for severe speech and language difficulties in the Netherlands were matched by date of birth and sex with control children attending mainstream education. This study analysed the predictive validity for having SLI at a mean age of eight years and three months (range 4-11 years) using combinations of six language milestones that were registered at 24, 36 and 45 months and retrieved from the children's healthcare files in 2012. RESULTS: We included 253 pairs of children with and without SLI. During a single visit, combinations of two milestones at one age achieved a specificity of at least 97% and sensitivities ranged from 32% to 64%. However, the concise tool, which combined five milestones at three different ages - 24, 36 and 45 months - had a specificity of 96% (95% confidence interval 94-99%) and a sensitivity of 71% (95% confidence interval 66-77%). CONCLUSION: Combining milestones at different ages provided a concise tool that could help to detect children with SLI at a young age.

Children with specific language impairment are more likely to reach motor milestones late.

BACKGROUND: Delayed language development without an obvious cause is considered an isolated developmental disorder and is called specific language impairment (SLI). SLI is probably the most prevalent developmental disorder in childhood with a generally cited prevalence of 7%. This study aimed to investigate whether SLI is always an isolated disorder or if children with SLI also have delayed motor development. METHODS: We used data of an earlier study with a prospective nested case-control design in which developmental data were collected from child health care files. Cases were children (4-11 years) with diagnosed SLI. They were matched by sex and date of birth with control children attending mainstream education. Data of both groups on seven gross and six fine motor milestones which had been registered in the Dutch Developmental Instrument between the ages of 15-36 months were retrieved from child health care files. McNemar tests were performed to test for differences in reaching motor milestones at the age norm between the case and control group. RESULTS: Data from 253 children in each group were available. A significant difference was found between both groups in the proportion failing to reach three of the seven investigated gross motor milestones at the age norm (p < 0.05). The proportion of children not reaching the motor milestone at the age norm was significantly higher for five of the six fine motor milestones in children with SLI compared with control children (p < 0.05). CONCLUSIONS: More children with SLI are late in reaching motor milestones than children without SLI. This means that it is debatable whether SLI can be regarded as a "specific" impairment, which is not associated with other developmental problems. A broader developmental assessment is therefore indicated when diagnosing SLI.

Mortality in Children With Early-Detected Congenital Central Hypothyroidism.

Context: Approximately 60% to 80% of patients with congenital central hypothyroidism (CH-C) have multiple pituitary hormone deficiencies (MPHDs), making CH-C a potentially life-threatening disease. Data on mortality in patients with CH-C are lacking. Objective: To study the mortality rate in pediatric patients with early-detected and treated CH-C in the Netherlands and to investigate whether causes of death were related to pituitary hormone deficiencies. Methods: Overall mortality rate, infant mortality rate (IMR), and under-5 mortality rate were calculated in all children with CH-C detected by neonatal screening between 1 January 1995 and 1 January 2013. Medical charts were reviewed to establish causes of death. Results: A total of 139 children with CH-C were identified, of which 138 could be traced (82 with MPHD, 56 with isolated CH-C). Total observation time was 1414 years with a median follow-up duration of 10.2 years. The overall mortality rate was 10.9% (15/138). IMR and under-5 mortality rate were 65.2/1000 (9/138) and 101.4/1000 (14/138), respectively, compared with an IMR of 4.7/1000 and under-5 mortality of 5.4/1000 live-born children in the Netherlands during the same time period (P < 0.0001). Main causes of death were severe congenital malformations in six patients, asphyxia in two patients, and congenital or early neonatal infection in two patients. Pituitary hormone deficiency was noted as cause of death in only one infant. Conclusion: We report an increased mortality rate in patients with early-detected CH-C that does not seem to be related to endocrine disease. This suggests that mortality due to pituitary insufficiency is low in patients with early-detected and early-treated CH-C.

TSH and FT4 Concentrations in Congenital Central Hypothyroidism and Mild Congenital Thyroidal Hypothyroidism.

Context: In central hypothyroidism (CeH), free thyroxine (FT4) concentrations are low, whereas thyrotropin (TSH) concentrations may be low, normal, or even slightly elevated due to reduced bioactivity. Congenital CeH (CCeH) may be isolated or part of multiple pituitary hormone deficiencies (MPHD). Objective: We tested our hypotheses that (1) TSH concentrations have a more U-shaped distribution in children with CCeH compared with children with a normally functioning hypothalamic-pituitary-thyroid axis and (2) TSH concentrations in children with CCeH with MPHD are higher compared with children with isolated CCeH. We also studied whether FT4 levels are helpful in distinguishing CCeH from mild congenital hypothyroidism of thyroidal origin (CH-T). Methods: Dutch neonatal screening TSH and first diagnostic TSH and FT4 were analyzed in all children diagnosed with permanent CCeH between 1995 and 2012. Controls were children with T4-binding globulin deficiency. FT4 concentrations in CCeH were compared with those in CH-T with TSH values in the same range as those of CCeH. Results: We studied 120 children with CCeH (isolated CCeH, n = 50; MPHD, n = 70) and 350 control subjects. Screening TSH concentrations were not significantly different (P = 0.055), but diagnostic TSH values were significantly different between the CCeH group and the control group (P = 0.037). TSH was significantly higher in MPHD compared with isolated CCeH (P = 0.004). FT4 concentrations were significantly lower in CCeH compared with mild CH-T (P < 0.0005). Conclusion: TSH values in CCeH have a more U-shaped distribution compared with controls with the highest TSH concentrations in MPHD. FT4 levels were significantly lower in CCeH compared with CH-T.

Transient hypothyroxinemia of prematurity and problem behavior in young adulthood.

INTRODUCTION: Preterm newborns are at risk of developing transient hypothyroxinemia of prematurity (THoP), which has been associated with subsequent neurodevelopmental impairments. Behavioral outcomes at adult age after THoP have never been reported. AIM: To examine whether there is an association between THoP and problem behavior at young adult age. METHODS: This study was part of the follow-up of 19-year-old subjects born very preterm (i.e., <32 weeks) and/or with a very low birth weight (i.e.,<1500g) from the Project On Preterm and Small-for-gestational-age infants (POPS) cohort. We included 468 subjects of the POPS cohort; of whom 123 had THoP. Thyroxine (T4) concentrations were obtained through the national neonatal screening program for congenital hypothyroidism. THoP was defined as a T4 concentration <-3 SD (approximately 60nmol/L). At age 19, behavior was assessed using the Young Adult Self Report and the Young Adult Behavioral Checklist for parents. RESULTS: THoP was associated with a 1.8 (95% confidence interval (CI): 1.01-3.4) -fold increased odds of self-reported Internalizing behavior, as well as with a 1.9 (95% CI: 1.1-3.1) -fold increased odds of parent-reported Total problem behavior. These relations persisted after correction for demographic and perinatal variables. Similar associations were absent for the other self-reported and parent-reported syndrome and problem scales. CONCLUSIONS: THoP was associated with more internalizing and total problem behavior at age 19. While our observations warrant more awareness of problem behavior in preterm infants, at present, it is unclear whether these associations are causal and screening for THoP does not seem necessary.

Failure to meet language milestones at two years of age is predictive of specific language impairment.

AIM: This study established predictive properties of single language milestones for specific language impairment (SLI) after the age of four, as these had not previously been reported in the literature. METHODS: In this nested case-control study, children attending special needs schools for severe speech and language difficulties were matched with children attending mainstream schools. Data covering the ages of zero to four years were retrieved from well-child care clinics and the outcomes of 23 language milestones in the Dutch Developmental Instrument were analysed. The predictive properties were expressed as positive likelihood ratios, sensitivity and specificity. RESULTS: We included 253 pairs of children with and without SLI, aged from four to 11 years. The mean age was eight years and three months, and 77% were boys. From the age of 18 months, cases and controls differed significantly on all milestones (p < 0.01). After 24 months, the language milestones had positive likelihood ratios that ranging from 6 to 108. In general, language milestones had a high specificity (range 77-100%), but the sensitivity was relatively low (range 0-68%). CONCLUSION: Failure to meet language milestones from the age of 24 months was predictive of SLI, but the use of separate milestones had limited value due to low sensitivity.