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Introduction. The Danish Health Authority (DHA) recommends diagnostic evaluation of infants who develop prolonged jaundice and a serum conjugated bilirubin (CB) concentration ≥ 17 μmol/l. This study aimed to assess the efficacy of the programme in identifying infants with biliary atresia (BA) or other liver disease. Infants born in the Central Denmark Region from 2016 to 2021 were investigated. Methods. A total of 693 infants were identified in the Central Biochemical Database (Labka). From a review of all medical records, CB measurements, results from diagnostic procedures and the final diagnosis were documented. Results. Four infants were identified with BA. They had a mean CB concentration of 105 μmol/l. A total of 33 infants were diagnosed with other cholestatic diseases; this group had a mean CB concentration of 58.9 μmol/l. The remaining 656 infants with a mean CB of 20.5 μmol/l recovered spontaneously without any sign of cholestatic disease. Approximately 75% of all HIDA scintigraphies (100/134) were conducted in 647 infants with a maximum CB concentration < 30 μmol/l. They all had bile drainage to the intestines. Among these infants, twelve were diagnosed as heterozygote for alfa-1-antitrypsin deficiency. Conclusion. The CB threshold limit recommended by the DHA detected all patients with BA, but its use leads to over-investigation and over-diagnosing.

Aim: Although exclusive breastfeeding is recommended for all newborn in the first 6 months of life, only 13% of Danish premature infants complies with this. This trial aimed to examine whether oral stimulation prolonged exclusive breastfeeding in premature infants. Method: A randomised controlled trial was conducted at the Neonatal Intensive Care Unit, Hvidovre Hospital, Denmark between 2016 and 2018. Systematic oral stimulation was performed by the parents after training by occupational therapists. Primary outcome was exclusive breastfeeding duration with 6 months' follow-up, analysed by intention-to-treat. Results: Included were 211 infants (53% boys) with a mean gestational age of 231 days, allocated in ratio 1:1 to oral stimulation or standard care. There was no difference in exclusive breastfeeding duration between infants orally stimulated and control infants. Thus, for orally stimulated infants, median duration was 122 days (interquartile range 40-183) in contrast to 154 days (interquartile range 61-183) for the controls, P value.16. At 6 months of age, 27% of orally stimulated infants were exclusively breastfed compared with 25% of controls. Conclusion: In healthy premature infants, oral stimulation performed by parents has no long-lasting effect on breastfeeding duration. Attention should be directed to parental education and involvement.

Background Studies in low-income countries have shown that among Bacille Calmette-Guérin (BCG) vaccinated children, those who develop a BCG-scar have significantly better survival than those who do not develop a scar. In a Danish multicenter randomized clinical trial we assessed determinants for developing a BCG-scar and for BCG scar size following neonatal BCG vaccination. Methods At three Danish hospitals, newborns were randomized 1:1 to BCG vaccination or no BCG vaccination. The infants were invited for a clinical examination at the ages of 3 and 13 months. At 13 months, the scar site was inspected and scar size measured. We investigated three groups of determinants; external, parental, and individual-level determinants on relative scar prevalence and differences in median scar sizes. Results Among 2118 BCG vaccinated infants, 2039 (96 %) were examined at 13 months; 1857 of these (91 %) had developed a BCG-scar. Compared with Copenhagen University Hospital, Hvidovre (85 %), Copenhagen University Hospital, Rigshospitalet had a scar prevalence of 95 % (adjusted Prevalence ratio (aPR) = 1.24 [CI 95 %: 1.18 to 1.30]); it was 93 % at Kolding Hospital (aPR 1.27 [CI 95 %: 1.19 to 1.35]). Increasing vaccine experience was positively associated with developing a scar and with scar size. Conclusion Across multiple potential determinants of BCG scaring and size, logistical factors dominated. The results support that injection technique is an important determinant of developing a scar. Given the strong link between having a BCG scar and subsequent health, improved BCG vaccination technique could play a major role for child health., BCG vaccine; BCG scar; Non-specific effects; Heterologous immunity.

Background The Bacille Calmette-Guerin (BCG) vaccine against tuberculosis (TB) may have beneficial non-specific effects (NSEs) beyond the protection against TB. This may be related to modifications of the innate immune system. We investigated the effect of BCG at birth on differential white blood cell (WBC) count in healthy, Danish infants. Method The Danish Calmette Study randomised newborns to BCG at birth (Danish strain 1331, Statens Serum Institut) or no intervention. A sub-group of infants had blood samples collected 4 days after randomisation (n = 161), and at age 3 months (n = 152) and 13 months (n = 300). We evaluated the effect of BCG on WBC differential count (total leucocytes, lymphocytes, monocytes, eosinophil, neutrophil and basophil granulocytes (109 cells/L)) measured in peripheral blood. Results Overall, we found no effect of BCG on differential WBC counts at any time point. Conclusion BCG at birth did not affect WBC count in our cohort of healthy, Danish infants.

Objective To study the effect of antenatal magnesium sulphate (MgSO4 ) on cerebral palsy (CP) in a manner that also provides adequate power for a linked trial sequential analysis. Design Double-blind, randomised, placebo-controlled, multi-centre trial. Setting Fourteen Danish obstetric departments. Population In total, 560 pregnant women at risk for preterm delivery before 32 weeks of gestation were randomised from December 2011 to January 2018. Those women gave birth to 680 children. Methods Women were randomised to receive either a loading dose of 5 g MgSO4 followed by 1 g/hour or a placebo in identical volumes. The children were followed up at a corrected age of 18 months or older with a review of their medical charts and with the Ages and Stages Questionnaire. Main outcome measure The primary outcome measure was moderate to severe CP. Secondary outcomes included mortality, neonatal morbidity, blindness and mild CP. Results The crude rates of moderate to severe CP in the MgSO4 group and the placebo group were 2.0% and 3.3%, respectively. The adjusted odds of moderate to severe CP were lower in the MgSO4 group than in the placebo group (odds ratio 0.61; 95% CI 0.23-1.65). Conclusions Antenatal MgSO4 before 32 weeks of gestation decreases the likelihood of moderate to severe CP; these results are entirely consistent with other randomised evidence summarised in the linked trial sequential analysis. Tweetable abstract Antenatal magnesium sulphate may decrease the risk of moderate to severe cerebral palsy in children born before 32 weeks of gestation.

Several studies have shown increased in vitro cytokine responses to non-related pathogens after Bacillus Calmette-Guérin (BCG) vaccination. A total of 158 infants (80 BCG administered within 7 days of birth; 78 controls) were bled 4 days post-randomization, and at age 3 and 13 months. Geometric mean concentrations of IL-1β, TNF-α, IL-6 (24 h stimulation) and IFN-γ, IL-10, IL-17, IL-22 (96 h stimulation) in response to in vitro stimulation with RPMI, LPS, PHA, Escherichia coli, Streptococcus pneumoniae, Candida albicans and BCG were compared among BCG vaccinated children and controls. BCG vaccination did not affect in vitro cytokine production, except IFN-γ and IL-22 response to BCG. Stratifying for 'age at randomization' we found a potentiating effect of BCG on cytokine production (TNF-α, IL-6, IL-10) in the 4 days post randomization stimulations, among children who were vaccinated at age 2-7 days versus age 0-1 days. BCG vaccination did not potentiate cytokine production to non-BCG antigens. At 4 days post randomization, BCG was associated with higher cytokine production in the later randomized children.

AIM: Exclusive breastfeeding is recommended for the first 6 months of life, but the breastfeeding rate in premature infants is low. We examined the effect of oral stimulation on infant's strength of suction and the relation between this intra-oral vacuum and breastfeeding duration.METHOD: Between 2016 and 2018, 211 infants in a Danish neonatal unit were randomised 1:1 and of these 108 to oral stimulation intervention and 103 to control. Suction was measured as peak vacuum at enrolment and a corrected age of 6 weeks. Breastfeeding duration was registered.RESULTS: Vacuum increased from enrolment to a corrected age of 6 weeks in all infants, and no effect of oral stimulation intervention was demonstrated P = .08. Infants born ≤32 gestational weeks had lower vacuum compared with infants born after, 350 vs 398 mbar P < .001. For infants born after 32 gestational weeks, the odds ratio for exclusive breastfeeding at 6 months was 1.99 per 100 mbar increase in vacuum P = .01.CONCLUSION: In our study, infant's intra-oral vacuum increased with age and was not affected by the oral stimulation intervention. For infants born after 32 gestational weeks, the exclusive breastfeeding rate was positively associated with a strong vacuum.

Background The bacillus Calmette-Guérin (BCG) vaccine against tuberculosis might reduce the non–tuberculosis-related child mortality rate in low-income settings. We tested the hypothesis that BCG vaccination at birth would reduce early childhood hospitalization for infection in Denmark, a high-income setting. Hospitalization for infection was a secondary outcome in a randomized trial with the primary aim to estimate the potential non-specific effects of BCG vaccination at birth on all-cause hospitalization. Methods A total of 4262 children included in the Danish Calmette Study were assigned randomly to either receive the BCG vaccine or not and were followed through the Danish National Patient Register. The outcome was number of hospitalizations for infection until the age of 15 months. Data were analyzed by Cox regression in intention-to-treat (ITT) and per-protocol (PP) analyses. Results In the ITT analysis, we observed 588 hospitalizations for infection (mean, 0.28 hospitalization per child) among the 2129 children allocated to receive the BCG vaccine and 595 hospitalizations for infection (mean, 0.28 hospitalization per child) among the 2133 children allocated to the control group (hazard ratio [HR], 0.99 [95% confidence interval (CI), 0.85–1.15]). The PP analysis yielded an HR of 1.00 (95% CI, 0.86–1.16). Predefined interaction ITT analyses showed that among 740 children with a BCG-vaccinated mother, the HR for BCG-vaccinated children was 0.65 (95% CI, 0.45–0.94); the HR for children who had a non–BCG-vaccinated mother was 1.10 (95% CI, 0.93–1.29) (P = .01, test of no interaction). Cesarean delivery modified the effect of BCG vaccination (HRs, 0.73 [95% CI, 0.54–0.99] in children born by cesarean section vs 1.10 [95% CI, 0.92–1.30] in other children; P = .02). When the outcome was defined as time to first hospitalization, the HR for premature children after BCG vaccination was 1.81 (95% CI, 0.95–3.43), whereas the HR was 0.94 (95% CI, 0.82–1.08) for children born at term (P = .05). Conclusion BCG vaccination did not affect the rate of hospitalization for infection up to the age of 15 months in Danish children. In future studies, the role of maternal BCG-vaccination, premature birth, and cesarean delivery needs further exploration.

Background Bacillus Calmette-Guerin vaccine (BCG) induces a complex, pro-inflammatory immune response. Obesity is associated with low-grade inflammation. Aims The purpose of the study was to test whether BCG at birth has effects on infant growth and body composition. Study design, subjects, and outcome measures The Danish Calmette Study is a randomized, clinical trial. The study was conducted at three university hospitals and randomized 4262 children of gestational age ≥ 32 weeks to receive BCG within seven days of birth or to a no-intervention control group. Follow-up consisted of clinical examinations. Outcome measures were weight and length at 3 months, and weight, length, mid upper-arm circumference, and triceps and subscapular skinfold at 13 months. Data collectors were blinded to allocation. Anthropometric measurements were converted to z-scores using WHO reference population. Results Follow-up was 94% complete at 3 and 13 months after birth. The children were bigger than the WHO reference population. There was no effect of BCG on weight z-score at 13 months (− 0.028 [95% confidence interval: − 0.085 to 0.029], p = 0.34). There was no effect on weight and length at 3 months, or length, mid-upper-arm circumference, or triceps and subscapular skinfold at 13 months. Conclusion In this study, vaccination with BCG at birth did not have effects on child growth or body composition at 13 months. Trial registration www.clinicaltrials.gov , registration number NCT01694108 .

BackgroundThe BCG vaccine is administered to protect against tuberculosis, but studies suggest there may also be non-specific beneficial effects upon the infant immune system, reducing early non-targeted infections and atopic diseases. The present randomised trial tested the hypothesis that BCG vaccination at birth would reduce early childhood hospitalisation in Denmark, a high-income setting.MethodsPregnant women planning to give birth at three Danish hospitals were invited to participate. After parental consent, newborn children were allocated to BCG or no intervention within 7 days of age. Randomisation was stratified by prematurity. The primary study outcome was number of all-cause hospitalisations analysed as repeated events. Hospitalisations were identified using The Danish National Patient Register. Data were analysed by Cox proportional hazards models in intention-to-treat and per-protocol analyses.Results4184 pregnant women were randomised and their 4262 children allocated to BCG or no intervention. There was no difference in risk of hospitalisation up to 15 months of age; 2129 children randomised to BCG experienced 1047 hospitalisations with a mean of 0.49 hospitalisation per child compared with 1003 hospitalisations among 2133 control children (mean 0.47), resulting in a HR comparing BCG versus no BCG of 1.05 (95% CI 0.93 to 1.18) (intention-to-treat analysis). The effect of BCG was the same in children born at term (1.05 (0.92 to 1.18)) and prematurely (1.07 (0.63 to 1.81), p=0.94). The effect was also similar in the two sexes and across study sites. The results were essentially identical in the per-protocol analysis and after adjustment for baseline characteristics.ConclusionsBCG vaccination at birth did not reduce the risk of hospitalisation for somatic acquired disease until 15 months of age in this Danish study population.Trial registration numberNCT01694108, results.

Background: Childhood infections are common and Bacillus Calmette-Guérin (BCG) vaccination at birth may prevent these via nonspecific effects. Methods: A randomized, clinical multicenter trial. All women planning to give birth (n = 16,521) at the three study sites were invited during the recruitment period. Participating children were randomized to receive BCG within 7 d of birth or to a no intervention control group. Parent-reported infections (events) were collected using telephone interviews at 3 and 13 mo. Data collectors were blinded to allocation. Results: The analyses included 4,224/4,262 (99%) and 4,192/4,262 (98%) children at 3 and 13 mo. From 0 to 3 mo, there were 291 events in the BCG group vs. 336 events in the control group, incidence rate ratio (IRR) = 0.87 (95% confidence interval (CI): 0.72 to 1.05). In this age group, the IRR was 0.62 (95% CI: 0.39 to 0.98) if the mother was BCG vaccinated. From 3 to 13 mo, there were 7,028 vs. 6,791 events, IRR = 1.02 (95% CI: 0.97 to 1.07). Conclusion: This study did not find a nonspecific public health benefit of BCG on parent-reported infections. BCG may have reduced the incidence of infections in children of BCG-vaccinated mothers during the first 3 mo.

INTRODUCTION: Due to the design of Hvidovre Hospital, the outpatient clinic of the Department of Paediatrics has windowless consultation rooms. Work environment surveys revealed that nurses and doctors working in these windowless rooms considered the lack of natural light a considerable health problem. This study evaluated the effects of installing light-emitting diode (LED) virtual windows in these rooms.METHODS: Four similar windowless consultations rooms located next to each other were used in the study. All had older T-5 fluorescent luminaires installed. In two of these rooms, Servodan LED virtual windows depicting various natural scenes were installed. The illuminance and correlated colour temperature (CCT) of each room's lighting was measured, and a work environment questionnaire was filled out by nurses and doctors working in each room.RESULTS: A total of 113 questionnaires were collected and evaluated. LED virtual windows produced an improved perception of lighting conditions, both at the desk (p < 0.001) and in the rooms in general (p < 0.001) and improved the overall positive experience of the rooms (p = 0.02). A tendency towards concentration difficulties was reported less often in the rooms with LED virtual windows, (p = 0.11). Retinal illuminance (p = 0.02) as well as CCT at the desk (p < 0.005) and at the retina (p < 0.01) alike were increased in rooms with LED virtual windows.CONCLUSIONS: LED virtual windows improved the lighting experience, the impression of the space, the retinal illuminance and the CCT at the desk and at the retina in the windowless rooms.FUNDING: none.TRIAL REGISTRATION: not relevant.

Dual-energy X-ray absorptiometry (DXA) has been hailed as a golden standard for measuring body composition in adults but remains to be fully assessed for the infant population. A total of 64 newborn infants were allocated to 1 of 3 groups. All underwent 2 Hologic Discovery A DXA scans. Suboptimal scans were reconstructed, and an investigation into the success of adjustment was carried out. Depending on group, the factors of weight change and repositioning were investigated. Test-retest variation and coefficients of variation for DXA body composition estimates were calculated. Furthermore, the effects of flannel sheets and breast milk were investigated using a pediatric phantom. Reconstruction of suboptimal scans resulted in more accurate body weight estimates. Moderate weight change and repositioning had no significant effect on the variation between scans. No significant body composition changes occurred between scans. The test-retest variation varied between 6.3% and 11.8%. Flannel sheets and breast milk affected DXA results significantly. High precision of DXA measurements was obtained in our newborn population. Reconstructing scans is a viable way of correcting minor movement artifacts. Moderate weight changes and repositioning have no significant effect on DXA results, whereas flannel sheets and milk do.

Background The Bacillus Calmette-Guérin vaccine (BCG) against tuberculosis is administered intradermally, and vaccination is often followed by a scar at the injection site. Among BCG-vaccinated individuals, having a scar has been associated with lower mortality. We aimed to examine the impact of vaccination technique for scarring in a high income setting, by assessing the associations between the post injection reaction, the wheal size, and the probability of developing a scar, and scar size. Methods This study was nested within a clinical multicenter study randomizing 4262 infants to either BCG vaccination (BCG 1331 SSI) or no intervention. In this substudy, including 492 vaccinated infants, the immediate post BCG vaccination reaction was registered as either wheal (a raised, blanched papule at the injection site), bulge (a palpable element at the injection site), or no reaction. The presence or absence of a BCG scar and the size the scar was measured at 13 months of age. Results Of 492 infants included, 87% had a wheal after vaccination, 11% had a bulge, and 2% had no reaction. The mean wheal size was 3.8 mm (95% confidence interval 3.7–3.9). Overall, 95% (442/466, 26 lost to follow-up) of BCG-vaccinated infants had a scar at 13 months of age. In infants with a wheal, the probability of developing a scar was 96%, declining to 87% in the case of a bulge, and to 56% in the case of no reaction (p for same probability = 0.03). Wheal size was positively correlated with the probability of getting a scar and scar size. Conclusion Scarring after BCG vaccination has been associated with lower infant mortality. In a high-income setting, we found that correct injection technique is highly important for the development of a BCG scar and that registration of the category of BCG skin reaction (as wheal, bulge, or no reaction) may be used to identify infants at risk of scar failure. Finally, the wheal size was positively associated with both the probability of getting a scar and scar size. Trial registration The study was registered at www.ClinicalTrials.gov with trial registration number NCT01694108. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2641-0) contains supplementary material, which is available to authorized users.

The Bacillus Calmette–Guérin vaccine (BCG) has been associated with beneficial non-specific effects (NSEs) on infant health. Within a randomized trial on the effect of neonatal BCG on overall health, we investigated the possible immunological impact of neonatal BCG vaccination on lymphocyte subsets, determined by flow cytometry. In 118 infants blood samples were obtained 4 (±2) days post randomization to BCG vaccination or no intervention, and at 3 and 13 months of age. No effects of BCG were found at 4 days. However, BCG increased proportions of effector memory cells at 3 months (Geometric mean ratio (GMR) 1.62, 95% confidence interval (CI) (1.20–2.21), p = 0.002 for CD4+ T cells and GMR 1.69, 95% CI (1.06–2.70), p = 0.03 for CD8+ T cells), and reduced proportions of late differentiated CD4+ T cells (GMR = 0.62, 95% CI (0.38–1.00), p = 0.05) and apoptotic CD4+ T cells at 13 months (GMR = 0.55, 95% CI (0.32–0.92), p = 0.03). In conclusion, limited overall impact of neonatal BCG vaccination on lymphocyte subsets was found in healthy Danish infants within the first 13 months of life. This is in line with the limited clinical effects of BCG observed in our setting.

Contains fulltext : 169904.pdf (Publisher’s version ) (Open Access) INTRODUCTION: BCG vaccination has been associated with beneficial non-specific effects on child health. Some immunological studies have reported heterologous effects of vaccines on antibody responses to heterologous vaccines. Within a randomised clinical trial of Bacille Calmette-Guerin (BCG) vaccination at birth, The Danish Calmette Study, we investigated the effect of BCG at birth on the antibody response to the three routine vaccines against DiTeKiPol/Act-Hib and Prevenar 13 in a subgroup of participants. METHODS: Within 7days after birth, children were randomised 1:1 to BCG vaccination or to the control group (no intervention). After three routine vaccinations given at age 3, 5 and 12months, antibodies against DiTeKiPol/Act-Hib and Prevenar 13 (Streptococcus pneumoniae serotype type 4, 6B, 9V, 14, 18C, 19F and 23F) were measured 4weeks after the third vaccine dose. RESULTS: Among the 300 included children (178 BCG; 122 controls), almost all children (>96%) had antibody responses above the protective levels. Overall BCG vaccination at birth did not affect the antibody level. When stratifying by 'age at randomisation' we found a possible inducing effect of BCG on antibodies against B. pertussis and all pneumococcal serotypes, when BCG was given after the first day of life. Girls had significantly higher antibody levels for Haemophilus influenza type b and pneumococcus than boys. CONCLUSIONS AND RELEVANCE: Three routine vaccinations with DiTeKiPol/Act-Hib and Prevenar 13 induced sero-protective levels in almost all children. No overall effect of neonatal BCG vaccination was observed.

Background: The Bacillus Calmette-Guérin vaccine (BCG) has been associated with beneficial nonspecific effects on infant health. We aimed to examine the effect of BCG at birth on thymic size and the associations between thymic output, circulating lymphocytes, risk of infection, and thymic size. Methods: In infants randomized to BCG or no BCG, thymic index (TI), and thymic/weight index (TWI) were measured by ultrasound at birth and at the age of 3 mo. T cell subpopulations including CD4+ T cells, CD8+ T cells, and recent thymic emigrants (RTEs) were assessed by flow cytometry. Infections up to age 3 mo were parent-reported. Results: BCG vaccination did not affect thymic size at age 3 mo, measured as TI. At birth, the number of lymphocytes, CD4+ T cells, CD8+ T cells, and RTEs were positively associated with TI and TWI. Furthermore, a reduced risk of infections up to age 3 mo was associated with a large thymic size at birth. Conclusion: We found no effect of BCG vaccination on thymic size. The positive association between thymic output, lymphocytes, reduced risk of infections, and TI/TWI suggests that assessment of TI/TWI by ultrasound may be a predictor of the immunological capacity in the newborn.

Aim There is a lack of evidence on the best treatment option for umbilical granuloma. The primary aim of this study was to compare three treatments for umbilical granuloma: standard treatment with topical silver nitrate, clobetasol propionate cream (0.05%) and ethanol wipes. The secondary aim was to evaluate whether the treatment could be successfully administered by a parent at home, rather than in the outpatient clinic. Methods A total of 109 infants were randomised to one of three groups and 94 infants completed the assigned treatment: 30 infants received standard treatment with silver nitrate (99%) in the outpatient clinic, 30 infants had topical clobetasol propionate cream (0.05%) applied at home, and 34 infants received cleansing with ethanol wipes (82%) at home. Results Silver nitrate and clobetasol propionate cream (0.05%) were significantly superior to ethanol wipes, with shorter healing times and higher resolution rates (p = 0.0001). Healing time and resolution rates were identical for silver nitrate and clobetasol propionate cream (0.05%). Mild side effects were occasionally reported, all of which were self-limiting. Conclusion Treating umbilical granuloma with topical clobetasol propionate cream (0.05%) at home is as effective as treating it with topical silver nitrate (99%) in the clinic.

AIM: This study investigated whether newborn body composition is influenced by prepregnancy obesity and gestational weight gain (GWG) and explored any associations between body composition and birthweight standard score (z-score), categorised by size for gestational age.METHODS: We recruited 231 obese and 80 normal weight mothers and their newborn infants and assessed the babies' body composition using dual-energy X-ray absorptiometry.RESULTS: The total and abdominal fat masses of infants born to mother who were obese before pregnancy were 135 g (p < 0.001) and 18 g (p < 0.001) higher than the offspring of normal weight mothers. The infants' fat mass increased by 11 g (p < 0.001) for every kilogram of GWG. There were no associations between prepregnancy obesity and fat-free mass. The fat percentage was significantly higher in infants who were large for gestational age (15.3%) than small for gestational age (5.2%) and appropriate for gestational age (9.8%) (p < 0.001). Lower birthweight z-score was associated with a higher proportion of abdominal fat mass (p = 0.009).CONCLUSION: Infants born to obese mothers had higher fat mass at birth, with abdominal fat accumulation. Low birthweight was associated with a lower crude abdominal fat mass, but a higher proportion of total fat mass placed abdominally.

OBJECTIVE: To evaluate adverse reactions of the Bacillus Calmette-Guérin (BCG) Statens Serum Institut (SSI) (Danish strain 1331) used as intervention in a randomized clinical trial.DESIGN: A randomized clinical multicenter trial, The Danish Calmette Study, randomizing newborns to BCG or no intervention. Follow-up until 13 months of age.SETTING: Pediatric and maternity wards at three Danish university hospitals.PARTICIPANTS: All women planning to give birth at the three study sites (n=16,521) during the recruitment period were invited to participate in the study. Four thousand one hundred and eighty four families consented to participate and 4262 children, gestational age 32 weeks and above, were randomized: 2129 to BCG vaccine and 2133 to no vaccine. None of the participants withdrew because of adverse reactions.MAIN OUTCOME AND MEASURE: Trial-registered adverse reactions after BCG vaccination at birth. Follow-up at 3 and 13 months by telephone interviews and clinical examinations.RESULTS: Among the 2118 BCG-vaccinated children we registered no cases of severe unexpected adverse reaction related to BCG vaccination and no cases of disseminated BCG disease. Two cases of regional lymphadenitis were hospitalized and thus classified as serious adverse reactions related to BCG. The most severe adverse reactions were 10 cases of suppurative lymphadenitis. This was nearly a fivefold increase compared to what was expected based on the summary of product characteristics of the vaccine. All cases were treated conservatively and recovered. Six of 10 (60%) families of children experiencing suppurative lymphadenitis compared to 117/2071 (6%) of those with no lymphadenitis indicated that the vaccine had more adverse effects than expected (p-value CONCLUSIONS AND RELEVANCE: BCG vaccination was associated with only mild morbidity and no mortality. A higher incidence of suppurative lymphadenitis than expected was observed. All children were treated conservatively without sequelae or complications.TRIAL REGISTRATION: Trial registration number NCT01694108 at www.clinicaltrials.gov.

Objectives: To assess the non-specific effect of Bacillus Calmette-Guérin (BCG) vaccination at birth on psychomotor development. Design: This is a pre-specified secondary outcome from a randomised, clinical trial. Setting: Maternity units and paediatric wards at three university hospitals in Denmark. Participants: Children born at gestational age (GA) 32 weeks and above. All women planning to give birth at the three sites were invited during the recruitment period. Out of 4262 randomised children, 144 were premature (GA < 37 weeks). There were 2129 children (71 premature) randomised to BCG and 2133 randomised (73 premature) to the control group. Interventions: BCG vaccination 0.05 ml was given intradermally in the upper left arm at the hospital within seven days of birth. Children in the control group did not receive any intervention. Parents were not blinded to allocation. Main outcome measures: Psychomotor development measured using Ages and Stages Questionnaire (ASQ) completed by the parents at 12 months. Additionally, parents of premature children (gestational age < 37 weeks) completed an ASQ at 6 and 22 months. Developmental assessment was available for 3453/4262 (81%). Results: The mean difference in ASQ score at 12 months adjusted for age and prematurity was -0.7 points (BCG vs. control, 95% confidence interval; -3.7 to 2.4), p = 0.67, corresponding to an effect size of Cohen's d = -0.015 (-0.082 to 0.052). The mean difference in ASQ score for premature children at 22 months was -7.8 points (-20.6 to 5.0, p = 0.23), d = -0.23 (-0.62 to 0.15). Conclusions: A negative non-specific effect of BCG vaccination at birth on psychomotor development was excluded in term children. Trial Registration: ClinicalTrials.gov NCT01694108.

Aim: Despite widespread use, effects of volume boluses and dopamine in hypotensive newborn infants remain controversial. We aimed to elucidate if hypovolemia alone impairs cerebral autoregulation (CA) and if dopamine affects cerebral vasculature. Methods: In 12 piglets, cerebral perfusion (laser-Doppler flux) and oxygenation [near-infrared spectroscopy (NIRS)] were examined during dopamine (20–50 μg/kg per minute) and nonpharmacologically induced blood pressure (ABP) changes. Effect on cerebral perfusion and oxygenation was quantified as frequency gain between ABP and laser-Doppler flux (gain-LDF) and NIRS [gain-oxygenation index (OI)], respectively. Gain quantifies change in perfusion or oxygenation per ABP-change. CA was estimated as gain-LDF during nonpharmacologically induced ABP changes, that is, as degree of impairment. Dopamine’s cerebrovascular effect was estimated by contrasting gain during dopamine- and nonpharmacologically induced ABP changes. Measurements were conducted during both normovolemia- and haemorrhage-induced hypovolemia. Results: Hypovolemia elicited hypotension (p = 0.02) as well as increasing impairment of CA (p = 0.01). However, hypovolemia without hypotension did not affect CA significantly. Dopamine increased perfusion significantly compared to nonpharmacological challenges (mean difference: 1.5%/mmHg, 95% CI: 0.5–2.6, p = 0.007). Oxygenation was, however, similar (mean difference: 0.01 μmol/L per mmHg, 95% CI: −0.03 to 0.05, p = 0.7). Conclusion: Our findings do not support that hypovolemia alone impairs CA. Furthermore, dopamine seems to increase cerebral perfusion but not oxygenation.

BACKGROUND: Transmission of obesity across generations is of concern. Offspring of obese women have short- and long-term increased morbidities. A high intake of carbohydrate during pregnancy combined with impaired glucose tolerance is postulated to result in high birth weight, which is linked to subsequent metabolic disease.OBJECTIVE: The objective was to examine the association between carbohydrate intake in obese pregnant women and their offspring's body composition.DESIGN: Secondary analyses were performed in an observational setting of 222 pregnant women with a pregestational BMI (in kg/m(2)) ≥30 participating in a randomized controlled trial. Diet was assessed at gestational weeks 11-14 and 36-37 by using a semiquantitative food-frequency questionnaire. Body composition in the offspring was assessed at birth by dual-energy X-ray absorptiometry. Relative fat mass (%) was the primary outcome. Absolute measures (total fat, abdominal fat, and lean body mass) were secondary outcomes.RESULTS: Mean ± SD weight and absolute and relative fat mass in the offspring at birth were 3769 ± 542 g, 436 ± 214 g, and 11% ± 4%, respectively. Maternal intake of digestible carbohydrates was associated with the offspring's relative fat mass in late (P-trend = 0.006) but not early (P-trend = 0.15) pregnancy. A comparison of mothers in the highest (median: 238 g/d) compared with the lowest (median: 188 g/d) quartile of digestible carbohydrate intake showed a mean adjusted higher value in the offspring's relative fat mass of 2.1% (95% CI: 0.6%, 3.7%), which corresponded in absolute terms to a 103-g (95% CI: 27, 179-g) higher fat mass. Abdominal fat mass was also higher. In a strata of women with well-controlled glucose (2-h glucose values ≤6.6 mmol/L), no association between carbohydrate intake and offspring fat mass was observed, but the associations became significant and increased in strength with higher intolerance (strata with 2-h glucose values between 6.7-7.7 and ≥7.8 mmol/L).CONCLUSION: In obese women, even those without gestational diabetes but with impaired glucose tolerance, a lower carbohydrate intake at moderate levels in late gestation is associated with a lower fat mass in their offspring at birth. The TOP study was registered at clinicaltrials.gov as NCT01345149.

Please cite this paper as: Huusom L, Secher N, Pryds O, Whitfield K, Gluud C, Brok J. Antenatal magnesium sulphate may prevent cerebral palsy in preterm infants—but are we convinced? Evaluation of an apparently conclusive meta-analysis with trial sequential analysis. BJOG 2011;118:1–5.

Twenty-nine high-risk preterm born children, from a cohort with cerebral blood flow (CBF) measurements in the first 2 d of life, were examined prospectively at the age of 5.5—7 y neurologically, neuropsychologically and by magnetic resonance imaging (MRI). They were compared to 57 control children in terms of neurology and neuropsychology. Abnormal MRI was found in 19 children. Low oxygen delivery to the brain was found in 63% of them, in contrast to 12.5% in those with normal MRI, indicating neonatal hypoxia-ischemia as an important factor. The MRI abnormalities were mainly periventricular lesions (n = 19), especially periventricular leucomalacia (PVL, n = 17). Three of the very preterm children had severe cerebellar atrophy in addition to relatively mild periventricular abnormalities. MRI showed specific morphological correlates for the major disabilities, e.g. spastic CP (involvement of motor tracts), mental retardation (bilateral extensive white matter reduction or cerebellar atrophy) and severe visual impairment (severe optic radiation involvement). A morphological correlate for minor disabilities, i.e. functional variations in motor performance or intelligence, was not found, with the exception that symptoms of attention deficit hyperactivity disorder were related to mild MRI abnormalities. This could mean that with respect to cognitive functions, mild or unilateral periventricular MRI lesions could be compensated. However, as among preterms without mental retardation (n = 19), IQ was generally and significantly lower than in the control group; other, more chronic pathogenetic factors, not detectable by MRI alone, may play a role. □Attention deficit hyperactivity disorder, cerebral blood flow, cerebral palsy, magnetic resonance imaging, oxygen delivery, periventricular leucomalacia, prematurity

Aim: To describe and analyse neonatal care, short and long-term morbidity with special reference to ventilatory support and chronic lung disease (CLD) in a population-based study. Methods: During 1994 and 1995 a prospective, nation-wide, multicentre study was conducted, comprising 477 liveborn infants with gestational age (GA) >28 wk and/or birthweight >1000 g. Of these, 407 infants received active treatment. The ventilatory treatment was based on the principle of permissive hypercapnia and early nasal continuous positive airway pressure (NCPAP) supplemented with surfactant and ventilator therapy in case of CPAP failure. Results: Among actively treated infants 85% received CPAP and 23% mechanical ventilation from the first day of life. A total of 269 infants (56%) survived to discharge. Of these, 195 had a GA >28wk. One-hundred and five survivors with GA >28 wk survived with NCPAP as sole respiratory support. In surviving infants, periventricular leucomalacia/intraventricular haemorrhage grade 3–4 was found in 10%, retinopathy of prematurity grade >2 in 4%, and oxygen requirement at 36 and 40 wk of postmenstrual age (CLD) in 16 and 5%, respectively. Three infants either died of CLD (n= 1) or required oxygen therapy beyond 43 wk of postmenstrual age. Logistic regression analysis showed significant associations between oxygen requirement at 40 wk and GA, septicaemia, mechanical ventilation, symptomatic patent ductus arteriosus and Clinical Risk Index for Babies score. Only the two last-mentioned factors proved significant in infants with GA >28 wk. No infant died after discharge and 253 (94%) were followed up at 2 y of corrected age; one or more moderate to severe impairments were found in 66 (26%) of the examined children. Conclusion: Ventilatory treatment in extremely premature and extremely low-birthweight infants based on early NCPAP and permissive hypercapnia may result in comparable survival rates and sensorineural outcome; however, the incidence of CLD seems lower than that reported on conventional treatment.

BACKGROUND: Third trimester fetal growth is partially regulated by C-peptide and insulin-like growth factor I (IGF-I). Prenatal exposures including maternal obesity and high gestational weight gain as well as high birth weight have been linked to subsequent metabolic disease. We evaluated the associations between newborn regional body composition and cord blood levels of C-peptide and IGF-I.METHODS: We prospectively included obese and normal-weight mothers and their newborns; cord blood was collected and frozen. Analyses of C-peptide and IGF-I were performed simultaneously, after recruitment was completed. Newborn regional body composition was assessed with dual-energy X-ray absorptiometry scanning (DXA) within 48 hours of birth.RESULTS: Three hundred thirty-six term infants were eligible to participate in the study; of whom 174 (52%) infants had cord blood taken. Total, abdominal and arm and leg fat mass were positively associated with C-peptide (p < 0.001). Arm and leg fat mass was associated with IGF-I concentration: 28 g [95% confidence interval: 4, 53] per doubling of IGF-I. There was no association between total or abdominal fat mass and IGF-I. Fat-free mass was positively associated with both C-peptide (p < 0.001) and IGF-I (p = 0.004).CONCLUSION: Peripheral fat tissue accumulation was associated with cord blood C-peptide and IGF-I. Total and abdominal fat masses were related to C-peptide but not to IGF-I. Thus, newborn adiposity is partially mediated through C-peptide and early linear growth is associated with IGF-I.

Introduction. Offspring of obese women have both short-term and long-term increased morbidities. We investigated the relationship between maternal 2-h plasma glucose level determined by an oral glucose tolerance test, degree of obesity, gestational weight gain and total fat, abdominal fat, and fat-free masses in the offspring of obese mothers. Material and methods. Obese mother-newborn dyads were recruited and 2-h plasma glucose levels were assessed during gestational weeks 27-30; neonatal body composition was measured by dualenergy X-ray absorptiometry scanning (DXA) within 48 h of birth. Results. Among 264 term, healthy, and singleton infants eligible for inclusion, 248 were included. Of these, 205 (83%) obese mother-newborn dyads had a DXA scan and 2-h plasma glucose measurements. Linear regression analysis showed that birthweight z-scores correlated with 2-h plasma glucose levels (p = 0.002) after adjusting for gestational weight gain, maternal age, education, smoking, prepregnancy degree of obesity, parity, and birth length. Total (p = 0.012) and abdominal (p = 0.039) fat masses correlated with 2-h plasma glucose levels after adjusting for gestational weight gain, maternal age, education, smoking, prepregnancy degree of obesity, parity, gestational age, and newborn sex. There was no association between total (p = 0.88) and abdominal (p = 0.61) fat-free masses and 2-h plasma glucose. Conclusion. At 27-30 weeks of gestation, 2-h plasma glucose levels are related to total and abdominal newborn fat masses, but not to fat-free mass. Interventions targeting maternal postprandial glucose levels may induce more appropriate birthweight, thereby reducing the risk of subsequent morbidity.

Udgivelsesdato: 2005-Apr-15 Abnormal central dopamine (DA) neurotransmission has been implicated in the impulsivity, inattention, and hyperactivity of attention deficit hyperactivity disorder (ADHD). We hypothesized that a pharmacological challenge with methylphenidate (MP) at a therapeutic dose increases extracellular DA concentrations in proportion to the severity of these specific ADHD symptoms. To test this hypothesis, we measured by PET the effect of acute challenge with MP on the availability of striatal binding sites for [11C]raclopride (pB), an index of altered interstitial DA concentration, in nine unmedicated adolescents (1 female, 8 males; age 13.7 +/- 1.8 years) with a current diagnosis of ADHD. We estimated the pB of [11C]raclopride for brain dopamine D2/3 receptors first in a baseline resting condition, and again after an acute challenge with MP (0.3 mg/kg, p.o.), and calculated the percentage change in (%DeltapB) in left and right striatum. On another day, measurements of impulsivity and inattention were performed using a computerized continuous performance test. There was a significant correlation between the magnitude of %DeltapB in the right striatum and the severity of inattention and impulsivity. MP-evoked %DeltapB correlated with standard scores for impulse control (r = 0.68; P = 0.02), attention (r = 0.81; P = 0.005), information processing (r = 0.66; P = 0.02), and consistency of attention, or variability (r = 0.60; P = 0.04). In conclusion, the results link inattention and impulsivity with sensitivity of brain DA receptor availability to an MP challenge, corroborating the hypothesis that MP serves to potentiate decreased DA neurotransmission in ADHD.

Aim Even short periods of hyperoxia may induce prolonged cerebral vasoconstriction in newborn infants, and this could theoretically lead to cerebral ischaemia even once normoxia is re-established. This study aimed to investigate the effect of brief hyperoxic exposures on regional cerebral tissue oxygen saturation (rStO2) and to evaluate whether any observed prolonged cerebral vasoconstriction was related to maturity. Methods The study included 30 infants with a postmenstrual age of more than 32 weeks, who were treated with nasal continuous positive airway pressure and a fraction of inspired oxygen of ≤0.3. The INVOS 5100C oximeter was used to measure rStO2 before, during and after two hyperoxic exposures. If hyperoxia induced a prolonged cerebral vasoconstriction, posthyperoxic rStO2 would be expected to decrease. Results rStO2 increased slightly after the first hyperoxic exposure, with a mean difference of 1.37% (95% CI 0.15, 2.6). After the second oxygen exposure, rStO2 remained unchanged with a mean difference of −0.4% (95% CI −1.6, 0.78). Differences in rStO2 were not related to gestational age in either of the two hyperoxic episodes. Conclusion We found no evidence to support the theory that transient hyperoxia induces prolonged cerebral vasoconstriction in infants with a postmenstrual age above 32 weeks.

Thirteen Danish women with postpartum thyroiditis were HLA-A, B, C and -DR typed. Nine of ten unrelated probands were DR4-positive which is significantly (corrected p = .01) different from the frequency (34.7%) of this antigen in unrelated controls.

Background: Obese women often have difficulties breastfeeding. Objective: We evaluated whether telephone-based support could increase the duration of breastfeeding in obese women and, thereby, reduce offspring growth. Design: We recruited 226 dyads of obese mothers and their singleton, healthy, term infants. The women were randomly assigned to 6 mo of breastfeeding support or standard care controls. At 6 mo, there were 207 dyads in the study; 105 dyads received support, and 102 dyads were control subjects. One International Board Certified Lactation Consultant carried out the intervention, which was based on structured interviews and consisted of encouraging telephone calls. Results: The support group breastfed exclusively for a median of 120 d (25th‐75th percentiles: 14‐142 d) compared with 41 d (3‐133 d) for control subjects (P = 0.003). Any breastfeeding was maintained for a median of 184 d (92‐185 d) for the support group compared with 108 d (16‐185 d) for control subjects (P = 0.002). Support increased the adjusted ORs for exclusive breastfeeding at 3 mo and the ratios for partial breastfeeding at 6 mo to 2.45 (95% CI: 1.36, 4.41; P = 0.003) and 2.25 (95% CI: 1.24, 4.08; P = 0.008). Although the duration of exclusive breastfeeding was inversely associated with infant weight (b = 24.39 g/d; 95% CI: 20.66, 28.11 g/d; P = 0.021) and infant length at 6 mo (b = 20. 012 cm/d; 95% CI: 20.004, 20.02 cm/d; P = 0.004), the breastfeeding support did not achieve a significant effect on infant growth at 6 mo (n = 192). Conclusions: Telephone-based advisory support was very effective in prolonging breastfeeding in obese mothers who often terminate the breastfeeding of their infants prematurely. A longer duration of breastfeeding may decrease risk of noncommunicable diseases in these infants. This trial was registered at clinicaltrials.gov as NCT01235663. Am J Clin Nutr doi: 10.3945/ajcn.113.059600.

Objective The objective of the study was to assess physical activity intervention assessed by a pedometer with or without dietary intervention on gestational weight gain (GWG) in obese pregnant women by comparing with a control group. Study Design This study was a randomized controlled trial of 425 obese pregnant women comparing 3 groups: (1) PA plus D, physical activity and dietary intervention (n = 142); (2) PA, physical activity intervention (n = 142); and (3) C, a control group receiving standard care (n = 141). All participants routinely in gestational weeks 11-14 had an initial dietary counseling session and were advised to limit GWG to less than 5 kg. Physical activity intervention included encouragement to increase physical activity, aiming at a daily step count of 11,000, monitored by pedometer assessment on 7 consecutive days every 4 weeks. Dietary intervention included follow-up on a hypocaloric Mediterranean-style diet. Instruction was given by a dietician every 2 weeks. The primary outcome measure was GWG, and the secondary outcome measures were complications of pregnancy and delivery and neonatal outcome. Results The study was completed by 389 patients (92%). Median values of GWG (ranges) were lower in each of the intervention groups (PA plus D, 8.6 [–9.6 to 34.1] kg, and group PA, 9.4 [–3.4 to 28.2] kg) compared with the control group (10.9 [–4.4 to 28.7] kg [PA+D vs C]; P = .01; PA vs C; P = .042). No significant difference was found between the 2 intervention groups. In a multivariate analysis, physical activity intervention decreased GWG by a mean of 1.38 kg ( P = .040). The Institute of Medicine's recommendations for GWG were more frequently followed in the intervention groups. Conclusion Physical activity intervention assessed by pedometer with or without dietary follow-up reduced GWG compared with controls in obese pregnant women.

BackgroundDespite widespread use in sick infants, it is still debated whether vasopressor-inotropes have direct cerebral effects that might affect neurological outcome. We aimed to test direct cerebrovascular effects of three commonly used vasopressor-inotropes (adrenaline, dopamine and noradrenaline) by comparing the responses to those of nonpharmacologically induced increases in blood pressure. We also searched for reasons for a mismatch between the response in perfusion and oxygenation.MethodsTwenty-four piglets had long and short infusions of the three vasopressor-inotropes titrated to raise mean arterial blood pressure (MAP) 10 mmHg in random order. Nonpharmacological increases in MAP were induced by inflation of a balloon in the descending aorta. We measured cerebral oxygenation (near-infrared spectroscopy), perfusion (laser-Doppler), oxygen consumption (co-oximetry of arterial and superior sagittal sinus blood), and microvascular heterogeneity (side stream dark field video microscopy).ResultsVasopressor-inotropes increased cerebral oxygenation significantly less (p≤0.01) compared to non-pharmacological MAP increases, whereas perfusion was similar. Furthermore, cerebral total hemoglobin concentration increased significantly less during vasopressor-inotrope infusions (p = 0.001). These physiologic responses were identical between the three vasopressor-inotropes (p>0.05). Furthermore, they induced a mild, although insignificant increase in cerebral metabolism and microvascular heterogeneity (p>0.05). Removal of the scalp tissue did not influence the mismatch (p>0.05).ConclusionWe demonstrated a moderate vasopressor-inotrope induced mismatch between cerebral perfusion and oxygenation. Scalp removal did not affect this mismatch, why vasopressor-inotropes appear to have direct cerebral actions. The statistically nonsignificant increases in cerebral metabolism and/or microvascular heterogeneity may explain the mismatch. Alternatively, it may simply reflect a vasopressor-inotrope-induced decrease in the arterial-to-venous volume ratio as detected by near-infrared spectroscopy.

Despite widespread use, effects of volume boluses and dopamine in hypotensive newborn infants remain controversial. We aimed to elucidate if hypovolemia alone impairs cerebral autoregulation (CA) and if dopamine affects cerebral vasculature.In 12 piglets, cerebral perfusion (laser-Doppler flux) and oxygenation [near-infrared spectroscopy (NIRS)] were examined during dopamine (20-50 μg/kg per minute) and nonpharmacologically induced blood pressure (ABP) changes. Effect on cerebral perfusion and oxygenation was quantified as frequency gain between ABP and laser-Doppler flux (gain-LDF) and NIRS [gain-oxygenation index (OI)], respectively. Gain quantifies change in perfusion or oxygenation per ABP-change. CA was estimated as gain-LDF during nonpharmacologically induced ABP changes, that is, as degree of impairment. Dopamine's cerebrovascular effect was estimated by contrasting gain during dopamine- and nonpharmacologically induced ABP changes. Measurements were conducted during both normovolemia- and haemorrhage-induced hypovolemia.Hypovolemia elicited hypotension (p = 0.02) as well as increasing impairment of CA (p = 0.01). However, hypovolemia without hypotension did not affect CA significantly. Dopamine increased perfusion significantly compared to nonpharmacological challenges (mean difference: 1.5%/mmHg, 95% CI: 0.5-2.6, p = 0.007). Oxygenation was, however, similar (mean difference: 0.01 μmol/L per mmHg, 95% CI: -0.03 to 0.05, p = 0.7).Our findings do not support that hypovolemia alone impairs CA. Furthermore, dopamine seems to increase cerebral perfusion but not oxygenation.

Meta-analyses indicate that prophylactic probiotics for preterm infants reduces mortality and necrotising enterocolitis significantly. Despite the robust evidence clinicians are reluctant to implement probiotics because the beneficial mechanism is not clearly understood and due to concerns about the safety, the long-term effects, and the optimal treatment regimen. Hence, only few countries and only two-thirds of the Danish neonatal departments use probiotics. Currently three large randomised trials on probiotics vs. placebo are ongoing and it is an ethical dilemma whether to proceed or terminate the trials.

Impaired cerebral autoregulation (CA) is common and is associated with brain damage in sick neonates. Frequency analysis using spontaneous changes in arterial blood pressure (ABP) and cerebral near-infrared spectroscopy (NIRS) has been used to measure CA in several clinical studies. Coherence of the NIRS and ABP signals (i.e. correlation in the frequency domain) detects impairment of CA, whereas gain (i.e. magnitude of ABP variability passing from systemic to cerebral circulation) estimates the degree of this impairment. So far, however, this method has not been validated. In 12 newborn piglets, we compared NIRS-derived measures of CA with a conventional measure of CA: cerebral blood flow was measured by laser Doppler flowmetry, and changes in ABP were induced by inflating a thoracic aorta balloon. CA capacity was calculated as %ΔCVR/%ΔABP (i.e. percentage of full autoregulatory capacity), where CVR (i.e. cerebral vascular resistance) was estimated as ABP/Doppler flux. Correlation between coherence and CA capacity (r = −0.34, n = 24, p > 0.05) and between gain and CA capacity (r = −0.11, n = 24, p > 0.05) was limited. As expected, however, gain was significantly associated with CA capacity in measurements with significant coherence (r = −0.55, n = 15, p = 0.03). In conclusion, our data validate frequency analysis for estimation of CA in clinical research. Low precision, however, hampers its clinical application.