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.
A randomized clinical multicenter trial, The Danish Calmette Study, randomizing newborns to BCG or no intervention. Follow-up until 13 months of age.
Pediatric and maternity wards at three Danish university hospitals.
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.
Trial-registered adverse reactions after BCG vaccination at birth. Follow-up at 3 and 13 months by telephone interviews and clinical examinations.
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
OBJECTIVE: To test the hypothesis that suboptimal factors in perinatal care services resulting in perinatal deaths were more common among immigrant mothers from the Horn of Africa, when compared with Swedish mothers. DESIGN: A perinatal audit, comparing cases of perinatal deaths among children of African immigrants residing in Sweden, with a stratified sample of cases among native Swedish women. POPULATION AND SETTING: Sixty-three cases of perinatal deaths among immigrant east African women delivered in Swedish hospitals in 1990-1996, and 126 cases of perinatal deaths among native Swedish women. Time of death and type of hospital were stratified. MAIN OUTCOME MEASURES: Suboptimal factors in perinatal care services, categorised as maternal, medical care and communication. RESULTS: The rate of suboptimal factors likely to result in potentially avoidable perinatal death was significantly higher among African immigrants. In the group of antenatal deaths, the odds ratio (OR) was 6.2 (95% CI 1.9-20); the OR for intrapartal deaths was 13 (95% CI 1.1-166); and the OR for neonatal deaths was 18 (95% CI 3.3-100), when compared with Swedish mothers. The most common factors were delay in seeking health care, mothers refusing caesarean sections, insufficient surveillance of intrauterine growth restriction (IUGR), inadequate medication, misinterpretation of cardiotocography (CTG) and interpersonal miscommunication. CONCLUSIONS: Suboptimal factors in perinatal care likely to result in perinatal death were significantly more common among east African than native Swedish mothers, affording insight into socio-cultural differences in pregnancy strategies, but also the suboptimal performance of certain health care routines in the Swedish perinatal care system.
The article introduces the Parental Sensitivity Assessment Scale (PSAS) and examines the influence of the PSAS score and other factors on the general cognitive level in pre-school children born with very low birth weight (VLBW). McCarthy general cognitive index (GCI) was obtained for 102 VLBW and 92 normal birth weight (NBW) control children in Denmark in the mid-1980s. The mean ages of the two groups were 52.4 vs. 53.1 months. Parental sensitivity was assessed using PSAS. There was no significant difference in the mean PSAS score between the two birth weight groups (p > 0.3). Birth weight group (p 0.5) - the prematurely born children were not more affected by low parental sensitivity than were the control children.
Studies from low-income countries report positive non-specific effects of early Bacillus Calmette-Gu?rin (BCG) immunisation on childhood health and survival. Neonatal immunisation with BCG may prime the immune system and offer partial protection against other infectious and possibly allergic diseases. The potential clinical value of these non-specific effects has not yet been examined in a large randomised trial in high-income countries.
The Danish Calmette Study is a multicentre randomised clinical trial conducted between October 2012 and November 2015. Within the first 7 days of life, infants were randomly assigned to intra-dermal vaccination with BCG or no intervention. At 3 and 13 months of age structured telephone interviews and clinical examinations of the children were conducted. In a subgroup of children blood samples were drawn and stool samples collected at age 4 days, 3 and 13 months. Thymus index was assessed by ultrasound in a subgroup at randomisation and at 3 months. The primary study outcome is hospitalisation within the first 15 months of life as assessed in Danish health registers. Secondary outcomes include infectious disease hospitalisations, wheezing, eczema, use of prescribed medication, growth, development, thymus index, T- and B-cell subpopulations assessed by flow cytometry, in vitro cytokine responses and specific antibody responses to other vaccines. Adverse reactions were registered.
With participation of 4184 families and more than 93% adherence to clinical follow-up at 3 and 13 months, this randomised clinical trial has the potential to create evidence regarding non-specific effects of BCG vaccination in a high-income setting.
The 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.
Pregnant 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.
4184 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.
BCG vaccination at birth did not reduce the risk of hospitalisation for somatic acquired disease until 15 months of age in this Danish study population.
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The aim of this study was to obtain Ages and Stages Questionnaire (ASQ) scores from the background population so that these may be used as a reference group to extremely preterm children at nine and 18 months of corrected age.
A total of 298 children were randomly chosen among the Danish population in three different groups: 9-, 18- and 21 month-old children. The parents received the 10-month ASQ when their child had reached a corrected age of nine months and the 24-month ASQ questionnaire when their child had reached the corrected age of 18 or 21 months.
The total scores were normally distributed in both groups. There was a highly significant (p
Being born small for gestational age (SGA) is associated with decreased insulin sensitivity and increased blood pressure in childhood, but the association with clinical disease in early adulthood is less certain. The Danish Medical Birth Registry has registered all births in Denmark since 1973, but due to variable data quality, data is most often used only from 1981 onwards, and birth registers in other countries may have similar problems for the early years. We wanted to examine whether the data can be used for identification of children born SGA and used in future research.
All persons born between 1974 and 1996 were identified in the Danish Medical Birth Registry (n = 1.704.890). Immigrants and children without data on gestational age and birth weight were excluded, and a total of 1.348.106 children were included in the analysis. The difference between the different variables used in the history of the registry were examined, and the quality of data in the birth registry from 1974-1981 was examined and compared to subsequent years. Data on birth weight and gestational age in the early years of the registry is inconsistent, and the identification of children born SGA is inaccurate, with 49% false-positives. The biggest source of error is due to the rough and inaccurate intervals used for gestational age. By using -3 standard deviations as a cut-off for the identification of children born SGA, the number of false-positives was reduced to 9%, while the amount of false-negatives were increased.
Choosing -3 standard deviations for identifying children born SGA is a viable, though not optimal solution for identifying children born SGA. Overall the data in the registry is of sufficient quality to be used in further medical research.
AIM: To evaluate the feasibility and validity of a structured telephone interview to assess the development of children born extremely preterm. METHODS: The parents of 88 children born with a gestational age below 28 wk admitted to the neonatal intensive care unit (NICU) at Rigshospitalet, Copenhagen, were interviewed by telephone when their child was 1 y of age, corrected for preterm birth. A fully structured questionnaire on psychomotor function was used (Revised Prescreening Developmental Questionnaire (R-PDQ)). The parents of 30 children born at term without complications were interviewed for comparison. The interview was conducted by NICU staff. To validate the R-PDQ, parents of 22 children in the preterm group and parents of 19 children in the reference group conducted an Ages and Stages Questionnaire (ASQ) when their children had reached the age of 3-3(1/2) y. RESULTS: The R-PDQ was easy to use by staff and well accepted by parents. The mean score in the preterm group was 14.9+/-3.9 vs 17.7+/-2.7 in the term group (p
When a child participates in a clinical trial, informed consent has to be given by the parents. Parental motives for participation are complex, but the hope of getting a new and better treatment for the child is important. We wondered how parents react when their child is allocated to the control group of a randomized controlled trial, and how it will affect their future engagement in the trial.
We included parents of newborns randomized to the control arm in the Danish Calmette study at Rigshospitalet in Copenhagen. The Calmette study is a randomized clinical trial investigating the non-specific effects of early BCG-vaccine to healthy neonates. Randomization is performed immediately after birth and parents are not blinded to the allocation. We set up a semi-structured focus group with six parents from four families. Afterwards we telephone-interviewed another 19 mothers to achieve saturation. Thematic analysis was used to identify themes across the data sets.
The parents reported good understanding of the randomization process. Their most common reaction to allocation was disappointment, though relief was also seen. A model of reactions to being allocated to the control group was developed based on the participants' different positions along two continuities from 'Our participation in trial is not important' to 'Our participation in trial is important', and 'Vaccine not important to us' to 'Vaccine important to us'. Four very disappointed families had thought of getting the vaccine elsewhere, and one had actually had their child vaccinated. All parents involved in the focus group and the telephone interviews wanted to participate in the follow-ups planned for the Calmette study.
This study identified an almost universal experience of disappointment among parents of newborns who were randomized to the control group, but also a broad expression of understanding and accepting the idea of randomization. The trial staff might use the model of reactions in understanding the parents' disappointment and in this way support their motives for participation. A generalized version might be applicable across randomized controlled trials at large.
The Calmette study is registered in EudraCT (https://eudract.ema.europa.eu/) with trial number 2010-021979-85.
One of the first European NICUs was established at Rigshospitalet in Copenhagen in 1965, and mechanical ventilation became the standard of care for preterm infants in 1971. After a failed attempt to extend this to the most immature infants in the early 1980s, a policy with minimally invasive support after birth with nasal continuous positive airway pressure was adopted from the neonatal unit in Odense. The conservative approach was consolidated by a national consensus conference; the lay panel concluded that a lower limit of gestation should be installed and priority should be given to parental counseling and support. This was confirmed some years later by the majority of the members of the Danish Council on Ethics, and questionnaire-based research revealed a significant proportion of the general population that would forego life support in extremely preterm infants. Since the year 2002, the treatment of infants 22 weeks' gestation to improve parental counseling and neonatal intervention.