Clinical, Intervention, Prospective, Single-blind, Trial
Conditions
Brief summary
In high-income societies the use of health care and medication is steadily increasing. Children have high morbidity, many visits at the general practitioner, an increasing number of hospitalisations, and an increasing use of medication. And, when children are ill, someone has to stay home to care for them. An un-explained global increase in the incidence of the allergic diseases eczema, wheezing, asthma and allergies means that 25% of high-income populations are affected. Cheap preventive measures are highly warranted. Recent studies have shown a positive, non-specific effect of early Bacille Calmette Guérin (BCG) immunisation on neonatal mortality in low-income countries and suggested a positive, non-specific effect on allergic disease in high-income countries. Non-specific means that the vaccine effect goes beyond prevention of the targeted disease, i.e. the BCG vaccine benefits the health status of the immunised individual in ways unrelated to protection against tuberculosis (TB). For instance, in a recent randomised trial in West Africa the investigators showed that the BCG vaccine at birth was safe in low birth weight (LBW) infants and significantly reduced neonatal mortality in these children, with a significant long-lasting effect on infant mortality in the smallest newborns with a birth weight \<1.5 kg. There is an urgent need to explore the huge potential of the BCG's beneficial immune-stimulatory effects among children in high-income populations. Therefore, the investigators will carry out a large prospective randomised clinical trial in Denmark primarily designed to test the hypothesis that infants who get the BCG vaccine at birth experience 20% fewer hospitalisations during early childhood. Secondary outcomes 1. To test the hypothesis that infants who get the BCG vaccine at birth are prescribed less antibiotics during early childhood than non-BCG-immunised infants. 2. To test the hypothesis that Danish infants who get the BCG vaccine at birth develop less eczema, asthmatic bronchitis/wheeze and food allergy at 3 and 12 months of age: self-reported, diagnosed by a physician, or found at clinical examination; and are prescribed less anti-eczema/asthma/allergy medication during early childhood than non-BCG-immunised infants. 3. To test the hypothesis that infants who receive the BCG at birth respond in paraclinical measures: Specific IgE, thymic gland size, leucocyte count and differentiation, monocyte memory, cytokine profiles, and antibody titres following immunisation against diphtheria, tetanus, pertussis, pneumococcus, hemophilus. 4. To test the hypothesis that infants who get the BCG vaccine at birth respond in growth measures: weight, length and head circumference. 5. To test the hypothesis that infants who get the BCG vaccine at birth respond with decreased morbidity: common cold, pneumonia, febrile episodes, diarrhoea and vomiting, acute otitis media, febrile convulsions. 6. To test the hypothesis that premature infants with gestational age less than 37 weeks who get the BCG vaccine at birth have unaffected psychomotor development measures: Ages and Stages scores. 7. To test the hypothesis that infants who get the BCG vaccine at birth has unaffected coverage with the subsequent vaccinations in the Child Vaccination Programme. 8. To test the above mentioned hypotheses specifically in the strata of premature and low-birth-weight Danish infants.
Interventions
BIOLOGICALBCG-vaccine (SSI)
Sponsors
Hvidovre University Hospital
Kolding Sygehus
Danish National Research Foundation
Research Center for Vitamins and Vaccines (CVIVA)
Lone Graff Stensballe
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 7 Days
Healthy volunteers
No
Inclusion criteria
* All parents planning to give birth at Rigshospitalet, Hvidovre Hospital and Kolding Hospital will receive at letter during 2nd/3rd trimester of pregnancy with information on the study and be offered inclusion in the study.
Exclusion criteria
* Infants born before gestational age 32 weeks and/or birth weight \< 1000g, infants with known congenital disease, anomaly or malformation, immune deficiency and HIV, will be excluded. Non-Danish speaking parents will be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Hospitalisations | 0-15 months of age | To test that infants who get the BCG vaccine at birth experience 20% fewer hospitalisations in early childhood than non-BCG-immunised infants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Antibiotics | 0-15 months of age | To test that infants who get the BCG vaccine at birth are prescribed less antibiotics during early childhood than non-BCG-immunised infants. Use of antibiotics was defined as one or more precriptions of systemic antibiotics (ATC groups J01, J02, J05, all subgroups inclusive). |
| Atopic Dermatitis | 13 months of age | To test if BCG vaccination within 7 days after birth influence the risk of atopic dermatitis defined by clinical examination at 13 months of age using scoring atopic dermatitis (SCORAD) or by parental report of physician diagnosed atopic dermatitis in the telephone interview at 13 months of age. |
| Specific IgE | 13 months of age | Number of participants with specific IgE (Phadiatop Infant) above the clinical cut-of level of 0.35. |
| Standardized Weight at 13 Months | 13 months of age | To test that infants who get the BCG vaccine at birth respond in weight.The Z-score indicates the number of standard deviations away from the mean weight-for-age of the WHO anthropometric reference population (http://www.who.int/childgrowth/standards/en/). A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean. |
| Psychomotor Development in Premature Infants | 13 months of age | To test that premature infants with gestational age less than 37 weeks who get the BCG vaccine at birth have unaffected psychomotor development measures: ASQ: Ages and stages questionnaire - a parent reported questionnaire that measures child psychomotor development. Total range of ASQ score: 0 to 300 points. Higher scores indicate higher level of psychomotor development. |
| DTaP-IPV-Hib Vaccination Coverage at 12 Months of Age | 13 months of age | To test that infants who get the BCG vaccine at birth has unaffected coverage with the subsequent 3rd diphtheria, tetanus, acellular pertussis, polio, Haemophilus influenzae type b (DTaP-IPV-Hib) vaccination scheduled to 12 months of age according to the Danish child vaccination programme. Since we did not expect all children to get their immunizations exactly at 12 months of age, the children were followed up until 13-months of age. |
| Standardized Weight, Length and Head Circumference of Premature Children at 13 Months | 13 months of age | The Z-score indicates the number of standard deviations away from the mean weight-for-age of the WHO anthropometric reference population (http://www.who.int/childgrowth/standards/en/). A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean. |
| Episodic Viral Wheeze | 13 months | Number of participants diagnosed with episodic viral wheeze by a physician and treated with anti-asthmatic medicine according to the telephone interview. |
| Food Allergy | 13 months | Number of participants with food allergy diagnosed by a physician and mentioned in the telephone interview at 13 months of age |
| Length at 13 Months of Age | 13months | To test if infants who get the BCG vaccine at birth respond in length. The Z-score indicates the number of standard deviations away from the mean weight-for-age of the WHO anthropometric reference population (http://www.who.int/childgrowth/standards/en/). A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean. |
| Standardized Head Circumference at 13 Months of Age | 13 months | To test if infants who get the BCG vaccine at birth respond in head circumference. The Z-score indicates the number of standard deviations away from the mean weight-for-age of the WHO anthropometric reference population (http://www.who.int/childgrowth/standards/en/). A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean. |
| Number of Events of Acute Otitis Media | 13 months of age | To test that Danish infants who get the BCG vaccine at birth develop less acute otitis media at 13 months of age than non-BCG-immunised infants. |
| Number of Events of Febrile Convulsions | 13 months of age | To test that Danish infants who get the BCG vaccine at birth develop less febrile convulsions at 13 months of age than non-BCG-immunised infants. |
| Thymic Gland Size at 3 Months of Age | 3 months of age | To test that infants who receive the BCG at birth respond in thymic gland size defined by ultra sound examination. First, the thymus gland was identified in a horizontal scanning plane and the largest transverse diameter of the thymus was obtained. Second, in a sagittal scanning plane, the area of the largest lobe was assessed. Both measurements were obtained twice, and in case of more than 15% difference, both measurements were repeated. The mean of the two measurements were multiplied and defined as the thymic index. |
| Leucocyte Count 4 Days After Randomisation/Vaccination | 4 days after randomisation/vaccination within 7 days after birth | To test if infants who receive the BCG at birth respond in leucocyte count (white blood cell count) measured as geometric mean (GM) cell concentrations (GM\*10\^9 cells/L). |
| Monocyte Count 4 Days After Randomisation/Vaccination | 4 days after randomisation/vaccination within 7 days after birth | To test if infants who receive the BCG at birth respond in monocyte count measured as geometric mean (GM) cell concentrations (GM\*10\^9 cells/L). |
| Interferon Gamma Response | 13 months of age | To test that infants who receive the BCG at birth respond in interferon-gamma response upon stimulation with BCG. The interferon gamma response was defined as a value above the cut-off value of 107 pg/ml. |
| Number of Participants With Antibody Concentration (AC) Against Tetanus of > 0.1 IU/mL | 13 months of age | To test the tetenus antibody response in BCG-vaccinated vs. non-BCG vaccinated children following routine immunisation against tetanus at 3, 5 and 12 months of age in blood samples obtained 13 months of age. |
| Number of Events of Common Cold | 13 months of age | To test that Danish infants who get the BCG vaccine at birth experience less events of common cold until 13 months of age than non-BCG-immunised infants. |
| Number of Events of Pneumonia | 13 months of age | To test that Danish infants who get the BCG vaccine at birth get less pneumonia at 13 months of age than non-BCG-immunised infants. |
| Number of Events of Febrile Episodes | 13 months of age | To test that Danish infants who get the BCG vaccine at birth get less febrile episodes at 13 months of age than non-BCG-immunised infants. |
| Number of Events With Diarrhoea and Vomiting | 13 months of age | To test that Danish infants who get the BCG vaccine at birth develop less episodes with diarrhoea and vomiting at 13 months of age than non-BCG-immunised infants. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Decisional Conflict Scale Score | The decisional conflict score was measured before randomisation | After parents having made the decision about whether to accept vaccination of their newborn through participation in The Danish Calmette Study, O'Connor's Decisional Conflict Scale was used to identify decisional conflicts. The score ranges from 0 (no decisional conflict) til 100 (maximum decisional conflict). Scores lower than 25 are associated with implementing decisions; scores exceeding 37.5 are associated with decision delay or feeling unsure about implementation; so a low score reflects a low level of doubt about the decision about participation/decline participation in the trial, and a high score reflects a high level of doubt. |
| Quality of Communication and Information | 2 days after the information was given | To test that the use of telephone and internet was acceptable in the study population using the Quality of Informed Consent (QuIC) questionnaire. The questionnaire was divided into six categories; five on study comprehension and one on satisfaction with the information process. The items in the first five categories could be answered with yes, no or do not know. The last category was rated on a 7-point Likert scale, with 1 being very dissatisfied and 7 being very satisfied. The primary outcome was the sum of the score for comprehension items and satisfaction items. Comprehension items were scored 1 point for each correct answer and 0 points for each incorrect answer. Satisfaction items were scored as rated on the 7-point Likert scale. Total score ranged from 7 to 69 points, comprehension score from 0 to 20 points and satisfaction score from 7 to 49 points. The higher score, the better comprehension and satisfaction. |
Countries
Denmark
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BCG-vaccine SSI strain 1331 standard dose | 2,095 |
| Control Children No intervention | 2,089 |
| Total | 4,184 |
Baseline characteristics
| Characteristic | BCG-vaccine | Control Children | Total |
|---|---|---|---|
| Age, Continuous | 32.0 years STANDARD_DEVIATION 4.6 | 31.9 years STANDARD_DEVIATION 4.4 | 31.95 years STANDARD_DEVIATION 4.5 |
| Premature birth | 61 participants | 60 participants | 121 participants |
| Region of Enrollment Denmark | 2095 participants | 2089 participants | 4184 participants |
| Sex: Female, Male Female | 1003 Participants | 985 Participants | 1988 Participants |
| Sex: Female, Male Male | 1092 Participants | 1104 Participants | 2196 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 233 / 2,129 | 123 / 2,133 |
| serious Total, serious adverse events | 65 / 2,129 | 45 / 2,133 |
Outcome results
Primary
All-cause Hospitalisations
To test that infants who get the BCG vaccine at birth experience 20% fewer hospitalisations in early childhood than non-BCG-immunised infants.
Time frame: 0-15 months of age
Population: Intention-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCG-vaccine | All-cause Hospitalisations | 637 Events |
| Control Children (no Intervention) | All-cause Hospitalisations | 633 Events |
Secondary
Antibiotics
To test that infants who get the BCG vaccine at birth are prescribed less antibiotics during early childhood than non-BCG-immunised infants. Use of antibiotics was defined as one or more precriptions of systemic antibiotics (ATC groups J01, J02, J05, all subgroups inclusive).
Time frame: 0-15 months of age
Population: Intention-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCG-vaccine | Antibiotics | 934 participants |
| Control Children (no Intervention) | Antibiotics | 931 participants |
Secondary
Atopic Dermatitis
To test if BCG vaccination within 7 days after birth influence the risk of atopic dermatitis defined by clinical examination at 13 months of age using scoring atopic dermatitis (SCORAD) or by parental report of physician diagnosed atopic dermatitis in the telephone interview at 13 months of age.
Time frame: 13 months of age
Population: This analysis includes children with follow-up data from clinical examination or telephone interview. As opposed to the register-based primary outcome, adherence to telephone-interview and clinical examination was slightly lower than 100%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCG-vaccine | Atopic Dermatitis | 466 participants |
| Control Children (no Intervention) | Atopic Dermatitis | 495 participants |
Secondary
DTaP-IPV-Hib Vaccination Coverage at 12 Months of Age
To test that infants who get the BCG vaccine at birth has unaffected coverage with the subsequent 3rd diphtheria, tetanus, acellular pertussis, polio, Haemophilus influenzae type b (DTaP-IPV-Hib) vaccination scheduled to 12 months of age according to the Danish child vaccination programme. Since we did not expect all children to get their immunizations exactly at 12 months of age, the children were followed up until 13-months of age.
Time frame: 13 months of age
Population: Per-protocol analysis excluding 11 children randomised to BCG who did not receive the vaccine, and 36 children randomised to control who received the BCG vaccine.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCG-vaccine | DTaP-IPV-Hib Vaccination Coverage at 12 Months of Age | 1175 participants |
| Control Children (no Intervention) | DTaP-IPV-Hib Vaccination Coverage at 12 Months of Age | 1207 participants |
Secondary
Episodic Viral Wheeze
Number of participants diagnosed with episodic viral wheeze by a physician and treated with anti-asthmatic medicine according to the telephone interview.
Time frame: 13 months
Population: This analysis only includes children with available follow-up telephone interview data. As opposed to the primary outcome, follow-up was lower than 100%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCG-vaccine | Episodic Viral Wheeze | 211 participants |
| Control Children (no Intervention) | Episodic Viral Wheeze | 195 participants |
Secondary
Food Allergy
Number of participants with food allergy diagnosed by a physician and mentioned in the telephone interview at 13 months of age
Time frame: 13 months
Population: This analysis only includes children with available follow-up telephone interview data. As opposed to the primary outcome, follow-up was lower than 100%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCG-vaccine | Food Allergy | 15 participants |
| Control Children (no Intervention) | Food Allergy | 10 participants |
Secondary
Interferon Gamma Response
To test that infants who receive the BCG at birth respond in interferon-gamma response upon stimulation with BCG. The interferon gamma response was defined as a value above the cut-off value of 107 pg/ml.
Time frame: 13 months of age
Population: This is a sub study using bloodsamples. Only a small sub population from the overall trial participated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCG-vaccine | Interferon Gamma Response | 41 participants |
| Control Children (no Intervention) | Interferon Gamma Response | 3 participants |
Secondary
Length at 13 Months of Age
To test if infants who get the BCG vaccine at birth respond in length. The Z-score indicates the number of standard deviations away from the mean weight-for-age of the WHO anthropometric reference population (http://www.who.int/childgrowth/standards/en/). A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.
Time frame: 13months
Population: This analysis only includes children with available follow-up data. As opposed to the primary outcome, follow-up for this outcome was lower than 100%.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BCG-vaccine | Length at 13 Months of Age | 0.54 Length z-score | Standard Deviation 0.99 |
| Control Children (no Intervention) | Length at 13 Months of Age | 0.55 Length z-score | Standard Deviation 1 |
Secondary
Leucocyte Count 4 Days After Randomisation/Vaccination
To test if infants who receive the BCG at birth respond in leucocyte count (white blood cell count) measured as geometric mean (GM) cell concentrations (GM\*10\^9 cells/L).
Time frame: 4 days after randomisation/vaccination within 7 days after birth
Population: This was a sub study among 153 children with blood-samples at 4 days after randomisation/vaccination.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| BCG-vaccine | Leucocyte Count 4 Days After Randomisation/Vaccination | 10.59 cell concentrations (GM*10^9 cells/L) |
| Control Children (no Intervention) | Leucocyte Count 4 Days After Randomisation/Vaccination | 10.70 cell concentrations (GM*10^9 cells/L) |
Secondary
Monocyte Count 4 Days After Randomisation/Vaccination
To test if infants who receive the BCG at birth respond in monocyte count measured as geometric mean (GM) cell concentrations (GM\*10\^9 cells/L).
Time frame: 4 days after randomisation/vaccination within 7 days after birth
Population: This was a sub study among 153 children with blood-samples at 4 days after randomisation/vaccination.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| BCG-vaccine | Monocyte Count 4 Days After Randomisation/Vaccination | 1.58 Cell concentrations (GM*10^9 cells/L) |
| Control Children (no Intervention) | Monocyte Count 4 Days After Randomisation/Vaccination | 1.71 Cell concentrations (GM*10^9 cells/L) |
Secondary
Number of Events of Acute Otitis Media
To test that Danish infants who get the BCG vaccine at birth develop less acute otitis media at 13 months of age than non-BCG-immunised infants.
Time frame: 13 months of age
Population: This analysis only includes children with available follow-up data. As opposed to the primary outcome, follow-up for this outcome was lower than 100%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCG-vaccine | Number of Events of Acute Otitis Media | 595 Events |
| Control Children (no Intervention) | Number of Events of Acute Otitis Media | 591 Events |
Secondary
Number of Events of Common Cold
To test that Danish infants who get the BCG vaccine at birth experience less events of common cold until 13 months of age than non-BCG-immunised infants.
Time frame: 13 months of age
Population: This analysis only includes children with available follow-up data. As opposed to the primary outcome, follow-up for this outcome was lower than 100%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCG-vaccine | Number of Events of Common Cold | 3990 Events |
| Control Children (no Intervention) | Number of Events of Common Cold | 3928 Events |
Secondary
Number of Events of Febrile Convulsions
To test that Danish infants who get the BCG vaccine at birth develop less febrile convulsions at 13 months of age than non-BCG-immunised infants.
Time frame: 13 months of age
Population: This analysis only includes children with available follow-up data. As opposed to the primary outcome, follow-up for this outcome was lower than 100%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCG-vaccine | Number of Events of Febrile Convulsions | 44 Events |
| Control Children (no Intervention) | Number of Events of Febrile Convulsions | 25 Events |
Secondary
Number of Events of Febrile Episodes
To test that Danish infants who get the BCG vaccine at birth get less febrile episodes at 13 months of age than non-BCG-immunised infants.
Time frame: 13 months of age
Population: This analysis only includes children with available follow-up data. As opposed to the primary outcome, follow-up for this outcome was lower than 100%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCG-vaccine | Number of Events of Febrile Episodes | 1385 Events |
| Control Children (no Intervention) | Number of Events of Febrile Episodes | 1302 Events |
Secondary
Number of Events of Pneumonia
To test that Danish infants who get the BCG vaccine at birth get less pneumonia at 13 months of age than non-BCG-immunised infants.
Time frame: 13 months of age
Population: This analysis only includes children with available follow-up data. As opposed to the primary outcome, follow-up for this outcome was lower than 100%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCG-vaccine | Number of Events of Pneumonia | 207 Events |
| Control Children (no Intervention) | Number of Events of Pneumonia | 162 Events |
Secondary
Number of Events With Diarrhoea and Vomiting
To test that Danish infants who get the BCG vaccine at birth develop less episodes with diarrhoea and vomiting at 13 months of age than non-BCG-immunised infants.
Time frame: 13 months of age
Population: This analysis only includes children with available follow-up data. As opposed to the primary outcome, follow-up for this outcome was lower than 100%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCG-vaccine | Number of Events With Diarrhoea and Vomiting | 870 Events |
| Control Children (no Intervention) | Number of Events With Diarrhoea and Vomiting | 845 Events |
Secondary
Number of Participants With Antibody Concentration (AC) Against Tetanus of > 0.1 IU/mL
To test the tetenus antibody response in BCG-vaccinated vs. non-BCG vaccinated children following routine immunisation against tetanus at 3, 5 and 12 months of age in blood samples obtained 13 months of age.
Time frame: 13 months of age
Population: This outcome was a sub-study with 158 participants. Antibody concentration (AC) of \> 0.1 IU/mL was considered protective
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCG-vaccine | Number of Participants With Antibody Concentration (AC) Against Tetanus of > 0.1 IU/mL | 80 participants |
| Control Children (no Intervention) | Number of Participants With Antibody Concentration (AC) Against Tetanus of > 0.1 IU/mL | 78 participants |
Secondary
Psychomotor Development in Premature Infants
To test that premature infants with gestational age less than 37 weeks who get the BCG vaccine at birth have unaffected psychomotor development measures: ASQ: Ages and stages questionnaire - a parent reported questionnaire that measures child psychomotor development. Total range of ASQ score: 0 to 300 points. Higher scores indicate higher level of psychomotor development.
Time frame: 13 months of age
Population: This analysis only includes children from a particular subgroup (premature children, N = 144), who had with available follow-up data. As opposed to the primary outcome, follow-up was lower than 100%.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BCG-vaccine | Psychomotor Development in Premature Infants | 141.8 Score on ASQ scale | Standard Deviation 53 |
| Control Children (no Intervention) | Psychomotor Development in Premature Infants | 153.5 Score on ASQ scale | Standard Deviation 53.5 |
Secondary
Specific IgE
Number of participants with specific IgE (Phadiatop Infant) above the clinical cut-of level of 0.35.
Time frame: 13 months of age
Population: This analysis includes children who participated with blood samples for this sub-study regarding specific IgE.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BCG-vaccine | Specific IgE | 55 participants |
| Control Children (no Intervention) | Specific IgE | 50 participants |
Secondary
Standardized Head Circumference at 13 Months of Age
To test if infants who get the BCG vaccine at birth respond in head circumference. The Z-score indicates the number of standard deviations away from the mean weight-for-age of the WHO anthropometric reference population (http://www.who.int/childgrowth/standards/en/). A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.
Time frame: 13 months
Population: This analysis only includes children with available follow-up data. As opposed to the primary outcome, follow-up for this outcome was lower than 100%.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BCG-vaccine | Standardized Head Circumference at 13 Months of Age | 0.78 Head circumference z-score | Standard Deviation 0.93 |
| Control Children (no Intervention) | Standardized Head Circumference at 13 Months of Age | 0.76 Head circumference z-score | Standard Deviation 0.95 |
Secondary
Standardized Weight at 13 Months
To test that infants who get the BCG vaccine at birth respond in weight.The Z-score indicates the number of standard deviations away from the mean weight-for-age of the WHO anthropometric reference population (http://www.who.int/childgrowth/standards/en/). A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.
Time frame: 13 months of age
Population: This analysis only includes children with available follow-up data from telephone interviews or clinical examinations. As opposed to the primary outcome, follow-up was lower than 100%.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BCG-vaccine | Standardized Weight at 13 Months | 0.58 Weight z-score at 13 months | Standard Deviation 0.9 |
| Control Children (no Intervention) | Standardized Weight at 13 Months | 0.61 Weight z-score at 13 months | Standard Deviation 0.94 |
Secondary
Standardized Weight, Length and Head Circumference of Premature Children at 13 Months
The Z-score indicates the number of standard deviations away from the mean weight-for-age of the WHO anthropometric reference population (http://www.who.int/childgrowth/standards/en/). A Z-score of 0 is equal to the mean. Negative numbers indicate values lower than the mean and positive numbers indicate values higher than the mean.
Time frame: 13 months of age
Population: Premature children born with gestational age 32-36 weeks. This analysis only includes children from a particular subgroup (premature children, N = 144), who had with available follow-up data. As opposed to the primary outcome, follow-up was lower than 100%.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BCG-vaccine | Standardized Weight, Length and Head Circumference of Premature Children at 13 Months | Weight | 0.33 z-score | Standard Deviation 0.95 |
| BCG-vaccine | Standardized Weight, Length and Head Circumference of Premature Children at 13 Months | Length | 0.10 z-score | Standard Deviation 0.97 |
| BCG-vaccine | Standardized Weight, Length and Head Circumference of Premature Children at 13 Months | Head circumference | 0.51 z-score | Standard Deviation 0.97 |
| Control Children (no Intervention) | Standardized Weight, Length and Head Circumference of Premature Children at 13 Months | Weight | 0.34 z-score | Standard Deviation 1.03 |
| Control Children (no Intervention) | Standardized Weight, Length and Head Circumference of Premature Children at 13 Months | Length | 0.02 z-score | Standard Deviation 1 |
| Control Children (no Intervention) | Standardized Weight, Length and Head Circumference of Premature Children at 13 Months | Head circumference | 0.57 z-score | Standard Deviation 0.99 |
Secondary
Thymic Gland Size at 3 Months of Age
To test that infants who receive the BCG at birth respond in thymic gland size defined by ultra sound examination. First, the thymus gland was identified in a horizontal scanning plane and the largest transverse diameter of the thymus was obtained. Second, in a sagittal scanning plane, the area of the largest lobe was assessed. Both measurements were obtained twice, and in case of more than 15% difference, both measurements were repeated. The mean of the two measurements were multiplied and defined as the thymic index.
Time frame: 3 months of age
Population: This outcome was a sub-study to The Danish Calmette Study with 301 (BCG 153, Control 148) participating children.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| BCG-vaccine | Thymic Gland Size at 3 Months of Age | 33.10 Thymic index |
| Control Children (no Intervention) | Thymic Gland Size at 3 Months of Age | 34.24 Thymic index |
Other Pre-specified
Decisional Conflict Scale Score
After parents having made the decision about whether to accept vaccination of their newborn through participation in The Danish Calmette Study, O'Connor's Decisional Conflict Scale was used to identify decisional conflicts. The score ranges from 0 (no decisional conflict) til 100 (maximum decisional conflict). Scores lower than 25 are associated with implementing decisions; scores exceeding 37.5 are associated with decision delay or feeling unsure about implementation; so a low score reflects a low level of doubt about the decision about participation/decline participation in the trial, and a high score reflects a high level of doubt.
Time frame: The decisional conflict score was measured before randomisation
Population: This outcome was a sub-study to The Danish Calmette Study with 667 participating mothers and 320 declining mothers.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| BCG-vaccine | Decisional Conflict Scale Score | 18.8 decisional conflict score |
| Control Children (no Intervention) | Decisional Conflict Scale Score | 17.2 decisional conflict score |
p-value: <0.001Wilcoxon (Mann-Whitney)
Other Pre-specified
Quality of Communication and Information
To test that the use of telephone and internet was acceptable in the study population using the Quality of Informed Consent (QuIC) questionnaire. The questionnaire was divided into six categories; five on study comprehension and one on satisfaction with the information process. The items in the first five categories could be answered with yes, no or do not know. The last category was rated on a 7-point Likert scale, with 1 being very dissatisfied and 7 being very satisfied. The primary outcome was the sum of the score for comprehension items and satisfaction items. Comprehension items were scored 1 point for each correct answer and 0 points for each incorrect answer. Satisfaction items were scored as rated on the 7-point Likert scale. Total score ranged from 7 to 69 points, comprehension score from 0 to 20 points and satisfaction score from 7 to 49 points. The higher score, the better comprehension and satisfaction.
Time frame: 2 days after the information was given
Population: This is a small, separate sub-study. 59 + 59 participants had sufficient follow-up data to participate in the analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| BCG-vaccine | Quality of Communication and Information | 61.40 Score on QuIC scale |
| Control Children (no Intervention) | Quality of Communication and Information | 64.42 Score on QuIC scale |