Nirupam 2008.

Methods	Randomised, controlled, parallel‐group trial with 3 groups
Participants	Trial setting: New Delhi, India. A child health promotion centre in a tertiary paediatric hospital Participants: infants (n = 150) aged 6 to 10 weeks attending between February 2008 and March 2009 for the first doses of a DTwP vaccine and a hepatitis B vaccine Exclusion criteria: weight < 2.5 kg, progressive neurological disorders, major congenital anomalies, "any illness and any skin disorder" 51% of the infants were male. The infants weighed 3.5 to 6.5 kg and were 50 to 66 cm in length. In the 22 G 25 mm, 23 G 25 mm, and 24 G 25 mm groups the mean weights (SD) were 4.8 kg (0.6) in 22 G 25 mm, 4.75 kg (0.48) in 23 G 25 mm, and 4.8 kg (0.49) in 24 G 25 mm, and mean lengths (SD) were 57 cm (2.9) 22 G 25 mm, 56.3 cm (2.3) in 23 G 25 mm, and 55.8 cm (2.1) in 24 G 25 mm.
Interventions	Needle sizes 22 G 25 mm (n = 50) 23 G 25 mm (n = 50) 24 G 25 mm (n = 50) The needle hubs were colour coded (manufacturer: Becton, Dickinson and Company; surgical grade stainless steel, regular bevel, regular wall type needles). Vaccines administered The first dose of DTwP (Triple Antigen, Serum Institute of India Ltd) and the first dose of a hepatitis B vaccine (GeneVac‐B, Serum Institute of India Ltd) GeneVac‐B consists of purified surface Ag of HBV obtained by culturing genetically engineered Hansenula polymorpha yeast cells expressing the surface Ag gene of the virus. There is no material of human or animal origin. Each paediatric dose of 0.5 mL contains 10 μg of surface Ag adsorbed on ≤ 1.25 mg of aluminium hydroxide, with ≤ 0.01% thimerosal added as a preservative.* Injection technique 2 nurses assisted with the vaccination procedure. 1 nurse injected the vaccine while the other held the child's lower limb steady. The vaccines were administered using the standard intramuscular injection technique for infants advocated by the WHO. The DTwP vaccine was administered in the left and hepatitis B vaccines in the right anterolateral aspects of the thigh with the skin stretched flat between the thumb and forefinger and the needle inserted at a 90° angle into the skin up to the hub.
Outcomes	Crying: persistent inconsolable crying Local reactions: redness, swelling, and tenderness at the injection site at 6 hours and on the following 3 evenings (days 1, 2, and 3) after vaccination Systemic reactions and medication use: fever, vomiting, drowsiness, irritability and refusal to feed, seizures. Use of analgesics (paracetamol), domperidone, or promethazine for vomiting
Methods used to measure the outcomes	Outcomes were recorded by parents using a diary card. Parents were contacted by telephone daily by a doctor (paediatric resident) "to ensure proper observations and entries." The doctor making the phone calls was blinded to needle gauge. The infants were examined in the hospital on day 4 after vaccination and the entries in the diary card were verified by a researcher (1 of the trial authors) who was blinded to the needle group Fever: defined as an axillary temperature > 37.4 °C as measured with a digital thermometer. Parents were asked to take the infants temperature at 6 p.m. each evening and at any time when parents considered that the infant might be febrile (information provided by trial author). Persistent inconsolable crying: defined as persistent crying for > 3 hours Vomiting: defined as regurgitating a large amount of ingested milk 30 minutes after ingestion Drowsiness: graded by parents on a 1 to 4 scale: 1 = normal sleep duration; 2 = more sleepy than usual in terms of duration of sleep, but arouses on own; 3 = more sleep duration but needs to be aroused; 4 = not arousable from sleep Irritability: graded by parents on a 1 to 4 scale: 1 = none; 2 = easily consolable; 3 = requiring increased attention but consolable; 4 = inconsolable Refusal to feed: recorded as either 'Yes' or 'No' Redness: parents were provided with a measuring tape and were asked to measure and record the widest part of any visible redness at the injection site at 6 p.m. each evening. Parents were instructed in the measurement technique "with the use of pictorial representation and visual cues" (information provided by trial authors). Swelling: parents used the measuring tape to record the circumferential diameter of both thighs at the site of maximum swelling at 6 p.m. each evening. This measurement was compared with the baseline measurement taken just prior to vaccination. Parents were instructed in the measurement technique "with the use of pictorial representation and visual cues" (information provided by trial authors). Any swelling was defined as an increase in thigh circumference measurement of 5 to 20 mm from baseline; significant swelling was defined as an increase in thigh circumference measurement of > 20 mm from baseline. Tenderness: parents touched the vaccination site and graded tenderness on a 1 to 4 scale: 1 = no effect on infants activity on touching the site; 2 = makes non‐specific grimace when vaccination site was touched; 3 = withdrew their legs on touching; 4 = cried when vaccination site was touched. Each thigh was tested separately when the child was comfortable and awake prior to touching the site. Parents were instructed that it should be a "gentle press" and that too much force should not be applied at the vaccination site. When analysing the trial data, the trial authors used a dichotomous classification for each reported outcome (i.e. outcome present/absent) and compared the incidence of each local reaction between the groups at 6 hours and on days 1, 2, and 3 after vaccination.
Missing outcome data	Only 1 trial participant was lost to follow‐up (in the 23 G 25 mm group). The family was reported as "having moved out of the city for personal reasons."
Funding	The trial authors state that "this study was not funded by any agency and the authors did not take any grant from any agency."
Notes	*Details obtained from Shivananda 2006
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The trial authors describe a random component in the sequence generation process (use of a computer‐generated randomisation sequence).
Allocation concealment (selection bias)	Low risk	We judged that participants and investigators enrolling participants could not have foreseen needle size allocations in advance of, or during, enrolment due to the use of sequentially numbered, sealed, opaque envelopes to conceal allocation.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The nurses who administered the injections were not blinded (needle hubs were colour coded). We deemed blinding of the parents of infants undergoing vaccination as incomplete. However, we judged that the trial outcomes were not likely to be influenced by lack of blinding (see Risk of bias in included studies for an explanation of this judgement).
Blinding of outcome assessment (detection bias) Crying	Low risk	We deemed blinding of the outcome assessors (parents) as incomplete. However, we considered it unlikely that parental assessment and reporting of persistent inconsolable crying for > 3 hours would be influenced by knowledge of needle size.
Blinding of outcome assessment (detection bias) Reactogenicity outcomes (other than pain, crying)	Unclear risk	Parents recorded local reactions in a diary, and the diary entries were "verified" by a researcher blinded to needle gauge. As the needle hubs were colour coded and as parents were present during the vaccination procedure, we considered that there was uncertainty over the potential for detection bias for these outcomes (see Risk of bias in included studies for an explanation of this judgement).
Incomplete outcome data (attrition bias) Reactogenicity outcomes	Low risk	Outcome data were missing for only 1 trial participant.
Selective reporting (reporting bias)	Unclear risk	We considered that there was insufficient information to permit a judgement of low risk or high risk (see Risk of bias in included studies for an explanation of this judgement).
Other bias	Low risk	This trial appeared to be free of other sources of bias.