Methods

RCT. 3‐arm trial. Parallel design.

Participants

Low‐income communities in San Pedro Sula, Honduras. Primiparous, breastfeeding mothers and their infants (n = 152) recruited from public maternity hospitals.

Interventions

Trial from 4 to 6 months and longitudinal study of infants from birth to 12 months.

At 16 weeks, infants assigned to:

1. control (exclusive breastfeeding to 26 weeks; no other liquids (water, milk or formula) or solids);

2. solid foods (introduction of solid foods at 16 weeks, with ad libitum breastfeeding); or

3. solid foods and maintenance (introduction of solid foods at 16 weeks with maintenance of pre‐intervention breastfeeding frequency).

After 6 months, mothers continued to breastfeed and also fed their infants.

Outcomes

Infant weight measured weekly between 16 and 26 weeks and monthly from 7 to 12 months. Infant length measured at 16, 21 and 26 weeks and monthly from 4 to 12 months.

Infant motor development following 10 motor milestones.

Maternal height and weight measured at birth of infant and weight was re‐measured according to the infant weight measurement schedule. Maternal supra‐iliac and thigh skinfold thickness and circumference at the bust, below the bust, waist and hip were measured at 16, 21 and 26 weeks. Maternal % body fat measured at each timepoint.

Breast milk intake measured by test weighing for 48 hours at 4, 5 and 6 months. After this period, breast milk samples were collected for 24 hours and samples were pooled and frozen for later lipid and lactose analysis. For the solid food groups, solid food intake measured at 19, 24 and 26 weeks.

Infant morbidity was tabulated at 4‐6 months and 6‐12 months. Morbidity prevalence was calculated as % of days ill in each category of illness (diarrhoea, fever and upper‐respiratory illness).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

By week of birth (i.e. all infants born in the same week were randomly assigned to the same group).

Allocation concealment (selection bias)

High risk

Participants were not informed of their assignment until they had completed the first (non‐RCT) section of the study.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information available.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

152 women entered the intervention trial, 11 (7%) dropped out prior to 26 weeks (9, 1, and 1 in the EBF, SF, and SF‐M groups, respectively; P < 0.01). Reasons for leaving the study between 16 weeks and 26 weeks were reported: 2 had to return to work (both in EBF) and 5 were refused permission to continue participating (4 EBF and 1 SF‐M). The other 4 (3 EBF and 1 SF) were excluded because they did not exclusively breastfeed (or introduced other milks in the SF group). Characteristics of non‐participants who dropped out at commencement of the intervention trial were similar to those of participants.

141 participants completed the study (50 EBF, 47 SF, 44 SF‐M). 20% of infants weighed less than 2500 g at birth. The groups were similar in infant birthweight and sex; maternal age, weight, BMI, education, and marital status; and household income. Mothers in the SF‐M group were less likely to have received prenatal care than mothers in the 2 other groups.

Selective reporting (reporting bias)

Unclear risk

Data on all the outcomes mentioned in the 'Methods' section of the published papers were reported. We did not retrieve the protocol or raw data of the trial and thus did not identify whether outcomes other than those reported within the published papers were collected but not reported on.

Other bias

Low risk

No issues.

Methods

Prospective observational study followed by a randomised intervention trial (from 4 to 6 months). 2‐arm. Parallel design.

Participants

222 (of which 128 were eligible for the intervention phase of the study) full‐term (≧ to 37 weeks' gestation) low birthweight infants (weighing 1500‐2500 g at birth) from 2 maternity hospitals in San Pedro Sula, Honduras whose mothers (aged ≧ 15 years of age) were willing to exclusively breastfeed for 6 months and were not planning to work outside the home.

Interventions

At 16 weeks of age, infants who were still exclusively breastfed were randomly assigned to 1 of 2 groups: (1) continued exclusive breastfeeding to 6 months, or (2) complementary feeding (solid foods) plus breastfeeding from 4 to 6 months, with mothers encouraged to maintain baseline (16 week) breastfeeding frequency.

Outcomes

Growth and morbidity from 16 to 26 weeks were assessed for all infants. Morbidity data collected by maternal recall of illness symptoms (weekly).

Blood samples collected at 2, 4, 6 months of age. Any infants identified as anaemic, i.e. Hb < 100 g/L, were given iron supplements and re‐tested 2 weeks later.

Daily diary of infants stool frequency and consistency were recorded by the mothers.

For a sub‐sample (n = 63) measurements of breast milk intake and composition and total energy intake at 16 and 26 weeks were completed.

At 26 weeks, intake of solid foods by infants in the complementary feeding plus breastfeeding group was also determined.

Infant motor development following 10 motor milestones.

Maternal height (at time of birth) and weight (weekly).

Maternal consumption of any vitamin and mineral supplements were recorded.

Duration of lactational amenorrhoea.

Assessment of attitudes of mothers to exclusive breastfeeding.

After the intervention phase, infant growth was measured monthly until 12 months of age.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Assigned by week of birth (i.e. all infants born in the same week were assigned to the same group).

Allocation concealment (selection bias)

High risk

Participants were not informed of their assignment until they had completed the first (non‐RCT) section of the study.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not stated for outcome assessors, although appears to be same researchers at all points.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

For RCT part of study n = 128 at 4 months (study commencement). By the end of study 9 (8 in the EBF group) had dropped out with 119 completing study to 6 months. Mothers in the EBF group dropped out because: they moved away (n = 3), they went back to work (n = 2), they never intended to exclusively breastfeed (n = 1), they felt they were losing too much weight (n = 1). The 1 participant who dropped out of the SF group did so because she did not want to continue.

There were no significant differences between the 119 participants and the 9 dropouts in infant sex, gestational age, ponderal index, or weight and length gains from birth to 16 weeks, nor in maternal height, BMI, income or prenatal care.

However, dropouts had significantly lower birthweights, head circumferences, Apgar scores at 5 min, and maternal ages.

Of those who remained in the study through 6 months, 44% were male, and mean values were 2364 +/‐ 137 g for birthweight, 23.3 +/‐ 3.3 kg/m² for maternal BMI, and 5.7 +/‐ 2.7 years for maternal education.

The sample sizes at 4 and 6 months for the blood indices analysed using frozen samples were smaller than those analysed immediately (Hb, Hct and MCV) because of a robbery (of the freezer with contents) at the Honduras facility near the end of data collection. This resulted in a loss of approximately 30% of the 4‐month samples and approximately 30% of the 6‐month samples. To determine whether these losses introduced bias, the authors evaluated whether the characteristics of those with lost samples at 4 or 6 months differed from those with complete data in either intervention group. There was little indication that the loss of samples introduced bias in interpreting the effect of the intervention. Nevertheless, data were analysed in 2 ways: considering only those with information available at both 4 and 6 months, and considering all samples available at 6 months.

Selective reporting (reporting bias)

Unclear risk

Data on all the outcomes mentioned in the 'Methods' section of the published papers were reported. We did not retrieve the protocol or raw data of the trial and thus did not identify whether outcomes other than those reported within the published papers were collected but not reported on.

Other bias

Low risk

No issues.

Methods

RCT, 2‐arm, parallel design. 2‐4 days in first week after birth with follow‐up to 3 months. Designed to be a pilot to test feasibility.

Participants

40 exclusively breastfeeding healthy term infants > 37 weeks' gestation, 24 to 48 hours old, who had lost > 5% birthweight before 36 hours of age were randomly assigned to continue exclusive breastfeeding n = 20 (control) or to receive formula supplementation n = 20 (intervention).

"Infants were excluded if [at time of enrolment] they had lost > 10% of their birthweight, had received formula or water, required a higher level of care than a Level 1 nursery or had mothers who were ,18 years old, could not speak English or Spanish, or were making mature milk as assessed by a previously validated technique".

2 hospitals California, USA.

Interventions

“Early limited formula (ELF) intervention (10 mL formula by syringe after each breastfeeding and discontinued when mature milk production began) or control (continued exclusive breastfeeding).”

Nutramigen infant formula (stated as “extensively hydrolyzed").

Outcomes

Breastfeeding and formula use at 1 week and 1, 2, and 3 months. (Duration of breastfeeding).

Weight nadir in protocol, only weight loss reported (at age not stated).

Maternal breastfeeding self‐efficacy at 1 week.

Incidence of febrile illness.

Notes

Further details sought from trialist with some response.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

“The allocation sequence for randomisation was generated by an independent bio‐ statistician stratified on location; assignments were placed into sealed opaque envelopes by an independent administrative assistant."

Allocation concealment (selection bias)

Low risk

"Immediately after enrolment, a study investigator opened the sequential envelope in the presence of a second investigator and revealed the randomisation arm.”

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

“A blinded research assistant assessed outcomes at 1 week and 1, 2, and 3 months.”

Unfeasible to blind participant or personnel.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

1‐3 infants were missing data at various follow‐up time points according to the published table with no information regarding which group, or if the same participants were missing data at multiple points, or different participants at each point. Information requested from trialist but was not available.

Selective reporting (reporting bias)

High risk

Lack of definition of breastfeeding and particularly of exclusive breastfeeding. The rates of exclusive breastfeeding dropped from week 1 to 1 month then increased in the both groups in month 2 and dropped in month 3. This implies the definition of exclusive breastfeeding was not in accordance with WHO guidelines. The control group of exclusive breastfeeding may have received infant formula as only 53% of this group were exclusively breastfeeding by the end of week 1 and the amount of formula used in the control group in the first week was over double the amount used in the intervention group.

Other bias

High risk

Protocol as ClinicalTrials.gov Identifier NCT00952328 listed primary outcome as: Is infant receiving exclusively breast milk at 8 days of life, published paper refers to “1 week”. Protocol “Both groups will receive intensive lactation support” – published report does not mention “intensive” support.

Small sample size. Only 62% of those replying (6 out of 40 did not reply) at the start of the intervention had planned to exclusively breastfeed which may have affected their motivation to comply with the allocation. There were more multiparous women in the intervention group than the control group (70% vs 50%) and previous experience of breastfeeding is a well established predictor of subsequent feeding.

Effect on weight was an outcome however, the study did not specifically weigh infants; used hospital routine weights, and only reported loss, not gain.

Inclusion criteria was weight loss of ≥ 5% though this is well within the range of normality, and no infant in the study had a medical reason for supplementation. Unclear what was the support provided for breastfeeding, if mothers were instructed regarding how often to feed, to express milk if infant was not feeding well etc. No information on birth practices that may have affected commencing breastfeeding. No definition of a “feed” thus the instruction to give the 10 mL of supplement “after each feed” could be 8 times, 12 times or more and thus variable quantities consumed. As supplement was given by syringe the infant was not able to refuse the supplement if already content with the amount of breast milk received.

Funding: Supported by grants 5 K12 HD052 and 1K23HD059818‐01A1 from the National Institute of Children Health and Human Development. 1 of the trialists has served as a paid consultant to 4 companies in the formula industry including the company producing the supplemental formula used in the intervention. Report does not state if formula was supplied by the company or purchased; some participants were provided with small amounts of the formula to continue supplementation for a short time after discharge from hospital ("about 12 ounces" from additional information from trialists).

Methods

RCT. 2‐arm. Parallel design.

Participants

119 randomly assigned at 4 months. Full‐term (≥ to 37 weeks' gestation).

61 were allocated to the CF group and 58 to the EBF group. Although 1 mother‐infant pair was incorrectly instructed to group EBF and was therefore analysed in the EBF group, so N = 60 for CF; N = 59 for EBF.

At a screening visit all mothers stated willing to continue to exclusively breastfeed to 6 months.

Interventions

At 4 months of age, infants who were still exclusively breastfed were randomly assigned to 1 of 2 groups: (1) continued exclusive breastfeeding to 6 months, or (2) CF (solid foods) plus breastfeeding from 4 to 6 months.

Exclusive breastfeeding was defined as breastfeeding with no additional liquid or solid foods other than vitamins and medications,

Outcomes

For the CF group, mothers kept a diary to indicate the date that every new food item was added to the infant's diet from the time of enrolment into the study until 6 months of age. A 3‐day weighted food record was obtained when the infant reached approximately 5 months and 1 week of age. Energy and nutrient information were calculated.

For both groups

Anthropometric assessment: included infant's weight, length and head circumference. Measured at birth, 6 weeks, and 3, 4, 5 and 6 months of age (converted to z scores using the WHO Infant Growth Standards).

Blood samples: obtained to determine iron status. Obtained at 6 months of age ‐ blood for Hb, MCV, RDW, serum ferritin, and TIBC.

Breast‐milk intake: determined by the deuterium dose‐to‐the‐mother method.

Measures of developmental and behavioural status: assessed at both 18 months and 30 ‐ 35 months with the Parent's Evaluation of Developmental Status (PEDS) questionnaire and the Brigance Screens‐II.

The Jonsdottir trial retrospectively collected information on total duration of breastfeeding for all infants. However, we are unable to present these data as they were combined with data from an additional cohort of infants from a separate national prospective study.

Notes

EBF: the use of up to 10 feedings of formula or water during the first 6 months was allowed to avoid having to exclude infants who were otherwise exclusively breastfed.

Clinical Trial Registration: ISRCTN41946519.

Study was supported by the Primary Health Care organizations in the Reykavik Capital area, Akranes, and Sudurnes, and by the Directors of the participating health centres.

The study was supported by Mead Johnson and the Eimskip Fund for the University of Iceland. The sponsors of the study had no role in the study design, data collection, data analysis or interpretation, preparation of the report or the decision to submit for publication. None of the authors received honoraria, grants or other forms of payment to produce the manuscript.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

The randomisation method was prepared using Jerry Dallal's Tufts‐based software, and the trial statistician prepared the provided a computer‐generated randomisation code. Assignments were generated by using permuted blocks of 2 and 4, with the sequence presented in random order.

Allocation concealment (selection bias)

Low risk

Assignments were accessed by using a password‐protected web‐based application, after eligibility criteria were confirmed. Assignments were generated by 1 person (a nurse) who was not involved in any other aspect of the study.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Nurses who collected data on complementary food intakes and anthropometric outcomes were not blinded to participant group status, but all mass spectrometric analyses and isotopic modelling were blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

A total of 119 (n = 61 in CF group, n = 58 in EBF group) mother‐infant pairs were recruited, of whom 100 completed the trial protocol.

CF Group

10 pairs discontinued the intervention (n = 3 infant did not receive complementary foods; n = 3 infant did not want solid food; n = 1 mother stopped breastfeeding; n = 2 mother did not have time to finish study; n = 1 mother not contacted after randomisation).

EBF Group

9 pairs discontinued the intervention (n = 7 infant received complementary foods before 6 months; n = 1 mother wanted to leave study; n = 1 illness in family.

Also, after randomisation, 1 mother who was randomly assigned to the CF group was incorrectly instructed to the EBF group. The primary analysis was conducted with this mother included in the EBF group (n = 50 EBF, 50 CF) but reported outcomes for the baseline analyses with the participant in the CF group (n = 49 EBF, 51 CF).

The authors state that they were not able to test whether those who dropped out of the study were those with lower breast milk intakes ‐ i.e. potentially a self‐selected group.

Selective reporting (reporting bias)

High risk

In protocol states under secondary outcomes: "3. Occurrence of upper respiratory infections and diarrhoea episodes (dichotomous variables)".

But in Wells paper states "Finally, our study was designed to evaluate growth and energy intake and not other issues such as development of dietary preferences, mineral status, or effects on health such as diarrhea and allergy".

Other bias

Low risk

Stated that the study sponsors (Mead Johnson and the Eimskip Fund of the University of Iceland) had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the manuscript for publication. None of the authors declared a conflict of interest.

Methods

RCT. 2‐arm trial. Parallel design.

Participants

Full‐term newborns weighing between 2599 g to 4000 g (n = 180). Vaginal deliveries only, who had no congenital abnormalities and who represented no risk factors for hypo‐ or hyperglycaemia. General Hospital, Teruel, Spain.

Interventions

Group 1 called "glucose water" group (GW), received 5% glucose ad libitum from a bottle for the first 3 days of life in addition to breastfeeding. Group 2, the "non glucose water" group, was not given glucose water or any other type of alternative solution to human milk.

Outcomes

Weight change (6, 12, 24, 48 and 72 hours of life).

Serum glucose levels (6, 12, 24 and 48 hours of life).

Rectal temperature (every 6 hours for the first 72 hours of life). The maximum and minimum values during period of observation were used in the final analysis).

After discharge no contact for 5 months. Then telephone interview determined duration of exclusive breastfeeding, duration until introduction of infant formula, and duration until complete weaning were recorded. Time points of 4, 8, 12, 16 and 20 weeks were used.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Divided randomly into 2 groups."

Allocation concealment (selection bias)

Unclear risk

Not discussed.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information available

Incomplete outcome data (attrition bias)
All outcomes

Low risk

N = 180 (90 in each group). 3 children from the non glucose water group and 7 from the glucose water group were ineligible because of missing data or because it was impossible to assure correct transcription of data. Therefore 10 excluded = 5.5%.

Selective reporting (reporting bias)

Unclear risk

Data on all the outcomes mentioned in the 'Methods' section of the published papers were reported. We did not retrieve the protocol or raw data of the trial and thus did not identify whether outcomes other than those reported within the published papers were collected but not reported on.

Other bias

Unclear risk

Some information on partial or exclusive breastfeeding was obtained via telephone conversations (maternal recall of illness symptoms) and this is open to recall bias.

Methods

RCT. 3‐arm trial. Parallel design.

Participants

Primiparous mothers intending to breastfeed their full‐term infants. Intending to be in hospital (London, UK) for 5 days after delivery. 49 originally randomised.

Interventions

3 groups: water supplement (n = 14); glucose supplement (n = 17); no supplement (n = 16).

Outcomes

Infant weight (day 1, 3 and 5).

Plasma bilirubin (day 6).

Volume of supplement taken per day per kilo of baby's birthweight (ml/kg/day).

Average weight gain per breastfeed (mg/kg of baby's birthweight).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Described as "randomly allocated" to 1 of 3 groups (no supplement (n = 17); glucose supplement (n = 17), water supplement (n = 15)).

Allocation concealment (selection bias)

Unclear risk

Not discussed.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information available.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

4 mother/baby pairs defaulted from the 'no supplement' group because their babies were "too hungry" and were replaced by further randomised pairs. 2 infants were later excluded from the study because of: rhesus incompatibility (n = 1) and ABO incompatibility with positive haemolysins (n = 1). This reduced numbers in each group to: no supplement (n = 16); glucose supplement (n = 17); water supplement (n = 14).

Selective reporting (reporting bias)

Unclear risk

Data on all the outcomes mentioned in the 'Methods' section of the published papers were reported. We did not retrieve the protocol or raw data of the trial and thus did not identify whether outcomes other than those reported within the published papers were collected but not reported on.

Other bias

Low risk

No issues.

Methods

RCT. 2‐arm trial. Parallel design.

Participants

180 neonates delivered between October 1980 and January 1981 in 2 local maternity centres in Ile‐Ife, Oyo State, Nigeria were randomised. Criteria for selection were that birthweight be above 2.50 kg, no sign of congenital malformation, that mothers experienced uncomplicated birth with membrane rupture less than 24h prior to delivery, and no manifest sign of physical exhaustion or sickness after delivery to prevent them from performing their maternal responsibilities to the neonates.

105 kept strictly to instructions (60 (57%) on colostrum regimen and 45 (43%) on glucose water).

Interventions

1 group received glucose water feedings and the other colostrum. The mothers were told to keep strictly to these feeding regimens for the entire 3‐day stay at the maternity centre.

Outcomes

Stool specimens (2 daily) analysed for bacterial counts.

Bacterial counts in samples of colostrum and glucose water.

Notes

Did not report any data that were eligible for inclusion in the review

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Randomly assigned at birth to two groups....".

Allocation concealment (selection bias)

Unclear risk

Not discussed.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information available

Incomplete outcome data (attrition bias)
All outcomes

High risk

Participation was voluntary, and those mothers who failed to adhere were excluded from the study.

Of the 180 mothers chosen for the study, 105 kept strictly to the instructions. 60/105 were on the colostrum regimen (57%) and 45 were on glucose water (43%).

Selective reporting (reporting bias)

Unclear risk

Data on all the outcomes mentioned in the 'Methods' section of the published papers were reported. We did not retrieve the protocol or raw data of the trial and thus did not identify whether outcomes other than those reported within the published papers were collected but not reported on.

Other bias

Low risk

No issues.

Methods

RCT. 2‐arm trial. Parallel design.

Participants

Healthy term neonates (n = 136) in the first 3 days after birth.

78 babies nursed exclusively on demand, and 58 babies received supplemental water in addition to on‐demand nursing.

This study was performed in a maternity hospital in Philadelphia, Pennsylvania at which the patient population is highly motivated to breastfeed.

Interventions

Exclusive on‐demand breastfeeding versus on‐demand nursing plus supplemental water. The choice of sterile water or 5 % glucose water was left to the mother.

Outcomes

Mean total amount of water ingested by the supplemented group prior to the arrival of true milk.

The time in hours when true milk first "came in" was recorded for each mother as it occurred.

Notes

Did not report any data that were eligible for inclusion in the review

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not discussed.

Allocation concealment (selection bias)

Unclear risk

Not discussed.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information available.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No reference to dropouts reported.

Selective reporting (reporting bias)

Unclear risk

Data on all the outcomes mentioned in the 'Methods' section of the published papers were reported. We did not retrieve the protocol or raw data of the trial and thus did not identify whether outcomes other than those reported within the published papers were collected but not reported on.

Other bias

Low risk

No issues.