1. Objectives

To assess the effects of exclusive breastfeeding for six months versus exclusive breastfeeding for three to four months on child health, growth, and development, and on maternal health. A secondary objective was to assess the effects of prolonged exclusive breastfeeding (over six months) on child and maternal health in comparison to exclusive breastfeeding for six months

2. How studies were identified

The following databases were searched in June 2011:

• CENTRAL (The Cochrane Library 2011, Issue 6)
• MEDLINE
• EMBASE
• LILACS
• BIOSIS
• African Index Medicus
• Index Medicus for the WHO Eastern Mediterranean Region (IMEMR)

Reference lists were also searched and the authors directly contacted researchers

3. Criteria for including studies in the review

3.1 Study type

Controlled clinical trials and observational studies including an internal comparison group

3.2 Study participants

Lactating mothers and their healthy, term (≥37 weeks’ gestation), singleton infants

(Low birth weight infants were not excluded if born at term)

3.3 Interventions

Among infants exclusively breastfed for three months, continued exclusive breastfeeding until six months was compared to mixed breastfeeding (i.e., complementary foods such as solids, liquids or formula, given in addition to breastmilk)

(In some studies the definition of exclusive breastfeeding included the provision of water, teas, or juices)

3.4 Primary outcomes

Infant outcomes

• Growth: weight, length, head circumference and Z-scores (weight-for-age, length-for-age, and weight-for-length)
• Micronutrient status
• Morbidity: infections, asthma, atopic eczema, other allergic diseases, type 1 diabetes, blood pressure, and subsequent adult chronic diseases
• Mortality
• Neuromotor and cognitive development

Maternal outcomes

• Post-partum weight loss
• Duration of lactational amenorrhea
• Chronic diseases: breast and ovarian cancer, osteoporosis

4. Main results

4.1 Included studies

Twenty-three studies were included in this review

• Two studies were controlled trials and the remaining 21 were observational studies (predominantly cohort studies)
• Two studies were multinational, one of which was set in seven developed countries while the other was set in two developing and three developed countries
• Definitions of exclusive breastfeeding varied considerably between studies

4.2 Study settings

• Australia, Bangladesh (2), Belarus, Chile, Finland (2), Honduras (2), India, Iran, Italy, the Netherlands, Nigeria, Peru, the Philippines, Senegal, Sweden, the United States of America (3), and multinational (2)
• Eleven studies were in conducted in low- and middle-income settings, including the two controlled trials in Honduras, and 12 were in high-income settings

4.3 Study settings

How the data were analysed
Five comparisons were made: i) controlled trials of exclusive versus mixed breastfeeding for four to six months from developing countries; ii) observational studies of exclusive versus mixed breastfeeding for three to seven months from developing countries; iii) observational studies of prolonged (more than six months) exclusive versus mixed breastfeeding from developing countries; iv) observational studies of exclusive versus mixed breastfeeding for three to seven months from developed countries; and v) observational studies of prolonged (more than six months) exclusive versus mixed breastfeeding from developed countries. The multinational study including two developing and three developed countries was analysed with the developed country studies as all mothers were literate and of middle to high socioeconomic status

Results
Controlled trials of exclusive versus mixed breastfeeding for four to six months, developing countries
Growth
Weight gain was not significantly different between infants assigned to continued exclusive breastfeeding to six months versus those assigned to mixed breastfeeding from four to six months, with a mean difference (MD) in weight gain from four to six months of 20.78 g/mo (95% confidence interval (CI) [-21.99 to 63.54], p=0.34; 2 trials/265 infants) and from six to 12 months of -2.62 g/mo (95% CI [-25.85 to 20.62], p=0.83; 2 trials/233 infants). The MD in length gain was also non-statistically significant between four and six months (MD 0.10 cm/mo, 95% CI [-0.04 to 0.24], p=0.16; 2 trials/265 infants) and from six to 12 months (MD -0.04 cm/mo, 95% CI [-0.10 to 0.02], p=0.19; 2 trials/233 infants). There was no evidence of a difference in anthropometric Z-scores between groups at six months (weight-for-age Z-score MD 0.18, 95% CI [-0.06 to 0.41]; length-for-age Z-score MD 0.11, 95% CI [-0.11 to 0.33]; weight-for-length Z-score MD 0.09, 95% CI [-0.13 to 0.31]; 2 trials/260 infants). The risk of having a Z-score below -2 SD for any measure was also not significantly different between groups (weight-for-age Z-score <-2 (underweight) risk ratio (RR) 2.14, 95% CI [0.74 to 6.24]; length-for-age Z-score <-2 (stunting) RR 1.18, 95% CI [0.56 to 2.50]; weight-for-length Z-score <-2 (wasting) RR 1.38, 95% CI [0.17 to 10.98]; 2 trials/260 infants).

Morbidity
No differences between the exclusive breastfeeding group and the mixed breastfeeding group were found for the percentage of days with fever, cough, nasal congestion or discharge, hoarseness, or diarrhoea from four to six months (2 trials/260 infants), nor for fever, nasal congestion, or diarrhoea from six to 12 months (2 trials/258 infants).

Haematological indices
Mean haemoglobin concentration at six months was statistically significantly lower in the exclusively breastfed group by -5.00 g/L (95% CI [-8.46 to -1.54], p=0.0047; 1 trial/139 infants), as was haematocrit percentage (MD -1.20, 95% CI [-2.15 to -0.25], p=0.013; 1 trial/139 infants). Similarly, mean plasma ferritin concentration was statistically significantly lower at six months in the exclusively breastfed infants by -18.90 mcg/L (95% CI [-37.31 to -0.49], p=0.044; 1 trial/135 infants), with a RR for a low ferritin concentration (<15 mcg/L) of 2.93 (95% CI [1.13 to 7.56], p=0.027; 1 trial/135 infants). There was no evidence for an increased risk of haemoglobin below 110 g/L or 103 g/L at six months, however (RR 1.20, 95% CI [0.91 to 1.58] and RR 1.29, 95% CI [0.75 to 2.23], respectively; 1 trial/139 infants). No significant differences were noted for the proportion of infants with a low zinc concentration <70 mcg/L (RR 0.75, 95% CI [0.43 to 1.33], p=0.33; 1 trial/101 infants).

Neuromotor and cognitive development
Mothers of the exclusively breastfed group reported that their infants crawled an average of 0.80 months earlier than those of the mixed breastfed group (95% CI [1.26 to 0.34 months earlier], p=0.00063; 2 trials/240 infants). Mean age at which infants first sat from lying did not differ between groups, and there was no evidence of a difference in pooled risk of a delay in walking until after 12 months (2 trials/240 infants).

Maternal outcomes
Women in the exclusively breastfed group had statistically significantly greater weight loss from four to six months (MD 0.42 kg, 95% CI [0.02 to 0.82], p=0.041; 2 trials/260 women), and had a non-statistically significant reduced risk of resuming menses by six months post-partum (RR 0.58, 95% CI [0.33 to 1.03], p=0.064; 2 trials/189 women).

Observational studies of exclusive versus mixed breastfeeding for three to seven months, developing countries
Growth
Monthly weight gain between four and six months of age was non-significantly 10.10 g/mo lower in the exclusively breastfed infants compared with the mixed breastfed infants (95% CI [-27.68 to 7.48], p=0.26; 4 studies/1803 infants), and 6 g/mo lower between seven and nine months (95% CI [-54.15 to 42.15], p=0.81; 1 study/319 infants). The MD in monthly length gain was 0.04 cm/mo between four and six months (95% CI [-0.02 to 0.11], p=0.19; 4 studies/1803 infants), and also 0.04 cm/mo between seven and nine months (95% CI [-0.06 to 0.14], p=0.26; 1 study/319 infants). There was no evidence of a difference in anthropometric Z-scores or mid-upper arm circumference (MUAC) between groups at six to seven months (weight-for-age Z-score MD 0.13, 95% CI [-0.09 to 0.35]; length-for-age Z-score MD 0.04, 95% CI [-0.14 to 0.22]; weight-for-length Z-score MD 0.11, 95% CI [-0.09 to 0.31]; MUAC MD 0.20 cm, 95% CI [-0.04 to 0.44]; 1 study/370 infants) or at nine to ten months (weight-for-age Z-score MD 0.09, 95% CI [-0.15 to 0.33]; length-for-age Z-score MD 0.11, 95% CI [-0.09 to 0.31]; weight-for-length Z-score MD 0.01, 95% CI [-0.21 to 0.23]; MUAC MD 0.10 cm, 95% CI [-0.16 to 0.36]; 1 study/319 infants). No significant differences between groups were observed at six to seven months in the risk of underweight (RR 0.92, 95% CI [0.54 to 1.58], stunting (RR 1.20, 95% CI [0.57 to 2.53]), or wasting (RR 0.42, 95% CI [0.12 to 1.50]; 1 study/370 infants) or at nine to ten months (underweight RR 0.93, 95% CI [0.64 to 1.36]; stunting RR 1.21, 95% CI [0.62 to 2.37]; wasting RR 0.82, 95% CI [0.39 to 1.71]; 1 study/319 infants).

Morbidity
The risk of having one or more episodes of gastrointestinal infection between four to six months of age was statistically significantly reduced by 59% in infants exclusively breastfed until six to seven months relative to infants who were not (RR 0.41, 95% CI [0.21 to 0.78], p=0.0068; 1 study/193 infants). There was also a non-significant reduction in risk of having one or more episodes of respiratory infection at four to six months with exclusive breastfeeding (RR 0.68, 95% CI [0.43 to 1.06], p=0.089; 1 study/193 infants).

Maternal outcomes
The risk of resumption of menses by six to seven months post-partum was reduced by 81% in women who breastfed exclusively until this time (RR 0.19, 95% CI [0.05 to 0.79], p=0.023; 1 study/686 women).

Observational studies of prolonged (> six months) exclusive versus mixed breastfeeding, developing countries
Growth
In a small cross-sectional study conducted in India, a non-significant reduction of low weight-for-age (<75% of the reference mean) at six to 12 months of age was observed in the exclusively breastfed infants (RR 0.61, 95% CI [0.26 to 1.43], p=0.25; 1 study/31 male infants). However, the exclusively breastfed group was likely younger, and therefore less undernourished. Graphically presented data from a cohort study in Bangladesh showed similar weight and length gains in infants exclusively breastfed with supplements beginning at six to 11 months compared with those exclusively breastfed for 12 months and supplemented between 12 and 15 months.

Observational studies of exclusive versus mixed breastfeeding for three to seven months, developed countries
Growth
Among infants breastfed exclusively for six to seven months, monthly weight gain between three and eight months was non-significantly reduced compared with mixed breastfed infants (MD -7.95 g/mo, 95% CI [-31.84 to 15.93], p=0.51; 4 studies/4388 infants). However, monthly weight gain was non-significantly higher in exclusively breastfed infants between six and nine months (MD 21.11 g/mo, 95% CI [-44.70 to 86.91], p=0.53; 2 studies/3432 infants), and then lower again between eight to 12 months (MD -1.82 g/mo, 95% CI [-16.72 to 13.08], p=0.81; 3 studies/3450 infants). Monthly length gain was non-significantly lower among exclusively breastfed infants between three and eight months (MD -0.03 cm/mo, 95% CI [-0.11 to 0.06], p=0.51; 4 studies/4385 infants) and between six and nine months (MD -0.04 cm/mo, 95% CI [-0.10 to 0.01], p=0.15; 2 studies/3430 infants). However, monthly length gain between eight to 12 months was statistically significantly higher in exclusively breastfed infants by 0.09 cm/mo (95% CI [0.03 to 0.14], p=0.0017; 3 studies/3448 infants). Weight-for-age Z-scores were statistically significantly lower at six months among those exclusively breastfed (MD -0.09 Z-score, 95% CI [-0.16 to -0.02], p=0.016; 1 study/3455 infants), and at nine months (MD -0.10 Z-score, 95% CI [-0.18 to -0.02], p=0.011; 1 study/3400 infants), and 12 months of age (MD -0.09 Z-score, 95% CI [-0.17 to -0.01], p=0.029; 1 study/3458 infants). Length-for-age Z-scores were also significantly lower at six (MD -0.12 Z-score, 95% CI [-0.20 to -0.04], p=0.0044; 1 study/3454 infants) and nine months of age (MD -0.14 Z-score, 95% CI [-0.22 to -0.06], p=0.0012; 1 study/3398 infants) but non-significantly lower at 12 months (MD -0.02 Z-score, 95% CI [-0.10 to 0.06]). Weight-for-length Z-score was not significantly different between groups at any time point (6 mo MD 0.02, 95% CI [-0.07 to 0.11]; 9 mo MD 0.03, 95% CI [-0.06 to 0.12]; 12 mo MD -0.08, 95% CI [-0.17 to 0.01]; 1 study/3458 infants). The risk of underweight, stunting and wasting were not statistically significantly different between groups at six months (underweight RR 0.92, 95% CI [0.04 to 19.04]; stunting RR 1.53, 95% CI [0.84 to 2.78]; wasting RR 0.31, 95% CI [0.02 to 5.34]), nine months (underweight RR 1.52, 95% CI [0.16 to 14.62]; stunting RR 1.46, 95% CI [0.80 to 2.64]; wasting RR 1.14, 95% CI [0.24 to 5.37]) or 12 months (underweight RR 1.15, 95% CI [0.13 to 10.31]; stunting RR 0.66, 95% CI [0.23 to 1.87]; wasting RR 1.15, 95% CI [0.13 to 10.31]; 1 study/3406 infants). Head circumference was statistically significantly higher at 12 months among exclusively breastfed infants (MD 0.19 cm, 95% CI [0.06 to 0.32], p=0.0044; 1 study/3450 infants), but not significantly different at six or nine months.

Morbidity and mortality
The reported risk of food allergy at 12 months of age was statistically significantly reduced among exclusively breastfed infants relative to mixed breastfed infants by 81% (RR 0.19, 95% CI [0.08 to 0.48], p=0.00036; 1 study/135 infants); however, when double-challenged with food in the same study, the effect size was reduced and became non-significant (RR 0.77, 95% CI [0.25 to 2.41], p=0.66). The risk of one or more episodes of gastrointestinal infection in the first 12 months of life was reduced with exclusive breastfeeding (RR 0.67, 95% CI [0.46 to 0.97], p=0.033; 1 study/3483 infants), as was the risk of hospitalization for respiratory tract infection in the first 12 months of life (RR 0.75, 95% CI [0.60 to 0.94], p=0.013; 2 studies/3993 infants). There was a 28% increase in the risk of one or more episodes of otitis media in the first 12 months of life with exclusive breastfeeding (RR 1.28, 95% CI [1.04 to 1.57], p=0.017; 2 studies/3762 infants). Other outcomes in the first 12 months of life, including atopic eczema, wheezing, upper respiratory tract infection and death, were not different between groups.

Haematological indices
In one small study of 30 infants, mean haemoglobin concentration at 12 months was significantly greater among exclusively breastfed infants by 8.00 g/L (95% CI [4.03 to 11.97], p<0.0001), while no difference was seen for serum ferritin concentrations (MD 4.70 mcg/L, 95% CI [-6.30 to 15.70], p=0.40).

Long-term outcomes
Long-term outcome analyses were performed predominantly using follow-up data from one study at five to seven years of age. Height, leg length, head circumference, waist circumference, dental caries, atopic eczema, hay fever, asthma, food allergy, animal dander allergy, dust mite allergy, birch pollen allergy, grass allergy, and alternaria allergy were not different between groups. However, body mass index was greater in the exclusively breastfed group (MD 0.20 kg/m², 95% CI [0.02 to 0.38], p=0.026), as was triceps skinfold thickness (MD 0.90 mm, 95% CI [0.51 to 1.29], p<0.00001), subscapular skinfold thickness (MD 0.50 mm, 95% CI [0.25 to 0.75], p<0.0001) and hip circumference (MD 0.50 cm, 95% CI [0.05 to 0.95], p=0.030) (1 study/2951 children). Systolic and diastolic blood pressure were also increased in the exclusively breastfed group (MD 1.30 mmHg systolic, 95% CI [0.39 to 2.21], p=0.0049 and MD 1.00 mmHg diastolic, 95% CI [0.29 to 1.71], p=0.0058; 1 study/2951 children). In cognitive testing, the Wechsler block design test was higher among the exclusively breastfed group (MD 1.30, 95% CI [0.40 to 2.20], p=0.0047; 1 study/2950 children). However, teacher-rated reading, writing and subjects other than mathematics all scored lower in the exclusively breastfed group (all p≤0.033).

Observational studies of prolonged (> six months) exclusive versus mixed breastfeeding, developed countries
No differences in gains in weight and length were reported in the first 12 months of life in an observational study of infants who were exclusively breastfed beyond six months versus those exclusively breastfed for less than six months and mixed breastfed thereafter (actual data not reported). Lipid concentrations (very low density lipoprotein, low density lipoprotein, high-density lipoprotein-2, high-density lipoprotein-3, apoprotein B, and total triglycerides) were not different at nine months among infants exclusively breastfed for nine months versus those exclusively breastfed for six months and mixed breastfed from six to nine months.

5. Additional author observations*

Observational evidence demonstrates that exclusive breastfeeding until six months of age compared to mixed breastfeeding from three to four months of age reduces the risk of gastrointestinal infection in both developing and developed countries. In addition, in two controlled trials conducted in Honduras, there was no evidence for a deficit in growth with exclusive breastfeeding. Regarding evidence on growth outcomes from observational studies, the primary concern is confounding due to differences in socioeconomic status, water and sanitation facilities, parental height and weight, and infant weight and length at the time complementary foods were first introduced in the mixed breastfeeding group. The latter source of confounding arises if infants with poor growth are introduced to complementary foods earlier in an effort to promote growth. However, the results of observational studies from developing countries are consistent with the findings of the two Honduran trials, particularly with respect to growth.

Aside from improved iron status in one low-income setting (Honduras), there appear to be no benefits of introducing complementary foods between four and six months of age. However, iron status is effectively managed with supplemental iron, and thus the overall evidence demonstrates no apparent risk in recommending exclusive breastfeeding for the first six months of life as a general policy in both developing and developed countries.

Larger randomized trials of exclusive breastfeeding for the first six months are needed to confirm the findings reported here, and to exclude differences in the risk of malnutrition in developing countries. Cluster randomization would limit the potential for contamination, and longer-term studies are also warranted to investigate the ongoing effects of exclusive breastfeeding on health and development.