Benefits of breast-feeding the preterm infant

IPOKRaTES Seminar: Neonatal Neurology May 30th June 2nd , 2011 Cairo, Egypt
Saroj Saigal McMaster University, Hamilton, Ontario

Presentation today:
Problems in conducting studies on BF in preterm Properties of human milk, donor milk, fortified human milk Short-term effects of breast-feeding on infection, growth,

neurodevelopment, bonding
Long-term effects of breast-feeding on cognition, blood pressure,

allergies etc
HIV transmission via BF Summary and recommendations

Methodologic issues in conducting studies on breast-feeding

Problems in conducting nutritional studies in preterm infants

Availability of breast milk inadequate Inability to randomize breast-feeding for

ethical reasons
Confounded by severity of illness Feeding intolerances and NEC Proportion of total intake by TPN not reported No information on post-NICU feeding

Clinical application
Caution should be used in linking intention to breast-

feed with substantial milk consumption with actual breast-feeding.

Separating the emotional aspects of suckling from the

biochemical and immunologic properties of human milk (gavage-fed preterm infants may be a good model to delineate these effects)

Mothers choice to breast-feed and positive health behaviours

antenatal class attendance

smoking behaviour immunization motivation advantageous parenting lifestyles higher maternal education and SES Two-parent family Positive home environment

Properties of human milk and preterm formula

Composition of term human milk

(unit /L)
Energy (kcal)* Fat (g) * Protein (g) Calcium (mg) Sodium (mEq) Zinc (mg)

Foremilk
629 28.6 13.1 272 3.3 2.9

Hindmilk Drip milk

825 47.8 13.1 273 3.1 2.8 540 22.0 13.0 280

Valentine, JPGN 1994;18:474; McGuire, Arch Dis Child 03

Weight gain before and after hindmilk

20 15 10 5025 30 35 40 45 50 55 60 65
Valentine et al, 1996
Week 1 Week 2

Protein content of term and preterm human milk

3.5 3

Protein (g.dl.1 )

2.5 2 1.5 1 0.5 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Preterm Full term

Mean SEM

Schanler et al 1980

Protein content of preterm human milk ( 0 - 12 wks)

2.5
Protein Content (g/dL)

Preterm Formula

2 1.5 1 0.5

Human Milk

00 1

10

12

Schanler et al, 1980

Sodium content of preterm human milk: 0 - 12 wks

25

Sodium Content (mEq/L)

20 15 10 5 0

Human Milk Preterm Formula

0.5

10

12

Duration of Lactation (weeks) Schanler et al, 1980

Effect of maternal fasting during Ramadan on composition of BM and IQ of children

q During fasting, zn, mg, and potassium decreased

significantly in BM
q Although the nutritional status of the mother was

affected, there were no significant effects on the growth or IQ of the children

Rakicioglu et al, Pediatri Int 2006;48:278-83 Azizi et al, Int J Vitam Nutr Res 2004;74:374-80

Effect of maternal fasting during Ramadan on composition of BM and IQ of children (contd)

q Because all the nutrient intakes of the mother

were affected during pregnancy and lactation, it would be prudent to excuse these women from fasting during Ramadan, if possible

Rakicioglu et al, Pediatri Int 2006;48:278-83 Azizi et al, Int J Vitam Nutr Res 2004;74:374-80

Unfortified human milk: nutritional concerns

q Poorer rates of growth / nutritional deficits q Variations in macronutrient composition of EBM q Significant declines in protein and sodium conc. with

PNA
q Ca and Ph concentrations below requirements q Compounded by lack of ad libitum feeding and

frequent fluid restrictions

Growing preemies require fortified human milk

Schanler et al, 1999

Nutrient Composition of Fortified Human Milk

Nutrient Per 100 ml Energy (kcal) Protein g Calcium mmol Phosph mmol Vitamin A IU Vitamin D IU Sodium mmol Potassium mmol Iron mg Unfortified Fortified 1:50 75 1.85 1.98 1.43 670 60 1.3 2.2 0.29 Fortified 1:25 82 2.3 3.45 2.52 983 119 1.7 3 0.46 SSC 24

70 1.3 0.5 0.4 363 1.0 1.4 0.11

80 2.4 3.1 2.3 814 158 1.8 2.5 0.3

Note: maximum protein intake for infants with normal renal function = 4 g/kg/day

Donor Human Milk

RCT of donor HM vs Preterm formula in extremely preterm infants (<30 wks GA)
q No differences between groups in infections, late onset

sepsis, NEC or deaths.

q Infants receiving DM had intake and nutrients, but

slower wt gain than PTF

q Infants fed exclusive MM had infections, NEC and late

onset sepsis
q As a substitute for MM, DM offered little benefits over PTF,

exclusive MM best (21% of DM infants switched to PTF for poor wt gain)

Schanler, Pediatrics 2005; 116:400-6

Human donor milk vs formula for VLBW infants

In preterm infants, meta-analysis of 4 trials showed

infants fed DM were 3x less likely to develop NEC (RR 0.34, 95% CI 0.12, 0.99), McGuire W, Arch Dis Child 2003; 88:F11-14

In VLBW infants, feeding formula vs donor BM

results in short-term growth, but also risk of NEC (RR 2.5, 95% CI 1.2, 5.1) meta-analysis of 5 trials Quigley MA Cochrane database
Rev, 2007

Short-term effects of breast-feeding

Benefits of human milk

Relate to:
q Nutritional benefits q Improvements in host defences q Digestion with absorption of nutrients q Gastro-intestinal function q Neurodevelopment q Maternal psychological well-being

Schanler et al, 1999

Suitability of human milk for premature infants: host defense benefits

Human milk immune system

- Cellular functions - SigA, lactoferrin, lysozyme - Bioactive substances - oligosaccharides, nucleotides

Fecal Flora Enteromammary pathway

- Skin-to-skin care

Suitability of human milk for premature infants: gastrointestinal function

Trophic factors Gastric emptying better Gut motility improved Feeding tolerance better Bioactive substances

Effect of dose of mothers own milk on infection-related events and hospital stay
Human Milk >50 mL/kg/d Human Milk And Formula Preterm Formula

No. of Infants Human milk intake (ml/kg/d) Necrotizing enterocolitis, n (%) Late-onset sepsis (LOS), n (%) LOS and / or NEC, n (%) Hospital stay (d)

62 96 23 1 (2) * 19 (31)** 19 (31) 73 19 ***

63 20 15 16 (25) 29 (46) 35 (56) 87 43

42 0 6 (13) 22 (48) 25 (54) 88 47

*P <0.01; ** P = 0.07; *** P <0.05 Schanler RD, Pediatrics 99

Study

NEC: Human milk vs formula

Relative risk (95% CI)

Gross 1981 Lucas 1982 Svenningsen 1982 * Tyson 1983

Pooled estimate 0.25 (0.06 to 0.98)

0.001 0.02 1 50 1000

* Not estimable

Favours human milk

Favours formula

Relative risk of confirmed necrotising enterocolitis with human milk versus formula. Adapted from McGuire W, Anthony MY. Arch Dis Child 2003;88:11-14

Comparison growth with HM and fortified HM in premature infants

Human Milk
Weight gain (g/kg/d) Length increment (cm/wk) Head circumf (cm/wk) BUN (mg/dL) 13 1 0.8 0.2 0.8 0.2 5.0 2.8

Fortified Human Milk

17 2 * 1.1 0.2 * 1.0 0.2 * 9.4 4.5 *

Greer & McCormick, J Pediatr 1988;112:961-9

Adequacy of fortified human milk

q Fortified human milk provides adequate growth,

nutrient retention and biochemical indices

q Precise quantity of nutrients undetermined q Protection from infection and NEC q Adequate volume 180 ml/kg essential

Fortification of human milk and neurodevelopment outcome

Randomized trial of partially supplemented

human milk and human milk fortification in the NICU did not demonstrate any differences in neuro-developmental outcome at 18 months
q However, no adverse effects were noted

Lucas et al, 1996

Nutrient enrichment of MM post-discharge: Growth at 12 months

Prospective RCT of infants 24-32 wks GA: Unfortified MM, n = 102, fortified MM, n = 105, formula, n = 113 for 4 months.

Fortification did not affect duration of BF Growth with fortification was improved in females during intervention
period only, but not at 12 mths

Formula fed infants achieved better WT and L catch-up A lower dose of fortification than recommended was used in this study

Zachariassen et al, Pediatrics 2011;127:e995-1003

Fortification guidelines in NICU

Add fortifiers only when the infant is nearly fully fed orally: 1 package of human milk fortifier to 25 ml EBM = 84k cal / 100ml, and provides calories, vitamins, minerals and extra protein requirements

Fortification of Human Milk: Post-discharge

q Only 1 small RCT of fortified HM (39 infants) found improved growth

rates but no effect on neurodevelopmental outcomes at 18 mths CA

q Since fortifying BM for infants fed directly from the breast is

logistically difficult, fortifiers are offered only to infants with poor weight gain
q Further trials are warranted

McCormick FM, Cochrane Database Syst Rev. 2010

Fortification guidelines: Post-discharge

q Powdered formula 1 g = 5 K Cal q Addition of powdered formula to every 50 ml EBM:

tsp = 22 K cal/ oz tsp = 24 K cal/ oz tsp = 26 K cal/ oz 1 tsp = 28 K cal/ oz

q Aim for total fluid intake of 150 ml/ kg with fortified EBM,

8 - 10 feeds */ d (6-8 BF, 2 bottles of fortified EBM) * Frequent feeding will stimulate milk production

Supplementation of Vitamin D and Iron Post discharge

q Iron is essential for premature infants, particularly if

breast fed. Requirements total up to 15 mg / day

- < 1000g BW: 3-4 mg/ kg - > 1000g BW: 2-3 mg/ kg
q Vitamin D, aim for 400 IU of Vitamin d/ daily; infants

with darker complexion require 800 IU/ d

(feeds usually provide 40 IU / 100 ml)

Long-term effects of breast-feeding

Beneficial effects of breast milk: Term Infants

Improved cognitive scores (PPVT-R 3.6 points )Oddy 03

Improved maternal/child behavioural ratings (not evident

in randomized trial) Kramer 08

Decreased rates of GI infection
Kramer 01

No protective effect on asthma and allergies BP, type 2 diabetes and cholesterol levels Risk of overweight at adolescence
Gillman 01

Sears 02, Kramer 01

Owen 08, Stuebe 05

Kramer, Pediatrics 2008, BMJ 2007

Breast-feeding and brain function

BF appears to have a broad range of enhanced
q rapid maturation of visual function/acuity q acquired motor skills at an earlier age q fewer emotional or behavioural problems q fewer minor neurological problems q scores on Bayley Scales of Infant

brain functions:

Development

Breast milk feeding of ELBW in NICU: Outcomes at 18 and 30 months (NICHD)

At 18 and 30 months, ingestion of fortified BM was associated with:
q

higher Bayley MDI scores that persisted higher scores for emotional regulation fewer rehospitalizations post-discharge no differences in growth or CP

q q q

Beneficial effect of BM in the NICU persisted between 18 mths and 30 mths CA

Vohr et al, Pediatrics 2006;118:e115-23; 2007;120:e953-959

Association of breast milk feeding of ELBW at 30 months (NICHD)

For every 10ml/kg / day increase in BM
q MDI increased by 0.59 points q PDI increased by 0.56 points q BRS percentile score by 0.99 points q Sepsis rate by 5% q Risk of rehospitalization by 5%

Maximum benefit 0-2 years

Vohr et al, Pediatrics 2007;120:e953-59;

Weighted Mean Difference in Cognitive Developmental Score between Breast-fed and Formula-fed by Duration of Breast-feeding
Duration 4 - 7 wk 8 - 11 wk 12 - 19 wk 20 - 27 wk 28 wk
Anderson et al, 1999

Mean Difference (breast-fed - forumula-fed) - 0.02 1.68 2.15 2.78 2.91

95% CI - 0.71, 0.67 1.12, 2.25 1.41, 2.88 1.94, 3.61 1.73, 4.09

Adjusted advantage in WISC IQ at age 8 years for breast-fed infants

Advantage Verbal Scale p + 7.7< .001 + 7.9< .0001

Performance Scale

Overall IQ + 7.6< .0001

(RCT donor milk or formula supplementation to BF infant)

Lucas et al, 1992

Co-variables of breast milk feeding and IQ at age 8 yrs

Significant multiple factors affecting IQ: p
Received breast milk Social class Mothers education Female gender Mechanical ventilation
Lucas, Lancet 1992

+ 8.3 IQ - 3.5 / class + 2.0 /group + 4.2 - 2.6 / week

< .0001 .0004 .01 .01 .02

How good is the evidence linking breast-feeding and intelligence?

Breast-feeding and adult intelligence

Contrary to the studies by Lucas et al, the mechanisms that link type of infant feeding with later intelligence may have more to do with the childs social environment than with the nutritional quality of human milk (UK Study)

Gale et al, Lancet 1996;347:1072-5

Systematic review of breast-feeding studies

q Of 40 publications 1929-01, 27 (68%) concluded

breast-feeding promotes intelligence

q Evidence from 2 best higher quality studies is

less persuasive
q Conflicting evidence regarding breast-feeding

and intelligence
Jain et al, 2002

Breast-feeding and cognitive development: Summary of meta-analysis

successive ages
BW: LBW showed larger differences (OR 5.18; CI 3.5, 6.7)

Age: benefit seen at 6 - 23 mths and differences stable over

than NBW (OR 2.66; CI 2.1, 3.1)

Dose effect: Cognitive benefit increased

with

duration of BF

Anderson J et al, 1999

Other Outcomes

Longer term health benefits due to breast-feeding

Protective effect against:
Obesity
Owen GG 05 Owen CG 06

Hyperlipidemia Hypertension

Martin RM 05 Gdalevich M01

Insulin resistance and Type 2 diabetes Atopic disease

Gdalevich M 01 Anderson J 99

Cognitive ability

Breast milk and later blood pressure

Evidence from 2 randomized trials 216 of 926 (23%), children 13-16 yrs:
Lower mean and diastolic BP in infants fed BM

+ DBM vs Term or Preterm formula (mean 81.9 vs 86.1, 95% CI -6.6 - 1.6, p< .0001)
Supports long-term beneficial effects of BM

(caution: ascertainment bias, despite no difference in those not followed)

Singhal, Cole, Lucas, 2001

Implications of decreased blood pressure

3mmHg in diastolic has substantial public

health implications
2mmHg reduces hypertension by 17%, risk of

coronary heart disease by 6%, and stroke and ischaemic attacks by 15%
Singhal, Cole, Lucas, 2001

HIV and Breast-feeding

HIV and breast-feeding in developed countries

Because of 15% risk of HIV infection, HIV infected

mothers universally do not BF their infants.

Risk of infection is particularly greater in the cell-

rich colostrum of BM

Shearer, Pediatrics 2008;121:1046-7

Breast-feeding and transmission of HIV-1 randomized trial in Kenya N = 212 breast fed and 213 formula fed
q Cumulative probability of HIV transmission to

infant was 36.7% in BF and 20.5% in FF

q The rate of HIV-1-free survival at age 2 yrs was

58% in BF vs 70.0% in FF (P = .02)

q Use of breast milk substitutes should be

considered
Nduati et al, JAMA 2000;283:1167-74

Breast-feeding and HIV+ve mother: Debate Dilemma highlighted in poor countries

q Avoidance of BF recommended, if affordable q Otherwise exclusive BF is recommended during

the first 4-6 months of life

q Antiretroviral therapy for the mother and / or

infant extended for 6 months offers a reduction in transmission of 50% while maintaining BF
Coutsoudis, Early Human dev 2005;81:87-93 Shearer, Pediatrics 2008;121:1046-7

Breast-feeding: Conclusions

Conclusions
q Small, but statistically significant advantages for breast-fed

children from 2 to 5 years

q Advantages more consistent for cognitive skills q Consistent dose response shown q Covariables such as maternal education and birth order

advantage needs to be considered

q Although effect size is small, BF offers the potential for

enhancing the childs development at no risk and little cost.

Conclusions contd
Overall, despite methodologic problems, the

advantages of breast-feeding premature infants far outweigh any risks

Further research with fortified breast milk in

hospital and post-discharge is essential

Monitoring of infant feeding during infancy is

encouraged exclusive BF for 6 months

Maternal benefits to breast-feeding

q Positive health benefits post-partum,

lower risk of breast and ovarian cancer

q Promotes maternal-infant attachment,

improves sense of self-esteem and success with mothering

Labbok 1999

Breast-feeding: Recommendations

Canadian & American guidelines for breast-feeding preterm infants

First choice is mothers milk Fortification of human milk until breast-

feeding is effective
Exclusive breast-feeding until age 4-6

months CA
Longer duration if possible and desired
Pediatrics 2005; 115:496-506

Challenges in breast-feeding premature infants

BF a VLBW infant is a challenging and

experience for the mother who is considerable stress due to worries separation and isolation.

exhausting undergoing about her infant,

Infant support non-nutritive sucking and oral

stimulation in NICU has resulted in earlier BF, earlier discharge Rocha07 and e rates after discharge Pimnta08

initiation of increased BF

Kangaroo care may promote breast-feeding

Breast-feeding in NICU
q Assume that all women will breast-feed q Encourage breast milk expression soon after

delivery and provide advice re collecting and transporting BM from home to NICU
q Skin-to-skin contact facilitates increase volume q Continued breast-feeding encouragement and

advice in NICU and post- discharge

Schanler et al, 1999

Human donor milk banks

q WHO recommendation 1980: human milk banks

should be made available to supply high-risk infants when mothers milk is unavailable.
q When donor milk is pasteurized, it effectively

inactivates HIV and other infections, but still retains immunological properties
q Benefits of donor milk banks outweigh the costs
Wight. J Perinatology, 2001; 21:249-54

Metabolic syndrome
q Infants fed HM vs PTF had lower growth in neonatal

period
q However, there were lower rates of obesity,

hypertension and leptin and insulin resistance

q Therefore, the goal should be to promote careful

nutrition support but not excessive growth or nutrient intake

Lucas 2005; Singhal 2001, 2002, 2003