Background:

An exclusive human milk diet (EHM) including fortification with a human milk-based fortifier has been shown to decrease the occurrence of necrotizing enterocolitis (NEC) but growth velocity may be less for infants receiving EHM compared to a bovine diet.

Objective:

The objective of this study was to determine if growth is improved by earlier fortification of breast milk for preterm infants supported with a human milk based fortifier.

Study design:

A multi-center retrospective cohort study of the outcomes of infants of 500– 1250 g birth weight whose breast milk feedings were fortified at >60 mL/kg/day (late) versus <60 mL/kg/day (early) of enteral feeding volume.

Results:

Median±IQR range for gestational age (27.6±3.4 vs 27.0±2.9 weeks, p = 0.03) and chronic lung disease (CLD: 42.6 vs 27.6%, p = 0.008) were higher, and weight gain (12.9±2.6 vs 13.3±2.6 g/kg/day, p = 0.03) was lower in the late (N = 102) vs the early (N = 292) group. Adjusted multiple linear regression analysis found that early fortification was associated with improved growth velocity for weight (p = 0.007) and head circumference (HC) (p = 0.021) and less negative changes in z-scores for weight (p = 0.022) and HC (p = 0.046) from birth to discharge. Adjusted multiple logistic regression found that early fortification was associated with decreased occurrence of CLD (p = 0.004). No other outcomes, including NEC, were associated with early versus late fortification.

Conclusion:

The study results suggested that early HM fortification appears to positively affect growth for infants whose human milk feedings are fortified with a human milk based fortifier without adverse effects. The incidence of CLD was also reduced in the early fortification group.

Background: Long-term outcomes of preterm infants fed an exclusive human milk-based (EHM) diet using a donor human milk-based fortifier are not well defined.

Materials and Methods: Infants ≤1,250 g birth weight (BW) were studied prospectively at two outpatient visits: 12–15 and 18–22 months corrected age (CA). Dual-energy X-ray absorptiometry and Bayley Scales of Infant and Toddler Development III (BSID-III) were performed at 18–22 months CA.

Results: In this pilot study, 51 preterm infants (gestational age 27.8 ± 2.6 weeks and BW 893 ± 204 g) were evaluated. While anthropometric z-scores were significantly lower at discharge compared with birth, z-scores returned to birth levels by 12–15 months CA (length and head circumference [HC]) and 18–22 months CA (weight). Body composition at 2 years of age was similar to term-matched controls. Inpatient growth was significantly correlated with bone density, lean mass (LM), and fat-free mass at 18–22 months CA. Increased mother's own milk (MOM) was significantly correlated with decreased fat mass indices. BSID-III showed that 0% of cognitive composite scores were <70.

Conclusions: In addition to returning to BW, length, and HC z-scores by 2 years of age, body composition analysis revealed that increase in body size was appropriate as reflected by LM and bone density similar to matched term controls without an increase in fat mass. No child had severe cognitive developmental delay using a cutoff score of 70. Inpatient growth and increased receipt of MOM correlated with favorable growth and body composition outcomes. Positive outcomes as shown in this study to confirm postdischarge safety of an EHM diet during hospitalization.

For preterm and very low birthweight infants, the mother’s own milk is the best nutrition. Based on the latest information for mothers who give birth to preterm and very low birthweight infants, medical staff should encourage and assist mothers to pump or express and provide their own milk whenever possible.

(2) If the supply of maternal milk is insufficient even though they receive adequate support, or the mother’s own milk cannot be given to her infant for any reason, donor human milk should be used.

(3) Donors who donate their breast milk need to meet the Guideline of the Japan Human Milk Bank Association.

(4) Donor human milk should be provided according to the medical needs of preterm and very low birthweight infants, regardless of their family’s financial status.

(5) In the future, it will be necessary to create a system to supply an exclusive human milk‐based diet (EHMD), consisting of human milk with the addition of a human milk‐derived human milk fortifier, to preterm and very low birthweight infants.

Objective: An increasingly common practice is to feed preterm infants a base diet comprising only human milk (HM), usually fortified with a cow's milk (CM)-derived fortifier (CMDF). We evaluated the safety of CMDF in a diet of 100% mother's own milk (MOM) against a HM-derived fortifier (HMDF). To date, this has received little research attention.

Study Design: We reanalyzed a 12-center randomized trial, originally comparing exclusive HM feeding, including MOM, donor milk (DM), and HMDF, versus a CM exposed group fed MOM, preterm formula (PTF), and CMDF1. However, for the current study, we performed a subgroup analysis (n = 114) selecting only infants receiving 100% MOM base diet plus fortification, and fed no DM or PTF. This allowed for an isolated comparison of fortifier type: CMDF versus HMDF to evaluate the primary outcomes: necrotizing enterocolitis (NEC) and a severe morbidity index of NEC surgery or death; and several secondary outcomes.

Results: CMDF and HMDF groups had similar baseline characteristics. CMDF was associated with higher risk of NEC; relative risk (RR) 4.2 (p = 0.038), NEC surgery or death (RR 5.1, p = 0.014); and reduced head circumference gain (p = 0.04).

Conclusions: In neonates fed, as currently recommended with a MOM-based diet, the safety of CMDF when compared to HMDF has been little researched. We conclude that available evidence points to an increase in adverse outcomes with CMDF, including NEC and severe morbidity comprising NEC surgery or death.

Objective

To conduct a systematic review and meta-analysis of the efficacy and safety of fortification of human milk with human milk-based fortifier versus cow’s milk-based fortifier for use in preterm and/or very low birthweight infants.

Design

Randomised or quasi-randomised controlled trials comparing the effect of human milk fortification with human milk-based milk fortifier versus cow’s milk-based fortifier in infants born <34 weeks’ gestation and/or with birth weight <1500 g were identified by searching databases, clinical trial registries and reference lists until 5 November 2019. Two authors independently extracted data and assessed evidence quality. Meta-analyses were conducted using fixed or random effects models, as appropriate.

Main outcome measures

Necrotising enterocolitis (Bell’s stage II or higher) and late-onset sepsis.

Results

Of 863 unique records identified, 16 full-text trials were screened and 2 trials involving 334 infants were included. Primary outcome data were available for 332 infants. Use of human milk-based fortifier compared with cow’s milk-based fortifier reduced the risk of necrotising enterocolitis (risk ratio 0.47, 95% CI 0.22 to 0.98). There was no clear evidence of an effect on late-onset sepsis or any other outcomes. The quality of evidence was low to very low due to imprecision and lack of blinding in one study.

Conclusions

Findings suggest that there is a reduction in the incidence of necrotising enterocolitis with human milk-based fortifiers compared with cow’s milk-based fortifiers. The overall quality of evidence is low. Further appropriately powered trials are required before this intervention can be routinely recommended for preterm infants.

Objective

Compare the incidence of severe (grade III/IV) intraventricular hemorrhage (IVH) and/or periventricular leukomalacia (PVL) between two groups of ELBW infants based on diet until 34 weeks corrected gestational age (CGA): (1) Exclusive human milk (EHM)—mother’s own and/or pasteurized donor human milk, human milk-derived fortifier, and oral care with colostrum/human milk vs. (2) non-EHM—bovine formula or mother’s own milk with bovine-derived fortifier.

Study design

Retrospective observational study of two groups of ELBW infants based on diet until 34 weeks CGA.

Result

There were n = 306 infants, 127 EHM and 179 non-EHM. Demographics and morbidities were similar except higher antenatal steroids and NEC in EHM group. The rate of severe IVH/PVL was lower in EHM compared to non-EHM group (7 vs. 18%, p < 0.006).

Conclusion

EHM diet had an independent neuroprotective effect and was associated with decreased incidence of severe IVH/PVL, supporting the need of EHM in ELBW infants.

Recently we published a meta-analyses of morbidity seen with the use of cow’s milk derived fortifier (CMDF) rather than human milk derived fortifier (HMDF) in very low birthweight (VLBW) infants. Here, we further analyse these data to estimate the annual population risk of CMDF-related major morbidity in the United States and Canada. The outcome used was a mortality/morbidity index which was positive if the infants had one or more of death, necrotising enterocolitis, sepsis retinopathy of prematurity or bronchopulmonary dysplasia. Using the risk difference (RD) between the CMDF and HMDF groups we estimated, provisionally, that 4150 additional VLBW infants in the United States and Canada each year, or an additional infant approximately every 2 hours, may be expected to develop a positive mortality/morbidity index in relation to being fed CMDF – over and above the number of infants with a positive index if fed HMDF. We provide an in-depth discussion of the limitations of our estimate. This analysis provides preliminary evidence of the magnitude of population risk of major neonatal morbidity with use of CMDF versus HMDF in VLBW infants in current practice.

Background: Spontaneous intestinal perforation (SIP) and necrotizing enterocolitis (NEC) are complications of extremely low birth weight (ELBW, ≤1000 g) infants. ELBW infants at Texas Children's Hospital receive an exclusive human milk-based diet, which has been associated with a reduction of NEC.

Objectives: 1) Assess incidence of SIP and NEC (Stage II or greater) in ELBW infants receiving 100% human milk-based diet, 2) Describe mortality rates of ELBW infants with SIP and NEC.

Methods: Prospective single-center observational cohort study of ELBW infants born between 2010 and 2014 with SIP or NEC (exclusion: congenital anomalies and death within 48 h).

Results: Of 379 ELBW infants, 345 were eligible. Of these, 28 (8.1%) had SIP and 8 (2.3%) had NEC (medical n = 1, surgical n = 7). SIP infant mortality was 32% (n = 9) compared to 63% (n = 5) for NEC patients. Of SIP infants with PD (n = 25), 52% required subsequent exploratory laparotomy (LAP). Of NEC infants with peritoneal drainage (PD) (n = 2), both required subsequent LAP.

Conclusion: Using an exclusive human milk-based diet, the incidence of SIP exceeds NEC in ELBW infants at our institution. This shows a changing trend in the incidence of these two diagnoses in the era of human milk, as NEC had previously been more prevalent in ELBW infants. More than half of infants who initially received PD later required LAP. There were no differences in survival outcomes in both SIP and NEC groups based on surgical management.

Background: Several studies have confirmed the benefits of an exclusive human milk diet for premature infants; however, a donor human milk-based fortifier has not been available in Japan.

Case Presentation: A donor human milk-based fortifier was recently used for the first time ever in Japan, given in conjunction with mother’s own milk to three premature infants. Details of these three infant case studies are reported here. These infants received the donor human milk-based fortifier as part of a rescue nutritional intervention due to poor weight gain in the presence of meconium ileus and perforation. Infants demonstrated good tolerance and weight gain while receiving the exclusive human milk diet.

Conclusion: This is the first report of infants receiving an exclusive human milk diet in Japan, consisting of mother’s own milk with a donor human milk-based fortifier for additional calories and nutrients. Infants demonstrated good tolerance and experienced improved weight gain while receiving the product.

Background:

Very low birthweight (VLBW) preterm infants fed mothers own milk (MOM) need nutritional supplementation, tra-ditionally achieved with cow's milk (CM) derived fortifier CMDF) and preterm formula (PTF) if MOM is insufficient. CM products have been associated with diverse major morbidities. The current recommendation is to preferentially replace PTF with donor milk (DM) to produce a 100% human milk (HM) base diet, usually forti-fied with CMDF.

Objective:

To identify whether CMDF, even when fed with a 100% HM base diet, is related to an increased risk of major morbidities.

Methods:

We identified a randomized trial with an all-HM base diet, comparing CMDF with a fortifier derived from human milk (HMDF), and two additional studies of this design were generated from raw data as subgroup analyses of a randomized con-trolled trial and a quasi-experimental study. Using these studies, we calculated the impact of CMDF on major morbidities of death, necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), sepsis, bronchopulmonary dysplasia (BPD) and patent ductus arteriosus (PDA).

Results:

Each study individually provided support for an increase in major morbidities with CMDF. Meta-analyses of pooled data showed that compared to HMDF, the CMDF group had large in-creases in NEC (RR=3.3; P=0.001), ROP (RR=2.2; P=0.007), PDA (RR=1.6; P=0.009), interruption of feeding (RR=3.4; P=0.001) and a positive mortality/morbidity index based on one or more of death, NEC, sepsis, ROP and BPD (RR=1.4; P=0.006).

Conclusions:

Despite the increased use of HM in modern neonatal care as a base diet, we found a greater risk of critical morbidities with CMDF compared with HMDF. This burden of morbidity provides evidence that the benefits of an HM base diet, might be, in part, counteracted by multiple adverse outcomes relating to the use of CMDF.

Background:

An exclusive human milk diet (EHM) including fortification with a human milk-based fortifier has been shown to decrease the occurrence of necrotizing enterocolitis (NEC) but growth velocity may be less for infants receiving EHM compared to a bovine diet.

Objective:

The objective of this study was to determine if growth is improved by earlier fortification of breast milk for preterm infants supported with a human milk based fortifier.

Study design:

A multi-center retrospective cohort study of the outcomes of infants of 500– 1250 g birth weight whose breast milk feedings were fortified at >60 mL/kg/day (late) versus <60 mL/kg/day (early) of enteral feeding volume.

Results:

Median±IQR range for gestational age (27.6±3.4 vs 27.0±2.9 weeks, p = 0.03) and chronic lung disease (CLD: 42.6 vs 27.6%, p = 0.008) were higher, and weight gain (12.9±2.6 vs 13.3±2.6 g/kg/day, p = 0.03) was lower in the late (N = 102) vs the early (N = 292) group. Adjusted multiple linear regression analysis found that early fortification was associated with improved growth velocity for weight (p = 0.007) and head circumference (HC) (p = 0.021) and less negative changes in z-scores for weight (p = 0.022) and HC (p = 0.046) from birth to discharge. Adjusted multiple logistic regression found that early fortification was associated with decreased occurrence of CLD (p = 0.004). No other outcomes, including NEC, were associated with early versus late fortification.

Conclusion:

The study results suggested that early HM fortification appears to positively affect growth for infants whose human milk feedings are fortified with a human milk based fortifier without adverse effects. The incidence of CLD was also reduced in the early fortification group.

Human milk from the preterm's own mother is the enteral feeding of choice.

Background: An exclusive human milk (EHM) diet in extremely low birth weight (ELBW) infants (birth weight ≤1,000 g) is linked to an increased likelihood of extrauterine growth restriction (EUGR, weight <10% at discharge). Past studies associated EUGR with worse neurodevelopmental (ND) outcomes; however, its impact when an EHM diet is used is unknown.

Objective: Determine whether EUGR adversely affects 2-year ND outcomes of ELBW infants fed an EHM diet. Secondary aims were to compare short-term morbidities and growth through 2 years corrected age (CA).

Materials and Methods: Prospective cohort study of ELBW infants fed an EHM diet until 34 weeks corrected gestational age and assessed at 2 years CA. ND outcomes between EUGR and non-EUGR infants were compared using the Bayley Scales of Infant Development 3rd Ed (BSID-III).

Results: Eighty-one ELBW infants survived, 44 were seen for follow-up, and 16 (36%) were EUGR. Baseline characteristics and Neonatal Intensive Care Unit (NICU) morbidities were similar. There were no statistically significant differences (median [25–75%]) between EUGR and non-EUGR groups in cognition, (90 [80–99] versus 95 [90–104]), language (84 [68–105] versus 89 [75–100]), or motor composite scores (87 [74–96] versus 91 [88–96]). Weight z-scores during NICU stay dropped in both groups, more pronounced for the EUGR infants. There was no difference in linear or head growth.

Conclusion: In our institution, ND outcomes at 2 years CA for ELBW infants fed an EHM diet were similar regardless of EUGR status. This suggests a neuroprotective effect of EHM diet in the ELBW population, despite weight gain velocity during NICU stay.