Hospital Outcomes of Extremely Low Birth Weight Infants After Introduction of Donor Milk to Supplement Mother's Milk

Abstract

Aim:

This study evaluated the impact of an exclusive human milk diet to nourish extremely low birth weight infants in the neonatal intensive care unit.

Materials and Methods:

This multicenter pre–post retrospective study included all inborn infants <1,000 g admitted to four Level IV neonatal intensive care units either before or after implementing a donor human milk policy. The feeding protocol was unchanged in both periods. Collected data included maternal/infant demographics, infant clinical data, and enteral intake as mother's own milk, donor milk, and formula.

Results:

Two hundred one infants were enrolled. Infant growth and other clinical outcomes were similar in both groups. Exposure to mother's own milk at discharge was not different. Median time in oxygen and duration of mechanical ventilation were significantly higher among formula-fed infants (63 versus 192 hours [p=0.046] and 24 versus 60 hours [p=0.016], respectively).

Conclusions:

Our results add evidence supporting the safety of donor milk. This study also found an association between exposure to formula in preterm infants and the requirement for respiratory support, a finding that warrants further investigation.

Introduction

The health and developmental benefits of human milk for very low birth weight (VLBW) (<1,500 g) infants are well documented and continue to be reported.^1–3 To date, every study has shown beneficial effects of human milk feedings on clinical outcomes of preterm infants.⁴ In the preterm infant population, key factors influencing breastfeeding include infant health complications,^5,6 concerns about breastmilk insufficiency,⁷ poor infant latch, and lack of effective pumping.⁸ Because not all mothers of preterm infants produce sufficient milk to meet their infants' needs⁹ and some have medical contraindications,¹⁰ donor human milk (DM) has emerged as an alternative to mother's own milk (MOM).¹¹

Usually, DM is pasteurized, which, in combination with container changes and freeze/thaw cycle, can affect nutrient composition.^12,13 For this reason, the safety of DM must be considered separately from that of MOM when reviewing the literature. Despite the recent increase in DM utilization,¹⁴ there may be skepticism among healthcare workers around safety of DM. A speculative concern has been voiced among neonatologists that introducing DM may discourage efforts of mothers to produce their own milk,¹⁵ and a big concern in providing human milk to premature infants is suboptimal growth. We did not seek to investigate whether infants fed on DM had a better outcome than those fed on formula milk, as this has already been established as concluded in a Cochrane Review.¹⁶ This meta-analysis found that feeding with DM compared with formula is associated with a halving of the risk of developing necrotizing enterocolitis (NEC) but may decrease rates of short-term growth in low birth weight infants. Paradoxically, the poor postnatal weight gain of preterm infants may be protective against adverse long-term metabolic consequences.¹⁷ At present, there are two multicenter randomized control trials underway whose aim is to assess the impact of receiving DM as compared with formula when MOM is not available for VLBW infants: the American Milk Trial¹⁸ and the Canadian Donor Milk for Improved Neurodevelopmental Outcomes Trial.¹⁹

In our neonatal intensive care units (NICUs), we recently implemented the strategy to use DM for preterm infants whose mothers suffered from breastmilk shortage. We decided to analyze our data in order to verify the safety of providing DM.

Materials and Methods

Overview

We conducted a retrospective analysis of available data from all extremely low birth weight (ELBW) infants (weighing <1,000 g) admitted to the NICUs of four university hospitals in Barcelona—Sant Joan, Clinic, Dexeus, and Sant Pau—before and after the introduction of a policy of providing DM if MOM was not available in sufficient quantity to meet her infant's need. Neonates with congenital malformation were excluded. DM supplementation is standard of care for Sant Pau and Dexeus because it has become a routine process of health care. We use the term “preferred alternative” for Sant Joan and Clinic, as these units require informed consent for DM supplementation. We reviewed infants over a 6-year period and compared infants with any DM with those with formula.

We defined “exclusive diet of human milk” (HM) as feeding babies with no other milk, apart from DM alone or DM plus MOM. In addition, we defined “any formula” (PF) as feeding infants with any amount of preterm formula that is an addition of nutritional supplements for MOM (MOM plus preterm formula).

We compared outcomes of ELBW infants who received HM with those who received PF. DM has been available in the Sant Pau and Clinic NICUs since April 2009, in the Dexeus NICU since January 2010, and in the Sant Joan NICU since July 2011. Before the introduction of DM, feedings consisted of PF when there was an insufficient MOM supply. We arbitrarily chose the interval 2006–2012, as it is wide enough for us to be sure that we collect a convenience sample, but close enough to ensure that minimal changes in unit policies had occurred. Inclusion of standardized common variables allowed the four databases to be merged to prepare a common file for analysis of hospital outcomes that included infants in Sant Pau and Clinic from 2006 to 2012. No infants were found common in these databases. Institutional review boards at each study site reviewed and approved the consent process and the study protocol. Permission was obtained from at least one of the child's parents or the child's guardian so that data for research could be used.

Feeding policy

Trophic feeding (unfortified HM or PF) was introduced as soon as possible, usually within the first 24–48 hours of life. If human milk was not available or consent was not obtained, feeds were not held. Mothers were also encouraged to provide their own milk by initiation of breastmilk pumping in the first 12 hours. After a period of a few days of priming the infant's intestine, feedings were advanced at a rate of 15–30 mL/kg/day depending on the size, maturity, and feeding tolerance of the infant. When enteral feeds reached 120 mL/kg/day, all HM was fortified, and parenteral nutrition was discontinued. When infants tolerated 150 mL/kg/day of enteral feeds, replacement of fortified DM with PF was considered.

Preparation of DM

Initially, pasteurized DM was supplied to our four NICUs by the milk bank of the Balearic Islands (the first one to be opened in Spain). The milk bank of Barcelona was opened in 2011. Thereafter, it supplied our four NICUs with pasteurized DM. Milk banks in Spain are unregulated, except for the voluntary adoption of standards of practice laid down by the Spanish Association of Milk Banks (www.aeblh.org). The same guidelines apply for the Balearic milk bank and the milk bank of Barcelona. All donor mothers donate their milk for altruistic reasons. All mothers must undergo rigorous screening before donation, including an interview, medical approval, and serology. Once accepted as a donor, a mother is taught the techniques for safe collection and storage of her milk. She may express multiple feeds per day. This milk is then frozen, stored, and transported to the milk bank. At the milk bank, the milk is batched from up to four different mothers. The milk is then thawed, and a bacterial culture is taken. The milk then undergoes Holder pasteurization (62.5°C for 30 minutes) in an industrial-grade pasteurizer and is recultured. The milk is again frozen while awaiting final culture results. When an order for DM is received at the milk bank, the milk is transported, thawed, and dispensed as required.²⁰ These processes are consistent with published guidelines such as those from the United Kingdom Association of Human Milk Banks.²¹

Preterm infant formula

The same type was used in Sant Joan and Sant Pau Hospitals (Alprem^®; Nestlé Spain, Esplugues de Llobregat, Spain). Dexeus' ELBW infants received Nenatal^® (Nutricia Spain, Madrid, Spain). Clinic's ELBW infants received a mixture of Alprem^® and Prematura^® (Sandoz Spain, Madrid).

Data collection

All data were extracted from the Spanish medical and nutritional prospective VLBW network database, SEN1500 (which includes all infants weighing less than 1,500 g at birth), by a single investigator at each study site. Major morbidities were collected²²: proven early or late-onset sepsis (positive blood culture), bronchopulmonary dysplasia, intraventricular hemorrhage, retinopathy of prematurity, NEC, patent ductus arteriosus, respiratory status, oliguria, parenteral nutrition and any serious adverse event. Weight, head circumference (HC), and length were converted to standard deviation (z-scores) and corrected for postnatal age, using a recognized scale, the widely used and validated Fenton growth chart. Changes in z-scores were calculated by subtracting the current z-score from that at birth.

Statistics

Two sets of analyses were undertaken. First, descriptive characteristics of those children and their mothers who took part in the study were reported. The Kolmogorov–Smirnov test was used to decide if the sample belongs to a population with a normal distribution. All data except birth weight were highly skewed and not normally distributed. The only variables with p<0.10 in the univariate model were duration of mechanical ventilation and time in oxygen (which are not independent variables); therefore, parametric multivariate analysis was not performed. Nonparametric regression requires larger sample sizes than regression based on parametric models because the data must supply the model structure; one branch of our sample (PF) contained only 53 subjects, so therefore nonparametric analysis was not performed. Second, occurrence of major morbidities was analyzed. Results were considered significant at p<0.05. The Mann–Whitney U test was used for comparison of continuous data to avoid assumption of normal distribution. It was used because there are two groups for comparison: HM versus PF diets. Quantitative parameters are reported as medians with interquartile range (25th and 75th percentiles); qualitative parameters are reported as percentages.

Results

In the present study, 148 HM and 53 PF ELBW infants were enrolled, and 166 infants survived to discharge (119 HM and 47 PF). Neonatal survival was not affected by diet (p=0.2).

The HM and PF groups had similar baseline characteristics (Table 1). There were no differences in neonatal variables (gestational age, twin pregnancy, gender, or type of delivery) or in postnatal variables (Apgar score, patent ductus arteriosus, and use of cardiotonic agents or exogenous surfactant therapy). Growth parameters did not differ between the groups. Our incidence of cesarean section (CS) ranged from 59% to 61%.

Table 1.

Patients' Characteristics

Variable	HM (n=148)	PF (n=53)	p value
Prenatal
In vitro fertilization	17.1%	15.7%	0.82
No maternal antenatal steroids	9.2%	8.6%	0.2
Neonatal
Gestational age (days)	185 (161–236)	190 (166–239)	0.19
Twin pregnancy	32.2%	31%	0.88
Birth weight (g)	800 (410–995)	830 (440–998)	0.43
Birth weight z-score	−0.4 (−3.2 to 1.9)	−0.8 (−3.6 to 1.3)	0.06
Birth length (cm)	33.5 (31.5–35.0)	34.0 (32.0–36.0)	0.42
Birth length z-score	−0.66 (−1.93 to 0.13)	−0.60 (−1.69, 0.20)	0.52
Birth HC (cm)	23.5 (22.0–25.0)	23.75 (22.0–25.0)	0.45
Birth HC z-score	−1.1 (−2.1, −0.1)	−1.4 (−2.0, −0.7)	0.62
Gender (male/female)	58%/42%	50%/50%	0.3
Delivery type (vaginal/CS)	38%/61%	41%/59%	0.7
Postnatal
Apgar score
1-minute	5 (0–10)	6 (1–9)	0.39
5-minute	8 (1–10)	9 (4–10)	0.24
Epinephrine	3%	5%	0.4
Chest compressions	3%	5%	0.58
Cardiotonic agents	37%	28%	0.19
Surfactant use	26.6%	31%	0.48

Data are percentages or median (interquartile range) values, as indicated.

CS, cesarean section; HC, head circumference; HM, mother's milk and/or donor milk; PF, any formula.

Outcomes at hospital discharge are shown in Table 2, grouped by feeding type. No difference was detected between the two groups with respect to breastfeeding rate at discharge (69.5% versus 66.7% [p=0.74]). Median time in oxygen and duration of mechanical ventilation were significantly higher among formula-fed infants (63 versus 192 hours [p=0.046] and 24 versus 60 hours [p=0.016], respectively). Receipt of an exclusive diet of HM was not associated with lower rates of NEC (p=0.36) or infections (p=0.67). Common neonatal morbidities or change in weight, length, or HC z-score from birth to discharge did not differ significantly by milk type.

Table 2.

Hospital Outcomes

Variable	HM (n=148)	PF (n=53)	p value
Breastfeeding rate at discharge	69.5%	66.7%	0.74
Parenteral nutrition on Day 28	21.8%	14.8%	0.28
No ROP	48.7%	40.4%	0.53
ROP surgery	7.7%	10.3%	0.58
Any NEC	15.4%	20.7%	0.36
NEC surgery	7%	10.3%	0.4
Intestinal perforation	5.6%	8.6%	0.53
Early-onset sepsis	3.5%	1.7%	0.67
Blood red cell transfusion	75%	70.2%	0.49
Acute renal failure	9.8%	15.8%	0.23
Late-onset sepsis	42.3%	41.4%	0.91
Blood culture positive for CoNS	31.7%	27.6%	0.57
IVH grades 3–4	17.6%	7.1%	0.17
Weight (g) on
Day 28	999 (625–1980)	1,063 (456–1580)	0.41
Gestational Week 36	1,655 (1,007–2,320)	1,745 (853–2,550)	0.61
Change in z-score from birth to discharge
Weight	−1.6 (−2.4 to 0.8)	−1.4 (−2.0 to −0.9)	0.54
Length	−1.7 (−2.3 to −0.9)	−2.0 (−2.8 to −1.5)	0.84
HC	−0.2 (−0.8 to 0.9)	−0.01 (−0.9 to 1.0)	0.90
Length of stay (days) in
Intensive care	32 (3–158)	31.5 (4–118)	0.47
Hospital	73 (2–183)	72.5 (6–177)	0.63
Postconceptional age (days) at discharge	268 (170–379)	266 (180–359)	0.64
Medication use in PDA			0.053
Indomethacin	12%	24%
Ibuprofen	49%	50%
None	39%	26%
Surgical ligation of PDA	18.3%	19%	0.91
CPAP on Day 28	36.1%	31.5%	0.55
Nitric oxide	8.6%	1.7%	0.11
Duration (hours) of mechanical ventilation	24 (0–2400)	60 (0–1,248)	0.016a
Time (hours) in oxygen	63 (0–4,200)	192 (0–2,040)	0.046a
Death	19.6%	12.1%	0.2

Data are percentages or median (interquartile range) values, as indicated.

Represents a significant difference.

CoNS, coagulase-negative staphylococci; CPAP, continuous positive airway pressure; HC, head circumference; HM, mother's milk and/or donor milk; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; PF, any formula; ROP, retinopathy of prematurity.

Discussion

CS rates

Our incidence of CS is approximately 60%. It is double that reported in most countries for term births. The CS delivery rate has risen dramatically over the past two decades, but it is particularly elevated in preterm deliveries. Approximately 50% of neonates born before 34 weeks of gestation in the United States or Japan and 80% of growth-restricted fetuses in European countries are delivered by CS.²³

Although the changes in behavioral factors may contribute to the rise in the proportion of CS, obstetricians may also be prone to conduct CS in a more proactive manner. Overall, the optimal mode of delivery for women thought to be in preterm labor is controversial, but CS does seem to provide survival advantages for the most immature infants.²⁴ Accordingly, it can be inferred that obstetricians may intervene appropriately (i.e., conduct necessary interventions at appropriate periods).

Formula replacement

The onset of copious milk production (lactogenesis stage II) is often delayed in mothers who deliver ELBW infants.²⁵ Historically, many NICUs have provided PF early in hospitalization to infants whose mothers intend to exclusively breastfeed but whose milk supply is delayed; offering DM provides these mothers with another HM option. With the initiation of DM programs in Level IV NICUs in Barcelona, there has been a significant increase in the use of DM and a proportionate decrease in PF feedings. Provision of PF early in hospitalization has largely disappeared with the advent of DM trophic feeds. But as this program provided DM only until full enteral feeds, by the third week of hospitalization, infants not receiving MOM transitioned to PF.

Breastfeeding rate at discharge

Pasteurized DM is a dietary intervention that is increasing in usage in the VLBW population.¹⁴ Concerns have been expressed prior to the DM policy implementation that the use of DM might undermine breastfeeding.²⁶ Our four-center pre–post observational study is in line with recent reports that have not observed decrease in use of MOM.^27,28 We found that despite the increase in DM from 2006 to 2012, provision of MOM remained constant, indicating that offering DM did not negatively influence mothers to provide their own milk to their preterm infants in our NICUs.

Respiratory support

This study found an association between exposure to PF in ELBW infants and the requirement for respiratory support. This is in agreement with data from a recent study by Marinelli et al.²⁷ The aim of their work was to establish whether the introduction of DM discouraged maternal efforts to produce MOM; within the data presented in their report, they provide the evidence for less oxygen requirements associated with introduction of DM as a supplement.

NEC

Our study was not sufficiently powered to detect differences in NEC. Three meta-analyses have shown a reduction in NEC incidence in neonates fed DM versus formula.^16,29,30 The most recent Cochrane Review of formula-fed versus DM-fed preterm infants¹⁶ concluded that there was a decreased rate of NEC in infants who were supported with DM, with the number needed to treat to benefit of 25.

Infections

Our study did not show significant differences in rate of sepsis by feeding type. de Silva et al.³¹ published a systematic review including nine studies regarding the relationship between infection and human milk in VLBW infants. The authors' conclusions from all nine studies indicated that HM had a protective effect in reducing infection when compared with formula milk. According to their data, in order to detect this difference in a future study, 64 patients are required in each group with an addition for dropout. The population of our formula group is below this number.

In-hospital growth

Accelerated postnatal head growth is enhanced by exposure to breastmilk. This contrasts with the slower weight gain of breastfed infants than formula-fed infants. Colaizy et al.³² reported that infants fed >75% human milk experience significantly larger decreases in weight z-score from birth to discharge compared with infants fed <75%. In addition, the study of Schanler et al.³³ showed a weight z-score change of −1.86 for the human milk group compared with a weight z-score change of −1.34 for the formula group. O'Connor et al.³⁴ also found a negative dose–response relationship between human milk intake and in-hospital growth, with the largest decline seen among those fed the most human milk (−1.62) and the least decline seen with exclusive formula feeding (−0.64). The Cochrane Review¹⁶ of formula-fed versus DM-fed preterm infants concluded that formula-fed infants had higher in-hospital rates of increase in weight, length, and head circumference. Conversely, Cockerill et al.³⁵ reported a significant positive impact of breastmilk on HC z-score change from birth to discharge in a contemporary cohort of infants ≤32 weeks of gestation. Here we report no difference of weight, length or HC z-score from birth to discharge for HM versus PF infants. We also report that the decline in HC z-score between birth and discharge (−0.2 for HM infants and −0.01 for PF infants) is less significant than the weight or length decline. This is in agreement with previous reports on failure in weight and length gain among VLBW infants,^36,37 with greater variation in head growth.³⁸

Limitations

The primary use of our data is to support establishing a new DM program and to generate baseline data for future research. The pre–post design of this study reflects this. We were able to eliminate the possibility of reverse causality as neonatal complications were similar and were not the reason for the receipt of DM.

Our study's weaknesses include the limited sample size and observational nature. Our small sample size prohibited us from detecting any differences in relevant clinical outcomes such as rates of sepsis or NEC. This study was limited to time to achieve full enteral feeds. Accordingly, we could not assess any effect on length of hospitalization. In addition, we collected growth z-score data only at birth and discharge and were not able to assess the timing of the lowest growth z-score experienced by the infants or how the trajectory of growth may have changed from day to day or week to week during hospitalization.

Nonparametric methods have been used to analyze skewed data. The principal limitation of nonparametric methods is that they are not as powerful as parametric methods, which are based on a known underlying distribution: in cases where a parametric test would be appropriate, a larger sample size can be required to draw conclusions from nonparametric tests with the same degree of confidence.^39,40

Because this is a purely observational cohort on neonatal morbidities, it is not possible at this stage to identify specific changes in management that potentially could have led to improved outcomes over time. Further study is needed to determine whether these results generalize to other settings.

Conclusions

We demonstrate that in-hospital growth of ELBW infants can be adequate with predominant HM diets, both MOM and DM derived.

In addition, the use of DM did not decrease the provision of MOM, but replaced formula in the first 2 weeks of life.

Finally, our study supports findings from a previous study²⁷ suggesting that oxygen requirements can be decreased in ELBW infants when they are fed an HM diet versus a diet that contains PF.

Footnotes

Acknowledgments

We thank the families of patients who agreed to participate in the study. The authors would like to acknowledge the nurses and pediatricians working at the NICUs. We thank Dr. Toni Gayà and Dr. Gemma Valeta for running the breastmilk banks during the period of the study. We thank Berta Verd, MSc, for editing the manuscript and Dr. Jane Hawdon for helpful comments on the draft manuscript.

Disclosure Statement

No competing financial interests exist.

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