Cost Savings of Mother's Own Milk for Very Low Birth Weight Infants in the Neonatal Intensive Care Unit.

OBJECTIVE: The study aim was to determine the relationship between hospitalization costs and mother's own milk (MOM) dose for very low birth weight (VLBW; < 1500 g) infants during the initial neonatal intensive care unit (NICU) stay. Additionally, because MOM intake during the NICU hospitalization is associated with a reduction in the risk of late-onset sepsis, necrotizing enterocolitis (NEC), and bronchopulmonary dysplasia (BPD), we aimed to quantify the incremental cost of these potentially preventable complications of prematurity. METHODS: The study included 430 VLBW infants enrolled in the Longitudinal Outcomes of Very Low Birthweight Infants Exposed to Mothers' Own Milk prospective cohort study between 2008 and 2012 at Rush University Medical Center in Chicago, IL, USA. NICU hospitalization costs included hospital, feeding, and physician costs. The average marginal effect of MOM dose and prematurity-related complications known to be reduced by MOM intake on NICU hospitalization costs were estimated using generalized linear regression. RESULTS: The mean NICU hospitalization cost was $190,586 (standard deviation $119,235). The marginal cost of sepsis was $27,890 (95% confidence interval [CI] $2934-$52,646), of NEC was $46,103 (95% CI $16,829-$75,377), and of BPD was $41,976 (95% CI $24,660-59,292). The cumulative proportion of MOM during the NICU hospitalization was not significantly associated with cost. CONCLUSIONS: A reduction in the incidence of complications that are potentially preventable with MOM intake has significant cost implications. Hospitals should prioritize investments in initiatives to support MOM feedings in the NICU.

Mother's Own Milk Biomarkers Predict Coming to Volume in Pump-Dependent Mothers of Preterm Infants.

OBJECTIVE: To assess serial secretory activation biomarker concentrations (sodium [Na], potassium [K], Na:K, protein, lactose, and citrate) in mother's own milk (MOM) from breast pump-dependent mothers of preterm infants to determine associations with coming to volume (CTV), defined as producing at least 500 mL/day MOM by day 14 postpartum. STUDY DESIGN: We collected serial MOM samples and pumped MOM volume data for 14 days postpartum in mothers who delivered at <33 weeks of gestation. Regression models and the Mann-Whitney U test were used to evaluate associations. RESULTS: Among 40 mothers, 39 (mean gestational age, 28.8 weeks; 67% overweight/obese; 59% nonwhite) had paired MOM volume and biomarker data; 33% achieved CTV between postpartum days 6 and 14. In univariate models, MOM Na on postpartum day 5 and Na:K on days 3 and 5 were associated with CTV. Mothers achieving CTV were more likely to have postpartum Na:K ≤1 on day 3 (75% vs 25%; P = .06) and ≤0.8 on day 5 (69% vs 10%; P < .01). In a multivariable regression model, day 5 Na:K (1 unit decrease in Na:K: OR, 18.7; 95% CI, 1.13-311.41; P = .049) and maternal prepregnancy body mass index (BMI) (1 unit increase in BMI: OR, 0.88; 95% CI, 0.78-0.99; P = .04) were associated with CTV between postpartum days 6 and 14. CONCLUSIONS: Secretory activation and CTV were compromised in breast pump-dependent mothers with preterm delivery. CTV was predicted by MOM Na level and Na:K. These biomarkers have potential as objective point-of-care measures to detect potentially modifiable lactation problems in a high-risk population.

REVIEW OF OPHTHALMIC AND BREASTFEEDING MEDICINE EVIDENCE: Real and Theoretical Risks of Intravitreal Anti-Vascular Endothelial Growth Factor Administration in Lactating Women.

BACKGROUND/PURPOSE: There is limited research regarding the consequences of treating lactating mothers with intravitreal anti-vascular endothelial growth factor (VEGF) agents. Balancing the need for vision-saving treatment, the benefits of breastfeeding, and the concern for affecting the newborn can present a conflict for both mothers and ophthalmologists. This review summarizes the state of the literature regarding the use of intravitreal anti-VEGF agents during breastfeeding along with details about their pharmacology. RESULTS: Bevacizumab and aflibercept have Fc domains subjecting them to FcRn recycling and extending their half-life compared with ranibizumab which is an antibody fragment and lacks the Fc domain. Case reports and small studies have shown that ranibizumab has the lowest serum concentration after intravitreal injection and the least effect on plasma-free VEGF concentrations and breastmilk VEGF levels. CONCLUSION: Clinical and pharmacologic data suggest that ranibizumab has less systemic circulation and effect on maternal serum and breastmilk VEGF levels when compared to bevacizumab and aflibercept. However, there is significant need for further research on the degree and duration to which intravitreal agents circulate systemically, what fraction is transferred into breastmilk and is absorbed, and whether this results in any functional adverse effects to the infant. Other factors to consider in the medical decision-making of lactating mothers necessitating intravitreal anti-VEGF treatment include the gestational and post-natal age of the child and whether it is feasible to avoid breastfeeding for the half-life duration of the intravitreal agent rather than ceasing breastfeeding altogether.

Human milk and necrotizing enterocolitis.

NEC is a multifactorial disease that occurs when multiple risk factors and/or stressors overlap, leading to profound inflammation and intestinal injury. Human milk feedings, both from the infant's mother and donor human milk, have been associated with reductions in NEC in preterm infants. This article will review the protective factors in human milk, clinical studies of human milk and NEC, and practices to enhance human milk use in neonatal intensive care units.

Influence of own mother's milk on bronchopulmonary dysplasia and costs.

BACKGROUND: Human milk from the infant's mother (own mother's milk; OMM) feedings reduces the risk of several morbidities in very low birthweight (VLBW) infants, but limited data exist regarding its impact on bronchopulmonary dysplasia (BPD). OBJECTIVE: To prospectively study the impact of OMM received in the neonatal intensive care unit (NICU) on the risk of BPD and associated costs. DESIGN/METHODS: A 5-year prospective cohort study of the impact of OMM dose on growth, morbidity and NICU costs in VLBW infants. OMM dose was the proportion of enteral intake that consisted of OMM from birth to 36 weeks postmenstrual age (PMA) or discharge, whichever occurred first. BPD was defined as the receipt of oxygen and/or positive pressure ventilation at 36 weeks PMA. NICU costs included hospital and physician costs. RESULTS: The cohort consisted of 254 VLBW infants with mean birth weight 1027±257 g and gestational age 27.8±2.5 weeks. Multivariable logistic regression demonstrated a 9.5% reduction in the odds of BPD for every 10% increase in OMM dose (OR 0.905 (0.824 to 0.995)). After controlling for demographic and clinical factors, BPD was associated with an increase of US$41 929 in NICU costs. CONCLUSIONS: Increased dose of OMM feedings from birth to 36 weeks PMA was associated with a reduction in the odds of BPD in VLBW infants. Thus, high-dose OMM feeding may be an inexpensive, effective strategy to help reduce the risk of this costly multifactorial morbidity.

Transforming growth factor-ß2 is sequestered in preterm human milk by chondroitin sulfate proteoglycans.

Human milk contains biologically important amounts of transforming growth factor-ß2 isoform (TGF-ß2), which is presumed to protect against inflammatory gut mucosal injury in the neonate. In preclinical models, enterally administered TGF-ß2 can protect against experimental necrotizing enterocolitis, an inflammatory bowel necrosis of premature infants. In this study, we investigated whether TGF-ß bioactivity in human preterm milk could be enhanced for therapeutic purposes by adding recombinant TGF-ß2 (rTGF-ß2) to milk prior to feeding. Milk-borne TGF-ß bioactivity was measured by established luciferase reporter assays. Molecular interactions of TGF-ß2 were investigated by nondenaturing gel electrophoresis and immunoblots, computational molecular modeling, and affinity capillary electrophoresis. Addition of rTGF-ß2 (20-40 nM) to human preterm milk samples failed to increase TGF-ß bioactivity in milk. Milk-borne TGF-ß2 was bound to chondroitin sulfate (CS) containing proteoglycan(s) such as biglycan, which are expressed in high concentrations in milk. Chondroitinase treatment of milk increased the bioactivity of both endogenous and rTGF-ß2, and consequently, enhanced the ability of preterm milk to suppress LPS-induced NF-κB activation in macrophages. These findings provide a mechanism for the normally low bioavailability of milk-borne TGF-ß2 and identify chondroitinase digestion of milk as a potential therapeutic strategy to enhance the anti-inflammatory effects of preterm milk.

Economic benefits and costs of human milk feedings: a strategy to reduce the risk of prematurity-related morbidities in very-low-birth-weight infants.

Infants born at very low birth weight (VLBW; birth weight <1500 g) are at high risk of mortality and are some of the most expensive patients in the hospital. Additionally, VLBW infants are susceptible to prematurity-related morbidities, including late-onset sepsis, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis, and retinopathy of prematurity, which have short- and long-term economic consequences. The incremental cost of these morbidities during the neonatal intensive care unit (NICU) hospitalization is high, ranging from $10,055 (in 2009 US$) for late-onset sepsis to $31,565 for BPD. Human milk has been shown to reduce both the incidence and severity of some of these morbidities and, therefore, has an indirect impact on the cost of the NICU hospitalization. Furthermore, human milk may also directly reduce NICU hospitalization costs, independent of the indirect impact on the incidence and/or severity of these morbidities. Although there is an economic cost to both the mother and institution for providing human milk during the NICU hospitalization, these costs are relatively low. This review describes the total cost of the initial NICU hospitalization, the incremental cost associated with these prematurity-related morbidities, and the incremental benefits and costs of human milk feedings during critical periods of the NICU hospitalization as a strategy to reduce the incidence and severity of these morbidities.

Cost of morbidities in very low birth weight infants.

OBJECTIVE: To determine the association between direct costs for the initial neonatal intensive care unit hospitalization and 4 potentially preventable morbidities in a retrospective cohort of very low birth weight (VLBW) infants (birth weight <1500 g). STUDY DESIGN: The sample included 425 VLBW infants born alive between July 2005 and June 2009 at Rush University Medical Center. Morbidities included brain injury, necrotizing enterocolitis, bronchopulmonary dysplasia, and late-onset sepsis. Clinical and economic data were retrieved from the institution's system-wide data and cost accounting system. A general linear regression model was fit to determine incremental direct costs associated with each morbidity. RESULTS: After controlling for birth weight, gestational age, and sociodemographic characteristics, the presence of brain injury was associated with a $12048 (P = .005) increase in direct costs; necrotizing enterocolitis, with a $15 440 (P = .005) increase; bronchopulmonary dysplasia, with a $31565 (P < .001) increase; and late-onset sepsis, with a $10055 (P < .001) increase. The absolute number of morbidities was also associated with significantly higher costs. CONCLUSION: This study provides collective estimates of the direct costs incurred during neonatal intensive care unit hospitalization for these 4 morbidities in VLBW infants. The incremental costs associated with these morbidities are high, and these data can inform future studies evaluating interventions aimed at preventing or reducing these costly morbidities.

A TLR5 (g.1174C > T) variant that encodes a stop codon (R392X) is associated with bronchopulmonary dysplasia.

Current evidence supports a major role for inherited factors in determining bronchopulmonary dysplasia (BPD) susceptibility. The Toll-like receptor (TLR) family of proteins maintain pulmonary homeostasis in the developing lung by aiding pathogen recognition and clearance, regulating inflammation, and facilitating reparative tissue growth. We hypothesized that sequence variation in the TLR pathway genes would alter the susceptibility/severity of BPD in preterm infants. Very low birth-weight infants were recruited prospectively in a multi-center study involving collection of blood samples and clinical information. Nine TLR pathway single-nucleotide polymorphisms were genotyped using a multiplexed single-base extension assay. BPD outcomes were compared among infants with and without the variant allele using Chi-square or Fisher's exact tests. In our cohort (n = 289), 66 (23.6%) infants developed BPD, out of which 32 (11.2%) developed severe BPD. The TLR5 (g.1174C > T) variant was associated with BPD (P = 0.03) and severe BPD (P = 0.004). The TIRAP (g.2054C > T) variant was associated with BPD (P = 0.04). Infants heterozygous for the X-linked IRAK1 (g.6435T > C) variant had a lower incidence of BPD compared to infants homozygous for either the reference or variant allele (P = 0.03). In regression models that controlled for potential epidemiological confounders, the TIRAP variant was associated with BPD, and the TLR5 variant was associated with severe BPD. Our data support the hypothesis that aberrant pathogen recognition in premature infants arising from TLR pathway genetic variation can contribute to BPD pathogenesis.