The Practicality of Feeding Defatted Human Milk in the Treatment of Congenital Chylothorax

Abstract

Introduction:

Congenital chylothorax (CC) is a rare and life-threating condition. Since its treatment is founded on the elimination of long-chain fatty acids from the diet, breastfeeding has been traditionally contraindicated. However, breast milk could be very beneficial due to its immunological and nutritional benefits. Only limited research has been published about the usage of modified-fat breast milk (MBM) in chylothorax treatment.

Methods and Results:

Systematic review methods were used by two independent reviewers. Only a few case report studies (quality assessment on the domains of the GRADE approach), two small controlled studies, a retrospective study, and some test-tube-based laboratory research met the inclusion criteria. Despite this, we have observed a widespread clinical adoption of this novel treatment in health institutions. Data suggest that modified-fat breast milk does facilitate the resolution of chylothoraces. Refrigerated centrifuge (2°C, 3,000 rpm for 15 minutes) and syringe fat removal methods were the most efficient options in terms of fat reduction.

Conclusions:

Feeding of human milk is advisable in CC and feasible by means of a simple milk defatting procedure. Open questions remain, related to length and degree of fat restriction and need for individualized fortification of defatted breast milk.

Introduction

Chylothorax denotes the accumulation of chyle (lymphatic fluid) within the pleural space. In newborns, it can be either acquired, most often as a postoperative complication after cardiac surgery, or congenital, mainly due to lymphatic vessel anomalies. Congenital chylothorax (CC) is rare—1:5,000–10,000 live births—but challenging for the fetus and the newborn infant.^1–3 The prognosis is dependent on etiology, gestational age, and comorbidities such as pulmonary hypoplasia, fetal hydrops, or associated malformations.^2,3 Overall survival rates range from 30% to 70%.^1,3

Chyle composition consists of fat, proteins (similar in content to plasma), and immune system elements such as lymphocytes, antibodies, and complements. Due to this, loss of chyle to the pleural space may result in malnutrition and dehydration and increase the risk of infections. As it is a life-threatening condition, complex and invasive procedures have been used prenatally and postnatally to manage CC. Invasive therapies (drainage of pleural collections by indwelling chest tubes or pharmacological therapy with somatostatin analogs) are reserved for high-volume effusions or severe respiratory impairment, not without controversy.^3–6 Surgical intervention (pleuroperitoneal shunts, thoracic duct ligation, or pleurodesis) is only considered if conservative therapies fail.^1,2,4 The basis of the treatment is dietary modification to bypass the lymphatic system and reduce chyle production, leaving time for injured lymphatic vessels to heal or to develop collateral connections. Most protocols include a stepwise dietary strategy of cessation of enteral feeding and use of parenteral nutrition followed by enteral formula whose fat source is primarily medium-chain triglycerides (MCTs) instead of long-chain fatty acids. MCTs bypass the lymphatic system during digestion, as they are absorbed directly into the portal venous system.^4,6 Due to these considerations, breastfeeding was for a long time contraindicated.⁷

However, human milk offers many advantages to patients affected with CC, mainly due to its immunological properties. Besides, special milk formulas based on MCTs for enteral feeding are expensive and not easily available in all clinical settings. Very few experiences have been published dealing with the use of modified (defatted) breast milk in newborn and infant chylothoraces, mostly in secondary cases after cardiac procedures.^8,9

Although some methodological aspects have been described, together with or apart from clinical experiences, there is a lack of uniformity in the methodology and standardized protocols, both for milk defatting methods and for nutritional adjustment. We present an overview of the literature about this topic. There is some evidence that rapid reviews may improve the clarity and accessibility of research evidence for decision makers.

Materials and Methods

This rapid review utilized systematic review methods and was conducted according to a predefined protocol with clear inclusion criteria. A comprehensive search strategy was used, including published and gray literature written in English, French, Portuguese, and Spanish from 2004 onward. Data sources were PubMed/MEDLINE, PMC (PubMed Central), ScienceDirect Journals (Elsevier), Sage Journals (Sage Publications), and the Directory of Open Access Journals (DOAJ). The search strategy for PubMed used the following terms, including MeSH terms: (breastfeeding OR defatted milk OR fat free milk OR skimmed milk) AND (chylothorax OR congenital chylothorax).

All articles under MeSH term “Congenital Chylothorax” were revised. A similar strategy (key words and index/subject terms) was used for the other databases and gray literature. Randomized controlled trials (RCTs), observational studies, narrative reviews, systematic reviews, case reports, letters, editorials, and commentaries were included. Additional strategies for identifying studies included the use of the “related articles” feature on PubMed and the use of the “cited by” tool on other websites. Data extraction was carried out by one reviewer and checked by another.

Two reviewers assessed the methodological quality of the included studies independently. Methodological quality assessment of case reports/series was based on the domains of selection, ascertainment, causality, and reporting, and provides signaling questions to aid evidence-based practitioners in their assessment, following a GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach.¹⁰ GRADE literature describes five paradigmatic situations, in which a strong recommendation can be made based on low-quality evidence such as that provided by case series and reports. One of them is when the condition could be life threatening, for example, in the case of aspirin usage and Reye's syndrome development in children.

A 13-item CAse REport (CARE) set of guidelines that provide a framework for checking for completeness and transparency in published case reports was applied to all case reports.¹¹

Results

We found 578 articles just under the MeSH term “Congenital Chylothorax.” However, according to our whole source search strategy (all databases and search terms), only a few studies made reference to the use of fat-free human milk in infants with chylothorax. The main findings of the included studies are displayed in Table 1. Three of these selected studies consisted of test-tube-based laboratory research^12–14 and six were clinical studies, although some of them also included methodological questions.^8,9,15,17,18

Table 1.

Summary and Main Findings of All the Studies in Our Review

	Test tube lab	Clinical study	Based on	Main findings	Other findings
Czank et al.¹² Sample size = 72	+		Description of the methodology for fat separation (by centrifugation) and for resuspension of whole-fat milk and skim milk.	The fat content of the skim milk (1 g/mL) did not correlate with the whole milk fat content but remained relatively constant between samples.	Centrifugation and resuspension did not alter the fat globule. One equation was developed for calculating the amount of skim milk to be either removed or added.
Drewniak et al.¹³ Sample size = 31 randomization blinding the single operator in the milk extraction process	+		Evaluate: Centrifugation (three methods) and fat removal (syringe versus spoon, two methods).	For fat separation, the centrifuge (mean: 1.0 g/dL, 95% CI 0.8–1.1) left significantly less residual fat than the refrigerator method (3.4 g/dL, 95% CI 3.0–3.7; p < 0.0001).For fat removal, the syringe method (1.2 g/dL, 95% CI 1.1–1.4) left 34% less residual fat compared with the spoon method (1.9 g/dL, 95% CI 1.5–2.3).	Nonrefrigerated centrifuge provided similarly separated milk as refrigerated centrifuge.
Drewniak et al. (2014) N = 31 samples randomization operator blinded during the fat removal step	+		Effect of various human milk fat separating methods (see Drewniak et al.¹³) on the loss of IgA and protein.	The refrigeration method decreased IgA concentration by 17% (p = 0.035), while centrifugation and fat removal from the human milk samples led to a 38% decline in IgA. Protein declined by 11% with refrigeration while centrifugation decreased protein by 31% (p < 0.0001).	Limitations: IgA and protein analysis (IgA, ELISA, and DC Protein Assay Lowry Method) were not designed for use in the matrix of milk.Possible effect of long-time freezing.
Chan and Lechtenberg¹⁵ case series: 7 patients 1–8 months of age. 3/7 congenital chylothorax, 4/7 CCD	+	+	Description of the procedure for removing fat content from human milk and clinical experience in infants with chylothorax. Cold centrifugation, (2°C) 3,000 rpm, for 15 minutes.Determination of electrolyte content (by atomic absorption) of defatted human milk.	There was no reaccumulation of the chylous pleural effusions with the use of the fat-free mother's milk in any patient. Average diet time was 16 days.Mother's milk electrolytes were similar before and after processing.	The mean fat removed was 5 ± 1 g/dL (creamatocrit methodology), which was the same as the prefat content of the mother's milk.No report on weight gain.
Hamdan and Gaeta¹⁶ single case: 3-month-old infant with CCD		+	Clinical case: after a 5-day course of octreotide, low-fat breast milk diet was started.No references on centrifugation process.Analysis of the prepared breast milk (no method specified) showed only 0.02% of fat, compared with 3.5% in the regular human milk.	Chylothorax resolved after using a combination of parenteral octreotide and low-fat breast milk supplemented with MCT, sugar, and protein.	Adequate weight gain was referred.
Lessen¹⁷ single case: 1-month CCD, birth weight 3.8 kg		+	Fat-free milk was used since the moment chylothorax was diagnosed (36 days of life). Before that time, the patient has been breastfed.In hospital: refrigeration method. At home after discharge: defatting by the refrigeration and syringe method.	After 8 days of fat-free diet, drainage chyle tube was removed. No reaccumulation of chylous effusion into the pleural cavity was observed. Fortification: MCT formula+oils containing essential fatty acids.	Weight gain was 39 g per day.Fat content not specified in fat-free milk (no measure reported).
Gilgan et al.¹⁸ single case, CCD+thoracic duct ligation. Forty-two DOL Birth weight 3.8 kg		+	Novel approach to skimming mothers' breast milk when discharged home (DOL 56). Top-loading washing machine.At hospital: centrifugation, 3,000 rpm, for 20 minutes (2°C). Fat-free removal by syringe method.	Chylothorax was successfully treated without recurrence. Home skimming method maintained for 6 weeks. Newborn went on to be exclusively breastfed once the LCT-restricted diet was discontinued.	Adequate weight gain.Fat content 0.5 g/100 mL (creamatocrit analysis) in hospital and after discharge.
Kocel et al.⁸ 16 pt N = 8 per group, nonrandomized group 1 MBMGroup 2 MCT diet CCD infants <12 months of age.		+	Outcome (resolution of chylous chest tube drainage and weight game) between the two groups.Technical procedures for defattening human milk: cold centrifugation (4°C), 3,000 rpm, for 15 minutes. Spoon fat separation. Enrichment MCT oil+fortifier and/or MCT formula.Home centrifugation.	Daily volume and duration of chest tube drainage were not different between the MBM and MCT groups (diet until 6 weeks after chest tube removal). No statistically significant difference in rates of weight gain (g/d) between feeding groups. However, infants in the MBM group experienced a decline in mean weight (p = 0.04) and length (p = 0.01) for age z-scores. No differences found in emesis rate.	Difficulties with emulsification of the MCT into the fat-modified milk may have contributed to lower than expected fat intake. The frequent manipulations of the MBM may have had an effect on the macronutrient and energy content of the modified-fat breast milk (5-6 container changes).
Fogg et al.⁹ Sample size 35 pt CCD patients MBM (n = 14) versus MCT formula (n = 21). Retrospective cohort study <90 days of age.		+	Outcome (resolution of chylous chest tube drainage and weight game) between the two groups.Cold centrifugation, (2°C) 3,000 rpm, for 15 minutes.Creamatocrit measurement of defatted milk showed less than 3% calories from fat.Fortification individualized. MCT powder, parenteral nutrition. The goal caloric administration was 110–130 kcal/kg/day.	Daily volume and duration of chest tube drainage were not different between groups.The MBM treatment group had a significantly higher weight-for-age z-score at hospital discharge compared with the MCT formula group, with median z-scores of −1 (−2 to 0.5) and −1.5 (−2 to 0), respectively (p = 0.02).	Feeding intervention was sustained for 6 weeks after chest tube removal.Thoracic duct ligation was needed in 3/35 patients after failure of dietary and other therapeutic treatments (all in the MBM group).

CCD, congenital cardiac disease; CI, confidence interval; DOL, days of life; ELISA, enzyme-linked immunosorbent assay; IgA, immunoglobulin A; LCT, long-chain triglyceride; MBM, modified-fat breast milk; MCTs, medium-chain triglycerides.

We also found some tutorials that mention this topic as an established procedure in human milk banks and pediatric health institution routines.^19–22 Two clinical reports, set in low-resource settings, were excluded because they used skimmed milk but not human source.^23,24 Only a few case reports,^16–18 one retrospective case series,¹⁵ and two small cohort studies^8,9 met the inclusion criteria. Thus, the findings of this rapid review need to be treated with caution. Most patients, who presented with secondary chylothorax after cardiac surgery, were older than 1 month of age and had an average weight of 4.5 kg at the beginning of treatment. Patients differed between studies in their age at the onset of chylothorax, beginning of treatment (before and after chyle effusion resolution), and length of treatment.

Three in vitro studies^12–14 described some procedures for human milk defatting. Czank et al.¹² described a low-speed centrifugation technique for separating the fat component from human milk. Their study was not aimed at chylothorax patients; instead, it focused on the standardization of the energy content of donor breast milk for use in preterm babies in the neonatal intensive care units. They also described a procedure for resuspension of milk after defatting and developed an equation for calculating the amount of skimmed milk to be added to reach the target fat content. The authors demonstrated that neither centrifugation nor resuspension of milk at room temperature altered the fat globule distribution.

Another in vitro study reported by Drewniak et al.¹³ compared three different methods for separating breast milk into fat and low-fat milk portions: refrigerated centrifuge (2°C, 3,000 rpm for 15 minutes), nonrefrigerated centrifuge (room temperature, 3,000 rpm for 15 minutes), and the refrigeration method (storage in a refrigerator at 2°C for 24 hours). They reported that the refrigeration method was considerably inferior to both centrifuge methods for separating the fat from the milk samples. After centrifugation, two alternative ways of separating breast milk into the fat and low-fat milk components were studied by the same authors (the syringe and spoon methods). A blind operator in the milk extraction process discovered that the syringe method left 34% less residual fat compared with the spoon method, thus being more effective.¹³

Clinical experiences and human milk bank protocols have described variants of these methods, including some family home experiences with centrifuge⁸ or refrigeration,¹⁷ even using a washing machine as a centrifuge.¹⁸ Various methodologies such as creamatocrit^{9,12,15,16,18} or enzymatic tests^8,13 were used to determine the fat concentration in the skimmed milk.

All clinical studies reported successful experiences in the use of defatted breast milk for chylothorax alone or with coadjuvant therapies, such as octreotide.^9,16 Only 3 patients among 32 presented eventually needed thoracic duct ligation. Success was defined by the cessation or absence of reoccurrence of pleural effusion necessitating chest tube placement on ultrasound or chest X-ray. Two small nonrandomized cohort studies in infants with secondary chylothorax^8,9 demonstrated no differences in daily volume and duration of chest tube drainage between groups (MCT-formula and MBM). Feeding intervention was not discontinued until 6 weeks after chest tube removal in most studies, except in one where it took place earlier.¹⁵

All clinical study groups included fortification of the skimmed milk, mainly with protein-based fortifiers, MCT-based formula, or MCT oil. Some of them used supplemental intravenous lipids until chest tube output decreased. Essential fatty acids (EFAs) and fat-soluble vitamins and/or glucose polymers have also been included as supplements to provide additional calories.

Nevertheless, only two clinical studies reported on the growth of chylothorax patients with human defatted milk nutrition.^8,9 In the Kocel study,⁸ the infants with chylothorax fed with their mothers' low-fat milk experienced a decline in mean weight (p = 0.04) and length (p = 0.01) for age z-scores, while there was no statistically significant difference in rates of weight gain (g/d) between feeding groups. Conversely, Fogg et al.⁹ found a better growth pattern in the MBM treatment group who had had a significantly higher weight-for-age z-score at hospital discharge compared with the MCT formula group with median z-scores of −1 (−2 to 0.5) and −1.5 (−2 to 0), respectively (p = 0.02). On average, clinical cases show good results in weight gain after fortification.^16–18

Discussion

The clinical practice of using modified-fat breast milk as a treatment option for infants with chylothorax has been implemented in a number of pediatric institutions worldwide.^20–22 Defatting procedures have been adopted in protocols and clinical guidelines, although externally validated protocols are missing. Nevertheless, breast milk seems to be the best nutritional option especially for preterm CC patients due to multiple advantages.²⁵ Specifically, human milk possesses remarkable immunological properties. Although the study by Drewniak et al.¹⁴ demonstrated that immunoglobulin A (IgA) was reduced by centrifuging, the human milk did retain 61% of the IgA through this processing, which is still significant. Moreover, it is possible that the IgA levels in the study by Drewniak et al. could have been altered due to the long frozen storage time of the low-fat human milk samples (12 months) before analysis, as has been reported in other studies,²⁶ and also due to the fact that the analytical procedures were not designed to be used in the matrix of milk. More studies are needed to clarify the effects of centrifugation on immunological properties of human milk.

Almost half of the total energy in breast milk is fat, the majority of which (80–90%) is composed of long-chain triglycerides (LCTs) and should be processed for the nutrition of CC patients.³¹ Cold centrifugation milk processing and skimmed milk syringe extraction methods have achieved the best rate of fat reduction.^13,15 However, it is not yet clear to what extent should fat reduction be effected. Formulas based on MCT contain only 0.4–0.9 g/100 mL of LCTs according to the manufacturers; therefore, a <0.5 g fat/100 mL target is usually chosen in the milk defatting process to match the amount of LCTs found in MCT-enriched formulas. However, formulas may or may not represent the ideal composition.⁶

Only two nonrandomized open-labeled studies have investigated the effectiveness of a modified-fat breast milk (MBM) treatment compared with a high-MCT formula, both being equivalent in terms of chylothorax reduction.^8,9 Both studies, as well as clinical samples when specified,^15,18 did not exceed fat concentrations of 1 g/100 mL The F-TIR (Fourier transform infrared) technology, available at present at most human milk banks, increases accuracy in fat determination as a crucial step when reintroduction of fat is implemented.^27–30 Most review studies have used the simpler and easily available creamatocrit method. The accuracy of the creamatocrit for total lipid content in human milk has been shown to be almost 90% and could be an alternative if more precise technology is not available.^29–30

Clinical trials are needed to determine the duration and level of LCT restriction needed for optimal management of chylothorax and the progression in the reintroduction of fat. Patient evolution in terms of absence of chylous pleural effusion would be the crucial element for determining how long the restriction is to be maintained, although based on MCT experience, once effusion stops and the thoracostomy tube has been removed, 2-6 weeks of diet restriction could be sufficient.⁶ Feeding of human milk could also contribute to reducing the length of chylous pleural effusion through the effect of the somatostatin present in the composition of human milk.³¹

Evidence, although not good quality, shows good results in terms of chylothorax resolution, and also concerns about growth in these infants. Growth impairment could be related to macronutrient losses through chyle and/or during the milk defatting process if no adequate nutrient supplementation is established. In addition, milk handling procedures (e.g., container changes, freezing, and thawing) have been shown to affect the nutrient composition of breast milk.³² Growth impairment found by Kocel et al. was explained by the authors through a lower than expected macronutrient and energy intake in the MBM group related to a lack of emulsification of the MCT into the fat-modified milk or to losses of fat due to frequent milk manipulation.⁸ Skimmed human milk may contain approximately half the calories of regular breast milk (33 kcal/100 mL) and requires fortification.

Milk fortification procedures should be based on patient needs and losses and customized. Published studies on this topic have primarily focused on replacing the fat in the form of MCTs (oils and formula powder), fat-soluble vitamins, and EFAs. Target EFA levels should be 2–4% of the total calories to prevent EFA deficiency without contributing to increased chyle output.³³

Protein supplementation is also essential. Chyle extracted from infants has been reported to contain protein levels of 2.8 and 3.4 g/100 mL; some chyle samples even have a protein content >30 g/L.³⁴ Centrifugation and manipulation of milk do not seem to cause protein losses to a large extent, as higher centrifugal forces are required for casein sedimentation. Some studies have shown that the concentrations of protein in skimmed milk were at the levels expected for preterm milk.⁸ Protein fortification should take into account chyle losses and the patient's condition and energy requirements and follow recommendations for target fortification in preterm infants.^35–36

In conclusion, using fat-free human milk may be a beneficial dietary strategy to facilitate resolution of chylothoraces in infants. Procedures for skimming human milk are simple and could be easily integrated alongside present human milk bank activities. We suggest the incorporation of case reports/series into decision-making based on the GRADE approach when no other higher level of evidence is available. However, it would be necessary to confirm these findings through high-quality multicenter research.

Footnotes

Disclosure Statement

No competing financial interests exist.

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