September 1979

450

TheJournalofPEDIATRICS

Necrotizing enterocolitis in neonates fed human milk The incidence of necrotizing enterocolitis encountered in neonates fed only refrigerated human milk was comparable to that in infants fed human milk and isotonic formula or isotonic formula alone. The infants fed human milk were significantly (P < 0.05) smaller, less mature, had lower Apgar scores, and were fed later than the formula-fed infants. The mean age of onset and time between first feeding and onset of NEC was similar among the three groups. These data indicate that refrigerated human milk was not effeetive in lowering the incidence of NEC. Possible explanations for the occurrence of NEC in neonates fed human milk include: (1) the introduction of a pathogen via contaminated milk; (2) inadequate maternal antigenic stimulation bf; the neonatal gastrointestinal flora; and (3) adverse affects of storage on cell number and function.

R. M. Kliegman, M.D.,* W. B. Pittard, M.D., and A. A. F a n a r o f f , M . D . (Rand.), M . R . C . P . E . , D . C . H . , C l e v e l a n d , O h i o

BECAUSE NECROTIZING ENTEROCOLITIS is seen almost exclusively among" neonates who have received feedings, oral alimentation has been incriminated in its pathogenesis. 1' ~ The pathophysiologic contribution of the milk, however, is incompletely understood. It has been proposed that the milk may serve as a substrate for bacterial growth. Mizrah? first suggested human milk might be protective against the development of NEC, and subsequently Barlow et aP' 5 demonstrated a protective effect of breast milk feeding in a laboratory model. Although NEC has been reported in neonates fed only human milk, in each case the milk had been modified by freezing or heating or both to ensure sterility. This treatment may have altered the cellular and immunoglobulin components, reducing the milk's protective properties?, 7 To retain the benefit of the cellular and other immunoprotective factors, we have utilized refrigerated milk which has been neither heat-treated nor frozen. This report describes nine cases of NEC seen in high-risk neonates whose oral alimentation had consisted only of human milk. These nine patients were compared with From the Department of Pediatrics, Case Western Reserve University, and Rainbow Babies and Children's Hospital. *Reprint requests: Department of Pediatrics, Case Western Reserve University, Rainbow Babies and Children's Hospital. 2103 Adelbert Rd., Cleveland, OH 44106.

Vol. 95, No. 3, pp. 4504453

infants with NEC who were admitted over the same time period and were fed human milk and formula, or formula 9alone. The importance of culturing the milk is emphasized and recommendations for milk banking procedures outlined. METHODS Between January 1, 1970, and August 31, 1978, 109 patients with NEC who had been fed orally were diagnosed at Rainbow Babies and Children's Hospital. Abbreviations used NEC: nec(otizing enterocolitis RDS: respiratory distress syndrome The diagnosis of NEC was confirmed by examination of pathologic specimens or made clinically by the characteristic signs and symptoms including abdominal distention, retention of feedings, and positive guaiac stools in conjunction with radiographic evidence of pneumatosis intestinali~ free air in the abdomen or both. At the time of diagnosis each patient had cultures obtained from blood, spinal fluid, urine (suprapubic tap) and stool, and, more recently, from peritoneal fluid as well. Postmortem cultures are not included. The currentdncidence of NEC at Rainbow Babies and Children's Hospital was determined by relating the number of cases diagnosed between January 1, 1977, and

2

0022-3476/79/090450+04500.40/0 9 1979 The C. V. Mosby Co.

Volume 95 Number 3

Necrotizing enterocolitis and human m i l k

Table I. Patient populations*

Table II. Feeding histOry and nature of disease* B?

Number Male:female Gestational age (mean wk) Birth weight (mean gm) 1 rain Apgar (mean) 5 rain Apgar (mean) RDS (%)

451

B-

A:

Human

Human mi~

milk and formula

Formula

9 3:6 30.6 NSt

34 18:16 30.7:~

66 35:31 32.4w

1,216 NS

1,285~

1,630w

3.9 NS 5.8 NS 55 NS

4.8:~ 6.9 NS 38.2 NS

6.1w 7.411 43.9 NS

C:

*Footnotes depict significance between columns: notation after Column C depicts significance between Columns C and A. ~NS = Nonsignificant. :[:P < 0.005. w < 0.05.

lie < 0.01. August 31, 1978, to the total number of patients admitted during that period. (At the present time this period has the most complete records of the feeding histories of control patients.) To amplify the problem, the incidence during this time period is specifically expressed for patients with birth weight less than 1,500 gm and compared with (1) all patients less than 1,500 gm birth weight and (2) those less than 1,500 gm birth weight surviving long enough to be fed orally. The patients were categorized based on their feeding histories. Group A infants were fed exclusively refrigerated human milk before the onset of NEC (nine infants). Group B were fed human milk for at least 24 hours; because of inadequate supplies, feedings were then changed to formula (34 infants). Group C were fed only isotonic formula prior to the onset of NEC (66 infants). Mothers providing milk for their infants either expressed milk at home and transported it to the hospital or expressed milk with the aid of the Egnell pump while visiting in the neonatal unit. When milk was unavailable from a mother who intended to provide it for her infant, "donor" milk was used, after both donor and the parent of the recipient infant consented to the arrangement. Each milk sample obtained from healthy mothers was cultured aerobically and was not used until quantitative bacterial counts were determined. The milk was stored in glass bottles in a refrigerator at 4~ and used for a maximum of 48 hours after being expressed. If the milk was contaminated with greater than 105 colonies of diphtheroids, Staphylococcus epidermidis, or alpha hemolytic streptococcus, or any colonies of pathogenic bacteria, the sample was discarded and the mother was given

Human milk and formula

CFormula

9 5.1 NSt 6.7 NS

34 3.9:~ 8.7 NS

66 2.7w 7.0 NS

I 1.7 NS

12.6 NS

9.8 NS

55 NS

32 NS

33 NS

55 NS

35 NS

42 NS

11 NS

35 NS

33 NS

77.7 NS

52.9 NS

46.911

A: Human mi~

Number First day fed (mean) Number days fed (mean) Day of onset NEC (mean) Disseminated intravascular coagulation (%) Intestinal perforation (%) Positive blood culture (%)~ Survival (%)

*Footnotes depict significance between columns: notation after Column C depicts significance between Columns C and A. t N S = Not significant. :~P < 0.001. w < 0.005.

lie < 0.08. fllrther detailed instruction about proper handwashing techniques and breast hygiene. Milk was then expressed, recultured, and stored until culture reports were evaluated as above. Statistical analysis for this review was performed via a 2 • 2 contingency table and chi square o the Student t test with modifications for unequal sample sizes. RESULTS-PATIENT HISTORY

CATEGORIES

AND

The profiles of the patients with NEC are presented in Table I. Patients in groups A and B were similar with respect to gestational age and birth weight, whereas group C was significantly more mature and larger at birth. One-minute Apgar scores were lower in groups A and B; five-minute Apgar scores were lower only in group A when compared to formula-fed infants. The incidence of RDS was not significantly different in the three groups. The feeding history and nature of the disease are presented in Table II. Groups A and B were fed significantly later than group C; however, the duration of feeding or the mean age of onset of NEC was not significantly different among groups A, B, or C. The early manifestations and complications of the disease did not differ among the groups. Milk and patient culture reports are seen in Table III. One patient was inadvertently fed human milk prior to

452

Kliegman, Pittard, and Fanaroff

The Journal of Pediatrics September 1979

Table IlL Milk and patient's culture reports

Patient 1" 2*

3 4*

5 6*

7*

8*

982

Milk

Milk culture

source

Patient cultures

S. epidermidist a strep~ S. epidermidist gram negatives~ S. epidermidisqF Enterococcusw S. epidermidis'~

Maternal

No growth

Materr~al

S. epidermidist a strep No report

Donor

E. coli in peritoneum Enterococcus in blood Klebsiella in peritoneum No growth

No report

A. B. A. B.

S. epidermidisll gram negativesll S. epidermidisll S. epidermidisll and gram negativesll

Maternal Maternal

Donor

Donor

Donors Donors

E. coli intraabdominal abscess E. coli in intra-abdominal abscess E. coli in peritoneum Klebsiella and Clostridia in peritoneum

*Infanttransportedfrom outlyinghospital. i'lO~colonies/ml. :[:lOgcolonies/ml. w colonycount reported. tl104colonies/ml. 82Patientreported in part previously.13 culture. Subsequently, enterococcus was grown from the milk, and the infant had a blood culture positive for enterococcus at the onset of NEC. Milk samples in three other instances had undefined gram-negative organisms present, and the recipient infants subsequer/tly had either Escherichia coli or Klebsiella isolated from their peritoneal cultures. The precise amount of mother-infant contact is difficult to document from the records; however, five of the nine infants in group A received donor milk and in three of the other four infants the mothers were in outlying hospitals and transported the milk in, suggesting limited motherinfant contact in the initial days of hospitalization. INCIDENCE The overall incidence of NEC (during the period January 1977, to August 31, 1978) in all patients admitted to the neonatal unit, regardless of type of feeding, was 27/530 (5.1%). The incidence in all patients less than 1,500 gm birth weight was 22/215 (10.1%) (P < 0.025). When the denominator used to calculate the incidence was changed to infants less than 1,500 gm Surviving long enough to be fed, the incidence changed to 13.6% (Table IV). There were no significant differences among the

Table IV. Incidence of NEC in patients