Donor Human Milk for Infants With Neonatal Abstinence Syndrome
Conditions: Neonatal Abstinence Syndrome
Sponsor: Neolac Inc dba Medolac Laboratories

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Donor human milk for infants with Neonatal Abstinence Syndrome (NAS)   
Lori Devlin, DO, MHA, Paula Radmacher, MSPH, Ph.D., Scott Duncan, MD  
Background  
  
  
Neonatal Abstinence Syndrome (NAS) is a drug withdrawal syndrome that occurs primarily after 
antenatal exposure to opiates.  Symptoms may be present at birth, but often peak at 48-72 after 
delivery.  The onset of symptoms is affected by the half-life of the opiate used during pregnancy in 
combination with maternal and infant metabolism.  The incidence of NAS has increased substantially 
since 2000 both nationally and in the Commonwealth of Kentucky, leading to a significant increase in 
healthcare resource utilization and (Figure 1).  
    
  
The 2012 National Survey on Drug Use and Health found that illicit drug abuse affected 
~130,000 pregnancies in the United States from 2011-2012 and that approximately 20% of those 
pregnancies (26,000) involved opiates. (SAMSA Center for Behavioral Health Statistics and Quality, 
National Survey on Drug Use and Health, 2009-2012).  Patrick et al. utilized the Kids’ Inpatient Database 
(KID) from the Agency for Health Care Research and Quality to evaluate the incidence of maternal opiate 
use during pregnancy1. He and his team noted a substantial increase in the number of mothers using 
opiates - 1.19 per 1000 hospital births in 2000 to 5.63 per 1000 hospital births in 2009.  As a result, there 
was an increased diagnosis of NAS from 1.20 per 1000 hospital births in 2000 to 3.39 per 1000 hospital 
births in 2009.  This is a 2.8-fold increase which means that every hour of every day, 1 neonate in the 
United States undergoes drug withdrawal.   
  
  
The Kentucky Injury Prevention and Research Center reported that 824 infants in the state of 
Kentucky were hospitalized for neonatal withdrawal after exposure to opiates in 2012.  This represents 
an 18% increase from 2011 and a 4.5 fold increase from 2005. (Kentucky Injury Prevention and Research 
Center.  Data for 2010-2012). Neonatal Abstinence Syndrome is an issue of epidemic proportions both 
for Kentucky and the nation.  It results in prolonged hospitalizations and increased healthcare costs.  In 
2009, the total charges for NAS treatment were noted to be approximately $720 million nationally, up 
from approximately $190 million in 20001.  Kentucky data from 2012 report a $40 million dollar cost for 
neonatal drug withdrawal treatment, which has increased from $200,000 in 2000. (Kentucky Injury 
Prevention and Research Center.  Data for 2010-2012).  The majority of these costs (75-80%) are paid by 
the state Medicaid program (Figure 2).   
  
  
Precipitous removal of exogenous opiates at the time of delivery results in unopposed 
stimulation by cAMP and which increases norepinephrine levels and results in clinical symptoms of drug 
withdrawal in the neonate2.  Symptoms include central nervous system (CNS) signs (seizures, irritability, 
tremors), autonomic disturbances (sweating, yawning, nasal stuffiness, low grade fever, mottling) and 
gastrointestinal (GI) dysfunction (diarrhea, vomiting, poor feeding, and regurgitation).  The cohort of 
withdrawal symptoms is dictated by the location of µ opioid receptors, which are concentrated in the 
brain but are also found in sensory nerves, mast cells and in the GI tract3.   
  
  
Treatment of withdrawal symptoms includes symptomatic care for mild symptoms and 
pharmacological intervention in addition to symptomatic care for moderate to severe symptoms.  The 
American Academic of Pediatrics and experts in the field recommend opioid replacement therapy as the 

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first line pharmacologic intervention in opioid-induced withdrawal.  The most commonly used 
medication is oral morphine.  Phenobarbital and clonidine have been used as adjuvant therapies with 
some success in infants with more severe symptoms.  Initiation, escalation and weaning of 
pharmacologic therapy are based on observer rated scales, the most common of which is the Finnegan 
Scale4.  Although observer-rated scales are an essential component in the assessment and treatment of 
neonatal drug withdrawal, they lack rigorous psychometric testing to establish reliability and validity, are 
subjective and have been difficult to standardize across nurseries5.   
  
  
Infants undergoing opiate withdrawal, as noted above, have feeding difficulty, including spitting, 
regurgitation and diarrhea. The Finnegan scoring tool includes a series of feeding assessments within the 
total scoring algorithm (Table 1).  Human milk has been shown to be the best tolerated nutritional 
support for most infants and is cited by the AAP as the preferred method for feeding all infants6.  
However, the AAP considers the use of marijuana, cocaine, methamphetamines and unsupervised 
opiate use during pregnancy to be a contraindication to breastfeeding7.  For most street drugs, the risks 
to the infant of ongoing active use by the mother outweigh the benefits of breastfeeding because the 
doses of the drug(s) being used and contaminants within the drug are unknown8-11.  The AAP does 
recognize that if a mother is in a supervised methadone treatment center and is free from using other 
drugs of abuse then breastfeeding is an essential component of the infant’s care.  However, most infants 
with NAS are fed formula for a variety of reasons, including concerns about continued maternal use.  
  
  
Human milk is a complete nutritional food for the first 6 months of life in the term infant. Aside 
from its nutritional composition (specific for the support of the human infant), it contains hormones, 
immunoglobulins and growth factors that stimulate gastrointestinal growth and motility which, in turn, 
promote the maturation and protection of the GI tract. Mediators such as neurotensin and motilin 
promote GI motility while free amino acids feed intestinal growth 12, 13. Human milk feeding has been 
shown to increase gastric empyting14, 15 and lactase activity16 in the gut which improves feeding 
tolerance. A human milk diet is also associated with post-natal intestinal colonization by beneficial 
bacteria (Lactobacillus and Bifidobacteria).  In summary, when compared to formula feeding, human 
milk appears to be a more suitable diet for the neonate at risk for GI dysfunction.  
  
  
Two retrospective studies of the effect of breastfeeding on clinical symptoms of NAS have been 
reported.  McQueen et al reviewed 28 mother-infant pairs with maternal methadone exposure and 
infant symptoms of NAS17.  Maternal and infant demographics were recorded along with feeding type, 
Finnegan scores and infant medication utilization during withdrawal. Feeding cohorts were created by 
quantifying the duration of breastfeeding during hospitalization. Formula fed infants received >75% of 
all feedings as formula (n=9), breastfed infants received >75% of feedings at the breast (n=8). The rest 
were considered combination feeders (n=11).  Combination feeders were slightly less mature (35.6 
weeks) and of lower birth weight (2608 g) than breastfed (38.8 weeks and 3025 g) or formula fed (39.1 
weeks and 3302 grams). Breastfed infants received fewer scores, had significantly lower overall  
Finnegan scores and fewer scores >8 when compared to formula and combination fed infants (p≤0.001).   
  
  
Dryden et al. performed a retrospective cohort study of 437 infants born to women prescribed 
methadone in varying doses for their addiction18. Median gestational age at birth was 38 weeks and 
birth weight was 2730 grams.  Twenty-two percent of infants were breastfed for at least 72 hours. 
Multivariate logistic regression showed that the prescribed dose of methadone in these women 

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independently influenced the likelihood of pharmacologic treatment for NAS (p<0.001). However, for 
infants that were breastfed for at least 72 hours, the odds of needing pharmacologic treatment for NAS 
was significantly reduced (OR 0.55, 95% CI 0.34 – 0.88, p=0.013).  
  
  
Maternal opiates are transmitted through the breast milk to the infant.  The amount of 
methadone and buprenorphine transfered in the breast milk has been found to be small, but may be 
significant enough to lead to some improvement in scores.  
  
  
While these studies have reported improvements (decreases) in NAS scoring or reduced 
duration of treatment with breastfeeding, there are no reports that have looked at donor human milk, 
which is tested to be free of illicit drugs, and its effect on the GI sub-scores of the Finnegan algorithm.  
Given the general benefits of human milk for the human infant and these limited reports of improved 
neonatal well-being in breastfed infants with NAS, this study is designed to develop pilot data on the 
acceptability and benefit of donor human milk for infants undergoing pharmacologic treatment for NAS. 
Specifically, GI sub-scores, as well as total scores, will be compared between infants historically fed 
formula and those enrolled in a 2-week donor human milk study period.   
  
  
Purpose of study: to test the following null hypothesis:  
Infants with a diagnosis of neonatal abstinence syndrome (NAS) due to in-utero 
exposure to opiates, fed donor human milk, will have similar GI/feeding sub-scores of 
the Finnegan scoring tool when compared to (historic) infants fed formula.  
  
A rejection of the null hypothesis will be used to design a randomized trial of donor human milk in 
infants with NAS.  
  
Eligibility for study enrollment:  
   
Inclusion criteria:  
• 
Term infants (>37 completed weeks) with a diagnosis of NAS, due to maternal use of opiates 
(only)  
• 
Infants will have had moderate to severe NAS symptoms (Finnegan scores >8) that required 
pharmacologic therapy but have been stabilized (captured) on oral morphine (Finnegan scores 
less than 8 for 24 hours)   
• 
Breastfeeding is contraindicated or the mother has chosen formula feeding for her baby  
  
Exclusion criteria:  
• 
Preterm infants (<37 completed weeks at birth)  
• 
Infants with intrauterine growth restriction (BW <10th percentile for gestational age)   Mother 
is providing her own milk  
  
 
 

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Methods:  
Once the infant’s withdrawal symptoms have been stabilized with oral morphine and the mother has 
agreed to participation (signed ICF/RA), infants will be assigned to receive only donor human milk (Co-op 
donor milk, Medolac Laboratories, Lake Oswego, OR) for a period of 2 weeks. Vitamin supplementation 
or other nutritional adjustments will be at the discretion of the attending physician.    
  
Infant Finnegan scores will be assessed according to the current NAS protocol. Oral morphine dosing 
(increases or weaning doses) will be consistent with the current NAS protocol.    
  
Primary outcome:    
Acceptability (no increase in GI sub-scores compared to historic formula-fed controls) Appropriate 
growth  
  
See data collection sheet for detailed list of variables.  
  
Statistical analysis:   
Descriptive statistics will be provided. As this is a pilot study, no inferential statistics will be applied.  
  
  
  
  
Figure 1.  Cases of neonatal abstinence syndrome (NAS) in Kentucky 
(20002012)*  
  
  
 
*Data from Kentucky Injury Prevention Research Center, January 2014  
  
  
0   
200   
400   
600   
800   
1000   
2000  2001  2002  2003  2004  2005  2006  2007  2008  2009  2010  2011  2012  
824  
175  

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Figure 2.  Healthcare expenditures (in $ millions) for treatment of neonatal 
abstinence syndrome (NAS) in Kentucky (2000-2012)*  
  
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012  
*Data from Kentucky Injury Prevention Research Center, January 2014  
  
Table 1.  Modified Finnegan Scoring Tool4  
System symptoms  
Total (frequency)  
CNS   
  
High-pitched cry  
Continuous high-pitched cry  
2  
3  
Sleeps <1 h after feeding  
Sleeps <2 h after feeding  
Sleeps <3 h after feeding  
3  
2  
1  
Hyperactive Moro reflex  
Markedly hyperactive Moro reflex   
2  
3  
Tremors disturbed  
Mild tremors undisturbed  
Moderate severe tremors undisturbed  
2  
3  
4  
Increased muscle tone  
2  
Excoriation (specify area)  
1  
Myoclonic jerks  
3  
Generalized convulsions  
5  
0   
10   
20   
30   
40   
50   
$ 0.2  
$40.2  

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Metabolic  
  
Sweating  
1  
Fever 37.2°C – 38.3°C Fever 
>38.4°C  
1  
2  
Frequent yawning >4 x per interval  
1  
Mottling  
1  
Vasomotor  
  
Nasal stuffiness  
1  
Frequent sneezing >4 x per interval  
1  
Respiratory  
  
Nasal flaring  
2  
Respiratory rate >60/min  
Respiratory rate >60/min + retractions  
1  
2  
Gastrointestinal  
  
Excessive sucking  
1  
Poor feeding  
1  
Regurgitation  
2  
Projective vomiting  
3  
Loose stools Watery 
stools  
2  
3  
GI sub-score range: 0 to 10  
  
Total score range    
0 to 44  
  
  
REFERENCES  
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Patrick SW, Schumacher RE, Benneyworth BD, Krans EE, McAllister JM, Davis MM. Neonatal 
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2. 
Nestler EJ. Molecular mechanisms of opiate and cocaine additiction. Current Opinion in 
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3. 
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4. 
Kron RE, Finnegan LP, Kaplan SL, Litt M, Phoenix MD. The assessment of behavioral change in 
infants undergoing narcotic withdrawal: comparative data from clinical and objective methods. 
Addict Dis 1975, 2(1-2): 257-275.  
  
5. 
American Academy of Pediatrics. Neonatal drug withdrawal. Pediatrics 1998, 101(6): 1079-1088.  
  

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6. 
Academy of Pediatrics A. Breastfeeding and the use of human milk. Pediatrics 2012, 129(3):  
e827-841.  
  
7. 
American Academy of Pediatrics. Prenatal substance abuse: short- and long-term effects on the 
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8. 
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9. 
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10. 
Perez-Reyes M, Wall ME. Presence of delta9-tetrahydrocannabinol in human milk. New England 
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11. 
Steiner E, Villen T, Hallberg M, Rane A. Amphetamine secretion in breast milk. European Jouran 
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12. 
Rodriguez-Palmero M, Koletzko B, Kunz C, Jensen R. Nutritional and biochemical properties of 
human milk: II. Lipids, micronutrient, and bioactive factors. Clinics in Perinatology 1999, 26: 
335359.  
  
13. 
Sheard NF, Walker WA. The role of breast milk in the development of the gastrointestinal tract. 
Nutr Rev 1988, 46(1): 1-8.  
  
14. 
Billeaud C, Guillet J, Sandler B. Gastric emptying in infants with or without gastro-oesophageal 
reflux according to the type of milk. Eur J Clin Nutr 1990, 44(8): 577-583.  
  
15. 
Cavell B. Gastric emptying in infants fed human milk or infant formula. Acta Paediatr Scand 
1981, 70(5): 639-641.  
  
16. 
Shulman RJ, Schanler RJ, Lau C. Early feeding, feeding tolerance and lactase activity in preterm 
infants. Journal of Pediatrics 1998, 133: 645-649.  
  
17. 
McQueen KA, Murphy-Oikonen J, Gerlach K, Montelpare W. The impact of infant feeding 
method on neonatal abstinence scores of methadone-exposed infants. Advances in Neonatal 
Care 2011, 11(4): 282-290.  
  
18. 
Dryden C, Young D, Hepburn M, Mactier H. Maternal methadone use in pregnancy: factors 
associated with the development of neonatal abstinence syndrome and implications for 
healthcare resources. BJOG 2009, 116: 665-671.