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 Seminars in Fetal and Neonatal Medicine 27 (2022) 101345

Contents lists available at ScienceDirect

Seminars in Fetal and Neonatal Medicine

journal homepage: www.elsevier.com/locate/siny

Infection prevention for extremely low birth weight infants in the NICU
Noa Fleiss a, Samiksha Tarun b, Richard A. Polin b, *
a
Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA
b
Department of Pediatrics, Columbia University School of Medicine, New York City, NY, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Extremely preterm infants are particularly vulnerable to systemic infections secondary to their immature im­
Neonate mune defenses, prolonged hospitalizations, delays in enteral feeding, early antibiotic exposure, and need for life-
NICU sustaining invasive interventions. There have been several evidence-based practices for infection prevention in
Extremely low birth weight infant
this population, such as human milk feedings, utilization of “bundle checklists” and decolonization of pathogenic
Very low birth weight infant
Infection prevention
organisms. Other practices, such as the use of probiotics, human milk-derived fortifiers, and antifungal pro­
Late onset sepsis phylaxis are more controversial and require further investigation regarding the risks and benefits of such
NEC interventions.
Probiotics This chapter examines the susceptibility of the preterm newborn infant to invasive infections and describes
Antibiotics several strategies for infection prevention, along with the associated limitations of such practices. It also ad­
Fungemia dresses the various gaps in our understanding of preventing infections in this population, and the need for
SARs-CoV-2 additional large multi-center randomized controlled trials. Additionally, the role of the SARs-CoV-2 global
pandemic and associated strategies for infection prevention in the NICU are discussed.

1. Introduction exposure to genital microbes. Even with preterm labor and intact
membranes, the amniotic fluid (and secondarily the fetus) may become
The Preterm Infant and Susceptibility to Infection: colonized. The mode of delivery greatly influences the kind of bacteria
that colonize the newborn [13]. Caesarean-delivered infants bypass the
Preterm infants are at a significant disadvantage when it comes to
vaginal canal secretions, which are rich in Lactobacillus, Bacteroides and
infection prevention [1,2]. Very low birthweight (VLBW) and extremely
Bifidobacterium species [8], and have a microbiota composition that is
low birth weight (ELBW) neonates are particularly vulnerable to bac­
different from those infants born vaginally [14,15]. Several studies have
terial infections because of developmental immaturities in the immune
investigated the practice of ‘vaginal seeding,’ through swabbing the
system, need for prolonged hospitalizations and requirements for inva­
mouths and skin of caesarean-born infants in an attempt to mimic the
sive monitoring, testing and treatments which bypass skin barrier de­
microbiota exposure during a vaginal birth [14]. This practice has a
fense mechanisms [1–5]. Moreover, the preterm skin lacks a
controversial reliability profile, as it does not take into account the po­
well-formed stratum corneum (the outermost layer of the epidermis),
tential exposure of preterm infants to unexpected pathogenic organisms,
as well as the vernix caseosa (a lipid-rich waxy coating containing active
and therefore needs further investigation [16].
antimicrobial proteins and peptides), both of which are key for pre­
venting pathogen entry [1,4–6].
2. Infection prevention by disease process
Postnatal acquisition of the microbiome plays a critical role in im­
mune development and response [7,8]. The preterm infant’s micro­
2.1. Necrotizing enterocolitis
biome is largely driven by environmental exposures in the NICU [9].
Thus, repeated courses of antibiotics, the NICU ecological environment
Necrotizing enterocolitis (NEC) is a multifactorial disease in which
and choice of diet (formula or breast milk) are key regulators of the
the susceptibility of the preterm intestine, immunodeficiencies associ­
microbiome and may be important in the pathogenesis of late onset
ated with preterm delivery, nutritional practices and the intestinal
sepsis (LOS) [10–12] In the setting of preterm rupture of membranes, the
microbiome play critical roles [17]. The gastrointestinal microbiota is
sterile or partially sterile uterine environment is compromised by

* Corresponding author. Department of Pediatrics, Columbia University School of Medicine, 3959 Broadway, New York, NY, 10032, USA.
E-mail address: [email protected] (R.A. Polin).

https://doi.org/10.1016/j.siny.2022.101345

Available online 13 April 2022

1744-165X/© 2022 Elsevier Ltd. All rights reserved.
N. Fleiss et al. Seminars in Fetal and Neonatal Medicine 27 (2022) 101345

mostly composed of bacteria from two major phyla, Bacteroidetes (gram abnormal pattern of colonization may alter the structural barrier of the
negative bacteria) and Firmicutes (Lactobacillus and other gram-positive intestine resulting in increased permeability and bacterial translocation,
bacteria). Other important phyla, especially with regard to NEC devel­ ultimately leading to NEC (Fig. 1).
opment include Proteobacteria (pathogenic gram-negative bacteria) and No single bacterium has been causally linked to the development of
Actinobacteria (Bifidobacterium and other gram-positive bacteria). Until NEC. However, NEC has been associated with a “bloom” in Proteobac­
fairly recently, culture-based methods were used to identify and define teria, particularly Enterobacteriaceae, and a decrease in Firmicutes and
the microorganisms colonizing various body sites. Recent advances in Bacteroidetes [28]. This process termed dysbiosis is believed to precede
molecular techniques (16S RNA sequencing and shotgun metagenomics) the development of NEC. Enterobacteriaceae interact with toll like
have allowed investigators to characterize the microbiome of the pre­ receptor-4, which is known to regulate the balance between healing and
term infant with much greater precision and examine its role in the repair in the intestine [29] and is upregulated in infants with NEC [30].
pathogenesis of diseases such as NEC [18]. However, it is unclear if the “bloom” of gram-negative bacteria actually
Use of drugs which suppress gastric acidity has been shown to alter causes NEC or that NEC results from the concurrent decrease of
the microbiome [19] and potentially increase the risk of LOS and NEC in commensal bacteria (e.g., Firmicutes), which might be cytoprotective.
very low birthweight infants [20,21]. Both proton pump inhibitors and
H2-blockers have been correlated with increased abundance of coloni­ 2.2. Probiotics and NEC prevention
zation with Proteobacteria, Actinobacteria and Bacteroidetes. Antibiotics
for early-onset sepsis decrease the numbers of Firmicutes and increase the Probiotics are live microbial supplements which provide benefit to
abundance of Proteobacteria [22]. Intrapartum antibiotic prophylaxis the host beyond that of nutrition. Breast milk contains a variety of
has been shown to alter the microbiome for months postnatally, by probiotics, but unfortunately is not always available to the preterm in­
increasing Proteobacteria and decreasing Actinobacteria, Bifidobacterium fant. Donor breast milk provides suboptimal nutrition unless fortified
and Bacteroides [23]. Furthermore, prolonged treatment with antibiotics and does not contain viable bacteria once pasteurized. Probiotics have
for early-onset sepsis has been associated with an increased risk of been shown to increase mucin and β-defensin production, decrease
necrotizing enterocolitis and late onset sepsis [24,25]. In term infants, adherence of pathogens, enhance tight junctions, increase the number of
the abundance and diversity of bacteria is decreased at birth [26]. In IgA producing cells, kill pathogenic bacteria and dampen the inflam­
comparison, bacterial diversity is further decreased in infants delivered matory response [31].
preterm and is characterized by high numbers of Firmicutes and Proteo­
bacteria (e.g., Enterobacteriaceae) and low levels of Bifidobacterium. This

Fig. 1. Hackam, D. J. & Sodhi, C. P. Cell Mol Gastroenterol Hepatol (2018) [27].

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N. Fleiss et al. Seminars in Fetal and Neonatal Medicine 27 (2022) 101345

Dr. Angela Hoyos in Bogota Colombia was the first clinician to use conducted on samples from different countries on a limited number of
probiotics in a NICU setting [32]. She treated every baby with Infloran specimens. In Europe, probiotic containing foods and supplements are
containing Bifidobacteria and Lactobacillus acidophilus, which resulted carefully regulated. Over 3000 health claims for probiotics were rejected
in a marked decline in NEC and NEC related deaths. Similarly, Totsu by the European commission except for better lactose digestion when
et al. conducted a cluster-randomized double-blind, placebo-controlled used in yogurt cultures. In the United States, probiotics are considered
trial including 19 hospitals across Japan, evaluating the benefit of dietary supplements and health claims are not regulated. The phrase
administering the probiotic, Bifidobacterium bifidum to VLBW infants. “buyer beware” is appropriate when using off-the-shelf dietary supple­
The authors of this trial found that the probiotics group reached full ments in preterm infants. There is a great need for pharmaceutical grade
enteral feeds earlier with a significantly decreased incidence of LOS probiotic supplements.
compared to the placebo group [33]. The population of infants <28 week’s gestation is most susceptible to
Probiotics have been administered to thousands of newborn infants NEC. However, the majority of randomized trials examining effective­
in randomized clinical trials and observational studies. The encouraging ness of probiotics have not included large numbers of infants in this
news is that the use of probiotics is relatively safe, except for the rare gestational age stratum. Meta-analyses have been problematic because it
infant who develops sepsis with the probiotic organism or a contami­ is difficult to compare studies using different probiotic species. For
nant. However, there are several controversies surrounding probiotic example, Underwood et al. performed a dose escalation study
use. For example, the manufacturing processes for probiotics are not comparing two microbial strains (B infantis and B. lactis). Only B. infantis
tightly regulated in the United States. The Food and Agriculture Orga­ was able to colonize the gastrointestinal tract, B. lactis did not.
nization/World Health Organization has issued recommendations on Furthermore B. lactis is unable to utilize breast milk oligosaccharides
information that should be present on the product label, including; [45]. In addition, the quality of the meta-analyses differed considerably
genus, species, strain designation, minimal viable number of each pro­ and as of 2020 only one was rated as high quality based on AMSTAR
biotic strain at the end of shelf life, the recommended effective dose of criteria [46]. In a recent systematic analysis from the Cochrane library
the probiotic, health claims, storage conditions and corporate contact [47] Sharif et al. concluded that probiotics may reduce the incidence of
details. That information is not generally available for commercial NEC (conclusion rated as low certainty -number needed to benefit = 33).
probiotic products used in the United States. There have been a number The evidence was assessed as low certainty because of limitations in trial
of studies testing the purity and content of commercial probiotic sup­ design and publication bias. This meta-analysis also concluded that
plements. On the positive side, Shehata and Newmaster tested 182 probiotics probably reduced mortality and infection. However, sensi­
probiotic “dietary supplements” from the United States and Canada [34] tivity meta-analyses of 16 trials at low risk of bias showed that probiotics
and found that only 8% of samples were non-compliant with labelling. reduced NEC but had no effect on mortality or infection rates. Impor­
However, several studies found both contamination (with potential tantly, there was no significant benefit of probiotics on the incidence of
pathogens) and missing species in a high percentage of probiotic sup­ NEC in extremely low birth weight infants. These results should be
plements [35–42]. Other studies found that the number of viable counts cautiously interpreted as relatively few studies were included in these
were lower than indicated on the label [36,40,42–44]. It is important to analyses and the authors warn that estimates might be imprecise [47].
note that most of the studies assessing viable bacterial counts were In a strain specific meta-analysis by van den Akker et al. only a

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N. Fleiss et al. Seminars in Fetal and Neonatal Medicine 27 (2022) 101345

minority of single strains or combination of strains reduced mortality or • There is no difference in tolerance of feedings with donor milk or
morbidity in clinical trials [48]. Importantly, most randomized clinical formula.
trials have not confirmed the purity of the product used in each study. • Formula fed infants exhibited significantly better weight gain and
Fungal sepsis has been reported from a NICU in which the commercial linear growth. In the systematic review of Quigley et al., growth in
product contained the contaminating fungus [49]. Many manufacturers head circumference was also faster with formula, but not when donor
change the strains in the probiotic product without changing the label. breast milk was fortified [54].
Therefore, there is uncertainty what strain is actually being adminis­ • No long-term differences in neurodevelopment or growth have been
tered. Of the hundreds of probiotic trials, it is noteworthy that only two demonstrated
commercial probiotics studied in clinical trials have been shown to both • There is no evidence that human milk (donor or maternal) decreases
increase colonization with the probiotic strain in the intestine and the risk of late onset sepsis.
decrease colonization with Enterobacteriaceae [50]. Finally, most ran­
domized trials have not considered cross contamination of the probiotic Although controversial, there is no evidence that human milk-based
to the control group, which might benefit infants in the control group fortifiers decrease the risk of NEC vs. fortifiers prepared from bovine
and dilute any potential benefit of probiotics. sources. The recent meta-analysis of Grace et al., which concluded that
Based on a careful review of all available evidence, the Committee on human milk derived fortifiers resulted in a lower incidence of NEC
Fetus and Newborn of the American Academy of Pediatrics concluded included only two studies and is too small to make meaningful conclu­
that “Given the lack of FDA-regulated pharmaceutical grade products in sions [55].
the United States, conflicting data on safety and efficacy, and potential
for harm in a highly vulnerable population, current evidence does not 3. Late onset sepsis (LOS)
support the universal administration of probiotics to preterm infants,
particularly those with birthweights <1000 g” [51]. Importantly, there LOS, or sepsis occurring after 72 h of life, is a major contributor of
are still several NICUs in the United States and globally that routinely neonatal morbidity and mortality, with an incidence of 1–2 per 1000
choose to administer probiotics to their VLBW infants, despite the AAP live born newborns and a high overall mortality rate [56–58]. Gram
recommendations, based on results from various studies as well as from positive organisms, specifically Staphylococcus aureus, account for the
anecdotal experiences. Additional large randomized clinical trials using majority of LOS infections. Coagulase negative Staphylococcus (CoNS) is
pharmaceutical grade product are still necessary and in progress. often cited as a leading cause of LOS in the NICU [56,57,59]. However,
based on more recent definitions of true bacteremia, as opposed to blood
sample contamination with CoNS, the prevalence of CoNS LOS is likely
2.3. Human milk feedings for prevention of NEC less than previously reported [60,61]. Gram negative bacteria, such as
Escherichia coli, Enterobacter, and Klebsiella, as well as fungal species,
Human milk contains a variety of antimicrobial factors and immu­ primarily Candida albicans, are also responsible for LOS and have an
nomodulating agents and has a unique microbiome that may serve as a overall higher mortality rate than gram positive infections [56,57].
source of commensal bacteria (Bifidobacterium and Lactobacillus) [52,
53]. However, unpasteurized breast milk may contain a variety of spe­ 3.1. Central line associated bloodstream infections
cies, some of which may be pathogenic for the neonate. In preterm in­
fants, use of human milk is considered an evidenced based strategy to Episodes of LOS are often viewed as preventable hospital acquired
reduce the incidence of NEC. However, in mothers delivering very infections (HAI). Central line associated bloodstream infections
preterm infants, the supply of human milk may initially be inadequate (CLABSI) are the most common HAI in the NICU, due to sustained need
and require supplementation (donor breast milk or formula), or calori­ for vascular access and a lengthy hospital stay. A peripherally inserted
cally inadequate and require milk fortifiers (bovine or human). Obser­ central catheter (PICC) is most commonly used in neonates and several
vational studies of feeding infants with mother’s own milk demonstrate evidence-based practices have been implemented for CLABSI prevention
a reduction in the incidence of NEC. Randomized clinical trials, by ne­ [62–65]. Over the last decade, there has been a considerable shift in
cessity, have only included donor breast milk that was supplemented perception of CLABSI, from an unavoidable complication of a life-saving
with human-milk derived or bovine-derived fortifiers. Donor breast milk intervention to a preventable and reportable medical error that requires
is pasteurized which alters some of the immunological benefits, without intervention [64].
significantly affecting the nutritional composition. Furthermore, donor The Institute for Healthcare Improvement (IHI) together with the
breast milk is usually collected from women delivering infants at term, Centers for Disease Control and Prevention (CDC) and other national
in whom the nutrient supply is very different from that found in milk scientific organizations have issued evidence-based guidelines that
from women delivering preterm infants. As with the systematic reviews promote using central line bundles to improve CLABSI rates in the
of probiotics, the meta-analyses of human breast milk vs formula are healthcare setting [66,67]. Care bundles are an “all-or-nothing”
very heterogeneous and include studies of infants fed an exclusively approach of evidence-based practices, that when implemented simul­
human diet vs. those receiving varying amounts of bovine fortified taneously, improve outcomes. In the case of CLABSI prevention bundles,
donor milk or formula. Furthermore, the meta-analyses include studies there are 5 key best practices that require full compliance:
conducted over a number of years. However, a few generalizations are
still possible. 1) Focus on sterile barrier precautions during PICC insertion (mask,
sterile gown, sterile gloves and large sterile drapes)
• All meta-analyses demonstrated a reduction in the incidence of NEC 2) Hand hygiene
with donor milk compared with preterm formula. 3) Skin preparation with an antiseptic
• There is no difference in all-cause mortality in infants fed formula vs.
donor milk.

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N. Fleiss et al. Seminars in Fetal and Neonatal Medicine 27 (2022) 101345

4) Dressing changes when dressing becomes bloody, soiled or no longer and typically cause late-onset sepsis [57]. However, a few cases occur
occlusive through vertical transmission and may cause early-onset sepsis.
5) Daily review of line necessity with immediate removal of unwar­ Attempting to prevent invasive fungal disease in high-risk patients is
ranted lines imperative to avoid mortality and long-term sequelae.
Minimizing risk factors for fungal sepsis is an important way to
Additionally, frequent hands-on education of staff members and minimize the risk of disease. Modifiable risk factors include: prolonged
unannounced audit regarding adherence to these care bundles, are exposure to empiric antibiotics, exposure to 3rd generation cephalo­
recommended [68,69]. Statewide collaboratives using CLABSI preven­ sporins and other broad-spectrum antibiotics, and use of foreign bodies
tion bundles have been highly effective in reducing the incidence of (such as endotracheal tubes, central venous or arterial catheters and
infection [70–72]. other hardware) [91,92]. Other risk factors for invasive fungal disease
include positive pressure ventilation and intubation, gastrointestinal
3.2. MRSA/MSSA colonization and infection prevention pathology, previous blood stream infection, parenteral nutrition and
intravenous lipids [92]. In a matched case-control study, multivariate
Methicillin-sensitive Staphylococci aureus (MSSA) and Methicillin- analyses showed that candidemia was associated with prolonged cath­
resistant Staphylococci aureus (MRSA) are common causes of LOS in eter use, which had an odds ratio of 1.06 per day of use (95% CI of
preterm infants, and significant contributors of morbidity and mortality 1.02–1.10) and with previous blood stream infection, with an odds ratio
in the NICU [73–75]. A meta-analysis of MRSA colonization in neonates of 8.02 (95% CI of 2.76–23.30) [92]. It is well established that reducing
during NICU admission described a pooled prevalence of 1.9% (95% CI exposure to these risk factors is associated with a reduction in risk of
1.3%–2.6%) for MRSA colonization, with a relative risk to develop systemic fungal disease [91].
MRSA bloodstream infection (BSI) of 24.2 (95% CI 8.9–66) in colonized
infants [76]. Colonization with Staphylococci aureus (SA) is a well-known 4.1. Antifungal prophylaxis and infection prevention
risk factor for subsequent development of a BSI in the NICU population,
and several prevention strategies have been developed to mitigate Antifungal prophylaxis is used to reduce the risk of invasive fungal
spread [76–79]. Weekly surveillance of admitted neonates, effective disease; however, variations in this practice exist worldwide. Flucona­
hand hygiene, environmental and equipment decontamination, cohort­ zole seems to be emerging as the drug of choice for prophylaxis. It has a
ing of colonized infants, and implementing strict contact precautions long half-life, is excreted renally, and has a good safety profile, although
have all been shown to reduce endemic SA across NICUs [79–82]. more studies in neonates are needed [93]. Side effects reported include
Identifying MRSA and MSSA colonized neonates through weekly transaminitis [94] and cholestasis in ELBW neonates who received flu­
nasal swabs has led to decolonization efforts using topical antimicrobial conazole prophylaxis [95].
agents. Mupirocin applied to the nares combined with the use of In the first large, prospective, randomized, double-blinded clinical
chlorhexidine baths (relevant to gestational, >36 0/7 weeks and chro­ trial examining the efficacy of fluconazole prophylaxis in preventing
nological age, > 4 weeks old) have shown promising reductions in MRSA invasive fungal infection, 10 ELBW neonates developed invasive fungal
[83,84], as well as MSSA colonization and infections [85]. Both parents infection in the placebo group compared to 0 in the fluconazole pro­
and care providers can contribute to the spread of SA. Recently, Milstone phylaxis group (P = 0.0008) [96]. In a more recent large multicenter
et al., conducted a clinical trial randomizing parents of MRSA colonized study, Benjamin et al. concluded that prophylactic fluconazole reduced
neonates to either receive mupirocin and chlorhexidine cloths or pla­ the incidence of invasive fungal infection in infants <750 g, but did not
cebo [86]. These authors report that 14.6% of neonates with parents in reduce neurodevelopmental impairments at 18–22 months postnatally
the treatment group acquired a concordant SA strain compared with [97]. In addition to fluconazole, other agents including topical anti­
28.7% of neonates with parents in the placebo group (risk difference fungal medications and liposomal amphotericin B have been used to
− 14.1%, and hazard ratio of 0.43). This study opens the door for future reduce the incidence of fungal infections. Neither of these agents have
research examining decolonization of healthcare workers and been adequately studied in neonates. In a randomized control trial
care-takers of colonized neonates, with potential to reduce subsequent comparing prophylaxis with nystatin, fluconazole and placebo, the
nosocomial infections. It is important to mention, that the increased use incidence of fungal infections was 4.3% in nystatin group, 3.2% in flu­
of mupirocin ointment in critically ill preterm neonates has led to the conazole group and 16.5% in placebo group [98]. A 2015 Cochrane
emergence of mupirocin resistant Staphylococci aureus strains. While the Review concluded that prophylactic systemic antifungal therapy may
prevalence of these resistant strains remains low, this can have future reduce the incidence of invasive fungal infection in very low birth
implications for infection prevention and eradication [87,88]. weight infants, however, there was considerable heterogeneity in the
reported studies [99].
It is re-assuring that of the studies done, there seems to be a lack of
4. Fungal infections
emergence of resistant fungal species for neonates who have received
antifungal agents (IDSA) and there does not seem to be an emergence of
VLBW and ELBW neonates are at increased risk for invasive fungal
inherently resistant fluconazole fungal species [100]. Continued sur­
disease, which is associated with increased morbidity mortality and
veillance and monitoring of the fungal ecology in NICUs where flucon­
neurodevelopmental impairments [57,89]. The incidence of invasive
azole or nystatin prophylaxis is adopted is warranted to exclude these
fungal disease in these birth weight populations ranges widely with an
unwanted shifts in sensitivity to these agents.
average of 16% (range 4–43%) [90]. The majority of cases are caused by
Candida species, specifically Candida albicans and Candida parapsilosis,

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N. Fleiss et al. Seminars in Fetal and Neonatal Medicine 27 (2022) 101345

5. Infection prevention during COVID neonates due to transplacental transfer of SARs-CoV-2 antibodies after
covid19 vaccination during pregnancy, it is important to understand the
The emergence of the severe acute respiratory syndrome coronavirus safety of covid19 vaccine administration and promote its use in pregnant
2 (SARs-CoV-2) pandemic has dramatically changed the way we deliver and lactating women. Preliminary results for safety of mRNA covid19
healthcare globally. While SARs-CoV-2 has not had major clinical im­ vaccine in pregnant women concluded that there were no obvious safety
plications for preterm infants in the NICU [101,102], it has led to more concerns [109]. Injection-site pain was the most commonly reported
rigid infection prevention strategies (i.e., visitor restrictions, hand hy­ side effect; headache, myalgia, chills and fever were also reported. No
giene, environmental disinfection, and donning of personal protective neonatal deaths were reported. Only data from December 14, 2020 to
equipment). Maternal breastmilk has been more closely examined as a February 29, 2021 were available for analysis, indicating that more
potential protective mechanism for infants of women who were previ­ longitudinal studies are needed for better assessment of safety during
ously infected with SARs-CoV-2 or immunized with the vaccine. Multi­ and after pregnancy. Preliminary data suggests that it is safe to admin­
ple studies have shown that maternal spike specific IgA targeting ister mRNA covid19 vaccine to lactating individuals [110].
SARs-CoV-2 is found in breastmilk of mothers previously infected or
vaccinated [103–105] without evidence of SARs-CoV-2 transmission

Flow Diagram: Infection Prevention in the Very Low BirthWeight Infant:

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