Description of the condition

The microbiome is defined as the genomes and gene products of microbes that live within and on humans (Johnson 2012). Under normal conditions the microbiome of an infant is established through exposure with bacteria both prenatally and postnatally. The placenta, amniotic fluid and meconium have their own microbiota that influences the microbiome of the infant. Postnatal influences of the microbiome come from exposures mainly from the maternal microbiome which includes exposure to vaginal, oral, fecal, skin and breast milk bacteria, with a typical predominance of protective Lactobacillus and Bifidobacterium in the neonatal period.

Preterm infants are at risk for alterations in the normal protective microbiome due their increased cesarean delivery rate, exposure to antibiotics, nosocomial exposures to pathogens, lack of typical skin contact with maternal flora, as well as alterations in typical exposure to breast milk (Cilieborg 2012). Cesarean delivery alters colonization of neonates so their stool has lower bifidobacteria and more skin flora such as Staphylococcus, Corynebacterium and Propionibacterium (Faa 2013). Maternal intrapartum antibiotics and antibiotics given to mothers with prolonged rupture of membranes are associated with lower transfer of Lactobacillus to the infant, and even antibiotics given days before birth have been shown to alter the premature infant microbiome with less bacterial diversity of the first stool samples (Faa 2013; Keski‐Nisula 2013). Antibiotics given in the neonatal period have also been associated with decreased stool bifidobacteria (Faa 2013). This may lead to delayed colonization with low diversity of bacteria as well as colonization with pathogens and bacterial overgrowth which put infants at risk for necrotizing enterocolitis (NEC), sepsis and death in the neonatal period (Cilieborg 2012).

The development of NEC is typically associated with a dysregulation of inflammation in the gut that results in gas‐producing bacteria translocating through the bowel mucosa and is not usually caused by one single organism. It is a disorder that affects approximately 7% of infants with a birth weight of less than 1500 grams, with a death rate of approximately 20% to 30% (Neu 2011). Strategies to prevent NEC have been employed including exclusive human milk diet, standardized feeding protocols, human milk fortifiers and postnatal probiotics, but prematurity and alterations of gut flora still put premature infants at risk.

Modifications of the neonatal microbiome may have long‐term effects on health that may last until adulthood. Altered microbiomes have been associated with the development of atopy, inflammatory bowel disease, obesity and impaired glucose regulation. It is unknown to what extent early preterm infant alterations in the microbiome may influence their lifelong risk for these diseases.

Description of the intervention

Probiotics are defined as living microorganisms that confer a health benefit to the host (Othman 2012); they are often given enterally to colonize the gastrointestinal tract. Typical probiotic bacteria administered are bifidobacteria, Lactobacillus or Saccharomyces (Dugoua 2009; Thomas 2010). They have been given directly to preterm infants with intention to decrease the rate of NEC (AlFaleh 2014; Costeloe 2016; Deshpande 2010; Neu 2011), and there is emerging interest in promoting gastrointestinal colonization in preterm infants through administration of probiotics to their mothers instead of directly to infants. Probiotics have already been studied during pregnancy for other indications with the intention to treat genitourinary infections, prevent infant atopy, enhance metabolism and prevent preterm labor (Dugoua 2009; Gomez Arango 2015; Lahtinen 2009; Lindsay 2013; Reid 2003; VandeVusse 2013).

The focus of this investigation is the maternal oral administration of probiotics. Maternal probiotics can be administered to pregnant women at risk for preterm birth or to mothers of preterm infants after birth. Pregnant women administered probiotics in pregnancy will be compared to pregnant women receiving placebo or no intervention. Mothers of preterm infants administered probiotics after birth will be compared to either mothers of preterm infants administered placebo or no intervention, or to preterm neonates administered probiotics directly.

How the intervention might work

The microbiome of the pregnant and postpartum woman is influenced by the established microbiome, diet, probiotic exposures, and pregnancy itself as there are alterations of the microbiome that occur during pregnancy that are likely hormonally mediated. During pregnancy probiotics have been generally regarded as safe (Elias 2011; Gomez Arango 2015; Lindsay 2013), and beneficial for mothers in preventing and treating bacterial vaginitis, and reducing the risk of gestational diabetes, with hypotheses but no definitive evidence of their efficacy in preventing preterm birth (Gomez Arango 2015; Othman 2012). While studies have shown that probiotics taken by adults only change their microbiome while they are being taken, these short‐term alterations in maternal microbiome may have long‐term effects on establishment of the fetal and neonatal microbiome (Matamaros 2013).

Normal microbiome colonization occurs prenatally with bacteria found in the placenta, amniotic fluid and fetal meconium (Matamaros 2013), and postnatal colonization from the mother and environment, including vaginal Lactobacillus obtained at birth, maternal skin flora and bacteria in breast milk (Cilieborg 2012; Faa 2013). Especially predominant and beneficial to the healthy neonatal microbiome are lactobacilli and Bifidobacterium. Lactobacilli are facultative anaerobes that create an anaerobic environment in which bifidobacteria, anaerobic gram positive bacilli, can colonize and predominate in the colon (Bergmann 2014; Dugoua 2009). These bacteria help maintain the mucosa of the intestines, prevent pathogens from colonizing the colon, modulate inflammation along the mucosa and activate the immune system (Hickey 2012), which may help to decrease the risk of NEC and subsequent development of sepsis.

Breast milk consumption greatly contributes to colonization of newborn infants. Studies have shown that there are more than two hundred species of bacteria in human milk with a predominance of Lactobacillus and bifidobacteria in addition to Staphylococcus, Streptococcus and corynebacteria (Bergmann 2014). There is evidence that the neonatal gut microbiome reflects the bacteria found in breast milk and the mother’s stool (Bergmann 2014; Cilieborg 2012; Jost 2014). According to the theory of the enteromammary pathway, bacteria are deposited into the mammary milk ducts from the maternal gastrointestinal tract via active transport through the blood (Bergmann 2014; Jost 2014). Dendritic cells in the maternal gut lumen are thought to trap bacteria, and with the help of mononuclear cells, transport them through the blood to the breast (Bergmann 2014). This is thought to be hormonally mediated, occurring late in the third trimester, with the most bacteria present in the breast in the peripartum period (Bergmann 2014).

Studies have shown that lactobacilli taken orally by the mother are present in breast milk when taken prenatally and postnatally (Bergmann 2014). Supplementation with Lactobacillus reuteri during the third trimester prior to delivery resulted in a statistically significant increase in L reuteri in maternal colostrum (Abrahamsson 2009), and Lactobacillus GG taken by mothers for one month prior to delivery increased the diversity of fecal Bifidobacterium in neonates (Gueimonde 2006).

Why it is important to do this review

Probiotic administration in high risk very low birth weight (VLBW) infants has been shown to reduce the incidence of NEC as well as mortality (AlFaleh 2014; Deshpande 2010). Postnatal probiotic administration decreased the risk of developing stage II‐III NEC by more than half (AlFaleh 2014). In their analysis, Deshpande and coworkers suggest that routine use be implemented without the need for more placebo‐controlled trials (Deshpande 2010).

However, the studies included in these meta‐analyses are quite heterogeneous in regards to the specie(s), dose, timing and duration of administration, and there is concern about safety and quality assurance of probiotics which lie outside the purview of the Food and Drug Administration (FDA) regulation. A recent systematic review cautions universal use of probiotics in VLBW infants citing the lack of evidence of efficacy for specific strains (Mihatsch 2012), while others in the neonatal community cite both methodologic and safety concerns as cautions against universal adoption (Garland 2010; Soll 2010). The American Academy of Pediatrics 2010 Clinical Report written by the Committee on Nutrition states that there is insufficient data to recommend probiotics in infants weighing less than 1000 grams, and that since not all probiotics have been studied, they cannot all be generally recommended (Thomas 2010). The European Society for Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition counsels caution in introducing potentially infectious agents to VLBW infants due to their immunologic immaturity, and states that there are not enough data to conclude that probiotic administration to preterm neonates is safe (Agostoni 2010). While there are many studies that suggest the safety of probiotics (AlFaleh 2014; Costeloe 2016), there have been cases of sepsis with the strains of probiotics given to preterm infants (Bertelli 2015), as well as a death due to gastrointestinal mucormycosis from Rhizopus oryzae‐contaminated probiotic directly administered to a preterm infant (Health Alert Network CDC 2014). With these emerging safety concerns, the FDA has issued a warning against the use of probiotics in immunocompromised patients (FDA 2014). These same safety concerns may not be universal where there are regulatory organizations responsible for overseeing the safety of probiotics, such as the Natural Health Products Directorate in Canada (Janvier 2013).

Currently probiotic use in the VLBW population is not routine in many neonatal intensive care unit (NICUs) in the United States. A recent survey of United States' NICUs that are members of Vermont Oxford Network showed that 14% of these NICUs give VLBW infants probiotics (Viswanathan 2016). Of these 14%, 8.8% of NICUs routinely give all VLBWs probiotics, while another 5.2% of NICUs give probiotics to select VLBW infants (Viswanathan 2016).

With these safety concerns regarding the direct administration of probiotics to preterm infants and evidence showing that probiotics given to preterm infants decreases the rate of NEC and mortality (AlFaleh 2014; Deshpande 2010), there is interest in alternate methods for inducing a normal microbiome in a safe manner. Since maternal flora and breast milk bacteria are known to be transmitted naturally to fetuses and neonates, an alternative method of exposure to probiotics that avoids direct administration to preterm infants, and therefore direct administration of possible contaminants, is maternal probiotic administration to mothers of preterm infants or pregnant women at risk for preterm birth. While not all species of probiotics or timing of administration within pregnancy have been studied thoroughly enough to make definitive statements about safety for all probiotics (Dugoua 2009), probiotics in pregnancy have been generally regarded as safe (Elias 2011; Gomez Arango 2015; Lindsay 2013).

Maternal probiotic administration in pregnancy for prevention of preterm labor and preterm birth has been addressed in one systematic Cochrane review focusing on probiotics specifically as a treatment or prevention of urogenital infections (Othman 2012). Our review will also address probiotic administration to pregnant women at risk of preterm birth, but its focus will be on the preterm infant and it will include pregnant women at risk for preterm birth for any reason. To our knowledge, this will be the first systematic review of maternal probiotic administration with a focus on mothers of preterm infants given probiotics after birth, the first to address the comparison of probiotics administered to mothers of preterm infants versus administration to the preterm infants themselves, and the first to address prenatal and postnatal probiotic administration to mothers at risk for preterm birth.