Enteral lactoferrin supplementation for prevention of sepsis | Figure 1

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Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis

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Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants

Review question: Does administering lactoferrin with feeds decrease the risk of sepsis or necrotizing enterocolitis in preterm babies?

Background: Preterm babies are at risk for blood infection (sepsis) and/or gastrointestinal injury (necrotizing enterocolitis, or NEC). Many babies with sepsis or NEC die or develop long‐term brain and lung injury despite treatment with antibiotics. Lactoferrin, a protein that is present in human milk, has been shown to be effective against infection when tested in animals and in the laboratory. Lactoferrin also enhances the ability of babies to fight infection.

Study characteristics: Through literature searches updated to 20 January 2020, we found 12 studies that enrolled 5425 preterm babies and tested the effects of lactoferrin given with feeds. We also found ongoing studies that may increase the strength of our findings when their results become available.

Key results: Lactoferrin given with feeds with or without a probiotic decreases blood infection including fungal infection in preterm infants with no adverse effects. Lactoferrin with probiotics, but not lactoferrin alone, decreases gastrointestinal injury. Clarification regarding dosing, duration, type of lactoferrin (human or bovine), and development of preterm babies is still needed.

Certainty of evidence: Low to very low

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\ \ Does routine monitoring of stomach aspirates (partially digested milk and gut hormones withdrawn from the feeding tube) avoid necrotising enterocolitis in premature babies?\ Key messages\ Necrotising enterocolitis is a serious intestinal disease in premature babies that causes damage and death of gut tissue and may result in a hole in the intestine.\ • Routine monitoring of stomach aspirates to decide on feeding in premature babies probably has little or no effect on the risk of necrotising enterocolitis.\ • Monitoring stomach aspirates probably increases the time taken to reach full feeds, duration of parenteral nutrition (feeding through a vein) and the risk of infections. It may increase the time taken to regain birth weight and feed interruption episodes (time frames when feeds are stopped temporarily) in premature babies. The effect of stomach aspirates monitoring on other important outcomes is uncertain.\ • There is uncertainty whether using two different criteria of stomach aspirates to interrupt feeds has an effect on important outcomes in preterm infants.\ What did we want to find out?\ We wanted to look for evidence from studies that assessed whether routine monitoring of stomach aspirates is beneficial or harmful in premature babies.\ What did we find?\ We included five studies (423 babies) in this review.\ We found four studies on 336 premature babies that compared routine monitoring versus no monitoring of stomach aspirates in premature babies. We found one study comparing the usage of two different sets of criteria based on quantity and quality of stomach aspirates to decide on interrupting feeds while monitoring stomach aspirates.\ What are the limitations of the evidence?\ We are moderately confident about the evidence on the effect of monitoring stomach aspirates on outcomes such as necrotising enterocolitis, risk of infections, time taken to reach full feeds, and duration of parenteral nutrition.](https://app.figure1.com/case-detail/0e3a8dc0-7d53-4263-b27f-8fcfbcf24f64)

\ \ Monitoring of stomach aspirates to diagnose feed intolerance and necrotising enterocolitis is a common practice for preterm infants on tube feeds. There is no consensus on whether to re‐feed or discard the stomach aspirates. Although re‐feeding the aspirates may replace partially digested milk and gastrointestinal secretions that are essential for gastrointestinal maturation, re‐feeding abnormal aspirates may result in vomiting, necrotising enterocolitis, or sepsis. We have looked for evidence from clinical trials that assessed whether re‐feeding stomach aspirates is beneficial or harmful in preterm infants.\ Study characteristics\ The thorough literature search is up‐to‐date as of Febraury 2018. We found only one small randomised controlled trial (with 72 preterm infant participants) that addressed this question.\ Key results\ We are uncertain as to whether re‐feeding stomach aspirates has an effect on important outcomes such as incidence of necrotising enterocolitis, mortality before discharge, time to regain birth weight, time to reach full enteral feeds, duration of parenteral nutrition and duration of hospital stay.\ Quality of evidence\ Available evidence is insufficient to support or refute re‐feeding of stomach aspirates in preterm infants. More trials are needed to examine whether re‐feeding the stomach aspirates is beneficial or harmful in preterm infants.](https://app.figure1.com/case-detail/148f2130-2ae9-4e85-9d34-30bbe4d5a258)

\ \ Review question\ In preterm or low birth weight infants receiving gavage tube feedings, does push tube feeding compared with gravity tube feeding result in increased adverse events (low oxygen saturation, low heart rate, time to full suck feeding).\ Background\ Infants born prematurely (before 37 weeks) may be unable to co‐ordinate sucking, swallowing, and breathing, and require gavage feeding. In gavage feeding, milk is delivered intermittently through a tube passed via the nose or the mouth into the stomach. Intermittent bolus milk feeds may be administered by using a syringe to gently push milk into the infant's stomach (push feed). Alternatively, milk can be poured into a syringe attached to the tube and allowed to drip in by gravity (gravity feed).\ Study characteristics\ The search is up‐to‐date as of July 2020. We included one study (31 infants) in this updated review.\ Key results\ Evidence is insufficient to show whether use of push compared with gravity gavage feeding results in more rapid establishment of full gavage feeds without increasing adverse events in preterm or low birth weight infants, or both, who require intermittent bolus gavage feeding.\ Certainty of evidence\ Evidence from randomised trials comparing push versus gravity intermittent gavage tube feeding in preterm or low birth weight infants (less than 2500 grams) is insufficient to inform practice.](https://app.figure1.com/case-detail/40a89a04-f6a0-4c75-af62-b80b979fd054)

\ \ We analysed evidence from randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) investigating probiotic supplements alone or in combination with drug or non‐drug interventions for preventing gestational diabetes mellitus (GDM).\ What is the issue?\ GDM is a condition where the mother develops high blood sugar levels, usually after 13 weeks of pregnancy. GDM is different from type 2 diabetes in that blood sugar levels are normal before pregnancy, and the levels usually return to normal after pregnancy. GDM is associated with an increased risk of developing type 2 diabetes later in life. Women with GDM are at increased risk of high blood pressure with protein in the urine (pre‐eclampsia) and instrumental delivery or caesarean section. Their infants are more likely to be born large for their gestational age. Probiotics are 'good bacteria' that are usually taken in the form of capsules or drinks to add to the gut bacteria. We are dependent on our gut bacteria to help digest our food, produce certain vitamins, regulate our immune system and keep us healthy by protecting us against disease‐causing bacteria. Probiotics could change a person's metabolism and play a role in the prevention of GDM.\ Why is this important?\ Women who are overweight or obese, had GDM in a previous pregnancy or have an immediate family member with diabetes are at increased risk of GDM. Current treatment for GDM includes diet with or without medication but does not always prevent the problems associated with GDM. Probiotics could be a simple method for preventing GDM. This review looked at whether there is evidence to show if this is true.\ What evidence did we find?\ We searched for evidence from randomised controlled trials in March 2020 and identified seven studies with 1647 pregnant women comparing probiotics with inactive placebo (pretend treatment). Two studies were in overweight and obese women, two in obese women and three did not exclude women based on their weight. The overall risk of bias was low except for one study where the risk of bias was unclear.\ It is unclear how probiotics affect the risk of developing GDM due to the wide variation in the results of six studies (1440 women, low‐quality evidence). Probiotics increase the risk of developing pre‐eclampsia (4 studies, 955 women; high‐quality evidence). Probiotics make little to no difference to the risk of needing a caesarean section (6 studies, 1520 women; high‐quality evidence), and probably make little to no difference to weight gain during pregnancy (4 studies, 853 women; moderate‐quality evidence) or to the risk of giving birth to a big baby (4 studies, 919 women; moderate‐quality evidence). None of the studies reported information about the risk of perineal trauma (tears during vaginal birth or a surgical incision (episiotomy)), postnatal depression or developing subsequent diabetes.\ We do not know if probiotics affect the infant having medical problems after birth because of the variation in results between studies (2 studies, 623 infants; low‐quality evidence). It is also uncertain how probiotics affect infant death (either before birth or as a newborn) (3 studies, 709 infants; low‐certainty evidence), low blood sugar (2 studies, 586 infants; low‐certainty evidence) or body fat (2 studies, 320 infants; low‐certainty evidence). None of the studies reported information about the risk of infants developing diabetes or long‐term conditions that affect brain development.\ What does this mean?\ Low‐quality evidence from six trials has not clearly identified the effect of probiotics on the risk of GDM. However, high‐quality evidence suggests that probiotics probably increase the risk of pre‐eclampsia. Therefore, there is currently evidence of possible harm with little observed benefit for widespread use of probiotics in pregnancy.\ There are eight studies currently ongoing that may help to provide more clarity on the effects of probiotics. It is also important to explore the relationship between probiotics and pre‐eclampsia further.](https://app.figure1.com/case-detail/4dda97c1-6e16-4a50-85af-b81dfd072f2c)

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