About | PEPS Trial

What is the PEPS trial?

The PEPS Trial is an ongoing randomized controlled trial (also called RCT) in Sweden and Denmark. It enrolls extremely premature infants born between 22+0 and 27+6 weeks' gestational age.

Included infants will either receive probiotics (intervention group) or no probiotics/placebo (control group) given through breastmilk until they reach 34 weeks' gestational age.

The study will go on for approximately four years and will allow us to research the influence of probiotics on health outcomes in extremely preterm infants.

What is a double-blinded, randomized controlled trial?

Randomized controlled trial: this means that whether the included infants receive probiotics or not is completely random, or by chance. A randomization software is used to allocate the infants to probiotics or no probiotics/placebo. Study staff, medical personnel, and parental guardians have no influence on what each infant receives.

Double-blinded: this means that neither the researchers nor the infants/parental guardians know whether the infants receive probiotics or not. Only those mixing the breast milk know the infants' allocation, which they are not allowed to reveal. This is critical for the success of the study, as it is the only way to evaluate the true effect of probiotics in an unbiased manner.

What are we researching and why?

Extremely premature infants are at a high risk for serious adverse outcomes, including necrotizing enterocolitis (also called NEC), sepsis (bacterial infection in blood), and death. Necrotizing enterocolitis is inflammatory gastrointestinal disease and is regarded as the most severe gastrointestinal-related morbidity in preterm infants due to its high death rate. For this reason, recent research has focused on measures to prevent necrotizing enterocolitis and other serious illnesses in preterm infants.

The primary aim of this study is to assess whether probiotic supplementation can reduce the cases of necrotizing enterocolitis and/or death.
The secondary aims are to assess whether probiotic supplementation can reduce the cases of sepsis, lower the use of antibiotics, decease the duration of days spent in hospital, and investigate the effect of probiotics on infants' gut bacteria through stool analysis.
The tertiary aims of this study are to assess whether probiotic supplementation can improve feeding tolerance, postnatal growth, and body composition.

What are probiotics and how do they work?

Giving infants probiotics has increasingly gained clinical and research interest to help prevent necrotizing enterocolitis and other serious adverse outcomes. Probiotics are beneficial bacteria provided to increase microbiota diversity and gastrointestinal development. Probiotic supplementation has been shown to improve gastrointestinal tolerance and colonization of good bacteria in extremely preterm infants, ultimately helping their microbiota resemble that of a healthy, term infant.

Our study will use a probiotic product called ProPrems® that contains three strains of beneficial bacteria [Bifidobacterium infantis Bb-02 (DSM 33361), Bifidobacterium lactis (BB-12®), and Streptococcus thermophilus (TH-4®)]. You can read more about the product here.

ProPrems® is already used routinely in Sweden for infants born after 28 weeks' gestational age. It is not yet used in Sweden for infants born before 28 weeks' gestational age due to inadequate inclusion of these younger infants in previous studies. Thus, we hope to to fill this knowledge gap with our study.

What is the evidence for supplementing probiotics?

International studies have shown conclusive results on the effect of probiotics in reducing the incidence of necrotizing enterocolitis in preterm infants born after 28 weeks' gestational age (see references below). Due to this, the European Society for Paediatric Gastroenterology Hepatology and Nutrition published a Position Paper about probiotics use in preterm infants, listing safety criteria for probiotics products and addressing strain-specific efficacy. ProPrems® complies with listed safety criteria and its probiotic blend is recommended by the Society (see references below).

Despite research findings results and independent recommendations, the effectiveness of probiotic supplementation in these infants is not fully understood or supported in the youngest preterm infants due to the low number of infants born before 28 weeks' gestational age in studies. We hope that the results of our study can clarify whether the current Swedish and Danish national recommendations can be expanded to include these infants in routine probiotic use.

Why is the PEPS trial important?

Although results from previous international studies have been promising, Swedish and Danish recommendations have not yet recommended probiotic supplementation in extremely preterm infants. The only way to evaluate the effectiveness of probiotic supplementation in these infants is by conducting a large-scale, randomized controlled trial, such as the PEPS Trial.

To date, no study has investigated probiotic supplementation specifically in extremely preterm infants. Thus, any analyses on infants born before 28 weeks' gestational age have generally been small subgroup analyses of studies focusing on infants born at higher gestational ages, rendering the results potentially imprecise for the extremely preterm population. In addition, there is a wide variation in the probiotic strains used for supplementation, the dosages used, and the duration of treatment. As such, a sufficiently large trial focused on extremely preterm infants using only one probiotic product is needed.

Are there any risks?

ProPrems® is manufactured in a rigorously controlled process and complies fully to the safety criteria listed by The European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN). The product is already used in extremely preterm infants in many other countries and is used routinely in infants born after 28 weeks' gestational age in Sweden. For the duration of the trial, we will also have a Data Safety and Monitoring Committee in place to evaluate the safety of the infants.

In October 2023, the United States Food and Drug Administration (FDA) issued a warning about a probiotic product following a case of sepsis in a baby. The probiotic product used in this case was not one of the strains approved by ESPGHAN, and therefore not a strain we use in the PEPS Trial. To read the official response concerning this case from our principal investigator, please see here.

Where can I get more information?

If your child is enrolled in the PEPS Trial, you have already come into contact with local medical and research personnel responsible for the study at your hospital with whom you can take contact. You can also find the emails of relevant local staff on the Study Team page.

You can also contact the main research team at Karolinska in Stockholm, Sweden at peps.karolinska@regionstockholm.se for any additional questions or inquiries. We are happy to receive inquiries in English, Swedish, Danish, and German.

All results from this study will be added to the website after publication. Stay tuned!