Abstract
Introduction: Most recent clinical reports from the American Academy of Pediatrics (AAP) concluded current evidence does not support routine universal administration of probiotics to preterm infants, particularly those with birth weight <1000 grams. Despite this, the use of probiotics is increasing in US neonatal intensive care units (NICU).
Objectives: Collaborating with the Perinatal Neonatal Medicine of AAP, we conducted a national survey to obtain neonatologist opinion on probiotics use.
Methods: Survey questionnaires were sent to 3000 neonatologists via email.
Results: Of 3000 potential respondents, 249 (8.3 %) completed the survey. Seventy-five (30%) neonatologists working in 23 different NICUs reported using probiotics in their practice, while 168 (70%) neonatologists working in 54 different NICUs reported not using probiotics. Of those not currently use probiotics, 49% indicated they would consider using probiotics in the future vs. 12% indicating they would not use probiotics. The most common indication for probiotics use was average gestational age < 32 weeks and mean birth weight < 1500 grams. Probiotics were discontinued at mean gestational age of 35 weeks. Respondents who prescribe probiotics were more likely to work in a setting without fellowship or residency training (48% vs 20%). Probiotics users were more often from the West (29 % vs 7%) and less often from Northeast (5% vs 34%) compared to non-users. The proportion of those using probiotics did not significantly differ by NICU size, NICU level, or years working in a NICU. Similac Tri-Blend, Evivo, and Culturelle were the top three probiotics used in the respondent’s NICU.
Conclusion: Though a majority of respondents are not currently using probiotics in their NICU, a large number of nonusers are interested in using probiotics in the future. Differences continue to exist in the brand of probiotics used in US NICUs.
Probiotics are live microbial organisms supplemented to colonize the gut. Probiotics use in a neonatal population has been studied for more than 30 years for the prevention of necrotizing enterocolitis, late-onset sepsis, and all-cause mortality.1,2 Potential benefits in preterm neonates include improved intestinal mucosal junctional barrier, modulated immune response such as inflammation, modulated expression of the host, and prevention of colonization by pathogenic bacteria.3
In the United States, probiotics products are typically manufactured as a dietary supplement and are not regulated by the US Food and Drug Administration. Despite this, the use of probiotics is increasing in US neonatal intensive care units (NICUs). According to a survey done in 2015 among NICUs participating in Vermont Oxford Network, approximately 14% of the units reported using probiotics in very low birth weight (VLBW) neonates. More than 15 different commercial products were identified, and the majority of them were not evaluated by randomized control trials (RCTs) for their safety and efficacy.4
There is significant heterogeneity among the RCTs published globally regarding probiotics use in a neonatal population. Multiple strain probiotics have shown benefit in the reduction of necrotizing enterocolitis and mortality compared to single strain probiotics.5 Additionally, the available data do not clearly indicate an optimal start time or the duration of treatment. Long term safety is also unknown. The most recent clinical report from the American Academy of Pediatrics (AAP) concluded that the current evidence does not support the routine universal administration of probiotics to preterm infants particularly those with birth weight <1000 grams.2
Given the recent recommendations by AAP and increasing use of probiotics in US NICUs, it is important to gain an insight on neonatologists’ perspectives. Therefore, we conducted an online survey to solicit the opinion and practice of neonatologists in terms of probiotics usage, benefit, and challenges.
Methods
In collaboration with the section of Perinatal Neonatal Medicine of AAP, we conducted a national survey to obtain neonatologist opinions on probiotics use in NICUs. The study was approved by MCHS Institutional Review Board (IRB). A 16-question survey was developed by the research team, converted to electronic format, and validated by 10 neonatologists working in different US hospitals.
The first survey was sent to 3000 neonatologists using their email address in February 2022. A reminder email was sent one month later to increase the response rate. Respondents were first presented with a consent statement informing them about the confidentiality and intended use of their data. Each electronic link was restricted to allow only one responder to complete the survey. Study data were collected and managed using REDCap electronic data capture tool hosted at MCHS.
Using the response to question one (Probiotics Use), data from the remainder of the questions were split into two groups for comparison: Probiotics Users and Probiotics Non-Users. Summary statistics were used to describe continuous and categorical data. A chi-square test for independence was used to compare distributions of Likert scale responses between the two groups. Similarly, a Pearson chi-square test (two independent z- tests for proportions) was used to compare the proportions of selected categorical responses between the two groups. Tests with P <0.05 were considered significant. Multiple comparisons with a Bonferroni adjustment were used to further understand significant associations, but multiple comparison P value were not reported.
Results
Of 3000 potential respondents, 249 (8.3 %) completed the surveys. Five of the surveys were incomplete. One neonatologist submitted the response, but did not sign the consent. A total of 243 surveys were used for final analysis. A total of 75 (30%) neonatologists working in 23 different NICUs reported using probiotics in their practice, while 168 (70%) neonatologists working in 54 different NICUs reported not using probiotics.
The characteristics of respondents are reported in Table 1. More than 50% of the respondents in the probiotics prescribing group had more than 10 years of experience working as a neonatologist. The type of NICU settings differed significantly between those currently using probiotics and those not using probiotics.
Characteristics of survey participants
Respondents that prescribe probiotics were more likely to work in a setting without fellowship or residency training programs (48% vs 20%), while respondents that did not use probiotics more often worked in NICUs with fellowship or residency training compared to probiotics users (63% vs 35%). Probiotics users were more often from the West (29 % vs 7%) and less often from Northeast (5% vs 34%) compared to non-users. The other regions did not differ significantly. The proportions of those using probiotics did not significantly differ by NICU size, NICU level, or years of working in a NICU.
Neonatologist working at hospitals that use probiotics believe probiotics are beneficial, but those that do not were more varied (Table 2). This pattern does not change at the institution level. Of those that do not currently use probiotics, 49% indicated they would consider using probiotics in the future vs. 12% indicating they would not use probiotics. The remaining 39% were unsure or felt this did not apply to them. When discussing challenges, appropriate dosing and sufficient evidence seem to be where users and non-users disagree the most (P= <0.0001), followed by risk for clinical sepsis (P= 0.0007).
Survey participants perspective on probiotics
Of the neonatologists who responded, 91% stated they were aware of the probiotics brand used in their NICU. Similac Tri-Blend, Evivo, and Culturelle were the top three probiotics used in the respondents’ NICUs. Figure 1 illustrates reasons behind particular brand usage in the NICUs. Average feeding volume at which probiotics were initiated was 21.6 cc/kg/day. The most common indication for probiotics use was average gestational age < 32 weeks and mean birth weight < 1500 grams. Probiotics were discontinued at mean gestational age of 35 weeks. Of respondents who reported using probiotics, 11% reported they have discharged babies home on probiotics.
Word cloud illustrating reasons behind particular brand was chosen in the NICU. Word size relates to frequency of use.
Discussion
In our national survey, a majority of the respondents reported currently not using probiotics in their clinical practice. Among non-users, approximately 50% would consider prescribing probiotics in the near future. There is a wide range of variation among users on the brand being used, despite little evidence to support the cause.
There is limited data on neonatologist perspective on probiotics use in the United States. Viswanathan et al.4 reported increasing probiotics usage in US NICUs in 2015, with wide varieties of products being utilized. In our survey, a majority of neonatologists reported using multiple strain probiotics, unlike the 2015 study where a majority reported using single strain probiotics. Single strain probiotics are still being used, although studies suggest multiple strain probiotics are associated with a significant reduction in necrotizing enterocolitis.5
Interestingly, we also observed a geographic variation among the neonatologists prescribing probiotics. Neonatologists working on the West coast reported being more likely to prescribe probiotics than those in the Northeast. Additionally, we observed that neonatologists who use probiotics were more likely to work in a setting without fellowship or residency training programs. In our survey, we did not collect information on patient characteristics from those NICUs. Therefore, no definitive conclusions can be drawn on the above differences.
Study limitations include a low response rate with only 249 (8.3%) responses from an estimated 3000 electronic invitations sent. The survey anonymity does not allow validation of the data or clarification of the provided information. Responder bias remains a potential weakness of the survey with neonatologist not using or not believing in probiotics use not responding to our survey.
This is the first national survey of practicing neonatologist on probiotics use in the US after the most recent recommendations by AAP. Our study presents data from neonatologist working in 77 different US NICUs. The survey responses contained no individually identifiable information at the respondent level, in compliance with MCHS IRB determination. However, the name of the institution was requested and utilized to identify any inflation created by multiple respondents coming from a single institution.
Conclusion
This cross-sectional study indicates that many neonatologists, though currently not prescribing probiotics, are interested in prescribing in near future. Differences continue to exist in the brand of probiotics used in US NICUs. The apprehension from probiotics non-users regarding brand, dose, legal concerns, and long-term consequences might not be addressed immediately. Probiotics users must administer probiotics with extra caution, particularly in extremely low birth weight neonates, given the concern for sepsis.
Acknowledgments
Ethics approval was granted by the Marshfield Clinic Health System Institutional Review Board (IRB). The authors thank Marie Fleisner of the Marshfield Clinic Research Institute for editorial assistance in the preparation of this manuscript.
Footnotes
Financial support: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. The authors have no relevant financial or non-financial interests to disclose.
- Received April 27, 2023.
- Revision received December 18, 2023.
- Accepted January 19, 2024.
References
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- 4.↵Viswanathan S, Lau C, Akbari H, Hoyen C, Walsh MC. Survey and evidence based review of probiotics used in very low birth weight preterm infants within the United States [published correction appears in J Perinatol. 2017 Jan;37(1):104]. J Perinatol. 2016;36(12):1106-1111. doi:10.1038/jp.2016.144
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