This is an interim intervention report. We have spent limited time to form an initial view of this program and, at this point, our views are preliminary. We plan to consider undertaking additional work on this program in the future.

Summary

What is the program? Mortality rates are high among preterm newborns. Two causes of death in this population are necrotizing enterocolitis (NEC) and sepsis. Supplementation with probiotics (bacteria that are thought to confer health benefits) has been hypothesized to prevent NEC and sepsis and to reduce all-cause mortality among preterm newborns.

Mortality rates are high among preterm newborns. Two causes of death in this population are necrotizing enterocolitis (NEC) and sepsis. Supplementation with probiotics (bacteria that are thought to confer health benefits) has been hypothesized to prevent NEC and sepsis and to reduce all-cause mortality among preterm newborns. What is the evidence of effectiveness? A meta-analysis of randomized controlled trials from low- and middle-income countries provides strong evidence that probiotics lower all-cause mortality among preterm newborns and decrease the risk of NEC and sepsis.

A meta-analysis of randomized controlled trials from low- and middle-income countries provides strong evidence that probiotics lower all-cause mortality among preterm newborns and decrease the risk of NEC and sepsis. How cost-effective is it? Our current best guess is that the cost-effectiveness of probiotic supplementation for preterm newborns is within range of programs we would consider recommending funding in the future. While probiotic supplementation is more expensive than some other death-averting interventions we have reviewed, it is likely to have a large impact on mortality for preterm newborns. However, we have high uncertainty about the cost of probiotic supplementation and the appropriate value to place on averting the death of a newborn. Updates to our estimates for these parameters could substantially affect our cost-effectiveness estimate for this intervention.

Our current best guess is that the cost-effectiveness of probiotic supplementation for preterm newborns is within range of programs we would consider recommending funding in the future. While probiotic supplementation is more expensive than some other death-averting interventions we have reviewed, it is likely to have a large impact on mortality for preterm newborns. However, we have high uncertainty about the cost of probiotic supplementation and the appropriate value to place on averting the death of a newborn. Updates to our estimates for these parameters could substantially affect our cost-effectiveness estimate for this intervention. Is there room for more funding? We have not yet reviewed room for more funding or spoken to potential implementers of this intervention.

We have not yet reviewed room for more funding or spoken to potential implementers of this intervention. Bottom line: We will likely continue to consider probiotic supplementation for preterm newborns as we prioritize programs to recommend funding in the future. We may reach out to organizations implementing this intervention to learn more about costs and funding opportunities.

Published: December 2019

What is the problem?

Child mortality is highest during the neonatal period (i.e., the first 28 days of life), with low-birthweight and preterm newborns being at especially high risk of mortality.

Southern Asia and sub-Saharan Africa are the two regions with the highest rates of preterm birth.

While we have not found systematic data on the mortality rate among preterm newborns across countries or regions, the average mortality rate among preterm newborns from a recent meta-analysis of the effect of probiotic supplementation on mortality among preterm newborns in low- and middle-income countries was 8.6%, or 86 per 1,000 preterm newborns, for newborns not receiving the probiotic supplementation intervention.

Neonatal sepsis and necrotizing enterocolitis (NEC) are two conditions that can cause deaths among newborns.

Sepsis occurs when the body's response to an infection injures its own tissues and organs. Sepsis is most commonly caused by a bacterial infection but can be caused by viral, parasitic, or fungal infection as well. In 2018, sepsis was the third leading cause of death among newborns (15% of all neonatal deaths), with the greatest burden being in developing countries. Low birth weight and preterm babies have the highest susceptibility to sepsis.

NEC occurs when a portion of the bowel dies and is especially common among preterm newborns. There does not seem to be a clear understanding among medical researchers about what causes NEC, though bacterial colonization of the intestine is a prerequisite for its development.

What is the program?

The World Health Organization (WHO) recommends antibiotics as part of a treatment strategy for newborns with neonatal sepsis or NEC. However, some have proposed prevention of sepsis by providing probiotics to preterm newborns who may be at risk of these conditions.

Probiotics are bacteria that are thought to confer health benefits. Probiotics are hypothesized to prevent sepsis and NEC by suppressing the growth of disease-causing bacteria, limiting the spread of these bacteria outside of the intestine and enhancing immune function.

In studies to date with preterm newborns in low- and middle-income countries, probiotics are administered enterally (i.e., via the gastrointestinal tract) once or twice per day for one week to several weeks. These studies use many different strains, though the two most common classes in one meta-analysis were Lactobacillus and Bifidobacterium. In studies, probiotics have generally been delivered in hospital settings. However, we found one study that provided probiotics to households through community health workers, though this study involved full-term (rather than preterm) newborns.

Our impression, based on notes from an unpublished conversation with two researchers who study probiotic supplementation for newborns and two studies that mention the prevalence of this practice, is that probiotic supplementation for low-birth-weight or preterm newborns is becoming more common in the United States and other developed countries but is still not widely used. We have not independently vetted these claims.

What is the evidence of effectiveness?

There have been a large number of small-scale randomized controlled trials (RCTs) examining the impact of probiotic supplementation for preterm newborns on all-cause mortality in low- and middle-income countries, as well as higher-income countries. These provide strong evidence that probiotic supplementation lowers all-cause mortality among preterm newborns and that this may occur through its impact on NEC and sepsis.

In our cost-effectiveness analysis, we model the primary benefits of probiotic supplementation as coming through its effect on all-cause mortality, based on the meta-analysis by Deshpande et al. 2017, which focuses on low- and middle-income countries.

Meta-analysis of RCTs on probiotics in low- and middle-income countries

Deshpande et al. 2017 is a meta-analysis of 23 RCTs examining the impact of probiotics on preterm newborns from 10 low- and middle-income countries.

We view this as a high-quality meta-analysis. The search strategy used to identify papers appears consistent with other high-quality meta-analyses, and the authors provide extensive detail on their search strategy. The meta-analysis is limited to RCTs, and results are robust to excluding studies that may have a higher risk of bias according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework, a commonly used framework for assessing evidence quality.

We also place high weight on this review because it is limited to non-high-income countries, which we think are more relevant as potential settings of interest to us, and because it is relatively recent and therefore more likely to capture the current research available on probiotics, since it is our impression this is an active area of research.

However, we have not reviewed individual studies that are part of this meta-analysis, and it is possible that closer inspection would lead us to downgrade our assessment of this evidence. In addition, several of the included studies are small-scale, which may raise concerns about the generalizability of their findings or inflation of effect sizes due to p-hacking or publication bias (though the funnel plot provided does not indicate any evidence of publication bias).

Deshpande et al. 2017 find probiotic-supplemented preterm newborns had 27% lower all-cause mortality (95% CI 10%-41%, 19 trials, sample size 4196). Removing studies with low risk of bias for random sequence generation and allocation concealment gives a similar effect size.

Deshpande et al. 2017 also report effects separately for other subgroups, based on newborns' gestational age, use of different probiotics, and use of single-strain vs. multistrain probiotics. Effects on all-cause mortality are similar across these subgroups.

In addition to effects on all-cause mortality, the meta-analysis finds probiotic supplementation reduces risk of NEC by 54% (95% CI 39%-66%) and late-onset sepsis by 20% (95% CI 9%-29%). As with the effects on all-cause mortality, these impacts are still statistically significant, though smaller in magnitude, when the analysis is limited to studies with low risk of bias for random sequence generation and allocation concealment.

Meta-analyses of RCTs on probiotics that include developed countries

The findings of Deshpande et al. 2017 are broadly consistent with recent meta-analyses that are not limited to low-and middle-income countries:

AlFaleh and Anabrees 2014 is a Cochrane Review that includes studies published through 2013 that use RCTs and quasi-experiments and involve preterm newborns. They find preterm newborns who received probiotic supplementation had 35% lower all-cause mortality (95% CI 19%-48%, 17 studies, sample size 5112), 57% lower incidence of NEC (95% CI 44%-67%, 20 studies, sample size 5529), and 9% lower incidence of sepsis (95% CI -3%-20%, 19 studies, sample size 5338).

Sawh et al. 2016 updated the review in AlFaleh and Anabrees 2014 to include studies on the effect of probiotics published from 2013 to 2016. Included studies were RCTs involving preterm newborns. They find preterm newborns who received probiotic supplementation had 21% lower all-cause mortality (95% CI, 7%-32%, 29 trials, sample size 9507), 47% lower incidence of NEC (95% CI 34%-58%, 38 trials, sample size 10520), and 12% lower incidence of sepsis (95% CI, 0%-23%, 31 trials, sample size 8707).

These findings gives us further confidence in the findings from Deshpande et al. 2017, though we have not thoroughly reviewed these meta-analyses or the papers that are included.

Additional benefits

The research we reviewed also discusses the following additional benefits of probiotic supplementation for newborns, beyond reducing all-cause mortality and likelihood of NEC and sepsis:

Neurodevelopmental impacts. Some of the research we have reviewed indicates that NEC and sepsis may affect long-term brain development. This suggests that preventing NEC and sepsis among preterm newborns through probiotic supplementation may benefit newborns through improvements in brain development. We have not reviewed these claims and so do not know how reliable they are or how large the effects might be.

Some of the research we have reviewed indicates that NEC and sepsis may affect long-term brain development. This suggests that preventing NEC and sepsis among preterm newborns through probiotic supplementation may benefit newborns through improvements in brain development. We have not reviewed these claims and so do not know how reliable they are or how large the effects might be. Time to full enteral feeding. The meta-analysis by Deshpande et al. 2017 also includes as one of its primary outcomes time to full enteral feeding (i.e., days elapsed from after birth until the baby stops receiving food intravenously and starts receiving it through its gastrointestinal tract). That analysis finds probiotics led to a decrease of 3.09 days (95% CI 2.69, 3.49) in time to full enteral feeding. We have not prioritized understanding the benefits of reduced time to full enteral feeding and how we might model them in our cost-effectiveness analysis.

We do not currently factor these additional benefits into our assessment of the cost-effectiveness of probiotic supplementation.

Potential offsetting/negative impacts

Some have expressed concerns that widespread use of probiotics could have potentially serious adverse negative effects, including probiotic sepsis, antibiotic resistance and altered immune responses.

Our impression is that the available evidence suggests these events are rare, but we have not reviewed this evidence in depth.

Is it cost-effective?

A preliminary cost-effectiveness model for this intervention is available here. We estimate that the cost-effectiveness of probiotic supplementation for preterm newborns is within range of programs we would consider recommending funding in the future. Probiotic supplementation has a relatively large effect on mortality for preterm newborns, who have a high baseline mortality rate. This drives the cost-effectiveness of this intervention, despite its relatively high cost compared to other death-averting interventions we have reviewed. However, this estimate relies on several assumptions, about which we have a high degree of uncertainty.

Note that our cost-effectiveness analyses are simplified models that do not take into account a number of factors. There are limitations to this kind of cost-effectiveness analysis, and we believe that cost-effectiveness estimates such as these should not be taken literally due to the significant uncertainty around them. We provide these estimates (a) for comparative purposes and (b) because working on them helps us ensure that we are thinking through as many of the relevant issues as possible.

Key uncertainties in our cost-effectiveness analysis, which we would guess have a high potential to change our bottom line on probiotic supplementation for preterm newborns, are:

Cost of probiotic supplementation. The cost of probiotic supplementation per newborn is estimated to be $28, based on an estimate of $1 per day for the cost of the probiotic supplement and an estimate of roughly four weeks of duration for probiotic supplementation. However, we have high uncertainty about this parameter, as well as any additional costs of administering probiotic supplements. We estimate that reasonable deviations in this parameter could substantially affect our cost-effectiveness estimate. We may further refine our cost estimate if we decide to reach out to organizations implementing this intervention.

The cost of probiotic supplementation per newborn is estimated to be $28, based on an estimate of $1 per day for the cost of the probiotic supplement and an estimate of roughly four weeks of duration for probiotic supplementation. However, we have high uncertainty about this parameter, as well as any additional costs of administering probiotic supplements. We estimate that reasonable deviations in this parameter could substantially affect our cost-effectiveness estimate. We may further refine our cost estimate if we decide to reach out to organizations implementing this intervention. Valuation of a newborn life. Our current cost-effectiveness analysis does not assign moral weights for averting the death of a newborn. Our best guess is that this weight could range from 1% to 100% of the weight assigned to averting a death of a non-newborn child, so our current cost-effectiveness model for probiotic supplementation assumes a value of 50%. However, we are highly uncertain about this parameter. Updating the moral weight assigned to averting the death of newborn could substantially affect our cost-effectiveness estimate.

Additional uncertainties, which may also influence our cost-effectiveness estimate, are:

Healthcare costs. By reducing the likelihood of NEC and sepsis, probiotic supplementation may lower costs of treatment of these conditions. Our cost-effectiveness analysis currently excludes healthcare cost savings due to averted costs of treating NEC and sepsis. To the extent that households pay a large share of the costs of treating these conditions, incorporating averted treatment costs could meaningfully improve the cost-effectiveness of probiotic supplementation.

By reducing the likelihood of NEC and sepsis, probiotic supplementation may lower costs of treatment of these conditions. Our cost-effectiveness analysis currently excludes healthcare cost savings due to averted costs of treating NEC and sepsis. To the extent that households pay a large share of the costs of treating these conditions, incorporating averted treatment costs could meaningfully improve the cost-effectiveness of probiotic supplementation. Adverse events. As discussed above, some research we reviewed expressed concerns that widespread use of probiotics can have potentially serious adverse negative effects, including probiotic sepsis, antibiotic resistance and altered immune responses. We have not thoroughly reviewed the evidence for these claims. If these effects have sound evidence and are large, they would worsen our assessment of the cost-effectiveness of probiotic supplementation, though our current impression is that these events are rare.

As discussed above, some research we reviewed expressed concerns that widespread use of probiotics can have potentially serious adverse negative effects, including probiotic sepsis, antibiotic resistance and altered immune responses. We have not thoroughly reviewed the evidence for these claims. If these effects have sound evidence and are large, they would worsen our assessment of the cost-effectiveness of probiotic supplementation, though our current impression is that these events are rare. Additional benefits. As discussed above, some of the research we reviewed cited evidence that those newborns who survive NEC and sepsis may experience long-term impacts on brain development and that there may also be additional benefits due to shorter time to full enteral feeds. We have not reviewed the evidence for these claims. If these effects have sound evidence and are large, they could improve our assessment of the cost-effectiveness of probiotic supplementation.

As discussed above, some of the research we reviewed cited evidence that those newborns who survive NEC and sepsis may experience long-term impacts on brain development and that there may also be additional benefits due to shorter time to full enteral feeds. We have not reviewed the evidence for these claims. If these effects have sound evidence and are large, they could improve our assessment of the cost-effectiveness of probiotic supplementation. Development benefits. In our cost-effectiveness analysis for probiotic supplementation, we have included potential development benefits (i.e., increases in later-life income as a result of early-life health interventions) to be consistent with other death-averting interventions implemented by our top charities. However, while some have suggested averting NEC and sepsis can have long-term impacts on brain development, which could potentially improve adult income, we have not identified any direct evidence for these income effects, and as a result, we are highly uncertain about this parameter.

Our cost-effectiveness analysis explores how sensitive results are to adjustments in some key parameters that would make probiotic supplementation more or less cost-effective.

Is there room for more funding?

We have not prioritized reviewing room for more funding for probiotic supplementation to preterm newborns or identified organizations who deliver this intervention. In the future, we may reach out to organizations implementing this intervention to learn more about room for more funding, as well as costs of probiotic supplementation for preterm newborns and specific funding opportunities.

Key questions for further investigation

What are the costs of this intervention in new settings where it might be implemented?

How might a funder support implementation of this intervention?

What is the appropriate moral weight for averting the death of a newborn, relative to averting the death of older children or adults?

How would incorporating healthcare costs savings due to averted treatment for NEC and sepsis influence the cost-effectiveness of probiotic supplementation?

How would incorporating additional benefits of probiotic supplementation (i.e., long-term developmental effects and reduced time to full enteral feeding) influence cost-effectiveness?

How likely are adverse events associated with probiotic supplementation, and how would incorporating these adverse events influence cost-effectiveness?

Will a forthcoming Cochrane Review by Imdad et al. 2019 update our assessment of the impact of probiotic supplementation for preterm newborns on all-cause mortality?

Sources