Prebiotics and probiotics for prevention of allergic disease

INTRODUCTION — There is increasing evidence that disturbances in gut microbial composition play a role in the pathophysiology of immune-mediated disorders such as allergic disease [1]. Gut microbiota are key players in the early development of both local immune maturation and systemic immune programming. Differences in perinatal colonization patterns with both the level of industrialization and subsequent allergic outcomes provided a strong foundation for intervention studies designed to modify postnatal colonization in the prevention of allergic disease [2,3]. Consequently, the effects of beneficial bacteria (probiotics) or resistant starches or fiber (prebiotics) that selectively stimulate a limited number of beneficial bacteria have been evaluated in allergy prevention studies.

This topic reviews the evidence for prebiotics and probiotics in the prevention of allergic disease [4-11]. The use of prebiotics and probiotics for the treatment of allergic disease is discussed in detail separately. (See "Prebiotics and probiotics for treatment of allergic disease".)

The role of microbiota in the pathogenesis of food allergy and the use of probiotics for gastrointestinal diseases are discussed elsewhere. A detailed review of intestinal microbiota is also presented separately. (See "Pathogenesis of food allergy", section on 'Gut and skin microbiota' and "Probiotics for gastrointestinal diseases" and "Spatial organization of intestinal microbiota in health and disease" and "Evidence-based approach to prevention".)

DEFINITIONS — The terms "prebiotics," "probiotics," and "synbiotics" are defined as follows:

●"Prebiotics" generally refers to "a substrate that is selectively used by host microorganisms conferring a health benefit" [12]. Prebiotics are typically comprised of nondigestible carbohydrates but can also include noncarbohydrates such as fatty acids, phenolics, and phytochemicals (figure 1) [12]. The most widely accepted prebiotics are the fermentable oligosaccharides inulin, fructooligosaccharides (FOS or fructans), galactooligosaccharides (GOS), and lactulose (table 1).

●"Probiotics" is a general term, analogous to the term "antibiotics," for different strains and species of microorganisms with a wide and varying range of clinical and immunologic capacities. The United Nations Food and Agriculture Organization (FAO) and World Health Organization (WHO) have defined probiotics as "live microorganisms, which, when administered in adequate amounts, confer a health benefit on the host" [13]. Guidelines from a FAO/WHO expert group are available regarding evaluation of probiotics, including data necessary to substantiate health claims [14]. The most commonly used probiotics are lactobacilli and bifidobacteria strains, but other microorganisms have been used as probiotics, including the yeast Saccharomyces boulardii.

●"Synbiotics" refers to a combination of prebiotics and probiotics.

BACKGROUND — The prevalence of allergic rhinitis increased in the first half of the 20^th century, followed by an increase in asthma prevalence and then food allergies. The environmental changes that are driving the allergy epidemic are not fully identified, although the hygiene hypothesis makes a strong case that the reduction in general microbial exposure during early childhood [15], with corresponding changes in commensal microbiota [16], plays an important role. Normal immune homeostasis is dependent upon gut microbiota and may be influenced by differences in colonization patterns. The hygiene hypothesis provides the conceptual framework for pre- and/or postnatal dietary supplementation to prevent allergic disease by modifying early gut microbial composition, even if this hypothesis does not decisively explain all observations or provide definitive guidance on how to limit the allergy epidemic. (See "Increasing prevalence of asthma and allergic rhinitis and the role of environmental factors", section on 'Epidemiologic history' and "Food allergy in children: Prevalence, natural history, and monitoring for resolution", section on 'Prevalence of childhood food allergy'.)

Rationale for prebiotics and probiotics in allergic disease — Epidemiologic associations between declining microbial exposure and allergic disease [15] are supported by animal models demonstrating that early exposure to pathogenic or nonpathogenic microbial products can either prevent or modify allergic responses [17]. Gut microbiota confer specific immune-protective effects that are probably mediated through complex pathways within (and potentially even beyond) the gut-associated lymphoid tissue (GALT), the largest immune "organ" in humans. These effects include altered local immunoglobulin A (IgA) production and induction of tolerogenic dendritic cells and regulatory T cell populations, with production of immunomodulatory cytokines, such as interleukin (IL) 10 and transforming growth factor (TGF) beta [18]. These mechanisms appear to collectively inhibit local inflammation, improve gut barrier mechanisms, and consequently reduce the risk of inappropriate systemic immune responses.

Over the first months of life, there is an enormous shift from the "sterile" milieu in utero to microbial colonization with more than 10¹⁴ organisms, outnumbering total human host cells by more than 10:1. During the same period, the functionally immature neonatal immune system must also develop to attain a complex and finely tuned balance between host defense and immune tolerance. Studies in germ-free animals demonstrate that oral tolerance cannot be induced in the absence of gut microbiota [19]. Although full immune function and oral tolerance can be restored by introducing normal intestinal microbiota, this is age dependent and cannot be achieved in mature animals [19]. These observations underline the essential role of gut microbiota in the development of the immune system and exemplify the importance of the timing of initial colonization. (See "Pathogenesis of food allergy", section on 'The gut immune system'.)

A number of human studies have shown differences in the early colonization patterns of infants who develop allergic disease [20]. Early studies reported that low levels of bifidobacteria and early colonization with potentially pathogenic bacteria, such as Clostridioides difficile [2,3] and Staphylococcus aureus [2], were more prevalent in children who subsequently developed allergy. Subsequent larger, prospective studies have tried to link certain bacterial genera or species to the development of allergy with conflicting results [21,22]. Consequently, it has been suggested that a high gut microbial diversity might be more important than the absence or presence of specific genera or species in the context of immune system maturation and subsequent development of immune-mediated disorders. This view is supported by prospective studies that demonstrated reduced gut microbial diversity early in life in infants who later developed allergic manifestations [23-25].

Proposed mechanisms — The exact mechanisms are not clear, but both prebiotics and probiotics probably influence immune development through a number of different pathways that can be modulated by host and environmental factors. In addition, differences in the probiotic supplement, such as the strain, dose, viability, timing, duration, adherence, and method of administration, may result in differences in clinical effect.

Prebiotics — Prebiotic carbohydrates are a major substrate for bacterial growth, selectively stimulating the growth and/or activity of beneficial members of the gut microbiota, particularly bifidobacteria [26,27]. Thus, prebiotics could, at least in theory, have more global effects on colonization than adding a single probiotic strain. A second, more direct immune effect appears to be mediated by the fermentation products of prebiotics. Gut microorganisms ferment prebiotics to produce short-chain fatty acids (SCFAs) that have direct antiinflammatory effects [28]. SCFAs also promote intestinal integrity through effects on epithelial cell proliferation and differentiation [29]. Animal and human studies suggest that prebiotics may directly affect both mucosal and systemic immunity [30-32]. However, more studies are needed to confirm that these are clinically relevant effects.

Probiotics — Numerous mechanisms have been proposed to explain the potential effects of probiotics based upon evidence from in vitro studies and animal models [18]. Probiotics may alter gut microbial composition directly, or they may act indirectly by effects on microbial products, host products, or food components or by modulation of the host's immune system. Commensal gut bacteria can decrease local inflammation [33] and may stabilize intestinal barrier integrity [34], potentially reducing systemic antigen load. Certain strains of lactobacilli and bifidobacteria may influence immune function through effects on enterocytes, antigen-presenting cells (including both circulating monocytes and local dendritic cells), regulatory T cells, and effector T and B cells [18]. However, it is uncertain how (or if) these observations translate into clinically relevant effects. In addition, it is also not known to what degree the effects of a specific bacterial strain are similar to other strains, even of the same species. Finally, the immune-stimulating effects of probiotics in in vitro studies can be divergent from those observed in vivo [35]. More studies are needed to clarify these issues.

Modulating factors — The effects of prebiotics and probiotics are probably influenced by a range of host and environmental factors [18]. Host factors which contribute to this variability include variation in genetic predisposition to allergic disease (across multiple loci) and specific polymorphisms in microbial recognition pathways that may influence effects and susceptibility to colonization. A range of environmental factors, such as maternal microbiota, general microbial burden, mode of delivery, feeding practices and weaning diet, antibiotics, and other immunomodulatory influences may have secondary effects on colonization.

RECOMMENDATIONS FROM GUIDELINES — Many experts bodies such as the European Academy of Allergy and Clinical Immunology (EAACI) Food Allergy and Anaphylaxis Guidelines do not recommend using prebiotics, probiotics, or synbiotics for the prevention of any allergic condition, because of to the great heterogeneity in the studies and variability in results [36,37]. Others, such as the US National Institute of Allergy and Infectious Diseases (NIAID) have not given any specific recommendations on these products in their guidelines [38].

In contrast, the World Allergy Organization (WAO) suggests using prebiotics only in infants who are not exclusively breastfed [39] and probiotics in pregnant and lactating women and in infants when there is high risk of allergy in the children (defined as presence of a biologic parent or sibling with asthma, allergic rhinitis, eczema, or food allergy) [40]. The probiotic recommendation was based upon their analysis of the data that found a net benefit of prevention of eczema, but not any other allergic outcome, with probiotic treatment. In addition, the risk of possible adverse events was felt to be low.

The timing, duration, and choice of probiotic (strain and dose) are not specified in the WAO guidelines. Probiotics were given in the last four to six weeks of pregnancy in most of the studies reviewed, but there was much greater variability in timing and duration of postnatal therapy in the infant and/or breastfeeding mother. In addition, the only probiotic strain with reproducible data is Lactobacillus rhamnosus GG (LGG). (See 'Probiotics' below.)

OUR APPROACH — Meta-analysis data suggest that there is a modest preventive effect of probiotics on the development of eczema, but not other atopic diseases, in at-risk infants (defined as presence of a biologic parent or sibling with asthma, allergic rhinitis, eczema, or food allergy) [40]. However, the great heterogeneity of the studies makes it difficult to advise on specifics regarding therapy (eg, strains, dose, timing, and duration). Thus, we suggest not giving probiotics during pregnancy, lactation, and infancy for the prevention of eczema. We do not discourage this approach, however, if parents/caregivers are strongly interested, given the low risk of adverse events. Parents/caregivers who chose this approach should first discuss it with the appropriate clinician (eg, obstetrician, pediatrician, other primary care provider).

PROBIOTICS — Several meta-analyses have generally concurred that probiotics reduce the risk of eczema but not other allergic outcomes (when examined) [5,41-48]. However, more specific conclusions have varied due in part to the wide heterogeneity of the studies included. Further clinical studies are needed to identify if specific dosing regimens, as well as specific strains or combinations, are more effective than others. In addition, more studies are necessary to evaluate if interventions should be tailored to specific subgroups [49].

Efficacy — A number of randomized trials have evaluated the effects of probiotics in allergy prevention [50-80]. Most of these studies looked primarily at early outcomes of allergic disease, such as eczema and immunoglobulin E (IgE) mediated food allergy. Over one-half of them showed no significant reduction in the development of eczema, while there was benefit in the remaining studies, even when the same probiotic strain and a similar protocol were used. The majority of studies have shown no reduction in food allergy, allergic disease in general, or allergen sensitization. Few studies have assessed the long-term effects on respiratory-allergic disease (allergic rhinitis, asthma) in children greater than four to five years of age, and the results have been variable [49,58,60,71,73-75,81]. In addition to variability in results, there is also considerable heterogeneity in virtually all aspects of the conducted studies, including the strains used (different single strains or combinations of strains); the dose, the timing, and duration of administration; the method of probiotic delivery; and the outcome measures. The results are conflicting even for L. rhamnosus GG (LGG), the most extensively studied strain [50-52,58,69,70].

A meta-analysis from 2012 [44] included 13 prevention studies [50,52,54-57,59,61-63,65,66,82] and demonstrated that probiotic treatment reduced the incidence of eczema by 21 percent (risk ratio [RR] 0.79, 95% CI 0.71-0.88), from approximately 37 percent in the placebo group to 30 percent in the probiotic group. This effect was still present when the analysis was restricted to studies of patients with IgE-associated eczema (RR 0.80, 95% CI 0.66-0.96). However, this effect was seen only in the first two years of age and was lost by four years of age. Studies were reported to be fairly homogenous, and no clear difference emerged across various strata. A meta-analysis of trials through February 2014 that included 17 prevention studies reported nearly identical findings [46]. However, two subsequent randomized trials did not find a protective effect [76,79].

The definition of probiotics indicates that the microorganisms must be alive to exert their effects (see 'Definitions' above). However, there is preliminary evidence that dead microorganisms may also be beneficial. In a multicenter randomized trial, 129 infants at high risk of allergy were allocated to intake of a nonhydrolyzed formula with or without the addition of heat-killed Bifidobacterium breve C50 and Streptococcus thermophilus from birth until 12 months of age for prevention of early manifestations of allergic disease [83]. There was no decrease in the incidence of cow's milk allergy, but fewer infants were sensitized to cow's milk at 12 months in the active compared with the placebo group (1.7 versus 12.5 percent, respectively).

Target population — The allergic phenotype is often expressed within the first months of life [64]. Thus, prevention strategies are focused on pregnancy and/or the immediate postnatal period. Preventive measures may address the general population or target infants at high risk of developing allergic disease, characterized by a positive immediate family history of allergic disease. The latter group is more commonly targeted. It is not yet clear if specific subgroups may benefit from probiotic intervention.

The majority of studies have selectively recruited infants at high risk of allergic disease. Several studies have also compared outcomes according to maternal sensitization since maternal allergy confers a higher risk than paternal allergy. Reduced sensitization with L. reuteri and L. rhamnosus, respectively, was observed in two studies in the subgroup of high-risk infants with maternal sensitization compared with those with no maternal sensitization, although there was no benefit in the unsegregated primary analysis [53,56].

Only a few studies have included an unselected population (ie, participants both with and without a family history of allergic disease) [57,65,76]. Two showed a marked reduction in eczema risk, but the other showed no difference in risk. In one study, 415 pregnant mothers from an unselected population were assigned to a combination of B. lactis, L. rhamnosus, and L. acidophilus or placebo started at approximately 36 weeks of gestation and continued during breastfeeding for three months. The incidence of eczema was reduced at two years compared with placebo, and a subgroup analysis found that this preventive effect on eczema was most obvious in children without a family history of allergic disease [57].

Strain(s) and dose — Many different strains and combinations of probiotics have been used. Results are variable, even when the same strain is used. As an example, LGG reduced eczema in one study [50,51,58] but had no effect in two others [52,82], even though one of them [52] used a very similar protocol to that of the first study [50,51,58].

Several studies reported a significant reduction in eczema with a combination of probiotics (B. bifidum, B. lactis, and Lactococcus lactis [61]; B. bifidum, B. lactis, and L. acidophilus [59]; LGG, L. acidophilus, and B. lactis [57]; L. rhamnosus LPR and B. longum or L. paracasei and B. longum [72]) compared with placebo. However, combinations were not similarly effective in other studies (LGG and B. lactis [53,63]; L. rhamnosus LPR and B. longum [55]; L. salivarius, L. paracasei, B animalis subspecies lactis, and B. bifidum [76]). Treatment with a combination of L. rhamnosus, B. breve, and Propionibacterium freudenreichii was associated with decreased eczema at two, but not five, years of age compared with placebo [54,60].

Few studies have directly compared the effects of single strains or combinations of strains. One study showed differences in efficacy between two species [66]. In that study, a L. rhamnosus strain significantly reduced the prevalence of eczema at two, four, and six years of age while a B. lactis strain did not [66,75,81].

In studies designed for allergy prevention, doses have typically ranged between 10⁸ to 10¹⁰ colony-forming units (CFU). However, dose-response data are scarce. A study designed to investigate the dose-response relationship on intestinal colonization reported successful temporary colonization with LGG at all three doses used (10⁸, 10⁹, or 10¹⁰ CFU/day) [84]. These findings cannot be extrapolated to other probiotic strains, because probiotic strains differ in their capacity to temporarily colonize the intestine. In addition, evidence of temporary colonization does not necessarily translate into a clinically relevant effect.

Timing and duration of treatment — The majority of studies have included prenatal treatment, typically for four to six weeks, but the period of postnatal supplementation has ranged from three months to two years. In some studies, the mother is treated antenatally rather than the infant [72]. Animal studies with probiotics show antenatal effects [85], but effects of maternal probiotics on cord blood immune responses are conflicting [86,87]. The only randomized trial to specifically examine the prenatal effects of probiotics gave LGG or placebo for the last two to four weeks of pregnancy with no postnatal supplementation found no effect [82]. Only one study [65] has specifically examined the effects of probiotic supplementation with a L. paracasei strain during weaning from breastfeeding (from 4 to 13 months) and found a reduction in eczema. Another study reported a significantly reduced incidence of eczema in infants who received L. rhamnosus and B. animalis subspecies lactis during six months starting in late infancy (mean age 10 months) compared with placebo [88]. These studies suggest that prenatal administration is not necessary for clinical benefit.

Two studies assessed the effects of LGG in the secondary prevention of allergic disease and found little to no effect on the outcomes measured [68,89]. In one study, 131 children 6 to 24 months old with recurrent wheeze and an atopic family history were randomized to LGG or placebo for six months. There was no difference in rates of atopic eczema or asthma-related events after six months of therapy and after six months of follow-up compared with placebo [68]. Another study evaluated the effects of probiotics for treatment of eczema and secondary prevention of sensitization and respiratory allergic disease [89]. A total of 208 infants aged three to six months with diagnosed eczema were randomized to L. paracasei, Bifidobacterium lactis, or placebo while receiving an extensively hydrolyzed formula. The study showed no clinical benefit through three years of age.

One trial of 220 children aged 1 to 12 months with double-blind, placebo-controlled food challenge (DBPCFC) confirmed cow's milk allergy randomly assigned to extensively hydrolyzed formula with or without LGG found a decreased risk of any other allergic manifestation including eczema, urticaria, asthma, and rhinoconjunctivitis in the LGG group over 36 months (absolute risk difference -0.23; 95% CI, -0.36 to -0.10) [90]. However, the trial was not blinded, and randomization was not concealed.

PREBIOTICS — There are limited data on the use of prebiotics to prevent allergic disease. A systematic review and meta-analysis found no effect on the development of asthma (two studies, 226 infants) but did find a significant reduction in eczema (four studies, 1218 infants; risk ratio [RR] 0.68, 95% CI 0.48-0.97; number needed to treat to benefit, 25 [95% CI 14 to >100]) [91]. Further studies, particularly in areas such as population to target (high- versus low-risk infants), best combination of prebiotics, and effect on development of allergic diseases other than eczema, are needed before routine administration of prebiotics to prevent allergic disease can be recommended.

SYNBIOTICS — One large study has specifically assessed a synbiotic combination in the primary prevention of allergic disease. In this randomized trial, 1223 pregnant mothers whose infants were at high risk for atopic disease were assigned to a synbiotic combination or placebo [54]. The synbiotic consisted of a prebiotic (galactooligosaccharides [GOS]) in combination with three different probiotic strains. This was administered to mothers for two to four weeks prior to delivery and then to their infants for the first six months postnatally. A reduction in eczema (odds ratio [OR] 0.74, 95% CI 0.55-0.98), particularly atopic eczema (OR 0.66, 95% CI 0.46-0.95), was seen in the synbiotic group at two years of age compared with placebo. There were no effects on other allergic outcomes or sensitization, although IgE-associated (atopic) diseases tended to occur less frequently in the synbiotic group. A follow-up at 5 and 13 years of age did not show any differences in the cumulative incidence of eczema, atopic eczema, sensitization, allergic rhinitis, or asthma between the treatment and placebo group [49,60]. However, in a subgroup analysis, there was some reduction in allergic outcomes in infants born by cesarean section [60], again illustrating that more studies are needed to evaluate if specific subgroups are more likely to benefit from interventions that modify infant gut microbiota. (See 'Target population' above and 'Proposed mechanisms' above.)

One study suggests that synbiotics may have a role in secondary prevention, with a reduced risk of developing wheeze seen in children with existing eczema [92]. In the original study, 90 infants less than seven months of age with atopic eczema were randomized to receive an extensively hydrolyzed whey formula with or without synbiotics (B. breve and a mixture of 90 percent GOS and 10 percent fructooligosaccharides [FOS]) for 12 weeks [93]. There was no effect of the synbiotic on the severity of eczema. However, 75 infants were reevaluated one year after the intervention, and a reduced prevalence of frequent wheezing was seen in the synbiotic group. Fewer infants had started to use asthma medication compared with placebo [92]. These results are preliminary, and larger, long-term studies are needed.

SIDE EFFECTS AND SAFETY — Generally, the safety profile of both prebiotics and probiotics is good, with few side effects observed in the previously reported clinical studies.

Prebiotics — Two meta-analyses that analyzed the safety of prebiotics in infancy concluded that formula with added prebiotics is well tolerated in full-term [94] and preterm infants [95].

Prebiotics are designed to selectively stimulate beneficial microbiota. However, preterm infants may not have an established microbiota that can use prebiotics for promoting health. There is at least a theoretical concern that the substrate may promote the growth of either potential pathogens or commensal luminal organisms that could translocate across the immature gut epithelial barrier and cause systemic disease. Animal models have demonstrated increased bacterial translocation in the intestine of immature pups fed a milk formula containing GOS and inulin [96].

No adverse effects were observed in one randomized prebiotic trial [27]. Another randomized prebiotic trial reported normal and similar growth in both the treatment and placebo groups [97]. Results from a primary prevention study using a combination of prebiotics and probiotics showed no differences in side effects or growth between children given the synbiotic versus placebo up to five years of age [60,98].

Probiotics — Administration of probiotics appears to be a safe intervention in the prenatal and postnatal periods in healthy individuals.

Probiotics are a diverse group of microorganisms. The most commonly used probiotics in allergy prevention are bifidobacteria and lactobacilli, normal commensals of the mammalian microbiota. They have been available in various types of foods for many years and are "generally recognized as safe" (GRAS) [14]. Theoretically, probiotics may cause systemic infections, deleterious metabolic activity, excessive immune stimulation, and gene transfer [99]. Lactobacillus septicemia was reported in children with short bowel syndrome receiving LGG supplementation [100]. In addition, caution is advised when using probiotics in immunocompromised patients, including premature infants, due to an increased risk of adverse effects and, in rare cases, infection caused by fungal contamination [101,102].

The safety of probiotics during pregnancy was evaluated in a meta-analysis [103]. Intake of lactobacilli and bifidobacteria during pregnancy had no effect on the incidence of cesarean section, birth weight, or gestational age. Several primary prevention studies have reported a paradoxical increase in possible allergy outcomes with probiotics, including sensitization [62], respiratory symptoms such as wheeze [52,62], and trends toward more rhinitis and asthma [58]. An actual causal relationship has not been confirmed, and follow-up studies that have evaluated lung function measures [73-75,78] and exhaled nitric oxide (eNO) [73-75,104] showed no harm with respect to probiotic treatment.

Products used in clinical trials are carefully screened for contaminating allergens. However, it is not uncommon for commercially available probiotics to be contaminated with cow's milk protein [105,106]. There are reports of sensitization to contaminating milk proteins [105] and of anaphylaxis to probiotics in children with cow's milk allergy due to contamination with cow's milk proteins [106]. Clinicians should promote awareness of these risks.

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●Basics topic (see "Patient education: Probiotics (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Definitions – Prebiotics are nondigestible carbohydrates that stimulate the growth and/or activity of beneficial colonic bacteria. Probiotics are live microorganisms that benefit the host. Synbiotics are a combination of prebiotics and probiotics. (See 'Definitions' above.)

●Proposed mechanisms of action – There is evidence from animal models and in vitro studies that gut microbiota modulate immune programming and can prevent the allergic phenotype. However, there is still an incomplete understanding of the optimal patterns of colonization for promoting immune tolerance and the possible impact of prebiotics and probiotics in this process. (See 'Rationale for prebiotics and probiotics in allergic disease' above and 'Proposed mechanisms' above.)

●Outcomes – Meta-analyses suggest a benefit of probiotics in reducing the development of eczema, but not any other allergic outcomes, in at-risk infants (defined as presence of a biologic parent or sibling with asthma, allergic rhinitis, eczema, or food allergy). However, the effect is moderate, and the only probiotic strain with reproducible data is Lactobacillus rhamnosus GG (LGG). In addition, the great heterogeneity of the studies makes it difficult to advise on specifics regarding therapy (eg, strains, dose, timing, and duration). Prebiotics and synbiotics, which are anticipated to have a more global effect on the gut microbiota, have shown some promise, but further studies are needed. (See 'Prebiotics' above and 'Probiotics' above and 'Synbiotics' above.)

●Probiotics for prevention of eczema – We suggest not giving probiotics during pregnancy, lactation, and infancy for the prevention of eczema (Grade 2C). However, we do not discourage this approach if parents/caregivers express strong interest and there is a family history of atopic disease, given the low risk of adverse events and modest potential for benefit. Parents/caregivers who choose this approach should first discuss it with the appropriate clinician (eg, obstetrician, pediatrician, other primary care provider). (See 'Our approach' above.)