Randomized, Double-Blind, Placebo-Controlled Trial
of Probiotics for Primary Prevention: No Clinical
Matthias Volkmar Kopp, MD, Isabell Hennemuth, MD, Andrea Heinzmann, MD, Radvan Urbanek, MD
University Children’s Hospital, Freiburg, Germany
The authors have indicated they have no ﬁnancial relationships relevant to this article to disclose.
What’s Known on This Subject
Epidemiologic data show that children with allergy have a different intestinal ﬂora from healthy children. Based on these data, “harmless” microbial agents, that is, probiotics, have been tested for their efﬁcacy in the prevention of allergy in infants. However, the value of probiotics for primary prevention is controversial.
What This Study Adds
Supplementation withLactobacillusGG during pregnancy and early infancy did not reduce the incidence of atopic dermatitis or alter the severity of atopic dermatitis in affected children but was associated with an increased rate of recurrent episodes of wheezing bronchitis. Therefore,LactobacillusGG cannot be recommended generally for primary prevention.
BACKGROUND.The value of probiotics for primary prevention is controversial. Published
trials vary considerably in study design and the applied probiotics, thereby limiting comparability of the results.
OBJECTIVE.The purpose of this trial was to study the preventive effect of the probiotic
LactobacillusGG on the development of atopic dermatitis.
METHODS.In a double-blind, placebo-controlled prospective trial, 105 pregnant women
from families withⱖ1 member (mother, father, or child) with an atopic disease were randomly assigned to receive either the probioticLactobacillusGG (American Type Culture Collection 53103; 5 ⫻109 colony-forming units of Lactobacillus GG twice
daily) or placebo. Ninety-four families (89.5%) completed the trial. The supplemen-tation period started 4 to 6 weeks before expected delivery, followed by a postnatal period of 6 months. The primary end point was the occurrence of atopic dermatitis at the age of 2 years. Secondary outcomes were severity of atopic dermatitis, recurrent episodes of wheezing bronchitis, and allergic sensitization at the age of 2 years.
RESULTS.Atopic dermatitis was diagnosed in 14 (28%) of 50 in the LactobacillusGG
group and in 12 (27.3%) of 44 in the placebo group. The risk of atopic dermatitis in children on probiotics relative to placebo was 0.96 (confidence interval 0.38 –2.33). Severity of atopic dermatitis was comparable between the 2 groups. Notably, children with recurrent (ⱖ5) episodes of wheezing bronchitis were more frequent in the
LactobacillusGG group (26%;n⫽13), as compared with the placebo group (9.1%;n
⫽4). No difference was observed between both groups in total immunoglobulin E concentrations or numbers of specific sensitization to inhalant allergens.
CONCLUSIONS.Supplementation withLactobacillus GG during pregnancy and early
in-fancy neither reduced the incidence of atopic dermatitis nor altered the severity of
atopic dermatitis in affected children but was associated with an increased rate of recurrent episodes of wheezing bronchitis. Therefore,LactobacillusGG cannot be generally recommended for primary prevention.
ATOPIC DERMATITIS, ALLERGICrhinitis, and bronchial asthma in childhood represent a significantly large segment of chronic disease in the Western world.1,2 To combat the rising prevalence of allergy, there is still a need to
analyze the underlying mechanisms and to develop concepts that address primary prevention.
Improved hygiene, the increased use of antimicrobial medication, the consumption of sterile food, and reduced family size resulting in lower rates of infection during childhood have reduced early contact to microbes.3,4This may interfere
with the development of the child’s immune system, which tends to be directed toward a T-helper (Th)2 phenotype in infants, whereas postnatal maturation is associated with gradual inhibition of Th2 and increasing Th1 affinity.5–7
Exper-imental and epidemiologic data show strong evidence for the hypothesis that early microbial exposure is a critical feature for Th1-skewed immune response in healthy children during the postnatal period.8,9Less exposure to microbial agents at
We afﬁrm that the study has been registered at a qualiﬁed national registry, the registry for clinical studies at the University of Freiburg. Registration number is UKF000505.
allergy, prevention, probiotics,
LactobacillusGG, atopic dermatitis, neonates
Th—T helper LGG—LactobacillusGG AD—atopic dermatitis IgE—immunoglobulin E CI— conﬁdence interval OR— odds ratio
Accepted for publication Sep 21, 2007
Address correspondence to Matthias Volkmar Kopp, MD, University Children’s Hospital, Mathildenstrasse 1, D-79106 Freiburg, Germany. E-mail: Matthias.email@example.com
an early age would, therefore, result in reduced activation of the immune system and subsequent polarization toward a Th2 phenotype. In this context, the idea of modulating the intestinal flora has really caught on and is gaining in popularity. This concept is supported by epidemiologic data, which show that children with allergy have a differ-ent intestinal flora from healthy children with higher levels of clostridia and lower levels of bifidobacteria.10–12Based on
these data, “harmless” microbial agents, that is, probiotics, have been test administered for their efficacy in the treat-ment and prevention of allergy in infants. Probiotics are defined as products or preparations containing viable croorganisms in numbers thought to alter the host’s mi-croflora, thereby exerting beneficial health effects.13 One
strain of probiotics,Lactobacillus rhamnosus(LactobacillusGG [LGG]: American Type Culture Collection 53103), has proved safe at an early age.
So far there has been only 1 published double-blind, randomized, placebo-controlled trial that showed a pre-ventive effect of LGG on atopic disease in a population at high risk. The frequency of atopic dermatitis (AD) was reduced by half in infants given probiotics compared with those on placebo at the ages of 2, 4, and 7 years.14–16
However, no difference was observed in the number of sensitized children between the groups. Furthermore, the mechanism of action is largely unexplained.
Recently, these results have also been questioned by a trial conducted by an Australian group, who reported no difference in the development of AD but observed in-creased sensitization to allergens in neonates supple-mented with a different strain ofLactobacillus.17Therefore,
we used a prospective double-blind, placebo-controlled study to verify the importance of probiotics for primary prevention of atopic diseases. We hypothesized that LGG has a comparable clinical efficacy compared with the data reported by Kallioma¨ki et al.14–16
Participants and Study Design
The study design of this double-blind, randomized, pla-cebo-controlled trial was similar to the concept of the Finnish study published by Kallioma¨ki et al.14Two
mod-ifications of the protocol of Kallioma¨ki et al14were made.
First, we continued to supplement LGG for 3 months after birth exclusively to the breastfeeding mothers and the following 3 months only to the neonates. Second, pregnant women in our population commenced with LGG or placebo for 4 to 6 weeks, whereas Finnish moth-ers received supplementation only during the last 4 weeks of pregnancy. Pregnant women were recruited from outpatient departments of local gynecologists in Freiburg between July 2002 and June 2004. Inclusion criteria were as follows: (1) an uneventful pregnancy of the mother; (2) absence of underlying chronic disease of the mother (ie, diabetes mellitus, rheumatoid arthritis, or chronic infectious disease); and (3) a family history of atopic disease; that is, ⱖ1 family member (mother, fa-ther, or older sibling) with AD, allergic rhinitis, or asthma and a confirmed allergic sensitization against an inhalant allergen.
On the basis of our sample-size calculation before the study, where the efficacy of LGG supplementation was assessed based on the data published by Kallioma¨ki et al,14
50 families had to be researched in each group. At the beginning of the study, 105 mothers were randomly as-signed to receive 2 capsules of placebo (microcrystalline cellulose) or L rhamnosus GG (American Type Culture Collection 53103) containing 5⫻109colony-forming units
of LGG (Infectopharm, Heppenheim, Germany) daily for 4 to 6 weeks before expected delivery. Randomization was performed in blocks of 4 according to a computerized ran-domization list. LGG and placebo capsules were matched for appearance, taste, smell, and packing.
Capsules were taken postnatally for 6 months. Di-rectly after delivery, breastfeeding mothers took the cap-sules; otherwise, children received the agents (n⫽2 in the LGG group; n ⫽ 3 in the placebo group). After 3 months, capsules were given only to the neonates. The capsule contents were mixed with water and then ad-ministered with a spoon.
Questionnaires were distributed to the parents during the neonatal period and when the children were 6, 12, and 24 months of age. All of the children were examined at the age of 24 months. In the case of suspected eczema, children were also seen at the age of 12 months. The primary study end point was the manifestation of an atopic disease during the first 2 years of life. Children were grouped into those with this disorder (children with AD) and those without (healthy children). Secondary end points were the severity of AD (Scoring Atopic Dermatitis Index), the cumulative incidence of AD, the incidence of recurrent (⬎5 episodes) wheezing bronchitis, total immunoglobulin E (IgE) and the number of children with sensitization to an inhalant aller-gen at the age of 2 years. The recruitment of pregnant women started on July 1, 2002, and ended on June 30, 2006. The last follow-up visits at the age of 2 years were performed during September 2006. The study was ap-proved by the ethics committee of the University of Freiburg (local ethics committee of the University of Freiburg, code No. 46/02; 28.03.2003). Written informed consent was obtained from children’s parents.
Clinical Examination and Questionnaires
using United Kingdom Working Party criteria.18The
cri-terion “chronic relapsing course” was fulfilled if the child had had eczema forⱖ1 month. The severity scoring of atopic dermatitis (Scoring Atopic Dermatitis Index) was used to assess eczema severity.19 Possible confounders
that could influence the relationship of probiotics and allergic disease were obtained by means of a question-naire. These data included information about other clin-ical diseases and common exposures (vaccination, infec-tion, episodes of wheezing, period of breastfeeding, and use of antibiotics), the home environment (including carpeting, siblings, and pets), and recurrent obstructive bronchitis, which was diagnosed if the child had hadⱖ5 episodes of wheezing bronchitis during the first 2 years.
Treatment codes were kept by the supplier until data had been collected and analyzed, that is, until September 2006. Normally distributed data are expressed as means with 95% confidence interval (CI) and skewed data as geometric means with 95% CI. Values were compared between the groups by unpairedttest (Wilcoxon test). The 2 test was used to compare proportions between
the groups. A Pvalue of ⬍.05 was regarded as statisti-cally significant. To determine the odds ratio (OR) of developing AD in the probiotic group compared with placebo, logistic regression was used. Finally, we calcu-lated a linear regression model to describe a possible effect of LGG supplementation on the development of AD. Other than the LGG or placebo supplementation, the model includes mode of delivery; birth weight; gen-der; family history of mother, father, and siblings; use of antibiotics; and duration of breastfeeding as independent
variables. The regression model gives parameter esti-mates for the differences between the groups as a de-scription of possible LGG effects. Analyzing our data, information regarding the primary end point of our study was mandatory. Therefore, the analysis was per-formed in the “per protocol” group instead of the “in-tention-to-treat” population.
Characteristics of the Study Population
As shown in the trial profile (Fig 1), 108 pregnant women were recruited, and 105 were randomly as-signed for the study. Of these, 11 withdrew from the study (Fig 1) during follow-up or were excluded from the analysis because of major protocol violation. A total of 94 mothers and their healthy term infants completed the study (89.5%), 50 in the LGG group and 44 in the placebo group.
There were no significant differences between the neonates of the 2 groups in gender, birth weight, gesta-tional age, method of delivery, maternal or paternal age, or parity (Table 1). Furthermore, environmental vari-ables, which might be a potential confounder for the development of atopic disease, did not differ between the groups. The number of older siblings, the lactation period, the time point of introduction of solids, passive smoke exposure, and the number of pets at home were equally distributed (Table 1). The atopic status of the family is detailed in Table 2. No difference in the number of atopic family members was noted between the groups (Table 2).
105 families randomly assigned
54 assigned LGG 51 assigned placebo
50 completed study 44 completed study Lost to follow-up: n = 1 after 3 mo n = 1 after 6 mo n = 2 after 12 mo
Screening failure: n = 1
Protocol violation: n = 2 Lost to follow-up:
n = 1 after 6 mo n = 2 after 12 mo
Protocol violation: n = 1
147 families assessed for egilibility
108 families recruited
3 withdrew prior to randomisation
Effects of LGG on Clinical Outcomes
The primary aim of this study was to examine the effect of LGG supplementation on manifestations of AD at the age of 2. At that time, the rates of AD between the LGG
group (28%;n⫽14) and the placebo group (27.3%;n⫽
12;P⫽0.93; Fig 2) were nearly identical. The risk of AD in children on probiotics relative to placebo was 0.96 (OR; CI: 0.38 –2.33). Similarly, no significant difference was observed in the cumulative incidence of atopic symptoms during the first 2 years (Fig 3). In affected children, the difference of severity of AD between the LGG (median LGG: 18.5) and the placebo group (22.5;
P⫽0.8; Table 3) was not statistically significant. Factors that could account for possible confounding effects like mode of delivery, birth weight, gender, family history, use of antibiotics, or duration of breastfeeding were ex-amined in a regression model. The parameter estimate for the differences between the groups was 1.18 (CI: 0.45–3.11;P⫽0.73), indicating that possible confound-ing factors did not change the key study findconfound-ing.
Secondary clinical end points were the occurrence of episodes with upper respiratory tract infections, fever, use of antibiotics, and number of wheezing bronchitis. There was no evidence that LGG provides protection from upper respiratory infections. Episodes of fever and the use of antibiotics during the first year of life were equally distributed between both groups (Table 3). No difference was observed between both groups in total IgE concentrations or numbers of specific sensitization to inhalant allergens (Table 3). The median IgE concentra-tion was 17.9 kU/L (fifth to 95th percentile: 0.3–140.0 kU/L) in the LGG and 28.9 kU/L (fifth to 95th percentile: 1.3–279.0 kU/L) in the placebo group (Table 3). A
0 10 20 30 40
n = 14 n = 12
p = .93
Treatment effect of LGG on atopic diseases showing the proportion of 2-year-old children with AD.
LGG Placebo 0
10 20 30 40 50
n = 19 n = 14
p = .53
Treatment effect of LGG on atopic diseases showing the proportion of children with symptoms of AD during the ﬁrst 2 years of life.
TABLE 1 Characteristics of the Study Population
Characteristic LGG Placebo P
n 50 44
Male/female children,n/N 24/26 18/26 .49 (2) Birth weight, mean, g 3492.7 3379.4 .49 Birth weight, ﬁfth to 95th percentile, g 2820–4180 2660–3980 Gestational age, mean, wk 39.8 39.7 .74 Gestational age, ﬁfth to 95th
Normal delivery/cesarean section,n/N 41/9 36/9 .64 (2)
Smoke exposure at home,n 8 6 .70
Furry pets at home,n 10 5 .18
Age of the mothers, mean, y 32.92 33.75 .27 Age of the mothers, median, y 33.50 35.27 Age of the mothers, ﬁfth to 95th
Age of the fathers, y 35.29 37.26 .19
28.4–44.8 31.0–46.7 No. of mothers born in Germany (%) 49 (98) 42 (94.5) .84 No. of fathers born in Germany (%) 47 (94) 44 (100) .41 No. of siblings
None 25 14 .12
1 15 22
2 10 6
⬎3 0 2
Duration of breastfeeding, mean, mo 8.7 9.7 .38 Duration of breastfeeding, median, mo 9.0 8
Duration of breastfeeding, ﬁfth to 95th percentile, mo
Introduction of solids, mean, mo 6.18 5.60 .18 Introduction of solids, median, mo 6.0 6
Introduction of solids, ﬁfth to 95th percentile, mo
Statistical comparison between the 2 groups was made by Wilcoxon 2-sample test and2test, respectively.
TABLE 2 Family History of Atopy in Both Groups
Variable LGG Placebo P
n 50 44 NA
Mother, any allergic disease,n 37 27 .19
Allergic asthma 17 11 .34
Allergic rhinitis 20 13 .29
AD 7 9 .41
Father, any allergic disease,n 25 26 .38
Allergic asthma 5 10 .09
Allergic rhinitis 19 17 .95
AD 3 2 .75
Sibling, any allergic disease,n 20 17 .89
Allergic asthma 5 2 .32
Allergic rhinitis 4 3 .83
AD 6 12 .06
Total No. of affected family members 82 70 .78
cific sensitization against an inhalant allergen was ob-served in 4 (LGG) and 5 (placebo) children at the age of 2 years.
Notably, children with recurrent (ⱖ5) episodes of wheezing bronchitis were more frequently in the LGG group (26%; n ⫽ 13), as compared with the placebo group (9.1%;n⫽4;P⫽0.03, Fig 4). The administration of LGG was well tolerated without any notable adverse effects attributable to the supplementation of probiotics (data not shown).
To confirm the hypothesis that LGG is effective in the prevention of early atopic disease, as based on the results of the clinical study of Kallioma¨ki et al,14–16 a second
validating study in an independent population is deemed to be necessary. Therefore, we used a prospective dou-ble-blind, placebo-controlled trial to reevaluate the find-ings of the Finnish study and to characterize potential effects of LGG. In contrast to previous published find-ings, we have shown that the probiotic LGG has no preventive effect on the development or the severity of AD at the age of 2 years in a German population of infants at high risk. Instead, there was a significantly higher risk of ⱖ5 episodes with wheezing bronchitis
during the first 2 years in the LGG group, as compared with placebo.
Over the last few decades, public reports have shown increasing enthusiasm for the potential health effects of probiotics. However, clinical studies of the efficacy of probiotics showed no therapeutic effect in allergic rhini-tis20and little or no benefit in the therapy of AD.21,22
Until now, 3 clinical studies have been published that have focused on the use of probiotics for primary pre-vention. The Finnish study of Kallioma¨ki et al14was the
first report to describe that the frequency of AD in the probiotic group was half that of the placebo. We adapted the protocol of Kallioma¨ki et al14and continued to
sup-plement LGG for 3 months after birth to the breastfeed-ing mothers and the followbreastfeed-ing 3 months only to the neonates. This modification was made to achieve a more consistent probiotic delivery. Second, Finnish mothers received supplementation during the last 4 weeks of pregnancy, whereas pregnant women in our population commenced with LGG or placebo for 4 to 6 weeks. We extended the prenatal supplementation period, because a 4-week period is thought to possibly be too short for suspected in utero effects of LGG supplementation.
However, the discrepancy between the data of Kal-lioma¨ki et al14 and our study cannot be explained by
minor deviations in the study design. We observed no preventive effect of LGG on the development of AD in our population nor any trend in this direction. There are some differences in confounding variables that probably contributed to the discrepancy in these clinical findings. First, the number of atopic family members per individ-ual was 1.64 (LGG) and 1.75 (placebo) in our population as compared with 1.19 (LGG) and 1.11 (placebo) in the Finnish population. This may lead to our population being of higher risk compared with the Finnish popula-tion, which might account for the differing results. Sec-ond, we recruited more infants with older siblings (50% [LGG] and 68.2% [placebo] compared with 37% [LGG] and 34% [placebo] in the Finnish study), which might be also a potential confounder. Finally, the Finnish and German populations are of different genetic background. We recruited a fairly homogeneous ethnic group, with a proportion of ⬎95% of mothers and fathers born and raised in Germany. No data were presented by Kallio-ma¨ki et al14with respect to the ethnic background of the
Finnish population. In a second preventive study in a Finnish population, a mixture of prebiotic and 4 probi-otic bacterial strains failed to reduce the incidence of allergic disease by the age of 2 years but reduced the manifestation of AD eczema from 32% to 26%.23Even if
the effect in the intervention group was much smaller and the supplementation strategy was different com-pared with the study of Kallioma¨ki et al,14 these data
support our hypothesis that the susceptibility to probi-otics might differ between individuals because of differ-ent genetic backgrounds.
In support of our findings, a recently published, dou-ble-blind, placebo-controlled trial in a large Australian population failed to demonstrate a preventive effect of probiotics on atopic disease.17 Taylor et al17
supple-mentedL acidophilusdirectly postnatally to infants with
TABLE 3 Clinical Outcome at the Age of 2 Years
Variable LGG Placebo P
n 50 44 NA
Fever episodes at 12 mo,n(%) 30 (46.8) 34 (53.1) .22 airway infections at 12 mo,n(%) 36 (56.2) 28 (43.7) .23 antibiotics at 12 mo,n(%) 9 (19.1) 12 (27.3) .35 SCORAD
No. of vaccinations, mean 19.14 17.1 .28 No. of vaccinations, ﬁfth to
0–27 0–27 NA
Total IgE at the age of 2 y, mean, kU/L
33.12 61.7 .38
Total IgE at the age of 2 y, median, kU/L
17.9 28.9 NA
Total IgE at the age of 2 y, ﬁfth to 95th percentile, kU/L
0.3–140.0 1.3–279.0 NA
Children with sensitization to an inhalant allergen,n
4 5 .61
No signiﬁcant difference between the groups was observed. NA indicates not applicable.
LGG Placebo 0
10 20 30 40
n = 13 n = 4
p = .03
an allergic mother for 6 months. Similar to our results, not even a trend of different rates of AD was observed between the groups. After 12 months, 34 (43.2%) of 88 children in the probiotic group and 34 (39.1%) of 87 children in the placebo group developed an AD. The higher rate of children with AD in both groups compared with our study might be because of the higher risk for atopic disease in Australian children with maternal atopy. It is striking that the proportion of children with AD and allergic sensitization in the study of Taylor et al17
was significantly higher in the probiotic group. More-over, a significantly greater proportion of children in the probiotic group developed wheezing during the first 6 months of life. This finding also corresponds with data of our population, where we observed a significantly higher proportion of children with recurrent (ⱖ5 epi-sodes) wheezing bronchitis during the first 2 years in the LGG group. It is interesting that, in the study of Kallio-ma¨ki et al,15a nonsignificant trend toward an increased
rate of atopic disorders in the group treated with Lacto-bacillus, as compared with those given placebo at the age of 4 years, was also observed: 10 of 53 and 5 of 54 developed allergic rhinitis, and 3 of 53 and 1 of 54 developed asthma, respectively. Allergic rhinitis and asthma also tended to be more common in the probiotic group at the age of 7 years.16 However, one must be
careful when concluding that there is a causal relation-ship betweenLactobacillussupplementation and wheez-ing bronchitis. In our trial, episodes of wheezwheez-ing were based on both diagnosis by a physician and symptoms recorded by the parents. It was not feasible to confirm every episode of wheezing by a doctor of the study center. Nevertheless, with respect to the lacking data showing efficacy of probiotics for primary prevention and higher incidence of wheezing in the Lactobacillus
group observed in 2 independent studies, probiotics should not be recommended for allergy prevention.
Additional data from the Taylor et al17study point in
the same direction regarding allergic sensitization, also suggesting that the use of probiotics for primary preven-tion must be exercised with caupreven-tion. At the age of 12 months, the rate of sensitization to common allergens was significantly higher in the probiotic group. In our population, no significant difference in total IgE levels or number of children sensitized against inhalant allergens was observed. However, we tested a panel of inhalant allergens and screened for food allergens only on indi-vidual request. In line with our data, Abrahamsson et al24could not confirm a preventive effect of probiotics on
infant eczema in a recently published study. However, he observed that the treated infants had less IgE-associ-ated eczema at 2 years. Moreover, skin prick test reac-tivity was also less common in the treated group than in the placebo group, but this difference reached signifi-cance only for infants with allergic mothers. Again, there are differences in the administered probiotic (L reuterii) and the supplementation period (1 year), which might explain the discrepancy compared with the Taylor et al17
study and our study.
Based on the effects of LGG published by Kallioma¨ki et al,14we calculated 50 families to be researched in each
group. However, because 11 families from the originally randomly assigned 105 families were lost to follow-up, we ended up with 50 and 44 families in each group with complete data sets, so that we included fewer patients than planned. However, even if all of the randomly assigned families (LGG n ⫽ 54; placebo n ⫽ 51) had finished the study, and even if all the children who left the study had shown favorable results of LGG supple-mentation, this would not have changed our key end point (data not shown).
In the placebo group, we observed more families with older siblings, a slightly longer duration of breastfeeding, and less furry pets at home, factors that are discussed as allergy-protective determinants. On the other hand, children in the placebo group had slightly more siblings with a history of AD, but all of the differences between the groups were not statistically significant. Moreover, by using a regression model, all of these variables did not change the key study finding. Until now, many mecha-nisms have been proposed for the potential favorable effects of probiotics on allergy prevention. In addition to in vitro modulation of the cytokine response, probiotics have been observed to increase production of secretory immunoglobulin A,25to improve the barrier function of
the intestinal mucosa,26and to enhance enzymatic
deg-radation of dietary antigens by enzymes from probiot-ics.27 However, the exact modes of action are not yet
Supplementation with LGG during pregnancy and early infancy did not reduce the incidence of AD. In contrast, more children receiving LGG developed episodes of re-current bronchitis. Thus far, an allergen-preventive ef-fect of LGG could not be consistently established. There-fore, LGG cannot be generally recommended for primary prevention. Additional studies should clarify whether any susceptible subgroups exist, and how these sub-groups benefit from a specific supplementation with pro-biotics can be defined.
The study was supported by the University of Freiburg and by Infectopharm (Heppenheim, Germany).
Other members of the study group were: Michael Goldstein, Alicija Dietschek, Michael Moseler, Gabriele Ihorst, Hannah Arends, Franziska Feindt, Julia Soffke, and Claudia Seydi.
We thank the children and their parents for their tireless cooperation. We are indebted to Maria Lickert for her reliable work in the laboratory, as well for her active support during the study.
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DOI: 10.1542/peds.2007-1492 originally published online March 10, 2008;
Matthias Volkmar Kopp, Isabell Hennemuth, Andrea Heinzmann and Radvan
Prevention: No Clinical Effects of
Randomized, Double-Blind, Placebo-Controlled Trial of Probiotics for Primary
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DOI: 10.1542/peds.2007-1492 originally published online March 10, 2008;
Matthias Volkmar Kopp, Isabell Hennemuth, Andrea Heinzmann and Radvan
Prevention: No Clinical Effects of
Randomized, Double-Blind, Placebo-Controlled Trial of Probiotics for Primary
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