Volume 123, Issue 6 , Pages 1305-1311, June 2009
Intrauterine bacterial growth at birth and risk of asthma and allergic sensitization among offspring at the age of 15 to 17 years
Article Outline
Background
Microbial colonization of the airways and intestine during birth might have an effect on the risk of asthma and allergic diseases later in life.
Objective
We sought to evaluate the association between intrauterine microbial growth at the time of delivery and the development of asthma and allergic sensitization among offspring.
Methods
Intrauterine bacterial culture results were recorded at the time of cesarean delivery of 460 children who were born at Kuopio University Hospital during 1990–1992. When the children reached the age of 15 to 17 years, self-administered questionnaires were sent to the mothers, and 382 of the children were also examined by using skin prick tests.
Results
Intrauterine growth of potential pathogenic anaerobic bacteria and Streptococcus species at birth was associated with an increased risk of doctor-diagnosed asthma ever (odds ratio [OR], 4.51 [95% CI, 1.56–13.0]; OR, 2.53 [95% CI, 1.19–5.38]) and doctor-diagnosed current asthma (OR, 7.34 [95% CI, 2.44–22.03]; OR, 3.37 [95% CI, 1.46–7.76]) at the age of 15 to 17 years compared with the risk seen in subjects with negative microbial cultures. These findings remained significant also after applying the Bonferroni correction. No significant association after the Bonferroni correction was detected between intrauterine microbial growth and allergic sensitization among offspring.
Conclusion
The results of this study indicated that specific intrauterine microbial growth at the time of birth might increase the risk of asthma among offspring through inflammatory mechanisms. These results indicate new potential targets for future studies on the effects of maternal vaginal microflora and intrauterine infection in the development of asthma among children
Key words: Amniotic fluid, asthma, allergic sensitization, bacteria, cesarean delivery, intrauterine, ureaplasma, skin prick test
Abbreviation used: OR, Odds ratio
During normal vaginal birth, the fetus usually encounters, for the first time, microbes that colonize the maternal birth canal and genital tract. Before the onset of labor and membrane rupture, the uterine cavity is usually free of microbes, and intact membranes partly protect the fetus against infection and hinder microbial ascent during delivery. However, microbes might ascend into the uterine cavity during cervical dilatation, especially in the case of extended labor, after rupture of the membranes and a relatively long duration of internal monitoring, and with greater numbers of vaginal digital examinations. After rupture of the membranes, up to 70% to 90% of amniotic fluid becomes colonized with microbes, even during normal delivery.1, 2, 3, 4 Intrauterine bacterial infection or inflammation in the gestational tissues is commonly thought to be the cause of the onset of preterm labor, even when the membranes are intact.5
Several studies have focused on the effect of maternal infections and antibiotic administrations during pregnancy and at delivery on the development of asthma among offspring.6, 7, 8, 9, 10 Recently, Kumar et al11 showed that the highest risk of wheezing and physician-diagnosed asthma before the age of 7 years was present in the very preterm children born with maternal chorioamnionitis. On the other hand, the increasing frequency of allergic sensitization has also been hypothesized to result from reduced microbial stimulation and consequent insufficient maturation of the immunologic system during the early neonatal period. Neonates delivered by means of cesarean section have shown disturbances in the primary gut flora, even up to 6 months after birth.12, 13, 14 In addition, maternal antibiotic administration before birth and neonatal antibiotic administration during the early postnatal period might disturb the development of normal neonatal flora as well.15
We earlier studied intrauterine microbial invasion in the evaluation of peripartal intrauterine inflammation and maternal infection in 805 women who underwent cesarean delivery between the years 1990–1992. In these earlier prospective studies we showed that amniotic fluid microbial invasion was as common as 66% to 71% among women who underwent operations after the onset of labor and rupture of the membranes and less common in those undergoing operations with intact membranes (13% to 23%).4, 16 This cohort gave us a unique opportunity to investigate the effect of intrauterine microbial invasion in the development of asthma and allergic sensitization among offspring at the age of 15 to 17 years.
Methods
The initial study population consisted of 805 consecutive mother-child pairs who all underwent cesarean section at Kuopio University Hospital, Finland, in a 2-year period between March 1990 and February 1992 (Fig 1). They all belonged to the cesarean delivery infection study cohort. The infants were born after singleton gestations, and the mean gestational age at the time of delivery was 39 weeks (range, 23–43 weeks). The study population consisted of (1) 303 (37.6%) women who gave birth with intact membranes and before the onset of spontaneous labor and (2) 502 (62.4%) women who gave birth after rupture of the membranes, the onset of labor, or both. Three hundred thirty-nine (42.1%) of the 805 women were delivered by way of an elective operation. Six women were enrolled twice into the study.
Fig 1.
Flow chart of subjects during recruitment and those finally included in analyses. ‡Response rates were based on the number of recruited mother-child pairs divided by the total number of eligible pairs.
During the cesarean section, amniotic fluid was aspirated into a sterile syringe through a sterile catheter inserted into the amniotic sac. Intrauterine swab samples were taken for bacterial cultures in cases in which amniotic fluid was unavailable or because of the urgency of the operation. Both amniotic fluid and swab samples were cultured for aerobic and anaerobic bacteria, but only amniotic fluid samples were cultured for genital mycoplasmas. In total, microbial culture results were available for 702 (87.2%) women. The methods and results of initial intrauterine microbial cultures, maternal infections, and intrauterine histopathologic findings have been described in detail in our earlier reports.4, 16 A positive culture was defined as the presence of any organism. Microorganisms detected in the bacterial cultures were also analyzed on the basis of their species (eg, Lactobacillus species, Streptococcus species, and Staphylococcus species). Anaerobic species detected in the bacterial cultures were grouped according to their potential pathogenicity. Anaerobic streptococci, Bacteroides species, and Clostridium species were grouped as potential pathogens, whereas Veillonella parvula and Propionibacterium species were grouped as nonpathogens.
When the children were 15 to 17 years of age, a postal questionnaire was mailed to the mothers. All live children whose mothers were alive and lived in Finland with known mailing addresses were sent the questionnaire (n = 749) between October 2006 and autumn 2007 (Fig 1). Questions were based on the International Study of Asthma and Allergies in Childhood's standardized questionnaire.17 Doctor-diagnosed asthma was defined as a positive answer to the following question: “Has your child ever had doctor-diagnosed asthma?” Current asthma medication and symptoms were investigated through the following questions: “Has your child used asthma medication during the last 12 months?” and “Has your child had wheezing or whistling in the chest when breathing during the last 12 months?” Current asthma was defined as doctor-diagnosed asthma with recent asthma medication (last 12 months) or asthmatic symptoms during the last 12 months (current wheezing or whistling in the chest). Questionnaire data were available for 545 (72.8%) children (Fig 1).
The children living in the area of the Hospital District of Northern Savo (n = 688) were invited to a clinical examination, including skin prick tests, during the 4-month period from November 2006 to February 2007 (Fig 1). Allergic sensitization to cat, dog, horse, birch, timothy, mugwort, house dust mite (Dermatophagoides pteronyssinus), and Cladosporium herbarum allergens was assessed by means of skin prick tests with methods described earlier.18 Histamine dihydrochloride (10 mg/mL) and diluent of the allergen extracts were used as positive and negative controls, respectively. Skin reactions to each allergen tested were recorded after 15 minutes. The size of each wheal was calculated as the mean of the longest diameter and the diameter perpendicular to its midpoint. Allergic sensitization was defined as 1 or more reactions greater than or equal to 3 mm. All selected subjects had positive reactions to histamine and negative reactions to the negative controls. Skin prick tests were applied to 382 (55.5%) children. Four children were excluded because of positive reactions to the negative control or to the use of an antihistamine before skin prick testing.
The final study population was limited to 460 children for whom both maternal intrauterine microbial culture results and questionnaire data were available. Among these 460 children, 323 (70.2%) underwent skin prick tests (Fig 1).
Comparisons of proportions in univariate analysis were performed with the χ2 test. Logistic regression analysis was used to investigate the relationships between the prevalence of allergic outcomes and the adjusted effects of various predictors of allergic diseases, including the perinatal clinical variables. In logistic analyses we tested the following potential confounders: child's sex (female/male) and current body mass index (in tertiles: ≤20, 20.1–24.9, and ≥25 kg/m2), maternal age at delivery (≤28, 29–33, and >33 years), parity (0 and ≥1), maternal smoking during pregnancy (no/yes, including those who stopped in the first trimester), paternal occupation after delivery (farmer/nonfarmer), maternal allergy (no/yes, defined as mother being recorded as having asthma, hay fever, or atopic eczema), season of birth (March–May, June–August, September–November, and December–February), gestational age (≤36, 37–39, and ≥40 weeks), birth weight (≤2500, 2501–3500, and >3500 gr), electivity of the operation (elective/nonelective/emergency), maternal antibiotic administration during labor or delivery (no/yes), and neonatal antibiotic administration during the first postnatal week (no/yes). In the final logistic models, variables were included in a forward stepwise regression analysis if they were significant at a P value of less than .10 in univariate analysis or satisfied a change-in-estimate criterion (≥10% change in the odds ratio [OR]). The cutoff level of significance was .05. In addition, we applied Bonferroni corrections with significant findings.
Results
At the age of 15 to 17 years, 12.0% (55/460) of the children had ever had doctor-diagnosed asthma, and 8.7% (40/460) had current asthma. Of the subjects with current asthma, 39 (8.5%) had used asthma medication during the previous 12 months. The median age at the time of the first wheezing symptoms was 4 years (range, 0–15 years). The overall prevalence of allergic sensitization according to skin prick test results was 52.0% (168/323). Among the subjects with doctor-diagnosed asthma, 79.5% (35/44) were atopic.
Microorganisms were detected in 145 (31.5%) of the uterine cavity or amniotic fluid cultures, with 201 isolates recovered. The most frequent isolates were Lactobacillus species (n = 36) and Ureaplasma urealyticum (n = 26). Table I, Table II show the associations between intrauterine microbial culture results and the prevalence of doctor-diagnosed asthma ever and current doctor-diagnosed asthma among the offspring. There were significant associations between intrauterine Streptococcus species and pathogenic anaerobic bacterial growth and doctor-diagnosed asthma among offspring (Table I), and these remained significant after applying the Bonferroni correction (significance at P = .008). No significant associations were detected between Lactobacillus species or Staphylococcus species intrauterine growth and the prevalence of doctor-diagnosed asthma ever and doctor-diagnosed current asthma among the offspring (Table I, Table II). There were significant associations between any microbial, Streptococcus species, and pathogenic anaerobic bacterial growth and current doctor-diagnosed asthma among offspring (Table II). After adjustment by means of Bonferroni correction analysis, the significant association remained between Streptococcus species and pathogenic anaerobic bacterial growth and current asthma (significance at P = .008). If the outcome variable was current use of asthma medication, the significant associations were not changed.
Table I. Intrauterine microbial growth at birth and the prevalence of doctor-diagnosed asthma ever among offspring at the age of 15 to 17 years
| Variable | Doctor-diagnosed asthma, no. (%) | Unadjusted OR (95% CI) | Adjusted OR∗ (95% CI) |
|---|---|---|---|
| Microbial culture results | |||
 Negative | 31/315 (9.8) | 1 | 1 |
| Any positive microbial culture | 24/145 (16.6) | 1.82 (1.02-3.28) | 1.69 (0.93-3.05) |
| P < .039 | P = .086 | ||
| Specific bacteria species | |||
| Negative | 31/315 (9.8) | 1 | 1 |
| Lactobacillus species | 4/37 (10.8) | 1.11 (0.37-3.34) | 1.06 (0.35-3.23) |
| P = .852 | P = .918 | ||
| Negative | 31/315 (9.8) | 1 | 1 |
| Staphylococcus species | 5/30 (16.7) | 1.83 (0.66-5.13) | 1.66 (0.58-4.74) |
| P = .243 | P = .343 | ||
| Negative | 31/315 (9.8) | 1 | 1 |
| Streptococcus species | 12/55 (21.8) | 2.56 (1.22-5.36) | 2.53 (1.19-5.38) |
| P < .011 | P < .005 | ||
| Negative | 31/315 (9.8) | 1 | 1 |
| Potentially pathogenic anaerobes | 6/18 (33.3) | 4.58 (1.61-13.1) | 4.51 (1.56-13.0) |
| P < .002 | P < .005 | ||
| Amniotic fluid ureaplasma culture | |||
| Negative | 20/208 (9.6) | 1 | 1 |
| Positive | 5/26 (19.2) | 2.24 (0.76-6.58) | 1.96 (0.60-6.43) |
| P = .135 | P = .267 |
∗The following variables were included in stepwise models (see the Methods section): child's sex, current body mass index, maternal age and parity at delivery, maternal smoking during pregnancy, paternal occupation at the time of birth, gestational age, birth weight, season of birth, maternal allergy, maternal and neonatal antibiotic administration, and electivity of the operation. |
Table II. Intrauterine microbial growth at birth and the prevalence of current doctor-diagnosed asthma among offspring at the age of 15 to 17 years
| Variable | Current asthma, no. (%) | Unadjusted OR (95% CI) | Adjusted OR∗ (95% CI) |
|---|---|---|---|
| Microbial culture results | |||
| Negative | 20/315 (6.3) | 1 | 1 |
| Any positive microbial culture | 20/145 (13.8) | 2.36 (1.23-4.54) | 2.35 (1.21-4.58) |
| P < .008 | P < .012 | ||
| Specific bacteria species | |||
| Negative | 20/315 (6.3) | 1 | 1 |
| Lactobacillus species | 3/37 (8.1) | 1.30 (0.37-4.61) | 1.28 (0.36-4.65) |
| P = .682 | P = .703 | ||
| Negative | 20/315 (6.3) | 1 | 1 |
| Staphylococcus species | 3/30 (10.0) | 1.64 (0.46-5.87) | 1.64 (0.45-5.93) |
| P = .444 | P = .452 | ||
| Negative | 20/315 (6.3) | 1 | 1 |
| Streptococcus species | 10/55 (18.2) | 3.28 (1.44-7.45) | 3.37 (1.46-7.76) |
| P < .003 | P < .004 | ||
| Negative | 20/315 (6.3) | 1 | 1 |
| Potentially pathogenic anaerobes | 6/18 (33.3) | 7.38 (2.51-21.71) | 7.34 (2.44-22.03) |
| P < .0001 | P < .0001 | ||
| Amniotic fluid ureaplasma culture | |||
| Negative | 13/208 (6.3) | 1 | 1 |
| Positive | 5/26 (19.2) | 3.57 (1.16-11.00) | 3.34 (0.96-11.59) |
| P < .019 | P = .057 |
∗The following variables were included in stepwise models (see the Methods section): child's sex, current body mass index, maternal age and parity at delivery, maternal smoking during pregnancy, paternal occupation at the time of birth, gestational age, birth weight, season of birth, maternal allergy, maternal and neonatal antibiotic administration, and electivity of the operation. |
An additional analysis including only children who were born after term pregnancy (≥37 gestational weeks, n = 402) showed that the risk of current doctor-diagnosed asthma was higher among children delivered with pathogenic anaerobic bacteria (OR, 9.05; 95% CI, 2.87–28.53; P < .0001) and Streptococcus species (OR, 3.50; 95% CI, 1.43–8.56; P < .006) compared with children delivered with negative microbial cultures. The analysis could not be repeated among preterm cases because of their low numbers.
We further evaluated the joint association of neonatal antibiotic administration and the presence of specific microbes with current doctor-diagnosed asthma (Table III). The numbers were low for statistical testing, but the risk of current doctor-diagnosed asthma tended to always be increased with the growth of Streptococcus species, pathogenic anaerobic bacteria, or U urealyticum, both among subjects with and those without neonatal antibiotic administration. On the other hand, administration of antibiotics increased very little the risk of asthma among those with negative microbial cultures (6.7% vs 6.3%), but children with neonatal antibiotics and the growth of Streptococcus species or pathogenic anaerobic bacteria in intrauterine cultures had the highest risk of current asthma compared with other children.
Table III. The joint association of neonatal antibiotic administration with specific intrauterine microbial growth at birth and current doctor-diagnosed asthma among offspring at the age of 15 to 17 years
| No antibiotics (n = 369) | Antibiotics (n = 91) | |||
|---|---|---|---|---|
| Variable | Current asthma, no. (%) | Adjusted OR∗ (95% CI) | Current asthma, no. (%) | Adjusted OR∗ (95% CI) |
| Microbial culture results | ||||
| Negative | 16/255 (6.3) | 1 | 4/60 (6.7) | 1 |
| Any positive microbial culture | 9/114 (7.9) | 1.15 (0.48-2.71) | 11/31 (35.5) | 7.70 (2.20-27.0) |
| P = .760 | P < .001 | |||
| Specific bacteria species | ||||
| Negative | 16/255 (6.3) | 1 | 4/60 (6.7) | 1 |
| Streptococcus species | 5/40 (12.5) | 2.02 (0.68-6.03) | 5/15 (33.3) | 7.00 (1.60-30.7) |
| P = .206 | P < .010 | |||
| Negative | 16/255 (6.3) | 1 | 4/60 (6.7) | 1 |
| Potentially pathogenic anaerobes | 3/13 (23.1) | 3.75 (0.91-15.4) | 3/5 (60.0) | 21.0 (2.69-164) |
| P = .067 | P < .004 | |||
| Amniotic fluid ureaplasma culture | ||||
| Negative | 8/177 (4.5) | 1 | 5/31 (16.1) | 1 |
| Positive | 2/20 (10.0) | 2.74 (0.51-14.8) | 3/6 (50.0) | 5.20 (0.81-33.6) |
| P = .241 | P = .083 | |||
∗The following variables were included in stepwise models (see the Methods section): child's sex, current body mass index, maternal age and parity at delivery, maternal smoking during pregnancy, paternal occupation at the time of birth, gestational age, birth weight, season of birth, maternal allergy, maternal antibiotic administration, and electivity of the operation. |
There was a significant association between intrauterine U urealyticum growth and allergic sensitization among offspring (Table IV), but this did not remain significant after applying the Bonferroni correction (significance at P = .008).
Table IV. Intrauterine microbial growth at birth and the prevalence of allergic sensitization among offspring at the age of 15 to 17 years
| Variable | Allergic sensitization, no. (%) | Unadjusted OR (95% CI) | Adjusted OR∗ (95% CI) |
|---|---|---|---|
| Microbial culture results | |||
| Negative | 114/226 (50.4) | 1 | 1 |
| Any positive microbial culture | 54/97 (55.7) | 1.23 (0.77-1.99) | 1.19 (0.73-1.94) |
| P = .389 | P = .480 | ||
| Specific bacteria species | |||
| Negative | 114/226 (50.4) | 1 | 1 |
| Lactobacillus species | 19/28 (67.9) | 2.07 (0.90-4.78) | 2.07 (0.89-4.80) |
| P = .082 | P = .090 | ||
| Negative | 114/226 (50.4) | 1 | 1 |
| Staphylococcus species | 13/21 (61.9) | 1.60 (0.64-4.00) | 1.60 (0.64-4.00) |
| P = .315 | P = .318 | ||
| Negative | 114/226 (50.4) | 1 | 1 |
| Streptococcus species | 13/34 (38.2) | 0.608 (0.290-1.27) | 0.61 (0.29-1.28) |
| P = .184 | P = .187 | ||
| Negative | 114/226 (50.4) | 1 | 1 |
| Potentially pathogenic anaerobes | 6/11 (54.5) | 1.18 (0.35-3.97) | 1.16 (0.34-3.95) |
| P = .790 | P = .816 | ||
| Amniotic fluid ureaplasma culture | |||
| Negative | 73/145 (50.3) | 1 | 1 |
| Positive | 12/15 (80.0) | 3.95 (1.07-14.57) | 3.85 (1.03-14.42) |
| P < .032 | P < .046 |
∗The following variables were included in stepwise models (see the Methods section): child's sex, current body mass index, maternal age and parity at delivery, maternal smoking during pregnancy, paternal occupation at the time of birth, gestational age, birth weight, season of birth, maternal allergy, maternal and neonatal antibiotic administration, and electivity of the operation. |
Discussion
This is the first study in which the possible effects of intrauterine microbial growth on the development of asthma and allergic sensitization among offspring have been investigated.
A novel observation was the increased risk of doctor-diagnosed asthma ever and doctor-diagnosed current asthma at age 15 to 17 years in children whose mothers' uterine cavities at the time of cesarean section were colonized by Streptococcus species and by potential pathogenic anaerobic bacteria. Such an association was not detected between Lactobacillus species or Staphylococcus species intrauterine growth. Naturally, these mothers had more clinically defined chorioamnionitis or “silent” intrauterine infections during delivery and therefore also more antibiotic administration before delivery. Addition of maternal predelivery or neonatal antibiotic treatment into the analyses did not change the significance of the observation. No significant association was observed with allergic sensitization.
During normal vaginal birth, the fetus usually encounters, for the first time, microbes that colonize the maternal birth canal and genital tract. Sometimes these microbes can be harmful, and depending on the duration of the birth process, intrauterine infection can develop and the fetus can become infected congenitally. Various microbes, including aerobic and anaerobic streptococci, anaerobic rods (eg, Bacteroides species), and genital mycoplasmas, including U urealyticum, play an important role in the development of chorioamnionitis during delivery.19, 20, 21 Chorioamnionitis plays a central role in the pathogenesis of congenital early neonatal infection. Thus our findings showing the highest risk for current asthma in those children with neonatal antibiotics and specific bacterial growth in intrauterine samples at the time of birth are consistent with and extend those of Kumar et al,11 who showed that maternal chorioamnionitis increased the risk of early wheezing and doctor-diagnosed asthma but not eczema or food allergy. Chorioamnionitis causes a strong proinflammatory response, and fetal exposure to these cytokines presented in amniotic fluid has been associated with an increased risk of chronic lung disease.22, 23 On the basis of these studies, it seems likely that at least in some patients, the development of asthma could be a result of early subclinical or clinical chorioamnionitis at the time of birth through inflammatory mechanisms. It is also possible that early neonatal infection caused by bacterial colonization during delivery could be more probable in those children who are genetically more prone to allergy and asthma with a defective innate immune response in the early phase of life.24
Recently, it has been shown that early microbial colonization of the hypopharyngeal region was associated with increased risk of childhood asthma.25 It is conceivable that neonates whose mothers have potentially pathogenic vaginal or intrauterine microbial growth during delivery are at a higher risk of early pathogenic microbial colonization, either in the lungs or the gut. They might also be more prone to early bacterial infections and consequent antibiotic treatment during the late neonatal period. Interestingly, Kozyrskyj et al26 showed in a large epidemiologic study of 13,000 children that those who received antibiotics during their first year of life were significantly more likely to have asthma at the age of 7 years. However, such findings have been disputed because it has been difficult to exclude the fact that children with asthmatic symptoms receive more antibiotic treatments than nonasthmatic subjects.27 Unfortunately, we have no data beyond the first postnatal week regarding the use of antibiotics or neonatal infections, and we cannot evaluate whether there is an association between pathogenic intrauterine microbial invasion at the time of delivery and late neonatal infections or antibiotic treatment during the first postnatal year. There are no long-term follow-up studies of neonates followed during the late neonatal period and born after intrauterine infection, maternal chorioamnionitis, or prolonged delivery (except as regards neonatal cerebral injury in those born prematurely). The hypothesis is unresolved, and it remains to be explored in depth in future studies.
In the current study the prevalence of allergic sensitization was as high as 52%, but this is in line with the results of another recent Finnish study.28 In contrast to the hygiene hypothesis, newborns born with sterile amniotic fluids had no more allergic sensitization than seen in those born with intrauterine microbial isolation. In fact, children whose mothers were colonized with ureaplasmas tended to have higher risk of allergic sensitization (80%) compared with children whose mothers had no intrauterine microbial growth (50%). This finding did not, however, reach statistical significance after Bonferroni correction because mycoplasma cultures were not obtained from intrauterine swabs, which unfortunately limited this analysis to only 234 women.
A recent large Norwegian epidemiologic study showed that children delivered by means of cesarean section had a higher risk of asthma compared with spontaneously delivered children, and this risk was highest in those who were delivered by means of emergency cesarean section. This was observed in all gestational age groups.29 Laboring women with intrauterine microbial infection have higher risks of prolonged labor and of nonelective and emergency cesarean deliveries.30, 31, 32 The present results suggest a possible biologic explanation to the finding that children born by means of emergency cesarean section have a higher risk of asthma. However, to fully understand these results, larger cohort studies with microbial samples from mother and neonate pairs with a follow-up extending from pregnancy to late childhood are needed in the future.
Our study has several possible limitations. First, we cannot rule out that subjects who did not participate in our study had less allergic sensitization or asthma. However, the proportions of mothers undergoing elective operations (42.1% vs 43.0%) and with positive intrauterine microbial cultures (30.5% vs 31.5%) and the proportions of children who received antibiotics during the first neonatal week (21.7% vs 19.8%) were very similar between the original and the present study populations.
Second, in addition to skin prick testing, we did not have any objective measures of asthma. However, the diagnostic criteria for asthma in Finland are very strict because the diagnosis of asthma entitles the person to reimbursement for asthma medication. In the present analysis 97.5% of subjects with current asthma reported to have used asthma medication during the last year, and all of them had also doctor-diagnosed asthma.
Finally, all of our study subjects were delivered by means of cesarean section. It is possible that neonatal lung tissue does not clear itself of amniotic fluid so well after cesarean delivery as after vaginal delivery. This might have a potential effect on the development of asthma later, especially in cases of intrauterine infection.
We show here pioneering results on the possible association between intrauterine growth of specific microbes at the time of cesarean delivery and increased risk of asthma in offspring. Because there was no strong association with allergic sensitization, the association with asthma is likely to be mediated through nonatopic mechanisms. These results provide new potential targets for future studies on the effects of maternal vaginal microflora and intrauterine infection in the development of asthma among children.
Maternal vaginal and intrauterine microbial flora during delivery might be associated with the development of asthma among children.
We thank the study mothers and their children. This study was made possible by the technical assistance of Raija Juntunen, RN, and Pekka Tiittanen, MSc, for which the authors are very grateful.
References
- . Quantitative bacteriological analysis of amniotic fluid. Biol Neonate. 1982;42:166–173
- . Quantitative bacteriology of amniotic fluid from women with clinical intraamniotic infection at term. J Infect Dis. 1982;145:1–8
- . Infection markers during labor at term. Acta Obstet Gynecol Scand. 1995;74:33–39
- . Amniotic fluid U. urealyticum colonization: significance for maternal peripartal infections at term. Am J Perinatol. 1997;14:151–156
- . Infection and prematurity and the role of preventive strategies. Semin Neonatol. 2002;7:259–274
- . Maternal infections in pregnancy and the development of asthma among offspring. Int J Epidemiol. 1999;28:723–727
- Maternal vaginal microflora during pregnancy and the risk of asthma hospitalization and use of antiasthma medication in early childhood. J Allergy Clin Immunol. 2002;110:72–77
- . The importance of prenatal exposures on the development of allergic disease: a birth cohort study using the West Midlands General Practice Database. Am J Respir Crit Care Med. 2002;166:827–832
- Infectious and uterus related complications during pregnancy and development of atopic and nonatopic asthma in children. Allergy. 2004;59:99–106
- Maternal complications and procedures in pregnancy and at birth and wheezing phenotypes in children. Am J Respir Crit Care Med. 2007;175:16–21
- Prematurity, chorioamnionitis, and the development of recurrent wheezing: a prospective birth cohort study. J Allergy Clin Immunol. 2008;121:878–884
- . Fecal microflora in healthy infants born by different methods of delivery: permanent changes in intestinal flora after cesarean delivery. J Pediatr Gastroenterol Nutr. 1999;28:19–25
- Reduced enterobacterial and increased staphylococcal colonization of the infantile bowel: an effect of hygienic lifestyle?. Pediatr Res. 2006;59:96–101
- Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics. 2006;118:511–521
- . Could peripartum antibiotics have delayed health consequences for the infant?. BJOG. 2006;113:758–765
- . Cesarean delivery. Microbial colonization in amniotic fluid. J Reprod Med. 1997;42:91–98
- Prevalence of asthma symptoms in video and written questionnaires among children in four regions of Finland. Eur Respir J. 1997;10:1787–1794
- . Gestational age and occurrence of atopy at age 31—a prospective birth cohort study in Finland. Clin Exp Allergy. 2001;31:95–102
- . Bacterial vaginosis and anaerobes in obstetric-gynecologic infection. Clin Infect Dis. 1993;16(suppl):S282–S287
- . Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev. 2002;8:3–13
- . Group B streptococcus infection in pregnancy. Clin Perinatol. 2007;34:387–392
- . Reduced nitric oxide in amniotic fluid of patients with chorioamnionitis. Fetal Diagn Ther. 2006;21:77–80
- Elevated amniotic fluid levels of leukemia inhibitory factor, interleukin 6, and interleukin 8 in intra-amniotic infection. Am J Obstet Gynecol. 1998;179:1267–1270
- . Of attraction and rejection—asthma and the microbial world. N Engl J Med. 2007;357:1545–1547
- Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med. 2007;357:1487–1495
- . Increased risk of childhood asthma from antibiotic use in early life. Chest. 2007;131:1753–1759
- Does antibiotic exposure during infancy lead to development of asthma?: a systematic review and metaanalysis. Chest. 2006;129:610–618
- Microbial content of drinking water in Finnish and Russian Karelia—implications for atopy prevalence. Allergy. 2007;62:288–292
- . Cesarean section and risk of severe childhood asthma: a population-based cohort study. J Pediatr. 2008;153:112–116
- . Effect of amniotic fluid bacteria on the course of labor in nulliparous women at term. Obstet Gynecol. 1986;68:587–592
- . Risk factors for intraamniotic infection: a prospective epidemiologic study. Am J Obstet Gynecol. 1989;161:562–566
- . Duration of labor induction in nulliparous women at term: how long is long enough?. Am J Perinatol. 2008;25:205–209
Supported by the Finnish Medical Association, the Jalmari and Rauha Ahokas Foundation, the Kerttu and Kalle Viik Foundation, and the National Public Health Institute.
Disclosure of potential conflict of interest: L. Keski-Nisula received personal scholarships from the Finnish Medical Association, the Jalmari and Rauha Ahokas Foundation, and the Kerttu and Kalle Viik Foundation. J. Pekkanen received grant support from the European Union 7th Framework Programme, Finnish Foundation, and the Academy of Finland. The rest if the authors have declared that they have no conflict of interest.
PII: S0091-6749(09)00489-8
doi:10.1016/j.jaci.2009.03.021
© 2009 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Volume 123, Issue 6 , Pages 1305-1311, June 2009
