FETAL ENVIRONMENT AND EARLY LIFE FACTORS AND THE DEVELOPMENT OF ASTHMA AND ALLERGY

Project leader: Juha Pekkanen, Head of Unit of Environmental Epidemiology, National Public Health Institute (KTL), P.O.Box 95, FIN-70701 Kuopio, Finland, tel. +358-17-201 368, e-mail: Juha.Pekkanen*ktl.fi
 
 

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Researchers:
Baizhuang Xu, Unit of Environmental Epidemiology, National Public Health Institute, Lehdokkitie 7A 24, 01300 Vantaa , tel. +358-9 8364 7977
e-mail: Baizhuang.Xu@kiinahuamei.fi
Tuula Husman, Unit of Environmental Epidemiology, National Public Health Institute, P.O.Box 95, 70701 Kuopio, tel. +358-17-201325, e-mail: Tuula.Husman@ktl.fi
Marjo-Riitta Järvelin, Department of Public Health Science and General Practice, University of Oulu, Aapistie 1, 90220 Oulu tel. +358-40-5117246
Pentti Koskela, Laboratory of Prenatal Serology, National Public Health Institute. Aapistie, 90220 Oulu, tel. +358-8-537 6217, e-mail: Pentti.Koskela@ktl.fi
Johann Erikson, Department of Epidemiology and Health Promotion, National Public Health Institute, Mannerheimintie 166, 00300 Helsinki,
Matti Korppi, Department of Pediatrics, Kuopio University Hospital, P.O.Box 1777, 70211 Kuopio, tel. +358-40-513 0791, e-mail: Matti.Korppi@kuh.fi
Jukka Pelkonen, Department of Clinical Microbiology, University of Kuopio, P.O.Box 1627 70211 Kuopio, e-mail: Jukka.Pelkonenuku.fi
Sami Remes, Unit of Environmental Epidemiology, National Public Health Institute, P.O.Box 95 70701 Kuopio, Sami.Remes@ktl.fi

Financing SYTTY organisation: The Academy of Finland
Funding from SYTTY / Total funding of project (€): 107842 / 226690
Person-months of work funded by SYTTY / Total person-months of work: 17 / 48,5

KEY WORDS: asthma, allergy, perinatal factors
 

EXTENDED ABSTRACT

1 Introduction

The risk of allergic disorders have increased during last decades. The causes for the increase are still not clear. Changes in exposure to environmental allergens and genetic factors alone appeared incapable to explain the observed increase. Childhood asthma and atopic diseases are more common in the Westernized societies (von Mutius et al. 1994, Brabäck et al. 1994), and within the same society it is more common among higher socio-economic groups (Williams et al. 1994). Data also suggest that asthma and atopic disease are more common among residents in urban areas than those in rural areas (Braun-Fahrländer et al 1996).

It seems that the observed difference in asthma distribution among populations is due to a result of some 'Western factor', which is probably associated with high living standard. Whether the Western life-style is associated with an introduction of new, unknown adjutants enhancing sensitisation, or whether factors that are necessary for the induction of tolerance are absent is still unknown. A large body of studies indicates that outdoor air contamination, indoor pollutants, passive smoking and genetic factors are associated with the risk of asthma. However, none of these factors can readily explain the observed increase in allergic diseases.

The work of Barker and colleagues (1990) has demonstrated that fetal and early infant growth may be major determinants of disease in later life. Factors operating during pregnancy have also been implicated in the aetiology of atopy (Miles et al 1994, Warner et 1996, Olsen et al. 1997). Raised cord-blood T-cell proliferate responses are observed after stimulation with specific allergens at birth in babies who subsequently develop allergic problems in relation to those allergens (Warner et al 1994, Tang et al 1994). These studies suggest that the process of sensitisation starts as early as during pregnancy. It has been realised that the causes of asthma and allergy should be searched also from the intrauterine environment.

The aim of the study was to investigate the associations between the risk of developing asthma and allergy and intrauterine environment as well as early life factors, with special reference on the roles of following factors:
- Factors operating through pregnancy and delivery: maternal smoking, maternal infections, delivery styles, obstetric complications
- Size at birth, birth weight, length, head circumference, and body build in later life
- Early life factors: factors influencing the risk of infections in early life such as day care, family size, number of older siblings, socio-economic status, living environment

2 Methods

The study involved follow-ups of two existing birth cohorts, born in northern Finland in 1966 and 1985-86, respectively, and establishing a population-based case-control study:

1966 birth cohort
The original cohort consisted of 12058 live births from the two northernmost provinces of Finland, Oulu and Lapland, and covered 96% of the children born in that region between January 1, 1966, and December 31, 1966 (Rantakallio 1966). The data collection started during pregnancy and follow-up data on the health status of the children were collected at various ages.  In 1997, 8463 survivors, who were still living in Northern Finland or in the capital area were sent postal questionnaires and invited to clinical examinations. 6025 (71.2%) attended the examinations. The sensitivity to three most common allergens in Finland, i.e. cat, birch, timothy, and sensitivity to house dust mite (Dermatophagoides pteronyssinus) was assessed by skin prick tests during clinical examinations. Histamine dihydrochloride (10 mg per ml) and diluent of the allergen extracts were used as positive and negative controls, respectively. Skin reactions to each allergen tested were recorded after 10 minutes as the average of the maximum weal diameter and the diameter perpendicular to the maximum. People with a weal reaction >3mm to one or more of the four allergens tested were considered to be atopic. Data on doctor-diagnosed asthma ever in life and data on parental history of allergies were obtained using a postal questionnaire at the age of 31. All perinatal data were collected during or right after pregnancy.

1985-86 birth cohort
The study population was derived from all pregnancies in northern Finland with expected birth dates falling from 1 July 1985 to 30 June 1986 (Rantakallio 1990). The women were enrolled at the 24th week of gestation to the maternity health centre during pregnancy. The cohort consists of 9479 births, accounting for 99% of all births in the study area. Among them 9327 children were alive in 1993. The current analyses were limited to 8088 (86.7%, out of 9327) children with complete information on pregnancy and returned the questionnaire in 1993. Data on development of asthma among children at the age of 7 was collected using a structured self-administered questionnaire filled in by the mothers in 1993. The information on childhood asthma was supplemented by linking the cohort with the National Hospital Discharge Records. The information on pregnancy was obtained using a structured self-administered questionnaire that was distributed to mothers at their last antenatal visit. Information on delivery was collected from delivery records in hospitals. For few mothers who failed to fill in the questionnaire at the last antenatal visit the information was collected at midwifes’ first home visit after delivery.

Case-control study
800 asthmatic children and 800 controls have been randomly selected among 50000 Finnish babies born during Sep. 1st, 1992-Aug. 31th, 1993, for whom cord blood samples and mothers’ blood samples in pregnancy are available at the National Public Health Institute. A self-administered questionnaire to mothers has been performed and data on pregnancy and birth supplemented from the National Birth Registry at National Research and Development Centre for Welfare and Health. Among the selected study subjects, a further random sample of 200 cases and 200 controls have been selected for laboratory determinations, including maternal sex hormones.

3 Results and discussions

Results from 1966 cohort
- Body build and atopy
Atopy at the age of 31 years was positively associated with current BMI but negatively with maternal BMI, and had an U-shaped association with ponderal index at birth. The results were not substantially changed after adjusting for physical activity and other potential confounders. The association was confirmed also in more detailed analyses using quintiles of the variables examined and stratifying by sex. We also observed a weak non-significant interaction between ponderal index at birth and current BMI on atopy. Those people who were born with a smaller ponderal index and had a larger current BMI tended to have the highest risk. This is the first report of combined effect of maternal BMI as well as size at birth and current body build on atopy in adulthood. The mechanism underlying the observed associations was not clear. The results that not only current obesity but body build at birth as well as body of the mother appear to have substantial effects on atopy in adulthood highlight the importance of the perinatal period and early childhood.

- Maternal age at menarche and atopy among offspring
The prevalence of atopy at the age of 31 years was less common among those children whose mothers reached menarche at a later age, especially after age 15. As compared to children whose mothers started menarche at the age of 16 or over the adjusted odds ratios of being atopic were 1.43 (95% CI 1.12, 1.83), 1.29 (95% CI 1.03, 1.60), 1.15 (95% CI 0.93, 1.42) and 1.19 (95% CI 0.95, 1.48) for those children whose mothers started menarche younger or at 12, 13, 14 and 15 years, respectively. The results suggest potential influence of female hormones on occurrence of allergic disorders. However, the fact that daughters’ age at menarche was not significantly associated with her atopic status implys the intrauterine environment might be more important in later life in terms of development of adult atopy. The results encourage further evaluate the potential effect of maternal age at menarche on the later development of atopy among offspring, and explore the possible mechanism underlying the association.

- Gestational age and occurrence of atopy at the age of 31 years
The risk of atopy increased linearly with increasing length of pregnancy among babies born on the 35th weak of gestation or later. Gestational age equal to or over 40 weeks as compared to less than 36 weeks was associated with an increased risk of atopy (multivariate odds ratio 1.65, 95% CI 1.16, 2.34). The association was stronger among farmers’ children (p for interaction 0.01). High parity and being a farmer’s child (multivariate odds ratio 0.50, 95% CI 0.42-0.60) were associated with decreased risk of atopy. In contrast, no associations were observed for doctor diagnosed asthma. The results suggest the importance of pregnancy and very early childhood in the development of atopy and indicate that timing of the environmental exposures is of importance for the immune system. No association was observed for asthma, however, which may be due to the multifactorial origins of asthma.

- Caesarean section and risk of asthma and allergy in adulthood
The analysis was limited to 1953 subjects of 1966 cohort with complete information on asthma and information on obstetrics. The results indicated that caesarean section had a strong effect on current doctor-diagnosed asthma in adulthood with an adjusted OR being 3.23 (95% CI 1.53, 6.80). However, no substantial effects were observed for atopy, hay fever and atopic eczema. Given the fact that the frequency of caesarean section is largely increased during last few decades the results encourage further evaluate the potential influence of caesarean section on the development of asthma in later life, and explore the possible mechanism underlying the association. Based on the findings, the effect of caesarean section on microbial flora and the Th1/Th2 balance is probably not the mechanism underlying the association between caesarean section and asthma, as no associations were observed with atopy and other allergic diseases. It is possible that unknown factors associated with caesarean section or the consequences of caesarean section may explain the association observed. Alternatively, it could be hypothesised that foetuses that will later develop asthma may express this already in utero, which could lead to obstetric complications and increased risk of caesarean section.

- Body build from birth to adulthood and asthma and atopy
Ponderal index at birth had a U-shaped association with adult atopy, OR 1.30 (95% CI 1.11-1.52) for the lowest tertile and OR 1.33 (95% CI 1.13-1.55) for the highest tertile, as compared to the middle tertile. The association was independent of obesity later in life. Those obese (BMI >95th percentile) in adolescence (OR 2.09, 95% CI 1.23-3.57) and in adulthood (OR 1.99, 95% CI 1.14-3.47) had a higher occurrence of adult asthma than those with BMI < 85th percentile. Both estimates were reduced after mutual adjustment. The results suggest that size at birth has a long-lasting effect on atopy in adulthood, which is independent of weight in adolescence and adulthood. Those who were obese in adolescence and adulthood tended to have a higher risk of asthma in adulthood. The findings suggest the importance of considering the life course of obesity in analyses of asthma and atopy.

Results from 1985-86 cohort

- Maternal infections during pregnancy and astma

Data based on 8088 children in 1985-86 cohort indicated the prevalence of asthma at the age of 7 was 3.5%. Children had a higher risk of asthma if their mothers experienced vaginitis and febrile infections during pregnancy, odds ratio (OR) being 1.41 (95% confident interval (CI) 1.08–1.84) and 1.65 (95% CI 1.25–2.18), respectively, after adjusting for other covariates. There was a clear time trend in risk of childhood asthma corresponding to the timing of maternal febrile infections in pregnancy. The adjusted ORs for the first, the second and third trimester were 2.08 (95% CI 1.13–3.82), 1.73 (95% CI 1.09–2.75) and 1.44 (95% CI 0.97–2.15), respectively. Maternal history of allergic diseases, birth weight <2500g and male gender seemed to be also risk factors for childhood asthma. The results suggest that asthma phenotype could probably be programmed before birth, and further investigation of relation of maternal infections during pregnancy to asthma among children seems warranted.

- Obstetric complications and asthma
Haemorrhage during pregnancy, special delivery procedures, situations that required special procedures at delivery and low APGAR scores after birth were associated with an increased risk of childhood asthma and allergic rhinitis. After adjusting maternal age, social classes, maternal smoking in pregnancy, maternal history of allergic disorders, gestational age and number of old sibling, the odd ratio (OR) of haemorrage at the 1st trimester was 1.76 (95% confident interval (CI) 1.17-2.63) for asthma and 1.63 (95% CI 1.06-2.52) for allergic rhinitis. Among special procedures, other procedures except for caesarean section and vacuum extraction had a stronger association with asthma, adjusted OR being 2.14 (95% CI 1.06-4.33), and vacuum extraction had a stronger association with rhinitis, with a OR being 1.88 (95% CI 1.22-2.89. Exhaustion of mothers was a strongest risk factor among reasons for special procedures at delivery for both asthma and rhinitis, with adjusted OR being 2.17 (95% CI 0.98-4.78) and 3.16 (95% CI 1.65-6.08), respectively. The results suggest that obstetric complications were associated with childhood allergic disorders. This has provided further evidence of importance of pregnancy and intrauterine environment to later development of allergic disorders among children.

- Pregnancy factors and allergic disorders
The prevalences of allergic rhinitis and allergic eczema by the age of 7 years among 8,088 children were 3.3% and 6.7%, respectively. Having a low parity, febrile infections in pregnancy, the use of contraceptives before the pregnancy increased the risk of allergic disorders among children. Bleeding in the 1st trimester and a greater weight gain during pregnancy appeared to be risk factors for rhinitis only. Children whose mothers experienced infections in the 1st trimester had ORs of 2.65 (95% CI 1.50-4.69) for rhinitis and 1.63 (95% CI 1.00-2.69) for eczema after adjusting for potential confounders. The results suggest obstetric complications and infection in pregnancy may increase the risk of allergic disorders among the offspring.

4 Conclusions

The results support the hypothesis that development of asthma and allergies is programmed already in uterio. Complications that mothers suffer during pregnancy and delivery appear to increase the risk of allergic disorders among children.

5 References

Barker DJP. 1990. Fetal and infant origins of adult disease. BMJ 301:1111.

Bråbäck L, Breborowicz A, Dreborg S, Knutsson A, Pieklik H, Björksten B. 1994. Atopic sensitization and respiratory symptoms among Polish and Swedish school children. Clin Exp Allergy 24:826-35.

Braun-Fahrländer C, Gassner M, Grize L, et al. 1996. Lower risk of allergic sensitization and hay fever in farmers children in Switzerland (Abstract). European Respiratory Journal 9:377s.

Miles EA, Warner JA, Lane AC, Jones AC, Colwell BM, Warner JO. 1994. Altered T lymphocyte pnenotype at birth in babies born to atopic parents. Pediatr Allergy Immunol 5:202-208.

Olsen AB, Ellingsen AR, Olsen H, Juul S, Thestrup-Pedersen K. 1997. Atopic dermatitis and birth factors: historical follow up by record linkage. BMJ 314:1003-1008.

Rantakallio P and Oja H. 1990. Perinatal risk for infants of unmarried mothers over a period of 20 years. Early Human Development 22:157-169.

Rantakallio P. 1969. Groups at risk in low birth weight children and perinatal mortality. Acta Pediatric Scand 1969;Suppl 193:1-71.

Tang MLK, Kemp AS, Thorburn J, Hill DJ. 1994. Reduced interferon-  and subsequent atopy. Lancet 344:983-985.

von Mutius E, Martinez F, Fritsch C, Nikolai T, Reitmer P, Thiemann H-H. 1994. Skin test reactivity and number of siblings. Br Med J 306: 308-315.

Warner JA, Miles EA, Jones AC, Quint DJ, Colwell BM, Warner JO. 1994. Is deficiency of interferon gamma production by allergen triggered cord blood cells a predictor of atopic eczema? Clin Exp Allergy 24:423-430.

Williams HC, Strachan DP, Hay RJ. 1994. Childhood exzema: disease of the advantaged? Br Med J 308:1132-5.
 
 

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