BACKGROUND Influences of female hormones on the occurrence of allergic disorders have been suggested. Age at menarche may be a marker of endogenous oestrogen levels. Data from a Finnish birth cohort followed to adulthood were analysed to determine whether there is any association between maternal age at menarche and the occurrence of atopy among offspring.
METHODS The study was conducted in 5188 subjects born in northern Finland for whom data collections were started during pregnancy and a follow up examination was completed at the age of 31 years. Atopy was determined by skin prick tests with cat, birch, grass, and mite extracts, and doctor diagnosed asthma was ascertained by questionnaire at follow up. Maternal age at menarche was obtained from perinatal data. Logistic regression models were used to adjust for maternal age, parity, smoking, season of birth, parental allergy, and measures of adiposity and socioeconomic status.
RESULTS The prevalence of atopy at the age of 31 years was lower in children whose mothers reached menarche at a later age, especially after age 15. Compared with children whose mothers started menarche at the age of 16 or over, the adjusted odds ratios of being atopic for children whose mothers started menarche younger than or at 12, 13, 14 and 15 years were 1.43 (95% CI 1.12 to 1.83), 1.29 (95% CI 1.03 to 1.60), 1.15 (95% CI 0.93 to 1.42), and 1.19 (95% CI 0.95 to 1.48), respectively. Among girls, the offspring's own age at menarche was not significantly associated with atopy.
CONCLUSION Our results encourage further evaluation of the potential effect of maternal age at menarche on the later development of atopy and possible biological mechanisms.
- maternal age at menarche
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The prevalence of allergies is increasing in many countries, but most of the increase cannot be explained by factors so far known or identified.1 The potential influence of oestrogen on the occurrence of allergic disorders has been suggested.2 Age at menarche reflects endogenous oestrogen status.3 Early age at menarche has been shown to be associated with higher oestrogen levels among girls around the onset of puberty3 and also in adulthood.4 As a critical period in the later development of allergic disorders appears to be the prenatal and perinatal environment, we have examined the association between age at menarche of the mother and the occurrence of atopy among her offspring.
The study population was based on a geographically defined cohort of 12 058 live births in northern Finland in 19665 of whom 11 635 had survived up to 31 years of age in 1997. The 8463 subjects who were still living in northern Finland or had moved to the Helsinki area (in southern Finland) were invited to a clinical examination in 1997, and 6025 of these attended.6Sensitivity to the three most common allergens in Finland—cat, birch, and timothy grass—and also to house dust mite (Dermatophagoides pteronyssinus) was assessed by skin prick tests, together with histamine dihydrochloride (10 mg/ml) and diluent of the allergen extracts used as positive and negative controls. Skin reactions to the allergens were recorded after 15 minutes, taking the average of the maximum weal diameter and the diameter perpendicular to the maximum. Subjects with a weal reaction of 3 mm or greater to at least one of the four allergens tested were considered to be atopic. Twelve subjects with a positive reaction to the negative control were excluded. All subjects had a positive reaction to histamine. Information on doctor diagnosed asthma was obtained from a self-administered questionnaire that was completed by the subjects who attended for clinical examination. The final analyses were limited to 5188 subjects with information on atopy, asthma, and perinatal data and with signed consent to use their data for research.
The information on maternal age at menarche, weight, and height before pregnancy was collected from the mothers' first antenatal visit and size at birth was taken from hospital records.5 Current weight and height at 31 years were measured during the follow up clinical examinations. Ponderal index at birth was calculated using the standard formula of weight (100 g) divided by cube of length (cm3), and body mass index (BMI) as weight (kg) divided by the height squared (m2). The information on maternal age, paternal social class, maternal smoking during pregnancy, parity, and season of birth were obtained from perinatal data, and daughter's age at menarche, current physical activity, and vocational training at the age of 31 years from a postal questionnaire.
Logistic regression models were employed to estimate the effect of maternal age at menarche on risk of atopy at the age of 31 years. In multiple analyses those variables previously reported to be associated with atopy or asthma were adjusted. The adjusted variables were defined in the following ways: maternal age as ⩽20, 21–25, 26–30, 31–35, and ⩾36 years; paternal social classes I + II (professionals with the highest education and other white collar workers), III (skilled workers), IV (unskilled workers) and farmers; maternal smoking in pregnancy yes or no; parity 0, 1, 2–3, and ⩾4; seasons at birth March–May, June–August, September–November, and December–February; parental allergy yes if either parent had allergic disorders, otherwise no; current vocational training in five categories; maternal BMI before pregnancy, ponderal index at birth, and current BMI in quintiles.
The mean maternal age at menarche for the 5188 analysed subjects and for the other 3275 subjects who were invited for clinical examination but did not attend or who attended but were without complete data was 14.07 and 14.04, respectively (p = 0.34).
The prevalence of atopy at the age of 31 years for men and women was 33% and 28%, respectively. Atopy was less common in the children of mothers who had experienced menarche at a later age (table 1). After adjusting for potential confounders, the association was reduced for men but remained unchanged in women (table 1). In women the effect was seen mainly in mothers with menarche at the age of 16 or over, whereas in men a significant trend was observed in both univariate and adjusted analyses. We did not find any association between maternal age at menarche and asthma. The prevalence of doctor diagnosed asthma for maternal ages at menarche of ⩽12, 13, 14, 15, and ⩾16 was 7.9%, 7.4%, 7.6%, 6.3% and 7.7%, respectively (p = 0.89, Pearson χ2 test) among men and 11.0%, 8.2%, 6.5%, 9.3%, and 8.5%, respectively among women (p = 0.15).
Maternal age at menarche was correlated with that of the daughter (r = 0.19, p = 0.01). The mean age at menarche was 14.1 years for mothers and 12.9 years for daughters (p = 0.00). The prevalence of atopy was 29.8%, 27.5%, 27.4%, 26.4%, and 24%, respectively, for daughters with menarche at the age of ⩽12, 13, 14, 15, and ⩾16 years (p = 0.63, Pearson χ2 test; p = 0.14, test for trend). The corresponding prevalence of doctor diagnosed asthma was 8.6%, 9.0%, 7.3%, 8.2%, 12.2%, respectively (p = 0.67, Pearson χ2 test). After including daughter's age at menarche into the multivariate model, the association of maternal age at menarche with atopy remained unchanged.
The results of this study suggest that children are less likely to have atopic sensitisation at the age of 31 years if their mothers reached menarche at a later age. The observed association is not strong, but seems not to be explained by adjustment for potential confounders. To our knowledge, this is the first report of such an association. However, the biological mechanism underlying this finding is not clear. Age at menarche is mainly a marker of oestrogen status, and oestrogens have been shown to enhance histamine release in rats, probably via an IgE mediated mechanism.7 Clinical observations also indicate that a skin prick test is more sensitive to histamine in both atopic and non-atopic women on days 12–16 of the menstrual cycle, corresponding to ovulation and peak oestrogen levels.8 Female sex hormones can also affect immune function through their influence on T cell populations, the production of specific antibodies, and pro-inflammatory mediators.9It is possible that differences in the maternal oestrogen environment, represented by varying age at menarche, could programme the immune system of the fetus in a manner that could affect the atopic status later in life.
Age at menarche is one of the few established risk factors for breast cancer. Anthropometric, socioeconomic, lifestyle, and genetic factors are commonly documented as predictors for age at menarche.10 In the current analyses, maternal BMI before pregnancy, social class, and smoking during pregnancy were considered but none appeared to confound the observed association.
Age at menarche of the mother and the daughter were significantly correlated, even though the mean age at menarche of mothers was later than for their daughters (14.1 versus 12.9 years). Daughter's age at menarche was not significantly associated with her atopic status, but there was a suggestion of a similar trend as with maternal age at menarche. This result suggests that the intrauterine environment might be more important in later life in terms of development of adult atopy, at least for the mechanism underlying the association observed here.
Of the original birth cohort born in 1966 in northern Finland, only those still living in the same area or those who had moved to the Helsinki area were invited to participate in the study; 71% attended and complete data were available for 61%. However, only 45% of the original cohort was included in the present analyses. This introduces possibilities for selection bias if migration away from northern Finland or attendance for the clinical examination were associated with atopy and age at menarche. However, we consider that the possible effect of selection bias on the current analyses was only limited as we included the main area of migration (around Helsinki) and because there was no substantial difference in maternal age at menarche between those included in the analyses and other subjects (14.07 versus 14.04 years, p = 0.34).
In conclusion, atopy at the age of 31 years seems to be less common among those whose mothers experienced a late menarche. Our results need to be confirmed in other populations and with direct measurements of hormone status, but are encouraging for further research on the effect of sex hormones on the development of atopy.
The study was supported by the Finnish Academy, National Public Health Institute and University of Oulu.