C UADRO 5.1 M AGNITUDES DEL RÍO R UDRÓN Y SU CUENCA

The Hygiene Hypothesis was first proposed in 1989 to explain the inverse relation between large sibship size and prevalence of allergic rhinitis at age 11 and 23 years.5_{Children of large}

families had an increased risk of early respiratory infections6_{and sibship size could be}

therefore be seen as a marker of early life infections. Since then, inverse associations

between family size and atopic disease and skin prick positivity have been consistently found.7

A recent meta-analysis reported weighted average odds ratios for having three or more siblings of 0.66 for eczema, 0.72 for asthma or wheezing, and 0.44 for hay fever.8_{Family size}

and sibship structure has been examined to a greater extent by not only using sibling number and birth order, but also the number of older siblings, the number of younger siblings and interbirth interval to the next sibling. In asthma for example, having older siblings seems more important than having younger siblings, while in hay fever having both older and younger siblings seems important.9, 10_{It suggests that the apparent protective effect of large family size}

for asthma appears to operate during infancy, while for hay fever it seems to operate at the childhood as well as infant stage.9, 10_{Hay fever has been closely linked to ryegrass or pollen}

sensitisation, while asthma has been shown to be more strongly linked to house dust mite.11

The weaker associations with family size that are generally observed in asthma, might be related to the type of allergen that children are sensitised to, because family size was inversely related to asthma among children who had a sensitisation to rye grass but not to house dust mite, while this association was absent among children who had a sensitisation to house dust mite but not to rye grass.11

Although family size and sibship markers were thought of as surrogate markers for timing and frequency of infections after birth, Karmaus et al.12_{recently demonstrated that IgE levels of the}

umbilical cord also decreased with birth order, suggesting that birth order might also reflect foetal-maternal interactions during the prenatal period. Although it is conceivable that birth order, sibling number and the number of older siblings have their origin to some extent in utero, the number of younger children would be free of this effect and can only reflect events after the birth of the index case.

To prove that family size and sibship structure are surrogate markers of the timing and/or frequency of infections, cross-sectional and cohort studies have been conducted to directly link specific infections or the total burden of infectious illness in early life to allergic disease or birth order and family size. However, the results have been disappointing in that no substantial inverse relationships have emerged.7_{This may be because the wrong infections have been}

studied, or because the timing, rather than the nature, of the infection is particularly

important.7_{Alternatively, it might be that infections are not the influential exposure, but another}

developmental, lifestyle, or environmental influence that varies strongly with birth order and family size.7

In MS, migration studies have suggested that the timing of an environmental risk factor might be important. People migrating prior to age 15 years seem to obtain the risk of the host country, while people migrating after the age of 15 years retain the risk of the country of origin.13-15_{In fact, Leibowitz et al.}16_{proposed in 1966 (similarly to the Hygiene Hypothesis)} that:“In environments with a high sanitary level, infection may be postponed until an age when

the centralnervoussystem ismore susceptible to the processwhich provokesdemyelination”.

In line with this hypothesis it was observed that the frequency of MS was low in regions where childhood diseases were acquired early in life, while MS frequency was high in regions where childhood diseases tended to occur nearer adolescence.17_{Also, MS is less frequent among}

people belonging to low socioeconomic classes or living in countries where the general level of sanitation is low.18_{Animal studies on autoimmune diseases such as type 1 diabetes}

mellitus and collagen-induced arthritis showed that mice or rats develop disease earlier and at a higher rate among animals bred in a specific pathogen-free environment than among animals bred in a conventional environment.19, 20_{In addition, treatment with mycobacteria}

study on childhood diabetes showed that increased social mixing through attendance at daycare in early infancy appeared to confer protection.22

In contrast to the research on allergic disease and sibship structure, in MS the attention has been mainly focused on birth order, which reflects older sibling number, but not younger sibling number or total number of siblings. Younger sibling number, however, might also be important particularly when the putative protective infection is common in infancy and/or re- exposure to this infant infection is important. Re-exposure to active viral infection is known to cause immune boosting (as assessed by rising immunoglobulin (Ig) G titres) in seropositive individuals,23_{and repeated viral antigen challenge may lead to immune refinement.}24

If the hypothesis were true that having childhood infections later in life might increase the risk of MS, then one would expect that earlier born members (low birth order) have a higher risk compared to later born members (high birth order). Of the studies that compared the mean birth order of a sample of cases with the expected birth order that would have occurred by chance, most found no effect,25-28_{but some found, against the expectation, that the mean birth}

order was higher than expected.29, 30_{However, as outlined by James, this method is}

dependent on the assumption that family size is stable over time, which is not the case.31-33_A

case-control study would therefore be the preferred study design. Two case-control studies found no effect in birth order.34, 35_{Isager et al. and Visscher et al. found a reduction in risk for}

having a birth order higher than three, but the confidence interval was wide in the study from Visscher et al. (Isager et al.36_{:OR 0.29 {0.10―0.79};Visscheretal.}25_{:OR 0.52 {0.23―1.23}).}

A recent case-control study nested in a large cohort of nurses conducted a more detailed analysis of sibship structure. They found little effect for being first born or being an only child, a weak negative association with the number of older siblings, and there appeared to be an increased risk for first-born children in familieswith fourormore children (OR 2.1 {1.2―3.5}, which wasabsentin familieswith two orthree children (OR 0.8 {0.5―1.2}).37