Enfoque Integrado de Políticas Públicas

It has been scientifically accepted that the gestational environment to which a fetus is exposed can have direct effects on later, post-natal life. The effects of teratogens on development, such as alcohol or thalidomide, and the lack of folic acid intake implicated in the formation of neural tube defects are part of the public consciousness due in large part to effective public health campaigns (Boyle and Cordero 2005). Barker (1992, 2006) has posited that there is a relationship between low birth weight and coronary heart disease, stroke, diabetes, and hypertension. The mechanism behind this is developmental plasticity during critical periods of development (Barker 2006). Essentially, maternal nutritional stress signals to the developing fetus that it is being born in a period of dearth and consequently, “the baby responds to these signals by adaptations, such as reduced body size and altered metabolism, which help it to survive a shortage of food after birth” (Barker 2006:272). These infants are at higher risk for cardiovascular diseases in adulthood when the environmental conditions of early childhood do not match those for which their phenotype is most well suited. For example, when an infant with an altered metabolism best suited to famine conditions grows up in conditions where calories are amply available. Barker (2006) believes that there are three main processes that are

responsible for the higher risk of disease. Lower birth weight babies have “less functional capacity in key organs” (2006:273), insulin resistance and less adaptive responses to stress, and a higher vulnerability to environmental conditions. Birth weight is a gradient, with no particular ‘low birth weight’ threshold known to exist.19

Not only can low birth weight lead to a higher susceptibility to degenerative diseases, but it can also increase the risk of dying from an infectious disease later in life. Studying Gambian infants born during periods of food shortages, Moore and colleagues found that low birth weight led to greater risk of death from infectious diseases in young adulthood (between the ages of 14.7 and 47, Moore et al. 1999), such that: “intrauterine growth retardation . . . slows cell division during sensitive periods in the ontogeny of the immune system. This would provide a mechanism by which early insults could be ‘hard-wired’ such that they had a permanent impact” (Moore et al. 1999: 1093). Additionally, maternal malnutrition can result in underdevelopment of the fetal thymus and lymphoid- system, increasing the risk of auto-immune diseases. However, because the flu was of such short duration in Canada (limited mainly to January 1890), and because the clinical attack rate was so high (60%, interquartile range 45% to 70%, Valleron et al. 2010), being in utero or alive on January 15th, 1890 will be used as a proxy for exposure. These results have not been reproduced in other regions (Lawlor 2004); however, similar conclusions were reached by McDade and colleagues (2001) studying thymic production of Filipino adolescents who were of low and normal gestational weight for age. Those who had low birth weight had reduced thymic function, the result of which is reduced immunocompetency in adulthood. Thus, individuals who experienced maternal stress while in utero were found to be at higher risk for diseases in later life, including those from acute airborne infectious diseases.

Pregnancy, especially further along in development, was a dangerous state for both a mother and a fetus during the 1918 influenza pandemic. In 1920, Winternitz et al. explained that “although in the non-complicated cases of influenza, pregnancy does not influence the course of the disease, if pneumonia supervenes, the mortality for the

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Rasmussen (2001) cautions against using birth weight as a proxy for developmental growth restrictions as not all factors resulting in developmental impairments may impact birth weight.

mother, as well as for the child, is definitely increased” and posited that “the hemorrhagic lesion of influenza seems a plausible explanation for the frequency of abortions” (1920:39). A study of English mothers in 1918 found that influenza infection in the first and second trimester could lead to premature birth, a risk to both the mother and the infant (Reid 2005). For those infants who survived gestation, maternal infection with influenza has been known to have deleterious effects on the later-life health of their infants. Brown and colleagues (2004) conducted a case-control study of a cohort born between 1959 and 1966 in California who were diagnosed with schizophrenia in later life. They found that “the risk of schizophrenia was increased 7-fold for influenza exposure during the first trimester. There was no increased risk of schizophrenia with influenza during the second or third trimester” (Brown et al. 2004:774). To explain the mechanism behind this association, they state that since influenza does not usually cross the placenta (although it is possible), there must be indirect mechanisms affecting the fetal brain. These mechanisms could be maternal antibodies or cytokines that can damage the developing brain tissue, hyperthermia, fetal hypoxia, or harmful remedies taken to combat the flu (Brown et al. 2004:778). Studies linking maternal influenza exposure and psychiatric and neural conditions in later life are numerous (for example, Mattock et al. 1988, Adams et al. 1993, Takei et al. 1994). There are also studies linking maternal influenza exposure to the occurrence of childhood neoplasia (Leck and Steward 1972) and to mental retardation (Takei et al. 1995).

Similarly, using census returns from 1960 to 1980, Almond (2006) studied cohorts born in the United States immediately after the pandemic (1919 and 1920), who were thus in utero during the worst of the epidemic. He found that “cohorts in utero during the pandemic displayed reduced educational attainment, increased rates of physical disability, lower income, lower socioeconomic status, and higher transfer payments compared with other birth cohorts” (2006:672). The mechanism that he believes may be responsible is the fetal origins hypothesis (this has been challenged by Bengtsson and Helgertz (2013) who argue that the socioeconomic gradient resulted from differential enlistment in the First World War). Similarly, using retrospective cohort studies in the United States, Mazumder and colleagues (2010) found an elevated risk of heart disease for cohorts exposed to the 1918 influenza pandemic in utero. Using a retrospective cohort

survey, Almond and Mazumder (2005) found more evidence of long-term physiological effects of in utero influenza exposure. They found that being in utero at the height of the pandemic had a negative effect on the self-reported health of adults over 50, as well as increased the risk of developing cancer, diabetes, heart disease, kidney problems, hypertension, and stomach problems. This was also explained using the fetal origins hypothesis. Additionally, Myrskylä et al. (2013) found that such exposure in the last trimester of pregnancy increased risks for cardiovascular disease, positing a mechanism whereby resources are diverted to the maternal immune response at the detriment of fetal maturation.

However, the findings concerning the long-term sequelae of influenza have been mixed. Cohen et al. (2010) analyzed aggregated data from 24 countries including Canada and found no consistent effect of neonatal or perinatal exposure to the 1918 influenza and later life mortality differentials, although the only birth related data available was at the yearly level. A more fine-tuned, country specific, analysis may show results more consistent with the literature.

In this dissertation, I posit that individuals who were in utero during the 1890 influenza pandemic may have experienced fetal growth restrictions that placed them at higher risk of contracting the 1918 Spanish flu. As influenza was not a reportable disease in Canada in either 1890 or 1918 (Zhang et al. 2010), it is not possible to directly assess whether certain individuals’ mothers had contracted influenza in 1890. However, because the flu was of such short duration in Canada (limited mainly to January 1890), and because the clinical attack rate was so high (60%, interquartile range 45% to 70%, Valleron et al. 2010), being in utero or alive on January 15th, 1890 will be used as a proxy for exposure. As date of birth is known from records linkage to birth records, and it will be assumed that all infants who survived until 1918 were full-term (Toronto, and likely the rest of Ontario, had a high neonatal death rate in 1918, Hallman 2009), the age (or gestational age) of exposure to the 1890 flu can be known with precision at the monthly level.