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Matemal smoking during pregnancy is a known risk factor for low birthweight, sudden infant death syndrome, and increased respiratory morbidity through infancy.

However, there are well-recognised difficulties in objectively documenting tobacco smoke exposure during early life, and even in deciding who should be classified as ‘a smoker’.

There are several biochemical methods for the assessment o f tobacco smoke exposure in the mother and her young infant such as, nicotine or cotinine assay of serum, salivary, urinary or hair samples. However, nicotine is lipid soluble and readily absorbed and has an elimination half-life o f 1-3 hours, hence monitoring of this chemical is not likely to reflect the extent o f smoking (Eliopoulos et al. 1994; Perez-Stable et al. 1998). Cotinine, which is the major metabolite o f nicotine, has a much longer elimination half-life than nicotine (20-24 hours) (Benowitz et al. 1983) and thus provides a better index o f tobacco exposure than nicotine (Haddow et al. 1987; McNeill et al. 1987). Assay o f serum, salivary and urinary cotinine provides an assessment o f tobacco exposure at time o f test. It has been suggested that assay o f hair concentration of cotinine may reflect long-term systemic exposure to these toxins but this requires confirmation (Feher et al. 1996).

Self-reports o f smoking status have been widely used as the only measure to assess detrimental effects of smoking on fetal growth and to orient counselling (Sexton and Hebei, 1984; Ahlsten et al. 1993; Lieberman et al. 1994; Horta et al. 1997; Cooke, 1998; Wisborg et al. 2000). This method o f assessment can be unreliable if the subject is under pressure because o f social or medical disapproval. While population surveys o f adults generally find a high level of agreement between self-report and cotinine levels, previous studies of pregnant women have reported misclassification rates as high as 38% and 14% among those who claim to be non-smokers and smokers respectively (Bardy et al. 1993; Boyd et al. 1998; Klebanoff et al. 2001). In this study, 4.5% (5/110) o f mothers who were self-reported non-smokers were re­ classified as smokers on the basis of cotinine results, while 9% (7/78) who were classified as smokers because they reported minimal smoking or had given up smoking later than eight weeks gestation had salivary cotinine < 2ng.m L'\ Previous studies (England et al. 2001; Owen and McNeill, 2001) have concurred with our observation that there was considerable overlap in the cotinine levels o f those who reported smoking between 5 - 2 0 cigarettes per day (Figure 4.7). These findings

highlight the difficulties in assessing the ‘dose’ o f passive smoke exposure received by the fetus.

5,3,6,1 Assessment o f tobacco smoke exposure in the fetus and young infant

In this study, as mothers and their infants were recruited after delivery, it was not possible to assess tobacco smoke exposure prospectively. Thus assessment o f in- utero exposure in the fetus was dependent on matemal recall which may be unreliable (Section 5.3.4). While, cotinine assay o f the infant’s first urine following birth may offer a more precise method o f assessing in-utero exposure this will only reflect exposure during the last few days prior to delivery (Etzel et al. 1985; Jordanov, 1990; Hoo et al. 1998). In this study, where infants were recmited postnatally, the first objective measure o f tobacco smoke exposure in young infants was from cotinine assay o f the infant’s urine at time o f test. As in previous studies (Greenberg et al. 1984; Hoo et al. 1998; Dezateux et al. 1999), we found that infant urinary cotinine levels were significantly higher in those whose mothers smoked compared to those infants not exposed to matemal smoking (Table 4.5). Among those infants exposed to matemal smoking, there was a wide distribution o f cotinine levels (range: 0 .0 1 -1 9 1 .7 ng.mL'^).

A number o f factors may be responsible for the variation observed in passive exposure, including proximity to the source and amount o f smoke and ventilation in the environment (Henschen et al. 1997). For young infants such as in this study group, the main source o f tobacco smoke exposure is often the mother as she is the chief carer for her infant at this young age. Thus matemal salivary cotinine levels could be used as a proxy o f passive tobacco smoke exposure in the infant. In older children ( 5 - 7 years old), cotinine levels were related to the number o f sources o f exposure or smokers within the household, though it has been suggested that matemal smoking remains the most important influence (Cook et al. 1994). In addition, observations fi"om earlier studies have shown that nicotine and cotinine are present in breast milk of mothers who smoked, and therefore contribute to urinary cotinine levels in breast-fed infants (Luck and Nau, 1985; Schulte-Hobein et al. 1992; Mascola et al. 1998). However, the amount o f cotinine and nicotine ingested via the mother’s milk is dependent on the individual smoking pattems o f the mother

(e.g. depth o f inhalation, number o f puffs per cigarette) (Armitage et al. 1975; Forbes et al. 1976) and on the time difference between the last cigarette smoked and breast feeding (Hamada et al. 1994).

It is unclear whether ingestion o f cotinine and other tobacco products through breast milk contributes to adverse health consequences o f environmental tobacco smoke exposure by inhalation. As cotinine is only a quantitative biomarker for smoking, the identity o f the compounds in tobacco smoke that are actually responsible for the adverse health impact on infants and young children and the degree to which their concentrations in breast milk are correlated are largely unknown.

5,3,6,2 Misclassification o f smoking status

Earlier studies have shown that misclassification o f smokers as non-smokers is a source o f bias in epidemiological studies estimating the risk associated with tobacco smoking (Riboli et al. 1995; Suadicani et al. 1997). While self-report o f smoking can be validated by an objective biochemical method as described earlier, and smokers re-classified on the basis of cotinine levels, the question remains as to how smokers with low levels of exposure should be categorised. In this study, in an attempt to identify those infants whose exposure to matemal smoking was significant during the period o f airway growth and development in-utero, a smoker was defined as one who continued to smoke beyond eight weeks gestation (Section 3.1.4.3). When infants o f light smokers, as assessed by salivary cotinine were included in the smoking exposed group, we found that the effect o f matemal smoking on peripheral airway fimction, specifically MEF2 5, was attenuated (Section 4.6.2).

5,4 Study population - how representative?

5.4.1 Exclusion criteria

Since prematurity, respiratory disease and ventilatory assistance during the neonatal period are all likely to have a negative impact on airway fimction, such infants were excluded fi*om this study. As this potentially excludes those infants with more severe fetal growth retardation bom by elective premature delivery or with severe

respiratory disease, the SGA population studied may be potentially biased towards those with less severe growth restriction.

In order to maintain a clear dichotomy between SGA and AGA infants, those infants with birthweight between 15^^ - 19^^ centile according to CGF algorithm were excluded.