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Ambient air pollution exposure has been implicated in adverse birth outcomes including LBW, intrauterine growth retardation (IUGR), preeclampsia and PTB. These adverse birth outcomes have been significantly associated with increased infant morbidity; that ranges from neural to pulmonary conditions as well as infant mortality. They have also been shown to pre-dispose an individual to chronic diseases in adulthood [4].

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Low birthweight affects 20 million people worldwide [78], whilst PTB has been implicated in 75% of neonatal morbidities and 70% of neonatal deaths [38]. These adverse birth outcomes occur as a result of restricted foetal growth and/or reduced length of gestation; with neonates weighing <2500 g at birth and premature delivery of a foetus before 37weeks of gestation, respectively. Environmental factors have been associated with reduced BW and gestational age (GA) [79].

Many studies have been done to determine whether environmental tobacco smoke (ETS) elevates the risk for adverse birth outcomes, including LBW (reviewed elsewhere [32, 33]).

Among these Ahluwalia et al. found that ETS exposure increased the risk for adverse birth outcomes and was modified by maternal age [80]. However, exposure to ETS can potentially be avoided, unlike ambient air exposure.

The effects of AAP on foetal outcomes have become an important topic of study and are of great public health concern [51]. The first report of LBW babies were born to mothers living in highly polluted areas in Los Angeles (United States of America); in the early 1970s [81].

Following this initial report, publications sharply increased and extensive reviews were done which highlight all the current data about LBW [2, 4, 46, 57, 82] and PTB [4, 46, 83], and their association with AAP. Studies have shown both an association and no association between LBW, PTB and AAP; however, there is extensive evidence that supports the idea that exposure to AAP whilst pregnant, increases the risk for LBW and PTB (Table 1.1).

Table 1.1 Evidence of ambient air pollution and its association/non-association with low birthweight and pre-term birth

Author AAP type LBW- Association Trimester of Exposure Country (Year)

Wang et al. 1997 Total suspended particles (TSP), SO2, complex pollution mix

Increased risk of LBW 3^rd Trimester Beijing (1988-1991)

Ritz & Yu 1999 CO Significant increased risk for LBW 3^rd Trimester Los Angelas, CA (1989-1993) Bobak & Leon

1998

SO2, NO2, TSP LBW associated with SO2 and TSP Czech Republic (1986-1988) Bobak 2000 SO2, NO2, TSP LBW and PTB associated with SO2 and

TSP

1^st Trimester Czech Republic (1991)

Rogers et al. 2000 SO2, TSP VLBW associated with very high levels George Health Care

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3^rd Trimester North-eastern USA (1994-1998)

10µg/m³ increase in NO2 concentrations increased risk of PTB by 25%

1^st Trimester City of Kaunas (1998)

Liu et al. 2003 SO2, CO, Ozone, PM10, NO2

Increased SO2 associated with LBW PTB associated with SO2 and CO

Mishra et al. 2004 Biomass cooking fuels (wood,

3^rd Trimester Seoul, South Korea (2002-2003)

Nascimento &

Moreira 2009

SO2, ozone, PM10 SO2 and ozone associated with LBW – also risk factors for LBW

PM10 not associated with LBW

São Paulo State, Brazil (2001)

Ballester et al.

2010

NO2 Exposure to NO2 (>40µg/cm³) associated with reduced birth length, BW and head circumference

1^st Trimester Valencia, Spain (2003-2005)

Kloog et al. 2012 PM2.5 PM2.5 associated with increased risk of LBW and PTB Hao et al. 2016 NO2, CO, PM2.5 All pollutants investigated were

associated with PTB

1^st, 2^nd and 3^rd Trimester Georgia, USA (2002-2006)

17 1.3.2. Adverse birth outcomes and Oxidative stress

The aetiology of adverse birth outcomes due to AAP exposure is not fully understood.

However, factors that have been associated with AAP induced LBW and PTB pathology are OS, inflammation, endothelial dysfunction, reduced oxygen transport across the placenta and abnormalities of the placenta (Figure 1.5) [4].

Figure 1.5 Ambient air pollution’s potential mechanism for foetal toxicity leading to adverse birth outcomes. Inhaled AP enters the alveolus resulting in free radical production, which targets macromolecules present within the alveolus tissue. This results in OS and inflammation which is able to cross into the maternal blood stream and subsequently affect foetal growth through increased OS and inflammation within the placenta [98].

Pregnancy favours ROS production and presents with increased susceptibility to OS, due to the limited levels of foetal antioxidants [99], therefore several studies have investigated OS as a potential risk factor for LBW and PTB (Table 1.2). These studies demonstrate that increased OS markers as well as decreased antioxidant defence result in OS observed in LBW and PTB neonates.

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Table 1.2 Evidence for Oxidative stress as a mechanism for LBW and PTB

Although studies have reported AAP exposure and OS, individually increase the risk of adverse birth outcomes, and OS is implicated in AAP toxicity. Investigating the biological mechanisms through which OS induced by AAP affects neonatal birth outcomes, could allow for their targeted interventions and treatments. In addition, identifying other factors such as genetic predisposition and periods of infant vulnerability would allow for the better understanding of AAP induced toxicities and disease susceptibility.

Author Oxidative stress markers LBW- Association Country (Year)

Matsubasa et al.

2002

Urinary 8-OHdG levels Increased 8-OHdG levels associated with LBW and PTB

Kim et al. 2005 Maternal urinary 8-OHdG levels and MDA

Increased 8-OHdG and MDA levels associated with PTB and reduced BW in full-term neonates

Korea

Chadha et al. 2007 Maternal blood and urine NO metabolites levels

Increased levels of NO metabolites associated with PTB

India

Saker et al. 2008 Total antioxidant activity (ORAC), vitamin A, C and E, carbonyl proteins, hydro-peroxides, erythrocyte CAT, GPx, glutathione reductase, SOD, lipid and lipoprotein

Decreased ORAC, vitamin C and E values, high plasma hydro-peroxide and carbonyl protein, decreased SOD and CAT – OS associated with LBW

Mothers and babies exposed to OS associated with LBW

Placental LP may be associated with LBW pathophysiology

Croatia

Rossner et al.

2011

Placental- 8-OHdG levels Increased 8-OHdG associated with LBW Czech Republic (1994-1998) Negi et al. 2012 Cord blood – MDA, carbonyl proteins,

total antioxidant capacity, vitamin A, E and C

Increased LP and protein oxidation with decreased vitamin A, E, C and antioxidant capacity (OS) associated with preterm-LBW

India

Kumarathasan et al. 2016

Plasma 8-isoprostane (OS marker) The 8-isoprostane was negatively associated with BW and GA

Canada

19 1.4. Oxidative Stress

Interest in prenatal exposure to AAP and its subsequent effects on adverse birth outcomes is growing rapidly. As the pollutants discussed previously, act either as free radicals or have the potential to generate free radicals, and pregnancy favours ROS production due to its highly oxygen-rich and energy requiring state, OS has therefore been suggested as a mediator of AAP toxicity leading to adverse birth outcomes.

Oxidative stress, within the human body, is the biochemical imbalance of oxidants and antioxidants that refers to a disturbance in the excessive production of oxidants over antioxidants [105]. Human redox biochemistry is predominantly made up of oxygen, as cells and cellular mechanisms require a reducing environment to function. Therefore, human cells are under constant threat by highly ROS as a natural consequence of aerobic respiration [106]. In analogy to OS, RNS function and are able to react with ROS to potentiate OS-damage [107].

Oxidative stress has been implicated in pathological conditions such as Parkinson’s disease, Rheumatoid arthritis and adverse birth outcomes [105, 108].