Probable causes of preterm labour
The role of genetics in the pathogenesis of preterm labour has been duly recognised and well documented. Emerging evidence indicates that preterm birth appears to be transmitted primarily in a matrilineal manner across generations and is greatly influenced by mutual environmental factors. Thus, the risk of a woman having a preterm delivery is heightened if her maternal biological relations had preterm deliveries but appears not to follow paternal lines(20,21). In human genomic studies, changes in single gene sequence were found to be associated with disorders such as polyhydraminos, myotonic dystrophy, cervical incompetence(10,21,22) and twin gestation which increase the risk of preterm labour and may be transmitted from one generation to the next(23,24). These observed single nucleotide polymorphisms in the gene can respond to inflammatory stimuli such as infection resulting in the production of pro-inflammatory mediators and breakdown of extracellular matrix by matrix metalloproteinases leading to preterm labour (figure 1) (23). Also because of the genotypic variations among different individuals, exposure to environmental pollutants put them at increased risk of preterm labour(10,22).
Evidence has shown that maternal psychological stress, anxiety, financial difficulties and other life events increase endogenous catecholamines and cortisol release which stimulate premature production of placental corticotrophin-releasing hormone (CRH) thereby activating the biological cascade leading to the onset of preterm labour(24). Psychological stress also increases maternal vulnerability to infection and inflammation due to weakened immune system (figure 1) (24). Behavioural factors such as smoking and alcohol use are associated with increased risk of preterm labour. Given that smoking and alcohol have teratogenic effects and habitual engagement in these agents during pregnancy puts them at high risk of sudden infant death syndrome (SIDS) due to variability in autonomic nervous system function(25–27). The Nicotine and carbon monoxide contained in smoke cause foetal hypoxia due to carboxyhaemoglobin and vasoconstriction(27). They increase the risk of low birth weight, foetal defects and placental complications and compromise immune response to inflammation leading to preterm premature rupture of membranes and preterm labour (figure 1) (24,25,27). Consumption of alcohol during pregnancy has also proven to have detrimental effect on foetal growth and development leading to intrauterine growth restriction (IUGR) which poses a potential risk for preterm labour (figure 1) (24,28).
Furthermore, pervasive indulgence in illegal drugs such as marijuana and cocaine as well as the use of herbal medications in pregnancy have severe embryotoxic and teratogenic effects increasing the risk of small-for gestational age and foetal defects(29,30). Marijuana smoking also increases the risk of carboxyhaemoglobin leading to foetal hypoxia. On the other hand, cocaine causes elevated blood pressure due to vasoconstriction since these psychoactive agents appear to interfere with the reuptake of serotonin and catecholamines leading to compromised immune response to inflammation (figure 1) (24,29).
Nutritional deficiencies (e.g. deficiencies in iron, folate or zinc, low pre-pregnancy weight) have been implicated in preterm labour. For instance, deficiency in iron causes iron deficiency anaemia which increases the synthesis and hypersensitivity to endogenous catecholamines leading to maternal and foetal hypoxia which in-turn stimulates synthesis of foetal CRH and cortisol. The increased cortisol production may activate the biological cascade leading to preterm premature rupture of membranes, gestational hypertension, eclampsia IUGR and preterm labour (24,31,32). In another pathway, iron deficiency anaemia increases risk of infection and inflammation leading to preterm birth (figure 1) (31,32). Physiologically, vitamin C stimulates the synthesis of collagen fibres of connective tissue extracellular matrix of the amnionchorion and deficiency in vitamin C depletes collagens leading to preterm premature rupture of membranes and preterm labour(figure 1) (24,33,34). Similarly, folate, zinc and pre-pregnancy weight deficiencies increase the risk of restricted foetal growth and birth defects(figure 1) (24,35). To buttress the importance of specific nutrients, adequate maternal levels of fat-soluble nutrients provide antioxidative, anti-inflammatory, and immunomodulatory health benefits which are vital in preterm birth prevention. For instance, omega-3 fatty acids facilitate increased production of specialized anti-inflammatory mediators with resultant reduction in preterm birth risk (figure 1). Combined effects of these nutrients support appropriate placental organogenesis and function(36).