Maternal/fetal stress
Genomics
Stress can be difficult to quantify and disassociate from other risk factors such as smoking, poor nutrition, and low socioeconomic status. Stress in the fetus is thought to arise secondary to abnormal placentation, and may present with growth restriction.
This leads to maturation and activation of the fetal hypothalamic-pituitary-adrenal (HPA) axis. The events leading to fetal HPA activation are not fully understood, but it is thought that placental corticotrophin-releasing hormone (CRH) plays a central role. Conversely maternal stress increases biological effectors, including cortisol and adrenaline, which have been postulated to activate placental CRH gene expression. CRH is a neuropeptide of predominantly hypothalamic origin; it is also expressed in human placenta and membranes and released in increasing amounts over the course of pregnancy. The exponential rise of CRH has been associated with the length of gestation (27). These findings have led some researchers to suggest that placental CRH may act as a ‘placental clock' and regulate the length of gestation (27). Premature senescence of the placenta leading to an earlier trigger for birth or PPROM may be mediated by imbalances in reactive oxygen species causing damage mediated by p38 MAPK pathways (28).Genetics is estimated to play a role in approximately 30% of PTBs (31). In singletons, genetic susceptibility to PTB is based on the evidence of familial aggregation, identification of disease-susceptibility genes, and racial disparity in PTB rate that may be related to differences in risk-predisposing allele frequencies. PTB rates are higher in sisters of women with a history of PTB compared to their sisters-in- law (16% vs 9%). Mothers who were born preterm are more likely to deliver preterm by almost 20% (32). This suggests that PTB is inherited in a matrilineal manner across generations and is unaffected by patterns of PTB in the father's family (33). Several studies have confirmed a twofold increase in risk of sPTB for black American women compared to white American women, even after controlling for socioeconomic factors associated with PTB. The most commonly studied pathways for potential candidate genes are those involved in infection and inflammation. A recent pathway analysis of published studies of different polymorphisms in 274 genes suggested that there may be different gene pathways for women presenting with sPTB and PPROM. An autoimmune or hormonal regulation axis may exist for sPTB, while pathways implicated in the aetiology of PPROM include haematological/coagulation function disorder, collagen metabolism, matrix degradation, and local inflammation (34).