Multiple pregnancies, the myometrium and the role of mechanical factors in the timing of labour

Abstract

Multiple pregnancy remains a relatively common occurrence, but it is associated with increased risks of adverse outcomes for the mother and her babies and presents unique challenges to healthcare providers. This review will briefly discuss multiple pregnancies, their aetiology and their problems, including preterm birth, before reviewing the processes leading to normal labour onset and how they may be different in a multiple pregnancy. The mechanisms by which mechanical factors i.e., uterine distension or 'stretch' contribute to uterine excitability and the timing of labour onset will be the major focus, and how over distention may pre-dispose multiple pregnancies to preterm birth. This includes current thinking around the role of mechano (stretch) sensitive ion channels in the myometrium and changes to other important regulators of excitability and contraction which have been identified from studies using in vitro and in vivo models of uterine stretch. Physiological stimuli arising from the fetus(es) and placenta(s) will also be discussed. In reviewing what we know about the myometrium in multiple pregnancy in humans, the focus will be on twin pregnancy as it is the most common type of multiple pregnancy and has been the most studied.

Keywords: Mechanosensitive channels; Myometrium; Preterm birth; Stretch; Twin pregnancy; Uterus.

Fig. 1

Proposed mechanisms leading to increased myometrial excitability and preterm birth in multiple pregnancies Greater placental mass and fetal number lead to increased placental corticotrophin releasing hormone (CRH), fetal cortisol and fetal lung maturation which in turn reduces progesterone and increases estrogen, surfactant protein A and platelet activating factors promoting myometrial and fetal membrane (not shown) activation. Increased myometrial stretch promotes inflammatory signalling, focal adhesion signalling and pro-contractile gene expression as well as changes to expression of ion channels such as Ca-activated, voltage-sensitive K⁺ channels (BK_Ca) and L-type calcium channels (LTCCs) which affect intracellular calcium concentration and promote contraction. Increased expression of mechanosensitive channels acts to suppresses myometrial excitability by membrane hyperpolarisation. Dysregulation in their expression or activity could contribute to premature myometrial activation.

Fig. 2

Mechanosensitive channels in human myometrium: Their mechanism of action and changes in expression with stretch and pregnancy Human myometrium expresses the mechanosensitive canonical (TRPC3) and vanilloid (TRPV4) members of the Transient receptor potential (TRP) channel family, Piezo-1, and stretch-sensitive K⁺ channels (TREK-1 and TRAAK) of the two pore K⁺ (K2P) channel family. Stretch-mediated activation of TRPC3 results in Ca (or Na) entry and depolarisation. Activation may also require agonist-mediated generation of diacylglycerol (DAG). In human myometrium, Ca entry arising from activation of TRPV4 and Piezo1 results in BK_Ca channel activation, K⁺ efflux and hyperpolarisation. TREK-1 and TRAAK channels mediate K⁺ efflux which helps maintain the resting potential of the myometrium and contributes to myometrial quiescence during pregnancy. Table summarises the functional effect of channel activation and the reported changes in channel expression with stretch and gestation to date. Unless otherwise stated, data refers to human myometrium.