Intrauterine devices, the endometrium and the risk of pre‐eclampsia

Recently, Parker et al. in this issue reported a retrospective case–controlled study indicating that previous use of an intrauterine device is associated with a small, but significant, decrease in the risk of developing pre-eclampsia. Furthermore, this effect was time-dependent, being greatest when the device was removed within 12 months of the pregnancy. What biological mechanisms might underlie these findings? The pathophysiology of preeclampsia remains poorly understood, although defective placentation is often invoked as the principal cause. At least two sub-types of the syndrome can be recognised, early onset and late onset (Tranquilli et al. Pregnancy Hypertension 2013;3:44–7). The early-onset form (<34 weeks) is associated with failure of remodelling of the maternal spiral arteries, severe placental pathology, and high circulating levels of proinflammatory cytokines and anti-angiogenic factors (Yung et al. J Pathol 2014;234:262– 76). Fetal growth restriction is common. By contrast, placental changes are subtle in late-onset pre-eclampsia (>34 weeks), circulating factors are only mildly raised, and birthweight is often increased. Consequently, although the early-onset form can be attributed to poor placentation, the late-onset form may reflect maternal predisposition to endovascular dysfunction. Maternal spiral artery remodelling is key during early pregnancy, ensuring that blood flows into the placenta at an appropriately low velocity and pressure. The process is associated with migration of extravillous trophoblast cells from the placenta into the endometrium. Interactions between paternallyexpressed HLA-C antigens on the trophoblast cells and killer-like immunoglobulin receptors on uterine natural killer cells are known to influence birthweight and the risk of pre-eclampsia (Moffett et al. Philos Trans Roy Soc Lond B Biol Sci 2015;370:20140071). The mechanism is not fully understood but may involve release of proteases from the trophoblast or activated immune cells that assist in arterial remodelling. Maternal immune cells in the placental bed may also influence arterial remodelling through their effects on trophoblast invasion. Cytokines such as interleukin-6 promote invasion, whereas others, including tumour necrosis factor, are inhibitory. Intrauterine devices may act by causing an inflammatory response within the endometrium that either prevents fertilisation or leads to early death of the conceptus. Notably, increased concentrations of interleukin-6 have been reported in the uterine fluid of postmenopausal women using an intrauterine device delivering progesterone (Archer et al. Contraception 1999;59:175–9). The situation will be complex in the placental bed, being dependent on local concentrations and the degree of activation of immune cells. Perhaps prior use of an intrauterine device renders the endometrium more permissive to trophoblast invasion in the short-term, leading to a reduced risk of pre-eclampsia through enhanced spiral artery remodelling. Alternatively, prior use of an intrauterine device might be associated with longer exposure to sperm antigens that could affect the efficacy of the trophoblast-immune cell interactions. Either way, the acid test would be to determine whether the effects reported by Parker et al. apply to both forms of the syndrome, as on the basis outlined above one would predict only the risk of early-onset pre-eclampsia to be decreased. As so often, more studies are required.