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Title: An investigation into the combined tocolytic effect of magnesium and other tocolytics
Author: Osaghae, Blessing E.
ISNI:       0000 0004 8501 5913
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2019
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Preterm births are a leading cause of perinatal morbidity and mortality, and its occurrence has remained unchanged. To improve perinatal mortality, several tocolytics were developed; however, this has not been accompanied by an improvement in infant outcome (Keirse, 2003a). They delay labour long enough to administer corticosteroids. According to the NICE guidelines (NICE, 2016), women who are at risk of preterm birth before 30 weeks of pregnancy are to be administered magnesium sulphate (MgSO4) to help reduce the risk of cerebral palsy. So, although MgSO4 is not currently used for the treatment of preterm labour in the UK, it is being administered clinically in combination with a tocolytic which could either be indomethacin, nifedipine, or atosiban. This means that in certain preterm cases (< 30 weeks), a dual tocolytic therapy would be given The aims of this thesis were mainly to: (1) investigate the effect of magnesium sulphate at different gestations of pregnancy and how hormonal changes may affect its efficacy; (2) to investigate the dual tocolytic effect of magnesium sulphate (MgSO4) and other tocolytics (atosiban, indomethacin and nifedipine) (3) to determine the expression of L-type calcium channels especially the a1c subunit (Cav 1.2) across different gestational states of mouse, and in doing so, (4) establish a panel of stable housekeeping genes that could be used across gestational states of mouse myometrium. Magnesium sulphate concentration-dependently decreased spontaneous and oxytocin-induced contractions. In spontaneous contractions, MgSO4 showed a more potent effect at term and the least effect in non-pregnant tissues. In the presence of oxytocin however, there was no difference in the potency of MgSO4 across all gestations studied. Having established the effect of MgSO4 on my samples, I then investigated its combined effect with indomethacin, atosiban and nifedipine. In the presence of oxytocin, MgSO4 +atosiban produced a synergistic tocolytic effect on contractions, MgSO4 plus indomethacin produced an antagonistic effect while there was no significant difference in the effect of MgSO4 plus nifedipine compared to MgSO4. Although MgSO4 plus atosiban produced the greatest tocolytic effect compared to other combinations, I found that extracellular acidification reversed its effect, increasing force and frequency of contractions. Since magnesium acts at Ltype calcium channels, I investigated and quantified the expression of L-type calcium channel (Cav 1.2) and found that expression increased towards term with further increase postpartum. From this work I have shown that magnesium concentration-dependently reduces spontaneous contractions but its effect is reduced in the presence of oxytocin which may explain why magnesium is not effective clinically. The synergistic effect seen with MgSO4 plus atosiban suggests that oxytocin receptor antagonists may be the most efficient tocolytics in cases where magnesium is administered. The increase in Cav 1.2 expression towards term indicates its role in parturition.
Supervisor: Wray, Susan ; Wallace, Helen Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral