The Preeclampsia intervention with Esomeprazole (PIE) trial: A double blind, randomised, placebo-controlled trial to treat early onset severe preeclampsia

Cluver, Catherine Anne (2019-04)

Thesis (PhD)--Stellenbosch University, 2019.

Thesis

ENGLISH ABSTRACT: This body of work addresses the clinical dilemma posed by preterm preeclampsia. Firstly, we tested a potential therapeutic (esomeprazole) for the treatment of early preterm preeclampsia in a double-blind randomised controlled trial. The primary outcome of interest was prolongation of gestation, with secondary outcomes including maternal and perinatal outcomes. Importantly, this study was underpinned by extensive pharmacokinetic and biomarker studies on both plasma samples and placental tissue. We found that a daily dose of 40mg of esomeprazole did not prolong pregnancy in early preterm preeclampsia and there were no differences in maternal or neonatal outcomes or markers of endothelial dysfunction. The esomeprazole concentrations that were observed in our participants were within the lower range of concentrations used in our preclinical in vitro studies. We therefore concluded that 40 mg may not have been sufficient to have efficacy in treating preterm preeclampsia, and future studies should consider the role of a higher dose or intravenous administration, which has a higher exposure over time and peak concentration. Secondly, we assessed the impact of coexisting fetal growth restriction on pregnancy latency, obstetric, maternal and perinatal outcomes among women undergoing expectant management of early preterm preeclampsia. We found that the latency-to-delivery interval was significantly shorter among pregnancies with coexisting fetal growth restriction. These pregnancies were less likely to reach 34 weeks gestation and more likely to be delivered for suspected fetal compromise. More women with coexisting fetal growth restriction underwent an emergency caesarean section without a trial of labour induction and of those considered eligible for induction of labour, the rate of emergency caesarean section was higher among those with fetal growth restriction. Postnatally, the presence of coexisting fetal growth restriction was associated with a higher rate of postnatal death and necrotising enterocolitis. Interestingly, the rate of maternal complications did not differ between the groups. We concluded that coexisting fetal growth restriction, diagnosed at the same time as preeclampsia, is an important determinant of pregnancy outcome among women being managed expectantly for early preterm preeclampsia Thirdly, we sought to determine the role of expectant management of preeclampsia and the hypertensive disorders of pregnancy after 34 weeks gestation by assimilating the available data in a Cochrane systematic meta-analysis. Based on the limited data available, maternal outcomes appear better with planned early delivery for hypertensive disorders after 34 weeks’ gestation, but it is unclear whether this is associated with increased risks for the baby, especially at earlier gestations. It was not possible to determine whether planned early delivery was beneficial for different hypertensive conditions, particularly preeclampsia. We concluded that further studies are needed, preferably with reliable characterisation of hypertensive disease sub-types, to determine the ideal timing of delivery to optimise maternal and perinatal outcomes for hypertensive disorders of pregnancy occurring after 34 weeks gestation. This research provides new information about a candidate therapeutic for the treatment of preeclampsia. Clinical aspects of the hypertensive disorders of pregnancy that could further improve management are also discussed.

AFRIKAANSE OPSOMMING: Die inhoud van die werkstuk handel oor voortydse pre-eklampsie as ‘n kliniese probleem. Eerstens is ‘n potensiële terapeutiese middel (esomeprazol) vir die behandeling van voortydse pre-eklampsie getoets in ‘n dubble blinde ewekansige kliniese proef. Die primêre uitkoms van belang was verlenging van swangerskapsduurte, met moederlike en perinatale uitkomste as sekondêre uikomste. Daar was omvattende farmakokinetiese en biomerker studies op beide plasma en plasentale monsters gedoen gedoen. Ons vind dat ‘n daaglikse dosering van 40 mg esomeprazol nie swangskapsduurte met voortydse pre-eklampsie verleng het nie. Daar was ook geen verskille in moederlike en neonatale uitkomste en merkers van endoteel wanfunksie nie. Die esomeprazol konsentrasies soos waargeneem in deelnemers aan die studie was in die laer konsentrasie reikwydte van wat in die pre-kliniese in-vitro studies gebruik is. Ons gevolgtrekking is dus dat 40 mg nie voldoende was om pre-eklampsie te behandel nie. Toekomstige studies moet hoër of intraveneuse doserings oorweeg, met hoër blootstelling oor tyd en hoër piek konsentrasies. Tweedens het ons die impak ondersoek van meegaande fetale groei inkorting op swangerskaps latensie, verloskundige, moederlike en perinatale uitkomste van vroue met voortydse pre-eklampsie wat afwagtend hanteer is. Ons het gevind dat die latensie-tot-verlossing tydsverloop betekenisvol korter was in swangerskappe met meegaande fetale groei inkorting. Die swangerskappe het minder dikwels 34 weke swangerskapsduurte bereik en verlossing was meer algemeen vir vermoedelike fetal nood. Meer vroue met fetale groei inkorting het nood keisernsitte ondergaan sonder ‘n proef van induksie van kraam. Die met fetale groei inkorting wat kwalifiseer vir induksie van kraam het ook ‘n hoër noodkeisersnit insidensie gehad. Nageboorte was fetale groei inkorting geassosieër met ‘n hoër nageboorte sterftekoers en nekrotiserende enterokolitis. Moederlike komplikasies tussen die groepe het interessant genoeg nie verskil nie. Ons gevolgtrekking is dat meegaande fetale groei inkorting wat saam met die pre-eklampsie gediagnoeer word, ‘n belangrike bepaler van swangerskapsuitkoms is, indien vroue afwagtend hanteer word met voortydse pre-eklampsie. Derdens het ons die waarde van afwagtende hantering van pre-eklampsie en hipertensiewe toestande van swangerskap na 34 weke swangerskapsduurte ondersoek deur beskikbare data te versamel in ‘n Cochrane oorsig. Die beperkte inligting dui daarop dat met hipertensiewe toestande na 34 weke swangerskapsduurte beplande vroeë verlossing moederlike uitkomste verbeter. Daar is onsekerheid of die hantering geassosieër is met verhoogde risikos vir die baba veral met vroeër swangerskapsduurte. Dit is ook nie moontlik om ‘n betroubare aanbeveling te maak oor beplande vroeë verlossing met verskillende hipertensiewe toestande, veral pre-eklampsie nie. Ons het tot die gevolgtrekking gekom dat verdere studies nodig is, met by voorkeur, betroubare beskrywing van die hipertensiewe siekte sub-tipe. Die ideale tydstip van verlossing kan dan bepaal word vir optimale moederlike en perinatale uitkomste van hipertensiewe toestande wat na 34 weke swangerskapsduurte ontwikkel. Die studies moet moederlike uitkomste soos mortaliteit, erge morbiditeit soos eklampsie, ‘n serebrovaskulêre ongeluk, pulmonale edeem, erge renale inkorting, lewer hematoom of ruptuur, lewerversaking, HELLP sindroom, diffuse intravaskulêre stolling, trombo-emboliese siekte en abruptio plasentae insluit. Perinatale uitkomste wat ingesluit behoort te word is fetale en neonatale sterftes, graad III of IV intravertrikulêre bloeding of intraserebrale bloeding, nekrotiserende enterokolitis, respiratoriese nood sindroom of graad III of IV hialiene membraan siekte, klein-vir-datum en neonatale konvulsies. Uitkomste wat ook ingesluit behoort te word is keisersnit insidensie en duurte van hospitaal verblyf van beide moeder en baba. Die navorsing verskaf nuwe inligting oor ‘n kandidaat middel vir die behandeling van pre-eklampsie. Kliniese aspekte van hipertensiewe toestande van swangerkap wat hantering verder sal verbeter word ook bespreek.

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