Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial

Abstract

SummaryBackgroundProgesterone administration has been shown to reduce the risk of preterm birth and neonatal morbidity in women at high risk, but there is uncertainty about longer term effects on the child.MethodsWe did a double-blind, randomised, placebo-controlled trial of vaginal progesterone, 200 mg daily taken from 22–24 to 34 weeks of gestation, on pregnancy and infant outcomes in women at risk of preterm birth (because of previous spontaneous birth at ≤34 weeks and 0 days of gestation, or a cervical length ≤25 mm, or because of a positive fetal fibronectin test combined with other clinical risk factors for preterm birth [any one of a history in a previous pregnancy of preterm birth, second trimester loss, preterm premature fetal membrane rupture, or a history of a cervical procedure to treat abnormal smears]). The objective of the study was to determine whether vaginal progesterone prophylaxis given to reduce the risk of preterm birth affects neonatal and childhood outcomes. We defined three primary outcomes: fetal death or birth before 34 weeks and 0 days gestation (obstetric), a composite of death, brain injury, or bronchopulmonary dysplasia (neonatal), and a standardised cognitive score at 2 years of age (childhood), imputing values for deaths. Randomisation was done through a web portal, with participants, investigators, and others involved in giving the intervention, assessing outcomes, or analysing data masked to treatment allocation until the end of the study. Analysis was by intention to treat. This trial is registered at ISRCTN.com, number ISRCTN14568373.FindingsBetween Feb 2, 2009, and April 12, 2013, we randomly assigned 1228 women to the placebo group (n=610) and the progesterone group (n=618). In the placebo group, data from 597, 587, and 439 women or babies were available for analysis of obstetric, neonatal, and childhood outcomes, respectively; in the progesterone group the corresponding numbers were 600, 589, and 430. After correction for multiple outcomes, progesterone had no significant effect on the primary obstetric outcome (odds ratio adjusted for multiple comparisons [OR] 0·86, 95% CI 0·61–1·22) or neonatal outcome (OR 0·62, 0·38–1·03), nor on the childhood outcome (cognitive score, progesterone group vs placebo group, 97·3 [SD 17·9] vs 97·7 [17·5]; difference in means −0·48, 95% CI −2·77 to 1·81). Maternal or child serious adverse events were reported in 70 (11%) of 610 patients in the placebo group and 59 (10%) of 616 patients in the progesterone group (p=0·27).InterpretationVaginal progesterone was not associated with reduced risk of preterm birth or composite neonatal adverse outcomes, and had no long-term benefit or harm on outcomes in children at 2 years of age.FundingEfficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wa...

Ronda clínica y epidemiológica: club de revistas

“…Comentario: existe un interés actual en definir si el tratamiento con progesterona vaginal puede reducir el número de partos pretérmino en pacientes con alto riesgo de presentarlos (9)(10)(11). Lo anterior se deriva del efecto que tiene el parto pretérmino en la mortalidad neonatal y en menores de 5 años (12, 13), así como del alto costo que se deriva de la atención de estas madres y sus hijos (14).…”

Progesterone – a new look at an old drug

“…Кро-ме того, зафиксировано меньшее количество новорожден-ных с массой тела при рождении менее 2500 г по сравнению с группой, принимающей плацебо. Однако ввиду того, что в исследованиях принимали участие немногочисленные группы женщин, эти результаты должны быть подтверждены рандомизированными исследованиями [23].…”

Preterm Birth: An Inflammatory Syndrome, Not Just A Myometrial Disorder

“…In 2003, two RCTs reported that the use of daily vaginal progesterone administered between week 24 and 33 in high-risk pregnant women [26] or of daily 17α-hydroxyprogesterone caproate (slightly different pharmacological properties) administered between week 16 and 36 [27] decreased the rate of preterm deliveries. However, a recent multi-centre, placebo-controlled, double-blind RCT found no significant difference between vaginal progesterone prophylaxis and placebo in decreasing rates of PTB or improving outcomes at 2 years of age [28]. Because progesterone is safe and may be effective in some patients, many obstetricians use it as prophylaxis therapy to prevent PTB.…”

“…The mechanism of action suggested is downregulation of the expression of pro-inflammatory mediators such as iNOS and COX-2, and suppression of the produc-tion of eicosanoids such as prostaglandins. Although promise has been shown in murine models, clinical translation might not give the same results, as many human trials with progesterone have failed to curb PTB [28,61,62].…”