Vaginal compared with intramuscular progestogen for preventing preterm birth in high-risk pregnant women (VICTORIA study): a multicentre, open-label randomised trial and meta-analysis.

OBJECTIVE: To compare the efficacy of two types of progestogen therapy for preventing preterm birth (PTB) and to review the relevant literature. DESIGN: A multicentre, randomised, open-label, equivalence trial and a meta-analysis. SETTING: Tertiary referral hospitals in South Korea. POPULATION: Pregnant women with a history of spontaneous PTB or short cervical length (<25 mm). METHODS: Eligible women were screened and randomised at 16-22 weeks of gestation to receive either 200 mg of vaginal micronised progesterone daily (vaginal group) or an intramuscular injection of 250 mg 17α-hydroxyprogesterone caproate weekly (IM group). Stratified randomisation was carried out according to participating centres and indications for progestogen therapy. This trial was registered at ClinicalTrials.gov (NCT02304237). MAIN OUTCOME MEASURE: Preterm birth (PTB) before 37 weeks of gestation. RESULTS: A total of 266 women were randomly assigned and a total of 247 women (119 and 128 women in the vaginal and IM groups, respectively) were available for the intention-to-treat analysis. Risks of PTB before 37 weeks of gestation did not significantly differ between the two groups (22.7 versus 25.8%, P = 0.571). The difference in PTB risk between the two groups was 3.1% (95% CI -7.6 to 13.8%), which was within the equivalence margin of 15%. The meta-analysis results showed no significant differences in the risk of PTB between the vaginal and IM progestogen treatments. CONCLUSION: Compared with vaginal progesterone, treatment with intramuscular progestin might increase the risk of PTB before 37 weeks of gestation by as much as 13.8%, or reduce the risk by as much as 7.6%, in women with a history of spontaneous PTB or with short cervical length. TWEETABLE ABSTRACT: Vaginal and intramuscular progestogen showed equivalent efficacy for preventing preterm birth before 37 weeks of gestation.

Increased NFAT5 expression stimulates transcription of Hsp70 in preeclamptic placentas.

OBJECTIVE: We investigated the expression of heat shock protein 70 (Hsp70), nuclear factor of activated T cells 5 (NFAT5), and hypoxia-induced factor-1α (HIF-1α) in the placentas of normal and preeclamptic pregnancies and in human placental hypoxia models in vitro to examine the regulatory mechanisms of placental Hsp70 expression. METHODS: The expression levels of HIF-1α, NFAT5, and Hsp70 were examined in placental samples from 10 females with preeclampsia and 10 normotensive control patients and in human choriocarcinoma trophoblast cells treated with 1 mM CoCl2 by western blotting. Using models of placental hypoxia, pharmacological inhibition of HIF-1α with chetomin and shRNA knockdown and overexpression of NFAT5 were performed to investigate the roles of HIF-1α and NFAT5 in induction of Hsp70 by placental hypoxia. RESULTS: The levels of HIF-1α, NFAT5, and Hsp70 expression were significantly higher in the preeclamptic compared to normal placentas. In the placental hypoxia models, the expression of HIF-1α, NFAT5, and Hsp70 were significantly higher after 3, 6, and 12 h of 1 mM CoCl2 treatment, respectively. Pharmacological inhibition of HIF-1α suppressed the induction of NFAT5 and Hsp70 at the protein level. shRNA knockdown of NFAT5 suppressed the induction of Hsp70 protein and overexpression of NFAT5 stimulated the induction of Hsp70 mRNA and protein in models of human placental hypoxia in vitro. CONCLUSION: HIF-1α positively regulates the induction of NFAT5 and Hsp70 by placental hypoxia and NFAT5 stimulates transcription of Hsp70 in response to placental hypoxia in models of human placental hypoxia in vitro.