Objectives Women with a sonographic short cervix in the mid-trimester are at increased risk for preterm delivery. This study was undertaken to determine the ef cacy and safety of using micronized vaginal progesterone gel to reduce the risk of preterm birth and associated neonatal complications in women with a sonographic short cervix. Methods This was a multicenter, randomized, double-blind, placebo-controlled trial that enrolled asymptomatic women with a singleton pregnancy and a sonographic short cervix (10–20 mm) at 19 + 0to23 + 6 weeks of gestation. Women were allocated randomly to receive vaginal progesterone gel or placebo daily starting from 20 to 23 + 6 weeks until 36 + 6 weeks, rupture of membranes or delivery, whichever occurred rst. Randomization sequence was strati ed by center and history of a previous preterm birth. The primary endpoint was preterm birth before 33 weeks of gestation. Analysis was by intention to treat. Results Of 465 women randomized, seven were lost to follow-up and 458 (vaginal progesterone gel, n = 235; placebo, n = 223) were included in the analysis. Women allocated to receive vaginal progesterone had a lower rate of preterm birth before 33 weeks than did those allocated to placebo (8.9% (n = 21) vs 16.1% (n = 36); relative risk (RR), 0.55; 95% CI, 0.33–0.92; P = 0.02). The effect remained signi cant after adjustment for covariables (adjusted RR, 0.52; 95% CI, 0.31–0.91; P = 0.02). Vaginal progesterone was also associated with a signi cant reduction in the rate of preterm birth before 28 weeks(5.1%vs10.3%; RR, 0.50;95%CI, 0.25–0.97; P = 0.04) and 35 weeks (14.5% vs 23.3%; RR, 0.62; 95% CI, 0.42–0.92; P = 0.02), respiratory distress syndrome (3.0% vs 7.6%; RR, 0.39; 95% CI, 0.17–0.92; P = 0.03), any neonatal morbidity or mortality event (7.7% vs 13.5%; RR, 0.57; 95% CI, 0.33–0.99; P = 0.04) and birth weight < 1500 g (6.4% (15/234) vs 13.6% (30/220); RR, 0.47; 95% CI, 0.26–0.85; P = 0.01). There were no differences in the incidence of treatment-related adverse events between the groups. Conclusions The administration of vaginal progesterone gel to women with a sonographic short cervix in the mid-trimester is associated with a 45% reduction in the rate of preterm birth before 33 weeks of gestation and with improved neonatal outcome.

BACKGROUNDTransthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR. METHODSAfter conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study. RESULTSPreclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram. CONCLUSIONSIn a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.

The first formal qualification of safety biomarkers for regulatory decision making marks a milestone in the application of biomarkers to drug development. Following submission of drug toxicity studies and analyses of biomarker performance to the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) by the Predictive Safety Testing Consortium's (PSTC) Nephrotoxicity Working Group, seven renal safety biomarkers have been qualified for limited use in nonclinical and clinical drug development to help guide safety assessments. This was a pilot process, and the experience gained will both facilitate better understanding of how the qualification process will probably evolve and clarify the minimal requirements necessary to evaluate the performance of biomarkers of organ injury within specific contexts.

The relationship between maternal cigarette smoking during pregnancy and obstetric complications is well established. Previous studies suggest a dose-response relationship with increasing risks for complications associated with increased number of cigarettes smoked and duration of smoking during pregnancy. Little data are available for the risks of adverse pregnancy outcomes among nonsmoking women following exposure to environmental tobacco smoke (ETS; secondhand smoke). A number of meta-analyses have found that ETS reduces mean birth weight and may increase the risk of low birth weight but does not seem to affect gestational age or the rate of preterm birth. There is little or no information on other adverse perinatal outcomes.This retrospective cohort study investigated the effects of ETS on perinatal outcomes in a population of nonsmoking women with singleton pregnancies. The participants were identified using the Newfoundland and Labrador Provincial Perinatal Database. Perinatal outcomes were compared between women with self-reported exposure to ETS (n ϭ 1202; 11.1%) and those with no exposure (n ϭ 10,560; 89.9%). Multiple logistic regression models were used to compare outcomes between the 2 groups, adjusting for maternal age, parity, partnered status, work status, level of education, body mass index, alcohol use, illicit drug use, and gestational age at delivery. The primary study outcome measures were birth weight, head circumference, birth length, and stillbirth. Secondary outcomes examined were prelabor rupture of membranes, gestational age at delivery (including preterm birth Ͻ37 weeks and Ͻ34 weeks of gestation), Apgar score, endotracheal intubation for resuscitation, neonatal intensive care unit admission, congenital anomalies, respiratory distress syndrome, intraventricular hemorrhage, necrotising enterocolitis, neonatal bacterial sepsis, jaundice, and neonatal metabolic abnormalities.Independent risk factors associated with exposure to ETS included lower mean birth weight (adjusted odds ratio [aOR], Ϫ53.7 g; 95% confidence interval [CI], Ϫ98.4 to Ϫ8.9 g), smaller head circumference (aOR,Ϫ0.24 cm; 95% CI, Ϫ0.39 to Ϫ0.08 cm), shorter birth length (aOR, Ϫ0.29 cm; 95% CI, Ϫ0.51 to Ϫ0.07 cm), stillbirth (aOR, 3.35; 95% CI, 1.16-9.72), trends toward preterm birth Ͻ34 weeks (aOR,1.87; 95% CI, 1.00-3.53), and neonatal sepsis (aOR, 2.96; 95% CI, 0.99-8.86); all P values were Յ0.05.These findings show an association between exposure of nonsmoking pregnant women to ETS with several adverse perinatal outcomes, including reduced birth weight, smaller head circumferences, stillbirth, and shorter birth length.