Tafoxiparin, a novel drug candidate for cervical ripening and labor augmentation: results from 2 randomized, placebo-controlled studies.

BACKGROUND: Slow progression of labor is a common obstetrical problem with multiple associated complications. Tafoxiparin is a depolymerized form of heparin with a molecular structure that eliminates the anticoagulant effects of heparin. We report on 2 phase II clinical studies of tafoxiparin in primiparas. Study 1 was an exploratory, first-in-pregnant-women study and study 2 was a dose-finding study. OBJECTIVE: Study 1 was performed to explore the effects on labor time of subcutaneous administration of tafoxiparin before onset of labor. Study 2 was performed to test the hypothesis that intravenous treatment with tafoxiparin reduces the risk for prolonged labor after spontaneous labor onset in situations requiring oxytocin stimulation because of dystocia. STUDY DESIGN: Both studies were randomized, double-blind, and placebo-controlled. Participants were healthy, nulliparous females aged 18 to 45 years with a normal singleton pregnancy and gestational age confirmed by ultrasound. The primary endpoints were time from onset of established labor (cervical dilation of 4 cm) until delivery (study 1) and time from start of study treatment infusion until delivery (study 2). In study 1, patients at 38 to 40 weeks of gestation received 60 mg tafoxiparin or placebo daily as 0.4 mL subcutaneous injections until labor onset (maximum 28 days). In study 2, patients experiencing slow progression of labor, a prolonged latent phase, or labor arrest received a placebo or 1 of 3 short-term tafoxiparin regimens (initial bolus 7, 21, or 35 mg followed by continuous infusion at 5, 15, or 25 mg/hour until delivery; maximum duration, 36 hours) in conjunction with oxytocin. RESULTS: The number of participants randomized in study 1 was 263, and 361 were randomized in study 2. There were no statistically significant differences in the primary endpoints between those receiving tafoxiparin and those receiving the placebo in both studies. However, in study 1, the risk for having a labor time exceeding 12 hours was significantly reduced by tafoxiparin (tafoxiparin 6/114 [5%] vs placebo 18/101 [18%]; P=.0045). Post hoc analyses showed that women who underwent labor induction had a median (range) labor time of 4.44 (1.2-8.5) hours with tafoxiparin and 7.03 (1.5-14.3) hours with the placebo (P=.0041) and that co-administration of tafoxiparin potentiates the effect of oxytocin and facilitates a shorter labor time among women with a labor time exceeding 6 to 8 hours (P=.016). Among women induced into labor, tafoxiparin had a positive effect on cervical ripening in 11 of 13 cases (85%) compared with 3 of 13 participants (23%) who received the placebo (P=.004). For women requiring oxytocin because of slow progression of labor, the corresponding results were 34 of 51 participants (66%) vs 16 of 40 participants (40%) (P=.004). In study 2, tafoxiparin had no positive effects on the secondary endpoints when compared with the placebo. Except for injection-site reactions in study 1, adverse events were no more common for tafoxiparin than for the placebo among either mothers or infants. There were few serious or treatment-related adverse events. CONCLUSION: Subcutaneous treatment with tafoxiparin before labor onset (study 1) may be effective in reducing the labor time among women undergoing labor induction and among those requiring oxytocin for slow progression of labor. Moreover, tafoxiparin may have a positive effect on cervical ripening. Short-term, intravenous treatment with tafoxiparin as an adjunct to oxytocin in patients with labor arrest (study 2) did not affect labor time or other endpoints. Both studies suggest that tafoxiparin has a favorable safety profile in mothers and their infants.

The ADENO study: ADenomyosis and its Effect on Neonatal and Obstetric outcomes: a retrospective population-based study.

BACKGROUND: Adenomyosis is a benign gynecologic condition arising from the uterine junctional zone. Recent studies suggest a relationship between adenomyosis and adverse obstetrical outcomes, but evidence remains conflicting. There is no large-scale study investigating obstetrical outcomes in women with adenomyosis using the gold standard of histopathologic diagnosis. OBJECTIVE: This study aimed to investigate the prevalence of adverse obstetrical and neonatal outcomes in women with histopathologic adenomyosis and that of the general (Dutch) population. STUDY DESIGN: This retrospective population-based study used 2 Dutch national databases (Perined, the perinatal registry, and the nationwide pathology databank [Pathologisch Anatomisch Landelijk Geautomiseerd Archief], from 1995 to 2018) to compare obstetrical outcomes in women before histopathologic adenomyosis diagnosis to the general Dutch population without registered histopathologic adenomyosis. The adjusted odds ratios (95% confidence interval) were calculated for adverse obstetrical outcomes. The outcomes were adjusted for maternal age, parity, ethnicity, year of registered birth, induction of labor, hypertensive disorders in previous pregnancies, multiple gestation, and low socioeconomic status. RESULTS: The pregnancy outcomes of 7925 women with histopathologic adenomyosis were compared with that of 4,615,803 women without registered adenomyosis. When adjusted for confounders, women with adenomyosis had adjusted odds ratios of 1.37 (95% confidence interval, 1.25-1.50) for hypertensive disorders, 1.37 (95% confidence interval, 1.25-1.51) for preeclampsia, 1.15 (95% confidence interval, 1.07-1.25) for small-for-gestational-age infants, 1.54 (95% confidence interval, 1.41-1.68) for emergency cesarean delivery, 1.24 (95% confidence interval, 1.12-1.37) for failure to progress, 1.29 (95% confidence interval, 1.10-1.48) for placental retention, and 1.23 (95% confidence interval, 1.10-1.38) for postpartum hemorrhage. No increased risk of HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, placental abruption, or operative vaginal delivery or need for oxytocin stimulation was found. CONCLUSION: Women with a histopathologic diagnosis of adenomyosis showed an increased prevalence of hypertensive disorders of pregnancy and small-for-gestational-age infants, failure to progress in labor, and placental retention compared with the general population in previous pregnancies. This suggests that uterine (contractile) function in labor and during pregnancy is impaired in women with adenomyosis.

When does fetal head rotation occur in spontaneous labor at term: results of an ultrasound-based longitudinal study in nulliparous women.

BACKGROUND: Improved information about the evolution of fetal head rotation during labor is required. Ultrasound methods have the potential to provide reliable new knowledge about fetal head position. OBJECTIVE: The aim of the study was to describe fetal head rotation in women in spontaneous labor at term using ultrasound longitudinally throughout the active phase. STUDY DESIGN: This was a single center, prospective cohort study at Landspitali - The National University Hospital of Iceland, Reykjavík, Iceland, from January 2016 to April 2018. Nulliparous women with a single fetus in cephalic presentation and spontaneous labor onset at ≥37 weeks' gestation were eligible. Inclusion occurred when the active phase could be clinically established by labor ward staff. Cervical dilatation was clinically examined. Fetal head position and subsequent rotation were determined using both transabdominal and transperineal ultrasound. Occiput positions were marked on a clockface graph with 24 half-hour divisions and categorized into occiput anterior (≥10- and ≤2-o'clock positions), left occiput transverse (>2- and <4-o'clock positions), occiput posterior (≥4- and ≤8 o'clock positions), and right occiput transverse positions (>8- and <10-o'clock positions). Head descent was measured with ultrasound as head-perineum distance and angle of progression. Clinical vaginal and ultrasound examinations were performed by separate examiners not revealing the results to each other. RESULTS: We followed the fetal head rotation relative to the initial position in the pelvis in 99 women, of whom 75 delivered spontaneously, 16 with instrumental assistance, and 8 needed cesarean delivery. At inclusion, the cervix was dilated 4 cm in 26 women, 5 cm in 30 women, and ≥6 cm in 43 women. Furthermore, 4 women were examined once, 93 women twice, 60 women 3 times, 47 women 4 times, 20 women 5 times, 15 women 6 times, and 3 women 8 times. Occiput posterior was the most frequent position at the first examination (52 of 99), but of those classified as posterior, most were at 4- or 8-o'clock position. Occiput posterior positions persisted in >50% of cases throughout the first stage of labor but were anterior in 53 of 80 women (66%) examined by and after full dilatation. The occiput position was anterior in 75% of cases at a head-perineum distance of ≤30 mm and in 73% of cases at an angle of progression of ≥125° (corresponding to a clinical station of +1). All initial occiput anterior (19), 77% of occiput posterior (40 of 52), and 93% of occiput transverse positions (26 of 28) were thereafter delivered in an occiput anterior position. In 6 cases, the fetal head had rotated over the 6-o'clock position from an occiput posterior or transverse position, resulting in a rotation of >180°. In addition, 6 of the 8 women ending with cesarean delivery had the fetus in occiput posterior position throughout the active phase of labor. CONCLUSION: We investigated the rotation of the fetal head in the active phase of labor in nulliparous women in spontaneous labor at term, using ultrasound to provide accurate and objective results. The occiput posterior position was the most common fetal position throughout the active phase of the first stage of labor. Occiput anterior only became the most frequent position at full dilatation and after the head had descended below the midpelvic plane.