17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial.

BACKGROUND: Women with a history of spontaneous preterm birth (SPTB) are at a significantly increased risk for recurrent preterm birth (PTB). To date, only one large U.S. clinical trial comparing 17-OHPC (17-α-hydroxyprogesterone caproate or "17P") to placebo has been published, and this trial was stopped early due to a large treatment benefit. OBJECTIVE: This study aimed to assess whether 17-OHPC decreases recurrent PTB and neonatal morbidity in women with a prior SPTB in a singleton gestation. STUDY DESIGN: This was a double-blind, placebo-controlled international trial involving women with a previous singleton SPTB (clinicaltrials.gov: NCT01004029). Women were enrolled at 93 clinical centers (41 in the United States and 52 outside the United States) between 160/7 to 206/7 weeks in a 2:1 ratio, to receive either weekly intramuscular (IM) injections of 250 mg of 17-OHPC or an inert oil placebo; treatment was continued until delivery or 36 weeks. Co-primary outcomes were PTB < 35 weeks and a neonatal morbidity composite index. The composite included any of the following: neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, or proven sepsis. A planned sample size of 1,707 patients was estimated to provide 98% power to detect a 30% reduction in PTB < 35 weeks (30% to 21%) and 90% power to detect a 35% reduction in neonatal composite index (17%-11%) using a two-sided type-I error of 5%. Finally, this sample size would also provide 82.8% power to rule out a doubling in the risk of fetal/early infant death assuming a 4% fetal/early infant death rate. Analysis was performed according to the intention-to-treat principle. RESULTS: Baseline characteristics between the 1,130 women who received 17-OHPC and 578 women who received placebo were similar. Overall, 87% of enrolled women were Caucasian, 12% had >1 prior SPTB, 7% smoked cigarettes, and 89% were married/lived with partner. Prior to receiving study drug, 73% women had a transvaginal cervical length measurement performed and <2% had cervical shortening <25 mm. There were no significant differences in the frequency of PTB < 35 weeks (17-OHPC 11.0% vs. placebo 11.5%; relative risk = 0.95 [95% confidence interval (CI): 0.71-1.26]) or neonatal morbidity index (17-OHPC 5.6% vs. placebo 5.0%; relative risk = 1.12 [95% CI: 0.68-1.61]). There were also no differences in frequency of fetal/early infant death (17-OHPC 1.7% vs. placebo 1.9%; relative risk = 0.87 [95% CI: 0.4-1.81]. Maternal outcomes were also similar. In the subgroup of women enrolled in the United States (n = 391; 23% of all patients), although the rate of PTB < 35 weeks was higher than the overall study population, there were no statistically significant differences between groups (15.6% vs. 17.6%; relative risk = 0.88 [95% CI: 0.55, 1.40]. CONCLUSION: In this study population, 17-OHPC did not decrease recurrent PTB and was not associated with increased fetal/early infant death.

PROLONG Clinical Study Protocol: Hydroxyprogesterone Caproate to Reduce Recurrent Preterm Birth.

The objective of this commentary is to describe the background, rationale, and methods of the PROLONG (Progestin's Role in Optimizing Neonatal Gestation) trial, which is a multicenter, multinational, placebo-controlled, randomized clinical trial (RCT) designed to assess the safety and efficacy of Makena (hydroxyprogesterone caproate injection, 250 mg/mL) in reducing the risk of preterm birth (PTB) and neonatal morbidity/mortality in women pregnant with a singleton gestation who had a previous singleton spontaneous PTB. The total sample size of the RCT will include 1,707 women. The trial has two coprimary outcomes: PTB less than 35 weeks and a composite neonatal morbidity and mortality index. This study sample size will provide 90% power to assess for a 35% reduction in neonatal morbidity and mortality. Secondary outcomes will include 2-year follow-up of infants. The trial is ongoing and targeted to complete recruitment in 2018.

Motivational interviewing versus prescriptive advice for smokers who are not ready to quit.

OBJECTIVE: Smokers who are not ready to quit are a very difficult group to treat. Physicians, nurses, and nurse practitioners are in a unique position to encourage patients to quit smoking. However, the best approach to do so is not clear. METHODS: A two-group randomized controlled trial with 218 pack-a-day precontemplative and contemplative smokers recruited from the community. The laboratory-based study was designed to simulate outpatient visits to general practitioners. Participants were randomized to a 15-min intervention to compare the effectiveness of brief motivational or prescriptive counseling by a health professional. Thirteen outcome variables included intentions to quit and verbal reports at 1 and 6 months with biological verification. A composite outcome measure was constructed to provide greater power to detect study differences. RESULTS: Approximately 33% of the sample reported at least one 24-h quit period during the 6 months they were followed after the trial. Results suggest that while neither treatment was superior, there were subgroup differences. Participants in the motivational condition were also more likely to respond to follow-up calls. CONCLUSIONS AND PRACTICE IMPLICATIONS: Motivational interviewing and prescriptive advice were equally effective for precontemplative and contemplative smokers. Practitioners should use the method that appeals to them.

A randomized multicenter study to determine the efficacy of activity restriction for preterm labor management in patients testing negative for fetal fibronectin.

OBJECTIVE: To assess the impact of activity restriction (AR) on the incidence of preterm birth in women treated for preterm labor testing negative for fetal fibronectin (fFN). STUDY DESIGN: Women who were diagnosed with preterm labor and tocolyzed with magnesium sulfate were concurrently screened with fFN for the purpose of subsequent management. Included were consenting patients with negative fFN, gestational age 23 0/7-33 6/7 weeks, cervical dilation < or =3 cm, and minimal vaginal bleeding. Patients were randomized to AR or no AR. Primary study outcome was incidence of preterm delivery and interval from randomization to delivery. RESULTS: A total of 73 women with negative fFN were randomized (36 with AR, 37 without AR). The overall preterm birth rate was 40%, with 44.4% of patients with AR and 35.1% of patients without AR delivering preterm, p=0.478. CONCLUSION: Maternal AR did not impact pregnancy outcome. The incidence of preterm birth in symptomatic women testing fFN negative was higher than previously reported.

Dystocia in nulliparous patients monitored with fetal pulse oximetry.

OBJECTIVE: A critical analysis of the United States randomized controlled trial of fetal pulse oximetry concluded that nonreassuring fetal heart rate patterns used for study entry may have been a marker for dystocia. We prospectively studied nulliparous women in labor whose progress was monitored with fetal pulse oximetry to examine the relationship between nonreassuring fetal heart rate patterns and operative delivery for dystocia. STUDY DESIGN: A prospective nonrandomized observational cohort study compared two distinct classes of nonreassuring fetal heart rate patterns (class I: intermittent, mildly nonreassuring; class II: persistent, progressive, and moderate to severely nonreassuring) among nulliparous patients with the use of fetal pulse oximetry to confirm fetal well-being. Definitions of dystocia included the cessation of labor progress in the first (3 hours) or second (2 hours) stage of labor, despite adequate uterine activity that was assessed with an intrauterine pressure catheter. Independent review confirmed the classification of nonreassuring fetal heart rate patterns and study entry criteria. RESULTS: Two hundred seventy-four patients met study criteria and had sufficient information for fetal heart rate tracing interpretation. Two hundred thirty-seven patients (86.5%) were class II, and 37 patients (13.5%) were class I. The two classes of patients were comparable in a variety of obstetric, demographic, and perinatal variables. Twelve percent of all patients were delivered for nonreassuring fetal status. Significantly more class II patients (22%) were delivered by cesarean for dystocia than were class I patients (8%). Higher doses and a longer number of hours of oxytocin were required among class II patients. Significantly more occiput posterior positions were noted among all patients who underwent cesarean delivery for dystocia compared with other modes of delivery. CONCLUSION: Significantly nonreassuring fetal heart rate patterns predict cesarean delivery for dystocia among nulliparous patients with normally oxygenated fetuses in a setting of a standardized labor management protocol. This confirms the observations in the randomized controlled trial of fetal pulse oximetry in the United States and may provide insight into the treatment of nonprogressive labor in contemporary practice.

A randomized controlled trial of nerve stimulation for relief of nausea and vomiting in pregnancy.

OBJECTIVE: To evaluate the effectiveness of low-level nerve stimulation therapy over the volar aspect of the wrist at the P6 point to treat nausea and vomiting in early pregnancy. METHODS: Pregnant volunteers (n = 230) with symptoms of mild to severe nausea and vomiting between 6 and 12 weeks' gestation participated in a 21-day clinical trial. Participants were randomly assigned to receive a device for nerve stimulation therapy or an otherwise identical but nonstimulating placebo device. The primary outcome measure was self-recorded symptoms according to the Rhodes Index of Nausea, Vomiting, and Retching (Rhodes Index). Secondary outcome measures were medication use, weight gain, and presence of urinary ketones. RESULTS: Baseline characteristics were similar in both groups. A total of 187 women (81%) completed the trial. Pretreatment Rhodes Index scores for the entire population demonstrated no significant differences between study and control groups. The time-averaged change in Rhodes Index total experience of 6.48 for the study group was significantly better than the control value of 4.65 (P =.02). Study patients gained more weight than controls (2.9 versus 1.2 lb, P =.003). There were no statistically significant differences in medication use or urinary ketone measurements. CONCLUSION: Nerve stimulation therapy is effective in reducing nausea and vomiting and promoting weight gain in symptomatic women in the first trimester of pregnancy.

The effect of intraabdominal irrigation at cesarean delivery on maternal morbidity: a randomized trial.

To determine if intraabdominal irrigation with normal saline at cesarean delivery is associated with increased maternal morbidity. One hundred ninety-six women undergoing routine cesarean delivery at at least 37 weeks' gestation were prospectively randomized to receive 500-1000 mL of normal saline intraabdominal irrigation versus no irrigation after closure of the uterine incision, but before abdominal wall closure. Data were collected for comparison of demographic factors, intrapartum and postpartum complication rates, and maternal and neonatal outcomes. The primary outcome measure was the combined incidence of maternal morbidity, defined as at least one of the following: postoperative infectious morbidity, postpartum hemorrhage, severe anemia, and urinary retention.Ninety-seven patients were randomized to the irrigation group and 99 to the control group. The demographic characteristics of the two groups were similar. Thirteen patients (13.1%) in the control group and 14 patients (14.4%) in the irrigation group experienced maternal morbidity (P =.84). There were no statistically significant differences between the groups in estimated blood loss, operating time, incidence of intrapartum complications, hospital stay, return of gastrointestinal function, incidence of infectious complications, or neonatal outcomes.Routine intraabdominal irrigation at cesarean delivery in a low-risk population does not reduce intrapartum or postpartum maternal morbidity.