Rising preterm birth rates: Time to double down on our efforts
Increasing use of 17 α-hyroxyprogesterone caproate (17-OHP) in women with prior spontaneous PTB. The original NICHD Maternal-Fetal Medicine Units Network study randomized 459 women with a history of spontaneous singleton preterm delivery to weekly intramuscular injections of 17-OHP versus placebo from 16 to 20 weeks until 36 weeks and demonstrated a reduction in births before 37 weeks (relative risk [RR] of 0.66; 95% CI: 0.54–0.81), 35 weeks (RR 0.67; 95% CI: 0.48–0.93), and 32 weeks (RR 0.58; 95% CI: 0.37–0.91).13 Meta-analysis of 36 trials of either 17-OHP or vaginal progesterone versus placebo in women with a history of spontaneous PTB demonstrates that progesterone reduces perinatal mortality (risk ratio [RR] of 0.50; 95% CI: 0.33–0.75), births <37 weeks (RR 0.55; 95% CI: 0.42–0.74), births <34 weeks (RR 0.31; 95% CI: 0.14–0.69), assisted neonatal ventilation (RR 0.40; 95% CI: 0.18–0.90), necrotizing enterocolitis (RR 0.30; 95% CI: 0.10–0.89), and admission to a neonatal intensive care unit (RR 0.24; 95% CI: 0.14–0.40).14 Thus, I contend that all patients with prior spontaneous PTB should be offered weekly 17-OHP injections, and if not available, vaginal progesterone from 16 to 36 weeks.
Implementing universal screening for short cervices and intervening with vaginal progesterone or cerclage as indicated. Consensus has not been reached on the utility of universal cervical length screening at mid-gestation, or on at what gestational age to initiate the process or even what cervical length cut-off to use. However, there is evidence that vaginal progesterone therapy (via 90-mg gel or 200-mg suppository) reduces PTB in women with shortened cervices (≤20 mm) before 24 weeks who have no history of spontaneous PTB.14 Moreover, there is also evidence that either placement of a cerclage or the addition of vaginal progesterone in women found to have a shortened cervix (15 to 20 mm) at mid-gestation and who had a prior PTB will lower recurrence rates.15 Nonetheless, the Society for Maternal-Fetal Medicine has opined that universal cervical length screening is “reasonable.”16 Indeed, an abstract presented at this year’s ACOG Annual Clinical Meeting reported that 68% of centers with MFM fellowships had implemented cervical length screening.17 However, neither intervention is helpful in multiple gestations or following preterm fetal membrane rupture. Moreover, weekly 17-OHP does not appear to reduce PTB in nulliparous women with short cervices.18
One cautionary note comes from the recent UK OPPTIMUM trial.19 This was a complex double-blind trial in which women were randomized to vaginal progesterone (200 mg per day) (n=618) versus placebo (n=1228) from 22–24 to 34 weeks if they had a prior PTB at ≤34 weeks, or a cervical length ≤25 mm, or a positive fetal fibronectin test combined with other clinical risk factors for PTB. The authors noted that progesterone did not affect the primary obstetric outcome of fetal death or birth <34 weeks (adjusted OR of 0.86, 95% CI: 0.61–1.22) or a composite neonatal outcome (OR 0.62; 95%CI: 0.38–1.03). However, this study mixed various risk categories and may have been underpowered for these outcomes. Also the presence of an elevated fetal fibronectin suggests that pro-parturition inflammatory processes may well have been under way by the time progesterone therapy was initiated. This is important because we have shown that both abruption (via thrombin) and infection (via interleukin-1β) are associated with significant down-regulation of decidual cell progesterone receptor levels20,21 and in the absence of its receptor even pharmacologic levels of progesterone will be ineffective.