By John C. Hobbins, MD

Professor, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora

Dr. Hobbins reports no financial relationships relevant to this field of study.

Synopsis: One recent study has questioned the efficacy of the ability of 17 alpha-hydroxyprogesterone caproate to prevent preterm birth, and the other suggests that indomethacin, used to stop preterm labor, may have unwanted neonatal consequences.

Sources: Winer N, et al. 17 alpha-hydroxyprogesterone caproate does not prolong pregnancy or reduce the rate of preterm birth in women at high risk for preterm delivery and a short cervix: A randomized controlled trial. Am J Obstet Gynecol 2015;212:485.e1-10. Hammers AL, et al. Antenatal exposure to indomethacin increases the risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia: A systematic review with meta-analysis. Am J Obstet Gynecol 2015;212:505.e1-13.

Spoiler alert (maybe)! The April issue of the American Journal of Obstetrics and Gynecology contained two papers that warrant discussion, one on the efficacy of 17 alpha-hydroxyprogesterone caproate (17P; a commercial product offered in France) for prevention of preterm labor (PTL) and the other on possible adverse fetal/neonatal effects of indomethacin when used to treat PTL.

Winer et al enrolled 105 “high-risk” women with short cervices (cervical lengths < 2.5 cm) who were between 20 and 32 weeks of gestation and who had a history of prior preterm birth, uterine anomalies, DES exposure, or cervical surgery.1 Fifty-one patients were randomized to weekly injections of 500 mg of 17P and 54 patients were designated as controls. About half of the patients in each group had cerclages, all placed before 23 weeks, based on the judgment of their managing clinicians.

The rates of preterm birth (PTB) were 45% and 44% (P > 0.99) prior to 37 weeks, 24% vs 30% (P = 0.50) at 34 weeks, and 14% vs 20% (P = 0.44) at < 32 weeks, for 17P and controls, respectively. The median number of days between recruitment and delivery was 77 days for the 17P group and 74 days in the control group. After interim analysis, the investigators decided that the data suggested no benefit from 17P, and the authors “stopped because of futility” based on their power analysis.

In the second study, the authors searched the literature for prospective and retrospective observational trials, as well as earlier meta-analyses, and lumped together data that were extracted from the studies that had adequate neonatal information.2 The idea was to determine if there was an increase in adverse neonatal events between patients who had and had not received indomethacin therapy for preterm labor. The total analysis involved 1731 patients who had received this medication and 6723 who had not.

There were no significant differences in respiratory distress syndrome, patent ductus, neonatal sepsis, bronchopulmonary dysplasia, or total amounts of intraventricular hemorrhage (IVH) (all grades). However, there were increased rates of severe IVH (grade 3 and 4) (relative risk [RR], 1.29; 95% confidence interval [CI], 1.06-1.56), necrotizing enterocolitis (RR, 1.36; 95% CI, 1.08-1.71), and periventricular leukomalacia (RR, 1.59; 95% CI, 1.17-2.18) in women given indomethacin compared to controls. The authors concluded that the use of indomethacin “should be avoided.”

Commentary

It has been 12 years since Meis at al published the seminal study showing a decrease in the rate of PTB by 40% in patients with a history of prior PTB who were prescribed 17P.3 Since then, weekly injections of 17P have been a part of the lives of, seemingly, most patients with a history of a prior delivery at less than 37 weeks. Along the way, the finding of a short cervix also began playing a role in strategies to prevent PTB. In fact, a 2011 study by Hassan et al4 showed that progesterone halved the rate of PTB < 37 weeks and decreased the rate of respiratory distress syndrome when a natural progesterone product was inserted daily into the vagina. This study had a mixture of high- and low-risk patients. Very recently, there has been a suggestion that even in low-risk patients with short cervices, this regimen can be cost-effective.5 Although it is tempting to surmise that all progesterones are the same, no matter how they are applied, thoughtful physicians have been in a quandary as to which product to use in various situations. Now the above study casts some doubt as to whether 17P works at all in those with short cervices and a history of predisposing factors — the very patients who are at greatest risk. However, before abandoning 17P, it should be stated that this study has its own set of problems, including the possible confounding factors of cerclage and the small numbers in the study. Interestingly, the percentage of patients who delivered preterm in the study (45%) is far greater than other RCTs involving PTB. This was particularly surprising since this high-risk group of study patients represented a heterogeneous group, which included some with only a history of cervical surgery (such as LEEP procedures) whose risk of PTB is still relatively low. Also, importantly, before immediately switching over to vaginal progesterone (based on this one 17P study), this vaginal delivery method still needs to stand up to further scrutiny.

Regarding indomethacin, there have been a few older studies6 suggesting its efficacy in stopping preterm labor, but the greatest concern has always been its possible ability to prematurely close the fetal ductus arteriosus.7 This concern has caused us to avoid its use during a critical time (28-32 weeks) when the ductus is most vulnerable to this effect. In fact, we have mostly been using it to diminish uterine activity after placing a cerclage, since its mechanism of action (prostaglandin synthetase inhibition) suits a situation where surgical trauma to the cervix can theoretically increase prostaglandin release.

This study also is far from pristine. Since there were not enough useful data in the literature regarding randomized clinical trials, the authors had to use pooled data from observational studies. These studies, as the authors later pointed out, are “inherently more prone to bias.” Also, it was impossible to tease out which patients were exposed to other tocolytics at the same time, and the indomethacin might have been used as a “last-ditch” effort in pregnancies most prone to neonatal problems. Last, with this type of pooled data, any result with an RR < 2.0 must be interpreted with caution since meta-analyses are truly a mixed bag covering a wide range of confidence intervals. To quote Leon Speroff (the past chief editor of OB/GYN Clinical Alert), “To combine a large number of studies into one large pooled analysis is not bringing together a bunch of apples to make a Big Apple, but simply mixing fruits to make a fruit salad.”

REFERENCES

  1. Winer N, et al. 17 alpha-hydroxyprogesterone caproate does not prolong pregnancy or reduce the rate of preterm birth in women at high risk for preterm delivery and a short cervix: A randomized controlled trial. Am J Obstet Gynecol 2015;212:485.e1-10.
  2. Hammers AL, et al. Antenatal exposure to indomethacin increases the risk of severe intraventricular hemorrhage, necrotizing enterocolitis, and periventricular leukomalacia: A systematic review with meta-analysis. Am J Obstet Gynecol 2015;212:505.e1-13.
  3. Meiss PJ, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003;348:2379-2385.
  4. Hassan SS, et al. Vaginal progesterone reduces the rate of preterm birth in women with a sonographically short cervix: A multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2011;38:18-31.
  5. Werner EF, et al. Universal cervical-length screening to prevent preterm birth: A cost-effectiveness analysis. Ultrasound Obstet Gynecol 2011;38:32-37.
  6. Bessinger RE, et al. Randomized control trial of indomethacin and ritodrine for long-term treatment of preterm labor. Am J Obstet Gynecol 1991;164:981-986.
  7. Moise KJ Jr, et al. Indomethacin in the treatment of preterm labor. Effects on the fetal ductus arteriosus. N Engl J Med 1988;319:327-331.