A landmark study by leading obstetricians from around the globe shows that women with a short cervix should be treated with vaginal progesterone to prevent preterm birth. The study published early online in the American Journal of Obstetrics and Gynecology (AJOG), demonstrated that vaginal progesterone lowered the risk of preterm birth by 42%, and substantially reduced the rate of respiratory distress syndrome, the need for mechanical ventilation, as well as a multitude of several complications in premature newborns, such as infection, necrotizing enterocolitis, intracranial hemorrhage, etc.

Leading researcher Dr. Roberto Romero, Chief of the Perinatology Research Branch and Head of the Program in Perinatal Research and Obstetrics of the Division of Intramural Research for the NICHD/NIH/DHHS in Bethesda, MD and Detroit, MI explains:

“Our analysis provides compelling evidence that vaginal progesterone prevents preterm birth and reduces neonatal morbidity/mortality in women with a short cervix. Importantly, progesterone reduced early preterm birth (those occurring before 33 or 28 weeks of gestation). These immature babies are at the greatest risk for complications, death, and long-term disability (e.g. cerebral palsy). Progesterone also decreased a fraction of ‘late preterm births,’ which are the most common preterm deliveries.

The profile of adverse events was no different from placebo. Follow-up studies of babies exposed to progesterone in utero to the age of 18 or 24 months showed no evidence of any behavioral or physical problems. The authors of this study recommend that transvaginal sonographic measurement of the cervix be performed in all pregnant women between 19 to 24 weeks of gestation to assess the risk of preterm delivery. This strategy also allows the identification of women at risk for preterm delivery during their first pregnancy. Other strategies, which are based on treating women with a previous preterm birth, do not address the challenge of prevention in women with their first pregnancy.”

The worldwide leading cause of perinatal morbidity and mortality is preterm birth, which is also the main cause of infant mortality, i.e. children dying before their first birthday. From 12.9 million preterm births worldwide 92.3% occur in Africa, Asia, Latin America, and the Caribbean, whilst 1 million preterm births occur annually in the U.S.

During the menstrual cycle and in early pregnancy women’s ovaries naturally produce progesterone that is subsequently produced in the placenta. A fall in progesterone levels is considered to be significant for the onset of labor, however, if progesterone levels decrease during the mid-trimester, cervical shortening may cause the onset of preterm labor. The management of progesterone is specified to work by maintaining a high concentration of the hormone in the uterine cervix.

Several studies have already evaluated the administration of vaginal progesterone compared with placebo to prevent preterm birth in women with a short cervix found by ultrasound in the mid-trimester of pregnancy, however, what makes this study unique is that researchers from all around the world have pooled data from the different studies to perform a meta-analysis, the ‘gold standard’ for summarizing evidence across clinical trials of individual patient data (IPD). Its advantage is that it increases the potential of identifying variations in efficacy and adverse events, and also enables researchers to perform subgroup evaluations that may have been impossible in each individual study.

The IPD meta-analysis of five high-quality trials of vaginal progesterone compared with placebo was carried out at multiple centers in developed and developing countries. It included a total of 775 women and 927 infants with the primary endpoints determined as preterm birth of 33 weeks or less, as well as a multiple index of perinatal morbidity and mortality. The researchers also examined other secondary endpoints on progesterone action, such as investigating the effect of cervical length, a history of previous preterm birth, race/ethnicity, body mass index, and maternal age.

They discovered that the results of the world wide conducted trials were incredibly consistent. Asymptomatic women who were diagnosed with a short cervix by sonogram in the mid-trimester and who received vaginal progesterone were associated with a reduction rate of 42% in giving birth preterm before 33 weeks, with other substantial reductions noted in the risk of preterm birth before week 28, 34 and 35 of gestation.

Findings also revealed that mortality and neonatal morbidity was reduced by 43% in the vaginal progesterone group with a substantial reduction of 52% in the risk of respiratory distress syndrome. In comparison to the placebo group (20.7%), the vaginal progesterone group also achieved a significantly lower admission of NICUs (29.1%).

Findings of earlier trials regarding the effects of vaginal progesterone or injectable progestins, i.e. synthetic compounds with progesterone action, in women with a twin gestation proved to be negative, whereas this study focused on a subset of patients with twin gestation and a short cervix.

Vaginal progesterone in this specific subgroup reduced the rate of preterm birth before 33 weeks by 30% and also substantially reduced the composite neonatal morbidity and mortality of twins. Dr. Romero pointed towards the urgency of needing a study of vaginal progesterone in twin pregnancies with a short cervix to support these findings, as the reduction in preterm birth was not significant. There is a high possibility that this could be due to the small number of twins being available for the study.

The study’s most significant finding is that progesterone is not only beneficial in women with a short cervix, it is also of benefit to those who had given birth preterm previously and who have a short cervix. The practical and financial implications of this finding are that vaginal progesterone is less expensive but also less invasive compared with the alternative therapy of placing a cervical suture (cerclage) in patients with a history of preterm birth and a short cervix.

AJOG Co-Editor-in-Chief, Thomas J. Garite, MD concluded:

“The results of this analysis of five large randomized trials have the potential to result in a sea change in obstetrical practice in the U.S. and Europe and eventually in the rest of the world. Prematurity is the leading cause of death and damage for newly born babies and despite enormous efforts, no impact has been made in the rate of preterm birth, which is actually rising in recent years.”

C. Andrew Combs, MD, PhD, at the Obstetrix Medical Group in San Jose, CA, argued in an accompanying editorial of the Journal, that reducing premature deliveries could potentially be achieved by implementing routine vaginal ultrasound for all pregnant women in their mid-term of pregnancy to measure the length of the cervix. In those patients where a short cervix is detected, these patients should be treated with progesterone. Given that the majority of premature births occur in women with no risk factors, this approach has real potential to make an impact on the overall premature birth rate. According to two recently published cost analysis studies an approach like this can not only save lives and prevent serious damages often caused by premature births, it can save almost ½ billion dollars per year in health care costs in the U.S. alone.

Written by Petra Rattue