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Progesterone to Prevent Preterm Birth Effective Only in Women with Short Cervix, Study Finds

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A systematic review and meta-analysis just published in the September 2022 issue of the American Journal of Obstetrics and Gynecology found no convincing evidence supporting use of vaginal progesterone to prevent recurrent preterm birth in women with a singleton gestation and a history of spontaneous preterm birth.

Baseline guidance and updates

Since 2003, the American College of Obstetricians and Gynecologists (ACOG) had recommended the administration of 17a-hydroxyprogesterone caproate (17-OHPC) to patients with a singleton gestation and a history of spontaneous preterm birth, with the goal of preventing preterm birth, reported the researchers.

In 2021, ACOG updated its guidelines on the prediction and prevention of spontaneous preterm birth and recommended offering either vaginal progesterone or 17-OHPC. These guidelines were endorsed by the Society for Maternal-Fetal Medicine.

What was reviewed?

In this review, the researchers reviewed randomized controlled trials that compared vaginal progesterone to placebo or no treatment in asymptomatic women with a singleton gestation and a history of spontaneous preterm birth.

Their sources included MEDLINE, Embase, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane databases, Google Scholar, bibliographies, and conference proceedings.

Ten studies (2,958 women) met the inclusion criteria: 7 with a sample size <150 (small studies) and 3 with a sample size >600 (large studies).  Among the 7 small studies, 4 were at high risk of bias, 2 were at some concerns of bias, and only 1 was at low risk of bias.  All the large studies were at low risk of bias.

Size matters

The researchers discovered that study sizes made a difference in outcomes.

In small studies, vaginal progesterone was associated with a large decrease in the risk of preterm birth <37 and <34 weeks of gestation, whereas it had no effect in large studies.

“Pooled treatment effect estimates from small studies showed that vaginal progesterone significantly reduced the risk of preterm birth <37 weeks of gestation and <34 weeks of gestation,” wrote the authors.

“By contrast, pooled treatment effect estimates from large studies showed little or no difference between the vaginal progesterone and placebo or no-treatment groups in the risk of preterm birth <37 weeks of gestation and <34 weeks of gestation.”

Other subgroup analyses showed that vaginal progesterone significantly decreased the risk of preterm birth <37 and <34 weeks of gestation in studies conducted in low- and middle-income countries, single-center studies, and unregistered studies, whereas its administration had no effect in studies conducted in high-income countries as well as low-, middle-, and high-income countries; multicenter trials; and registered studies, according to the review.

After adjustment for small-study effects, the data showed a markedly reduced and nonsignificant effect of vaginal progesterone on pre-term birth <34 weeks of gestation.

Authors’ proviso and key takeaway

The authors remarked that due to publication bias, lower methodological quality of small trials—or a combination of both—small-study effects lead to an exaggeration of the pooled treatment effect.

However, the researchers had previously determined in a 2018 study that vaginal progesterone administered to women with a singleton gestation and a mid-trimester sonographic short cervix significantly reduces the risk of preterm birth and improves perinatal outcomes.

“[V]aginal progesterone should be offered to patients with a singleton gestation and a history of spontaneous preterm birth only if they are diagnosed with a sonographic short cervix (cervical length ≤25 mm) in the midtrimester,” the researchers counseled.

In summary they wrote, “There is no convincing evidence supporting the use of vaginal progesterone to prevent recurrent preterm birth or to improve perinatal outcomes in singleton gestations with a history of spontaneous preterm birth.”

Find a link to the full review, “Does Vaginal Progesterone Prevent Recurrent Preterm Birth in Women with a Singleton Gestation and a History of Spontaneous Preterm Birth? Evidence from a Systematic Review and Meta-analysis” at  https://doi.org/10.1016/j.ajog.2022.04.023


The contents of this feature are not provided or reviewed by NPWH.

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