POPULATION 2: Women who are carrying a multiple gestation
Given the success of progesterone in preventing recurrent preterm birth, it was a matter of time before investigators began to consider its use in another high-risk group: women carrying a multiple gestation. In two double-blind, placebo-controlled trials—one from the United States and the other from the United Kingdom—17α-hydroxyprogesterone caproate or placebo was given, starting between 16 and 20 weeks’ gestation in women who were carrying a twin or triplet gestation.12,13 Neither trial demonstrated a benefit for the use of progesterone in this population.
The etiology of preterm birth is likely different in women with a previous preterm birth than it is in women carrying a multiple gestation. The former are more likely to have an inflammatory, immunologic, or infectious process that leads to recurrent preterm birth, whereas women carrying multiples are thought to be at risk of preterm birth by virtue of the “stretch hypothesis”—the theory that the uterus is stretched excessively, leading to an earlier trigger of labor. Women who had a history of preterm birth and who were carrying a multiple gestation were eligible for these trials.
In the US trial, progesterone failed to reduce the rate of preterm birth in women who were carrying twins or triplets.13 This lack of benefit was seen regardless of whether conception was spontaneous or the result of assisted reproductive technologies, whether placentation was dichorionic or monochorionic, and regardless of the cutoff for gestational age. On average, the women in this trial delivered at 34.8 weeks, compared with a national average of 35.2 weeks for women carrying twins.13
Similar findings were reported from the UK trial, which enrolled 500 women carrying a twin gestation who were randomized to daily vaginal progesterone gel (90 mg) or placebo from 24 to 34 weeks’ gestation.12
A meta-analysis of the three trials that included multiple gestation12-14 found progesterone to have no benefit in women carrying twins. The pooled odds ratio of the effect of progesterone on preterm delivery or intrauterine death before 34 weeks’ gestation was 1.16 (95% CI, 0.89–1.51).12
How progesterone might inhibit preterm birth
Progesterone is a familiar player in the ObGyn specialty. In its natural form, the steroid hormone is produced by the corpus luteum to promote pregnancy.
In target cells, progesterone binds to its receptor and forms a transcription factor. It also can be active independent of nuclear receptors, which may explain why it remains effective even when circulating concentrations are high, suggesting that its action may be local and not systemic.
Progesterone exerts biologic effects on the myometrium, chorioamniotic membranes, and cervix.
Myometrial effects include:
- a decrease in the conduction of contractions
- a reduction of spontaneous muscle activity
- a decrease in the number of oxytocin receptors
- prevention of the formation of gap junctions
- a rise in the threshold for stimulation.
Progesterone decreases myometrial estrogen responsiveness by inhibiting estrogen-receptor expression and appears to maintain uterine quiescence by limiting the production of prostaglandins and inhibiting the expression of contraction-associated protein genes, including gap junctions, ion channels, oxytocin, and prostaglandin receptors within the myometrium.27 Some investigators have suggested that progesterone prevents preterm birth predominantly by virtue of its anti- inflammatory properties28 and ability to prevent cervical ripening.29
The 17α-hydroxyprogesterone form of the hormone also affects salivary concentrations of estriol. In a secondary analysis, the ratio of salivary estriol to progesterone increased as pregnancy progressed among women who received placebo, but remained flat among women treated with 17α-hydroxyprogesterone.2 One theory is that labor may be triggered by an increase in the activity of estriol, compared with progesterone.
It also is notable that estriol concentrations in the mother’s blood and saliva derive mainly from the fetus and placenta (from the fetus’ production of cortisol), suggesting that the action of 17α-hydroxyprogesterone acetate may also affect the feto-placental unit.
POPULATION 3: Women who have a short cervix
Because women who have a short cervix have a heightened risk of spontaneous preterm delivery, the utility of progesterone in prolonging gestation was explored in this population—with less than definitive results. An editorial accompanying the main study of this issue concluded that it is too early to recommend use of progesterone in women who have a short cervix.15
Progesterone was effective overall, but not in subgroup analysis
Iams and associates expertly delineated the risk of spontaneous preterm birth in the setting of a shortened cervix at 24 weeks’ gestation. They found a cervical length of about 12 mm to be at the first centile, with a relative risk of preterm birth of 14.16 (Compare this with the average cervical length of 36 to 44 mm at 24 weeks.)