Can progesterone prevent prematurity—dependably?
Here’s what we know, after 30 years of study, about the usefulness of progesterone in 4 settings: recurrent preterm birth, multiple gestation, a short cervix, and preterm labor
IN THIS ARTICLE
The author reports no financial relationships relevant to this article.
CASE: Patient worries about recurrent preterm birth
Ms. Jones is 13 weeks into her fourth pregnancy when she arrives at your office for her first prenatal visit. Her obstetric history is significant. In 2003, her first pregnancy was complicated by preterm labor at 25 weeks, preterm premature rupture of membranes at 26 weeks, and spontaneous vaginal delivery at 27 weeks. The infant experienced respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, and grade III intraventricular hemorrhage, and she was given a diagnosis of mild cerebral palsy at age 3.
Two years later, the patient’s second pregnancy was complicated by preterm labor at 22 weeks and spontaneous vaginal delivery at 23 weeks, with an Apgar score of 3, 1, and 0. The infant did not survive.
In 2007, Ms. Jones was given a diagnosis of missed abortion at 8 weeks’ gestation and underwent dilation and curettage.
Today, she asks what you plan to do to optimize the outcome of her current pregnancy. Her risk of preterm birth is significantly higher than that of the general population, which is 12.7%.
What can you offer to her?
Progesterone supplementation is the best option for Ms. Jones. Data accumulating over the past 30 years suggest that progesterone reduces the likelihood of preterm birth in women who have a history of spontaneous preterm birth. In fact, a cumulative meta-analysis noted that evidence of progesterone’s benefit is striking enough that “statistical uncertainty” is not a valid reason for forgoing its use. 1
This article describes what’s been learned about progesterone supplementation to reduce preterm birth—specifically, the patients likely to benefit, the various formulations available, and the data on long-term outcomes—with an eye toward helping you weigh its utility in your practice.
The article focuses on four vulnerable populations:
- Women who have a history of preterm birth. Data suggest these patients are likely to benefit from progesterone.
- Women carrying a multiple gestation. Progesterone does not appear to prevent preterm birth in this group.
- Women who have a short cervix. Some data are promising. Further study is needed.
- Women who experience preterm labor. Data are promising, but preliminary.
Progesterone supplementation in high-risk women is one opportunity for prevention—but clearly not the complete answer. Despite progesterone administration, some women continue to deliver preterm. We have work ahead of us tailoring the therapy to the underlying mechanism, and the heterogeneity of preterm labor and delivery remains a limiting factor.
Why it’s vital to reduce preterm birth
Despite decades of research, initiative, and medical advances, the rate of preterm birth continues to rise, affecting one of every eight infants born in the United States—more than 500,000 babies each year. The impact of preterm birth is enormous, with implications that span from the immediate to the long-term.
In 2001, preterm birth surpassed birth defects as the leading cause of neonatal mortality. It is also the leading cause of infant mortality among African Americans and the second leading overall cause of all infant mortality.
The outlook for babies who survive preterm birth is concerning, as well. One of every five children who have mental retardation was born preterm, as was one of every three children who have vision impairment, and roughly one of every two children who have cerebral palsy. Low-birth-weight babies are commonly born preterm and face an increased risk of cardiovascular disease (including myocardial infarction, stroke, and hypertension), diabetes, and, possibly, cancer as adults.
Preterm birth not only affects the health of the baby and the family, but has long-term health and economic implications for society, costing at least $26 billion a year. 26
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POPULATION 1: Women who have a history of preterm birth
Women who have already delivered preterm face an elevated risk of doing so in any subsequent pregnancy ( TABLE 1 ). Three recent double-blind, randomized, controlled trials explored the efficacy of progesterone in the prevention of recurrent preterm birth. 2-4 All three trials enrolled women at high risk of preterm birth; two included only women who had a history of spontaneous preterm birth, and 90% of the participants of the third trial had such a history as their risk factor.
The trials involved three different formulations of progesterone:
- intramuscular injection of 250 mg of 17α-hydroxyprogesterone caproate
- 100-mg vaginal suppository of progesterone
- 90 mg of vaginal progesterone gel (Prochieve 8% / Crinone 8%).
Two of the trials found a significantly lower rate of preterm birth among women randomized to progesterone. The third found no difference between the progesterone and placebo groups.
A woman who gives birth prematurely once likely will the next time
Gestational age at first delivery
Relative risk of recurrent preterm birth (95% confidence interval)
Maternal–Fetal Medicine Units Network 30
Missouri database, 1989–1997 31
University of Texas Southwestern Medical Center, 1988–1999 32
Denmark, 1982–1987 33
Maternal–Fetal Medicine Units Network 30
Details of the trials
Meis and colleagues conducted a multicenter trial of 463 pregnant women who had a documented history of spontaneous preterm delivery. 2 Starting between 16 and 20 weeks’ gestation, participants were randomized in a 2:1 ratio to weekly injection of 250 mg of 17α-hydroxyprogesterone caproate or an inert oil placebo, with injections continuing until delivery or 36 weeks’ gestation.
Among the findings:
- Treatment with progesterone significantly reduced the risk of delivery at less than 37 weeks’ gestation, with an incidence of 36.3% in the progesterone group versus 54.9% in the placebo group (relative risk [RR], 0.66; 95% confidence interval [CI], 0.54–0.81).
- Progesterone reduced the risk of delivery at less than 35 weeks’ gestation, with an incidence of 20.6% in the progesterone group versus 30.7% in the placebo group (RR, 0.67; 95% CI, 0.48–0.93).
- Progesterone reduced the risk of delivery at less than 32 weeks’ gestation, with an incidence of 11.4% in the progesterone group versus 19.6% in the placebo group (RR, 0.58; 95% CI, 0.37–0.91).
- Progesterone was effective in African Americans and non–African Americans.
- Infants of women treated with progesterone had significantly lower rates of necrotizing enterocolitis and intraventricular hemorrhage and less need for supplemental oxygen.
In a trial by da Fonseca and colleagues, 142 high-risk women who were pregnant with a singleton fetus were given a 100-mg vaginal suppository of progesterone or placebo daily (at night) between 24 and 34 weeks of gestation. 3 Preterm birth occurred in 13.8% of the women treated with progesterone versus 28.5% of women in the placebo group (P<.05). More women were delivered before 34 weeks’ gestation in the placebo group (18.5%) than in the progesterone group (2.7%).
O’Brien and associates studied 659 pregnant women who had a history of spontaneous preterm birth. 4 Participants were randomly assigned to receive daily treatment with progesterone vaginal gel or placebo, starting between 18 and 22.9 weeks’ gestation and continuing until delivery, 37 weeks’ gestation, or premature rupture of membranes. The gel was administered in the morning.
In this trial, progesterone did not decrease the rate of preterm birth at 32 weeks’ gestation or less (10% in the progesterone group versus 11.3% in the placebo group; odds ratio, 0.9; 95% CI, 0.52–1.56).
It is unclear whether the formulation, timing, or dosage was responsible for the different outcomes in these trials ( TABLE 2) .
5 Progesterone formulations have been tested for the prevention of preterm birth
Gestational age at initiation
Gestational age at completion
17α-Hydroxyprogesterone caproate 2
Daily at bedtime
Daily at bedtime
Prochieve 8%/Crinone 8% 4
Vaginal suppository bioadhesive formulation/gel
After arrest of preterm labor
In this population, the number needed to treat is low
At least five strong meta-analyses have explored the prevention of recurrent preterm birth. 1,7-10 These analyses demonstrate that progesterone supplementation significantly reduces the incidence of low birth weight and preterm birth. In some cases, it also reduces the rate of respiratory distress syndrome and intraventricular hemorrhage.
Based on these data, Petrini and associates calculated that, if all pregnant women who had a history of spontaneous preterm birth had been offered progesterone in 2002, 10,000 preterm births could have been prevented. 11
The number needed to treat (NNT) to avoid one preterm birth was eight for 17α-hydroxyprogesterone caproate and 10 using another progesterone formulation. The NNT to prevent low birth weight was 12.
To put these figures in context, consider the use of low-dose aspirin to prevent stroke, which has a NNT of 102, and the use of a β-blocker to prevent cardiac death in patients who have suffered a myocardial infarction, which carries a NNT of 42.
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 gestation 12-14 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