Clinical Review

Can progesterone prevent prematurity—dependably?

OBG Manag. 2009 November;21(11):53-61

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

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IN THIS ARTICLE

Why it’s an urgent matter to reduce preterm births
Progesterone in women who have a short cervix
So when should you offer progesterone?

References

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8. Dodd JM, Crowther CA, Cincotta R, Flenady V, Robinson JS. Progesterone supplementation for preventing preterm birth: a systematic review and meta-analysis. Acta Obstet Gynecol Scand. 2005;84:526-533.

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10. Dodd JM, Flenady VJ, Cincotta R, Crowther CA. Progesterone for the prevention of preterm birth: a systematic review. Obstet Gynecol. 2008;112:127-134.

11. Petrini JR, Callaghan WM, Klebanoff M, et al. Estimated effect of 17 alpha-hydroxyprogesterone caproate on preterm birth in the United States. Obstet Gynecol. 2005;105:267-272.

12. Norman JE, Mackenzie F, Owen P, et al. Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis. Lancet. 2009;373:2034-2040.

13. Rouse DJ, Caritis SN, Peaceman AM, et al. National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N Engl J Med. 2007;357:454-461.

14. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH. Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med. 2007;357:462-469.

15. Thornton JG. Progesterone and preterm labor—still no definite answers. N Engl J Med. 2007;357:499-501.

16. Iams JD, Goldenberg RL, Meis PJ, et al. The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. N Engl J Med. 1996;334:567-572.

17. DeFranco EA, O’Brien JM, Adair CD, et al. Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2007;30:697-705.

18. Facchinetti F, Paganelli S, Comitini G, Dante G, Volpe A. Cervical length changes during preterm cervical ripening: effects of 17-alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol. 2007;196:453.e1-453.e4.

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24. Northen AT, Norman GS, Anderson K, et al. National Institute of Child Health and Human Development (NICHD) Maternal–Fetal Medicine Units (MFMU) Network. Follow-up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo. Obstet Gynecol. 2007;110:865-872.

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26. Preterm birth costs US $26 billion a year [press release]. Washington, DC: National Academies. July 13, 2006. Available at: http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=11622. Accessed October 5, 2009.

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Fast Track

Infants of women treated with progesterone had significantly lower rates of necrotizing enterocolitis and intravenous hemorrhage and less need for supplemental oxygen

Preterm birth likely arises from different causes in women with a previous preterm birth and women carrying a multiple gestation

A Cochrane review found no harm related to use of progesterone

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.