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Prenatal administration of progesterone for preventing preterm birth in women considered at risk of preterm birth

RHL Commentary by González R

1. INTRODUCTION

According to the World Health Organization, 3 million newborns die each year due to complications related to pregnancy and childbirth, and 99% of these deaths occur in developing countries (1). Preterm birth is a leading cause of neonatal and infant mortality as well as short- and long-term disability. Rates for preterm birth range between 6% and 12% in developed countries and are generally higher in developing countries. About 40% of all preterm births occur before 34 weeks and 20% before 32 weeks. The contribution of these preterm births to overall perinatal morbidity and mortality is more than 50% (2, 3).

Being born prematurely in an under-resourced setting puts a baby at extremely high risk of death in the neonatal period. The lower the gestational age at delivery, the greater the need for expensive interventions and support to improve the infant's chances of survival. The lack of skilled maternity care in developing countries leads to high rates of neonatal mortality and morbidity for premature babies. No significant advances have been made in the prevention or treatment of preterm delivery; on the contrary prematurity has been rising in both developed and developing countries (2, 3).

Progesterone is essential for many reproductive processes and it is believed to play an important role in continuation of pregnancy and keeping the uterus in a relaxed state. Antenatal administration of progesterone, irrespective of route and dose, appears to reduce the risk of delivering before term and delivering a low-birth-weight baby. Since it is not known whether prolongation of gestation leads to improved outcomes for mothers and their infants, caution is generally advised in the use of this intervention. This Cochrane review (4), which was updated in 2009, analysed the benefits and harms of progesterone for the prevention of preterm birth for women considered at risk of preterm delivery.

2. METHODS OF THE REVIEW

Based on predefined selection criteria, eleven randomized controlled trials of prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth were included in the Cochrane review (4). A total of 2714 women and 3452 infants were included in the meta-analysis. Early (1970–1975) and recent (2003–2007) studies were considered for analysis. Risk for preterm birth included: past history of spontaneous preterm birth, a short cervix (identified by ultrasound), women with a multiple pregnancy, threatened preterm labour and others risk factors. Primary outcomes considered were: perinatal mortality, preterm birth (less than 34 weeks), and major neurodevelopment handicap during childhood. Secondary outcomes were separated for maternal, infant and childhood complications.

3. RESULTS OF THE REVIEW

Progesterone use in women with a history of prior spontaneous preterm birth

Four studies with a total of 1329 women comparing progesterone versus placebo were considered for this analysis. Two of the studies compared weekly intramuscularly doses of 250 mg of 17 alpha-hydroxyprogesterone caproate starting at before 20 weeks and continuing up to between 24 and 37 weeks, and two used nightly intravaginal doses of 90–100 mg starting at between 24 and 28 weeks.

Progesterone was associated with a significant reduction in: (i) preterm birth at less than 34 weeks [one study; 142 women; risk ratio (RR) 0.15; 95% confidence interval (CI) 0.04–0.64]; (ii) preterm birth at less than 37 weeks (four studies; 1255 women; RR 0.80; 95% CI 0.70–0.92); and (iii) birth of a low-birth-weight infant of less than 2500 g (two studies; 501 infants; RR 0.64; 95% CI 0.49–0.83).

Progesterone use in women with a short cervix as measured by vaginal ultrasound

One study with 250 pregnant women with a short cervix (less than 15 mm) as measured by vaginal ultrasound was included. Doses of progesterone were 200 mg nightly intravaginally versus placebo, starting at 24–33 weeks. Progesterone was associated with a significant reduction in preterm birth at less than 34 weeks (one study; 250 women; RR 0.58; 95% CI 0.38-0.87) and in neonatal sepsis (one study; 274 infants; RR 0.28; 95% CI 0.08–0.97).

Progesterone in women with a multiple pregnancy

Two studies with 738 pregnant women with a twin pregnancy were included. Doses of progesterone were 250 mg weekly intramuscularly, starting at 16–20 or at 28 weeks to 35–37 weeks. Progesterone was associated with a significant reduction in the risk of tocolysis (one study; 654 women; RR 0.75; 95% CI 0.57–0.97), although no significant differences were observed for primary outcomes.

Progesterone in women with threatened preterm labour

Two studies with 130 pregnant women with threatened preterm labour were included. Gestational age at inclusion was between 24 weeks and 35 weeks. Doses of progesterone were of 400 mg daily via intravaginal pessary versus placebo, or 341 mg every 4 days until 36 weeks or until delivery.

Progesterone was associated with a significant reduction in: (i) preterm birth at less than 37 weeks (one study; 60 women; RR 0.29; 95% CI 0.12–0.69); (ii) incidence of low birth weight of less than 2500 g (one studies; 70 infants; RR 0.52; 95% CI 0.28–0.98); and (iii) respiratory distress syndrome (one study; 70 infants; RR 0.30; 95% CI 0.11–0.83).

Progesterone in women at risk of preterm birth for other reasons

Two early studies with a total of 267 patients were considered for analysis. A high preterm risk score or a condition of an active military service was the criteria used for inclusion. Authors compared three times per week or weekly intramuscular doses of 250 mg or 1000 mg of 17 alpha-hydroxyprogesterone caproate or placebo, starting at 16–20 weeks or 28 weeks to 32–36 weeks. Progesterone was not associated with significant differences for the outcomes reported.

Findings from recent trials not included in the review

Three new randomized control trials published in 2009 have provided more information on the effectiveness of progesterone (5-7). In one trial (5), the effect of oral administration of 100 mg of micronized progesterone at 18–24 weeks of gestation was studied in women with a history of preterm birth. A total of 150 women were allocated to receive oral progesterone or a placebo. Preterm birth between before 28–31 weeks was significantly less frequent in the progesterone group (RR 0.20; CI 0.05–0.73). A significant difference was found in neonatal age at delivery (34 versus 32 weeks, p 0.001) and birth weight (2400 g versus 1890 g, p 0.001); there were also fewer neonatal deaths, but this finding was not significant (3 versus 7, p 0.190).

Caritis et al. (6) studied the effect of weekly administration of 250 mg of progesterone or placebo in a population of 134 women with triplets pregnancies. There were no significant differences for a composite primary outcome of preterm delivery and fetal loss.

The findings of a multicenter randomized trial study on the prevention of preterm delivery in twins were published in 2009 (7). This trial studied the effect of daily administration of 90 mg of a vaginal progesterone gel or placebo in a population of 500 women with twin pregnancies. There were no significant differences between the women who received progesterone and those who did not with regard to either preterm delivery before 34 weeks or fetal loss.

In a long-term follow-up (mean age of 48 months) study (8) of children exposed to 17 alpha-hydroxyprogesterone caproate during second or third trimester of pregnancy, no differences were found in health status of children exposed or not exposed to the drug. There is no such information for natural progesterone – either vaginal or oral (micronized).

4. DISCUSSION

4.1 APLICABILITY OF THE RESULTS

In women with a singleton pregnancy and a history of previous preterm delivery, antenatal administration of progesterone reduces the risk of preterm labour before 37 weeks and 34 weeks. It also reduces the risk of a newborn being born with a low birth weight of less than 2500 g. Progesterone use can also be recommended for pregnant women who are found incidentally to have a short cervix. However, current data do not support the use of progesterone in women with multiple pregnancies. At the present time it is not known whether prolongation of gestation also leads to improved outcomes for mothers and their infants.

Most of studies included in the review were conducted in developed countries. However, there is no biological reason to expect that results of similar studies would be different in developing countries.

4.2 IMPLEMENTATION OF THE INTERVENTION

The American College of Obstetrics and Gynecology recommends that the use of antenatal progesterone to prevent preterm birth should be restricted to women with a documented history of prior spontaneous preterm delivery at less than 37 weeks or to women incidentally (i.e. without routine screening) found to have a short cervix with a short cervix (less than 15 mm) (9).

Although there is information that progesterone is effective in reducing the risk of preterm delivery in women with a short cervix, population-wide screening of pregnant women to identify and treat asymptomatic women at potential risk cannot be recommended until these findings are confirmed in further trials and the longer-term impact of exogenous progesterone on mothers and their children becomes known. Until then progesterone should be used with caution on a case-by-case basis.

4.3 IMPLICATIONS FOR RESEARCH

Future research should be oriented towards studying the effectiveness of antenatal progesterone in women in whom the symptoms (contractions) or specific conditions (short cervix, premature rupture of membranes) started for the first time in the current pregnancy. More research is also needed on the optimal dose, timing and route of administration of progesterone. The primary outcomes studied in these trials must be perinatal or neonatal mortality and preterm birth less than 34 weeks of gestation. Priority should be given to studying the longer-term consequences of progesterone administration for children born to women given this treatment.

At a more fundamental level, it is important to study also the potential harmful effects of prolonging a pregnancy with progesterone; for example, if preterm delivery is provoked by an infection, prolonging the pregnancy may compromise the safety and wellbeing of the fetus. In under-resourced settings it will not be possible to screen all women for the length of their cervix by ultrasound; it may be useful to evaluate a simple and less expensive method of predicting preterm delivery.

Finally, larger randomized controlled trials are required to determine if antenatal administration of progesterone reduces perinatal mortality and long-term serious neonatal and child morbidity.

References

• Maternal mortality in 2005: estimates developed by WHO, UNICEF, UNFPA, and The World Bank. Geneva: World Health Organization; 2007.
• Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth, The Lancet, 2008:371(9606);75-84.
• Lang C, iams J. Goals and strategies for prevention of preterm birth: an obstetric perspective. Pediatric clinics of North America 2009;56:537–563.
• Dodd JM, Flenady V, Cincotta R, Crowther CA. Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth. Cochrane Database of Systematic Reviews 2006;Issue 1. Art. No.: CD004947; DOI: 10.1002/14651858.CD004947.pub2 (last updated on 31 December 2008).
• Pushpanjali R, Shalini R, Neerja G, Gopalakrishnan RA, Agarwal R, Mehta M. Oral micronized progesterone for prevention of preterm birth. International journal of gynecology and obstetrics. 2009;104:40-43.
• Caritis S, Rouse D, Peaceman A, Scisciones A, Momirova V, Spong C, et al. Prevention of preterm birth in triplets using 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial. Obstetrics and Gynecology 2009;113:285-292.
• Norman J, Mackenzie F, Owen P, Mactier H, Hanretty K, Cooper S, et al. Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomized, double-blind, placebo-controlled study and meta-analysis. The Lancet 2009; 373: 2034-2040.
• Northen A, Norman G, Anderson K, et al and The National Institute of Child Health and Human Development (NICHD), Maternal-Fetal Medicine Units Network (MFMU). Follow up of children exposed in utero to 17 alpha-hydroxyprogesterone caproate compared with placebo. Obstetrics and Gynecology 2007;110:865-872.
• American College of Obstetricians and Gynecologists. Use of progesterone to reduce preterm birth. Committee Opinion No. 419. Washington, DC: American College of Obstetricians and Gynecologists; 2008.

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This document should be cited as: González R. Prenatal administration of progesterone for preventing preterm birth in women considered at risk of preterm birth: RHL commentary (last revised: 1 December 2009). The WHO Reproductive Health Library; Geneva: World Health Organization.