Replacement of estrogens and progestins to prevent morbidity and mortality in preterm infants

Preterm infants commonly have low levels of sex steroids (estrogen and progesterone) because of lack of placental supply. It is suggested that estrogens and progestins have a role in normal development. However, risks of giving sex hormones include abnormalities in babies such as vaginal cancers and narrowing of the urinary passage. The review authors searched the medical literature and found only one small controlled trial. Thirty female low birthweight preterm infants (less than 29 weeks gestational age and weighing less than 1000 g) were given combined estrogen (estradiol) and progesterone or placebo in the first six weeks of their life. There were no clinical benefits found with giving the sex hormones or any adverse effects during the study. The measured levels of estrogen and progesterone were similar to those found in babies in the womb.

Authors' conclusions: 

The one small randomised controlled trial demonstrated neither evidence of benefit or harm related to the replacement of estradiol and progesterone in preterm infants less than 30 weeks gestation. A properly powered randomised controlled trial is required to determine whether or not administration of estradiol or progesterone, either alone or in combination, and at varying doses, confers any clinically significant benefits, or poses any risk, to the preterm infant.

Read the full abstract...

A potential therapeutic effect of sex steroids on premature infants has been proposed from animal data and observational studies in humans. Purported benefits include reduction in chronic lung disease, improved bone density and improved neurodevelopmental outcome.


To determine if estrogens or progestins, either alone or in combination, when compared to placebo or no treatment, reduce morbidity and/or mortality in preterm infants.

Search strategy: 

The standard search strategy of the Cochrane Neonatal Review Group as outlined in the Cochrane Library (Issue 2, 2004) was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2004), MEDLINE 1966 to July 2004 inclusive, previous reviews including cross references, abstracts, conferences and symposia proceedings (Perinatal Society of Australia and New Zealand 1998-2004 and Pediatric Academic Societies meetings 1998-2004).

Selection criteria: 

Randomised controlled trials comparing the use of estrogens and/or progestins with placebo or no treatment in preterm infants born less than 30 weeks gestation were included in this review. The primary outcome measures were neonatal mortality and medium-term neurodevelopmental outcome. Other outcomes included length of hospital stay, incidence of chronic lung disease, osteopaenia causing fractures and adverse effects of sex steroid administration.

Data collection and analysis: 

Two reviewers independently selected, assessed the quality of and extracted data from the included studies. Meta-analyses were performed using relative risk and risk difference for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals.

Main results: 

Two randomised controlled trials were identified by the search strategy and one was included in this review, comprising 30 preterm infants. There was no significant effect of replacement of estradiol and progesterone on the outcomes of mortality or neurodevelopmental disability in survivors followed. No adverse effects of sex steroid replacement on short or longer term outcomes were detected.