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

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Authors

Hunt R, Davis PG, Inder T

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


Dates

Date edited: 25/08/2004
Date of last substantive update: 30/07/2004
Date of last minor update: / /
Date next stage expected / /
Protocol first published: Issue 4, 2002
Review first published: Issue 4, 2004

Contact reviewer

Dr Rod Hunt
Consultant Paediatrician
Department of Neonatal Medicine
Royal Children's Hospitals, Melbourne
Level 2, Royal Children's Hospital
Flemington Road
Parkville, Melbourne
Victoria AUSTRALIA
3052
Telephone 1: +61 3 9345 5522 extension: 5008
Facsimile: +61 3 9345 5067

E-mail: rod.hunt@rch.org.au

Contribution of reviewers

RH wrote the protocol and review with the assistance of PD and TI.
RH and PGD performed the literature search and data extraction.
All authors approved the final review.

Sources of Support

Internal sources of support

Murdoch Children's Research Institute, Parkville, VIC, AUSTRALIA
Royal Women's Hospital, Carlton, VIC, AUSTRALIA
Royal Children's Hospital, Parkville, VIC, AUSTRALIA

External sources of support

National Health and Medical Research Council Grant ID 216757, AUSTRALIA
NHMRC Grant ID 294102, AUSTRALIA

What's new

Date / Event Description

History

Date / Event Description

Synopsis

  • Synopsis pending

Abstract

Background

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.

Objectives

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 & 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.

Reviewers' 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.

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Background

Beneficial roles of sex steroids on the developing infant have been proposed from animal data and observational studies in humans. During pregnancy, the placenta is the primary site of estrogen secretion, utilising precursors that arise from both maternal and fetal compartments (Siler-Kohr 1992). Levels of unconjugated estrone and estradiol produced by the placenta are at least 100 times the levels found in the non-pregnant adult female (Kenny 1973) and the fetus is exposed to these high levels of estrogen following transplacental passage (Hercz 1985) . Following birth, this exposure to high levels of estrogen ceases within 24 hours. At term this state is physiological, ie. the normal development of organ systems progresses in the face of an acute withdrawal of estrogen at term. Placental progesterone synthesis is independent of fetal precursors, and most of the secreted progesterone enters the maternal circulation; however, fetal plasma concentrations are also significantly elevated (Tulchinsky 1994). The preterm infant is deprived of this elevated sex steroid exposure through to term, and the biological effects of this deprivation on developing organ systems are unknown.

Observation of preterm infants receiving either breast milk or pre-term formula has revealed that even when supplemented with vitamin D, accumulation of calcium and phosphorous is inefficient by comparison to the fetus in-utero, possibly due to poor gut absorption (Lyon 1984). Given the relative deficiency of sex steroids in the preterm infant, it has been postulated that replacement of these hormones may facilitate mineral accretion (Trotter 2002a). Human osteoblasts express estrogen receptors and estrogens have been shown to stimulate osteoblast proliferation. Estradiol may also prevent glucocorticoid-induced apoptosis of osteoblasts (Trotter 2000). In addition to a potential role early in life, estrogen clearly plays a protective role in post-menopausal osteoporosis (Lindsay 1988).

Animal studies have demonstrated that administration of estrogen to pregnant rabbits increases surfactant production by the fetus (Chu 1985), and accelerates morphologic maturation of the fetal lung (Khosla 1981). Whether or not sex steroid deficiency contributes to the pathogenesis of surfactant deficiency in the preterm infant is speculative.

It has also been postulated that the sex steroids have a role to play in the central nervous system. Two possible mechanisms exist for such a role. The first is in the minimisation of brain injury following an ischaemic event - a theory which derives plausibility from the observation of improved outcome in stroke patients who received estrogen replacement following their injury (Melton 2001). The second relates to a potential role of estrogens in the sequence of normal brain development (Beyer 1999). Specifically, estrogens have been shown to promote synapse formation (Matsumoto 1991) and progesterone has been shown to promote myelination (Baulieu 1996). Again, speculation exists about the role of these hormones on neurodevelopment in the human infant. There is evidence from observational studies of girls with Turner syndrome that estrogen therapy can improve verbal and nonverbal memory (Ross 2000) and that women with Turner syndrome have altered mental health (Downey 1989). Estrogen levels modulate the activity of platelet activating factor acetyl hydrolase, and platelet activating factor has been implicated in the pathogenesis of necrotising enterocolitis (Singh 2001). These links, whilst tenuous, raise biologically plausible possibilities about the potential role of sex steroids on various aspects of the preterm infant's wellbeing.

Administration of sex steroids is not without risk. In the 1960's, women with high risk pregnancies were treated with diethylstilbestrol (DES). Epidemiological studies have since demonstrated strong associations between such therapy and abnormalities in the offspring of these pregnancies. Specifically, in the daughters of treated women there is a significantly increased risk of vaginal adenocarcinoma (Herbst 1975) and of unfavourable outcome of pregnancies (Barnes 1980). Sons of treated women have also been shown to have abnormalities of the urogenital tract, specifically urethral stricture (Henderson 1976).

Maintenance of plasma levels of estradiol and progesterone similar to those measured in-utero have been achieved following the intravenous administration of these hormones (Trotter 1999). Postnatal treatment of the preterm infant with estradiol and progesterone resulted in the attainment of measures of uterine width similar to those of the fetus in-utero, compared to untreated infants whose uteri were significantly smaller than either fetuses of the same post menstrual age, or postnatally treated infants (Trotter 2002a). Whilst biological activity seems attainable, clinically important effects have yet to be established.

Objectives

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. Subgroup analyses will be performed as follows where the trial data allow. (1) To determine the effects of estrogen alone or progestin alone, or combined estrogen and progestin therapy according to gestation, (2) the effect of the dose and duration of treatment, (3) the effect of the route of administration of treatment and (4) gender of study participants.

Criteria for considering studies for this review

Types of studies

Randomised controlled trials comparing estrogens or progestins, either alone or in combination, with placebo or no treatment.
Trials should have adequate randomisation and >80% follow up of participants for outcomes measures as described below.

Types of participants

Preterm infants born before and including 29 weeks 6 days completed gestation, either with or without documented relative estrogen or progestin deficiency.

Types of interventions

Estrogen or progestin administration via any route and at any dose, compared with either no treatment or placebo. There will be no restrictions on postnatal age for initiating therapy or on required duration of treatment.

Types of outcome measures

Primary outcome measures will include any of the following:

  1. Neonatal mortality (to four weeks post delivery) and mortality to hospital discharge.
  2. Neurodevelopmental disability defined as neurological abnormality including cerebral palsy on clinical examination after 12 months of postnatal age, developmental delay more than 2 standard deviations below population mean on any standard test of development, or blindness (visual acuity < 6/60), or deafness (any hearing impairment requiring amplification) at any time after term corrected.

Secondary outcome measures will include any of the following:

  1. Length of stay in
    1. neonatal intensive care
    2. hospital
  2. Evidence of organ dysfunction
    1. Abnormal neurological examination at discharge
    2. Abnormal feeding defined as requirement for nasogastric feeds at discharge
    3. Severity of respiratory distress syndrome quantified by days of assisted ventilation (either via endotracheal tube or nasal continuous positive airway pressure)
    4. Chronic lung disease as defined by supplemental oxygen requirement at 36 weeks post menstrual age
    5. Bone mineral accretion (measured by bone densitometry) at any time after term corrected
    6. Severe osteopaenia of prematurity identified by presence of pathological fracture
    7. Necrotising enterocolitis
  3. Evidence of any adverse events from hormone administration
    1. feminisation of males
    2. long term psychological morbidity, defined as any psychological disorder that meets diagnostic criteria of DSM-IVR

Search strategy for identification of studies

The standard search strategy of the 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 Controlled Trials Register (The Cochrane Library, Issue 2, 2004), MEDLINE, 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).

The search of MEDLINE, 1966 to July 2004 inclusive, included MeSH searches using the following terms ("infant, premature" AND [progest$ OR oestr$]) and text searches using the terms "[progest$ and oestr$]". Searches were limited to "clinical trials". No language restrictions were applied.

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Methods of the review

This systematic review followed the Cochrane Collaboration methodology according to guidelines of the Neonatal Review Group. Three reviewers independently identified the studies which are included, assessed the quality of the studies and extracted the data. Agreement between reviewers was reached through discussion. Methodological quality assessment was based on 1) blinding of randomisation, 2) blinding of intervention, 3) completeness of follow-up and 4) blinding of outcome measurement. When necessary, additional information and clarification of published data was requested from the authors of individual trials. Meta-analyses were performed using the fixed effects model, and a heterogeneity test (I-squared test) was applied to ensure that pooling of data was valid. Relative risk (RR) and risk difference (RD) were calculated for dichotomous data and weighted mean difference (WMD) for continuous data, with 95% confidence intervals (CI) for all analyses. The number needed to treat (NNT) and associated 95% CI were determined for a statistically significant reduction in the RD.

When extracting data from the included studies for the secondary outcome chronic lung disease, variations in definition were accepted as a post facto departure from the original protocol.

Description of studies

Two relevant studies were identified by the search.

The study by Trotter 1999a, included in this review, reported a cohort of infants that were reported in several different publications. Preliminary pharmacokinetic data relating to this study were reported in Trotter 1999. No clinically relevant outcomes were reported in that paper. Various aspects of clinical outcome for this cohort were then reported in Trotter 2002a and Trotter 2002b. Neurodevelopmental follow-up at 15 months of age was reported in Trotter 2001. These reports will be collectively referred to hereafter as Trotter 1999a. Female infants with gestational age < 29 weeks and birthweight < 1000grams were eligible for this study. During the study period, there were 40 eligible infants and consent was obtained for 30 infants, with 15 infants enrolled into either a replacement or control group. Infants in the replacement group received 15 ml/kg/day continuous intravenous infusion of estradiol and progesterone lipid 5% mixture, while the control group received an estradiol-progesterone free lipid 5% mixture. The dosage of estradiol and progesterone was tailored for each individual infant based on measurements of hormones in cord blood and subsequent blood samples at day 1, 3, 5, 7 and then weekly until the seventh postnatal week. The investigators' aim was to maintain plasma levels of 2000-6000 pg/ml for estradiol and 300-600 ng/ml for progesterone, corresponding to intrauterine levels at the same gestation. Once intravenous access was no longer required, the replacement group received estradiol and progesterone transepidermally for a total intervention period of six weeks. Refer to Table of Characteristics of Included Studies.

There was one other randomised trial of estrogen replacement reported by Shanklin 1970. This study was conducted between 1964 and 1966. In this study, 'premature' infants, not defined by gestation or birthweight, received an intramuscular injection within one hour of birth of either equine estrogens or lactose in diluent. The vials had been randomised by one of the investigators, their labels removed and then numbered. In a table of results, only 16 of 287 infants included in this study had birthweights less than 1000 grams. On the other hand, 187 of 287 (65%) of included infants had a birthweight over 2001 grams, effectively excluding them from the gestational range of interest in this review. This study was therefore excluded (see Table of Characteristics of Excluded Studies).

Methodological quality of included studies

Randomisation: Eligible infants in the study of Trotter 1999a were randomly assigned in blocks of four to receive either estradiol and progesterone replacement or placebo (controls). Method of randomisation was unstated in all reports of this study. Sealed envelopes were used.

Allocation concealment: Allocation to replacement or control group was carried out with the use of sealed envelopes.

Blinding of intervention: Whilst intravenous access was required, treatment infants received 15ml/kg/day of estradiol and progesterone-lipid 5% mixture whereas control infants received 15ml/kg/day of an estradiol- and progesterone-free lipid 5% mixture. Dosage of estradiol and progesterone was individualised for subjects in the replacement group, and for some infants this involved a change in infusion rate. There was no change in rate of infusion reported for the placebo group, hence potentially unblinding the intervention.
Once intravenous access was no longer required, replacement group infants received estradiol and progesterone ointment transepidermally. There was no placebo equivalent reported for transepidermal administration of the intervention. Intervention was conducted for six weeks in total. The number of infants in either group requiring intravenous therapy for the first six weeks postnatal life is not reported.

Blinding of outcome measurement: In the reports of Trotter 1999a and Trotter 2002a no reference is made to blinding of outcome measurement. In the report of Trotter 2002b the investigator assessing vaginal cytology was blind to intervention. There was no blinding of any other short term outcome measurement. Importantly, in the report of Trotter 2001, the psychologist and paediatric neurologist performing assessments of long term neurodevelopmental outcome were blind to treatment group.

Completeness of follow-up: The report of Trotter 2001 states that 25 survivors of 30 infants randomised to replacement or placebo were eligible for long-term follow-up. 24 infants were subsequently examined, and Bayley results were reported for 21 infants (21/25 =84%). Three infants (two receiving sex steroid and one control) were excluded from this analysis because sensory impairment invalidated administration of the Bayley scales, or the infant was too tired to perform the tests.

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Results

Thirty female infants in total were randomised in the study of Trotter 1999a to receive either combined estradiol and progesterone replacement or placebo for the first six postnatal weeks.

PRIMARY OUTCOME MEASURES:

Neonatal mortality and mortality to hospital discharge: There was no significant difference in either neonatal mortality (RR 2.0, 95%CI 0.2 to 19.78) or mortality to hospital discharge (RR 0.67, 95%CI 0.13 to 3.44) between preterm female infants who received estradiol and progesterone and those who received placebo.

Neurodevelopmental impairment: Trotter 2001 report neurodevelopmental outcome at 15 months of age for 24 of the 30 subjects first reported in Trotter 1999a. They report a trend to reduction of psychomotor index on Bayleys Developmental assessment for control infants compared to those that received hormone replacement, but only median, minimum and maximum scores are reported. Those infants receiving estradiol and progesterone had median MDI scores (min, max) of 89 (71, 107) compared to controls who had median MDI 93 (49, 111). Steroid supplemented infants had median PDI (min, max) of 101 (49, 121) compared to controls who had median PDI 71 (49, 121). The report of Trotter 2001 also suggests that control infants had more neurological impairment than those that received hormone replacement. From the data presented, there were no significant differences in neurodevelopmental outcome between the two groups. There are no data allowing comparison of components of neurological impairment (blindness, hearing impairment and cerebral palsy).

SECONDARY OUTCOME MEASURES:

  1. Length of stay in newborn intensive care is not reported. Trotter 1999a report a reduction in median length of stay in hospital for those infants who received estradiol and progesterone replacement compared to controls, however further analysis is not possible from the data available.
  2. Evidence of organ dysfunction
    1. Abnormal neurological examination at discharge - not reported.
    2. Abnormal feeding defined as requirement for nasogastric feeds at discharge - not reported.
    3. Severity of respiratory distress syndrome quantified by days of assisted ventilation (either via endotracheal tube or nasal continuous positive airway pressure) - not reported. However, the number of infants who were endotracheally intubated in each group was reported, and there was no significant difference between the groups (RR 0.92, 95%CI 0.62 to 1.36). Trotter 1999a report that 9 of 13 hormone replaced, and 11 of 14 controls were intubated. We have assumed that those infants who died in the first few days of life (2 in the replacement group and 1 in the control group) were intubated prior to death.
    4. Chronic lung disease as defined by supplemental oxygen requirement at 36 weeks post menstrual age - Whilst the definition of chronic lung disease used by Trotter 1999a is not stated, they report no significant difference in chronic lung disease between hormone replacement and control groups (RR 0.12, 95%CI 0.01 to 2.02). They sspecifythat 3 of 13 infants receiving hormone replacement, compared to 7 of 14 control infants were given dexamethasone to prevent chronic lung disease, but the criteria for administration of dexamethasone are not stated. Acceptance of this data without definition is a post-facto departure from the original protocol.
    5. Bone mineral accretion (measured by bone densitometry) at any time after term corrected - Bone densitometry was not performed as part of the only included study. However, bone mineral accretion rates, calculated by the measurement of dietary calcium and phosphorus intake and fecal and urinary calcium and phosphate excretion, suggest no difference in bone mineral accretion between hormone replaced and control infants.
    6. Severe osteopaenia of prematurity identified by presence of pathological fracture - not reported.
    7. Necrotising enterocolitis - There was no significant difference in the incidence of necrotising enterocolitis between those infants who received hormone replacement and controls (RR 0.33, 95% CI 0.01 to 7.58).

No adverse events related to hormone administration are reported in the included study.

Planned subgroup analyses could not be performed. There was only one trial enrolling only female subjects and randomising them to receive both estradiol and progesterone or placebo. Thus effects of gender or of individual hormone replacement could not be addressed. Administration of hormone was initially intravenous and then transdermal once intravascular access was no longer clinically required, to a total of six weeks of hormone treatment. Analysis of differences based on route of administration was not possible.

Discussion

This systematic review reports the results of 30 preterm female infants, with gestational age less than 29 weeks and birthweight less than 1000 grams, who were randomised to receive either a combination of estradiol and pprogesterone intravenously and transepidermally, or placebo intravenously, for the first six weeks of postnatal life. The dosage of hormone administered was individually tailored to maintain plasma estradiol and progesterone levels similar to those found in-utero at the same post-conceptional age. Despite the potential benefits of sex steroid administration, no clinically significant benefits are detectable from the administration of a combination of estradiol and progesterone, although the number of infants studied to date is small. The study reported by Trotter 1999a is described as a pilot study justifying the small number of infants randomised. To date there has been no data to suggest that some infants will maintain hormone levels similar to the in-utero status without supplementation, nor have there been any studies examining the effect of individual hormone replacement, different routes of administration or hormone replacement in male preterm infants. The dramatic difference in hormone profiles between the fetus in-utero compared to ex-utero infants of the same post-conceptional age, coupled with the limited findings suggesting benefits of sex steroid replacement, leave this area open to further scientific evaluation.

Reviewers' conclusions

Implications for practice

There is no evidence from randomised trials to support the routine replacement of estradiol or progesterone, either alone or in combination, in preterm infants. Furthermore, the data available currently do not adequately address the possibility that the administration of sex steroids to the preterm infant may be detrimental to long term psychological wellbeing. However, the little data available to date suggest no short term adverse effects from the maintenance of estradiol and progesterone levels similar to those experienced in utero. Administration of sex steroids to preterm infants should only take place within properly constructed randomised controlled trials.

Implications for research

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. Such a trial should include neurodevelopmental follow-up to at least two years of age, and would ideally include psychological follow-up into at least adolescence.

Acknowledgements

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Study Methods Participants Interventions Outcomes Notes Allocation concealment
Trotter 1999a Random study: yes, method not stated.
Allocation concealment: sealed envelopes batched into groups of four.
Blinding of intervention: Initially, continuous intravenous infusions were commenced at a rate of 15ml/kg/day of either estradiol-progesterone-lipid 5% mixture for the replacement group or lipid 5% mixture alone for the control group. Dosage of estradiol and progesterone varied between subjects in the replacement group, and this was varied for some infants by changing the infusion rate or altering the concentration of hormone in the infusate. No changes in infusion rate were reported for the placebo group - thus potentially unblinding the intervention. Once intravenous access was no longer required, estradiol and progesterone were administered transepidermally with ointment. There is no mention in any of the reports that a transepidermal placebo was applied to control infants.
Blinding of measurement: variably reported. Neurodevelopmental outcome data were collected by a psychologist and paediatric neurologist blind to treatment group.
Losses to follow-up: yes,
Neurodevelopmental follow-up data available for 24/25 survivors.

Allocation concealment: adequate.
Blinding of intervention: no.
Blinding of outcome measurement: yes.
Losses to follow-up: minimal.

Female infants with gestational age < 29 weeks and birthweight < 1000g were eligible. During the study period, consent was obtained for 30 of 40 eligible infants, and 15 infants were randomised to each of replacement and control groups. Intervention commenced as soon as intravenous access was established on the first day of life. In the replacement group, a continuous infusion of estradiol-progesterone-lipid 5% mixture was commenced at 15 ml/kg/day, and the infusion rate or concentration of hormone in the infusate adjusted to achieve plasma hormone levels of 2000-6000 pg/ml of estradiol and 300-600 ng/ml of progesterone. Dosage adjustment was based on measurement of plasma hormones from cord blood, and then serial measurements on days 1, 3, 5, 7 and then weekly until the seventh postnatal week. Once intravenous access was no longer required, estradiol and progesterone were administered transepidermally with ointment. No transepidermal placebo is reported. Short term morbidity (intraventricular haemorrhage, retinopathy of prematurity, necrotising enterocolitis and chronic lung disease) and mortality. Calcium and phosphorus balance are reported for a subset of the cohort (11 replacement infants and 9 controls). Uterine and mammary growth, and vaginal cytology are reported for the 25 survivors (13 replacement and 12 controls) of the original 30 randomised subjects. Neurodevelopmental follow-up is reported for 24 of 25 survivors. A

Characteristics of excluded studies

Study Reason for exclusion
Shanklin 1970 'Prematurity' not defined for this study and only 16/287 included infants had a birthweight < 1000 grams, whereas 187/287 infants had a birthweight > 2000 grams. Thus most infants studied would have had gestations > 30 weeks.

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References to studies

Included studies

Trotter 1999a

{published data only}

Trotter A, Bokelmann B, Sorgo W, Bechinger-Kornhuber D, Heinemann H, Schmucker G et al. Follow-up examination at the age of 15 months of extremely preterm infants after postnatal estradiol and progesterone replacement. Journal of Clinical Endocrinology and Metabolism 2001;86:601-3.

Trotter A, Maier L, Grill H-J, Wudy SA, Pohlandt F. 17-Beta-estradiol and progesterone supplementation in extremely low-birth-weight infants. Pediatric Research 1999;45:489-93.

* Trotter A, Maier L, Grill HJ, Kohn T, Heckmann M, Pohlandt F. Effects of postnatal estradiol and progesterone replacement in extremely preterm infants. Journal of Clinical Endocrinology and Metabolism 1999;84:4531-5.

Trotter A, Maier L, Kohn T, Bohm W, Pohlandt F. Growth of the uterus and mammary glands and vaginal cytologic features in extremely premature infants with postnatal replacement of estradiol and progesterone. American Journal of Obstetrics and Gynecology 2002;186:184-8.

Trotter A, Maier L, Pohlandt. Calcium and phosphorus balance of extremely preterm infants with estradiol and progesterone replacement. American Journal of Perinatology 2002;19:23-9.

Excluded studies

Shanklin 1970

{published data only}

Shanklin DR, Wolfson SL. Aqueous estrogens in the management of respiratory distress syndrome. Journal of Reproductive Medicine 1970;5:53-71.

* indicates the primary reference for the study

Other references

Additional references

Barnes 1980

Barnes AB, Colton T, Gundersen J, Noller KL, Tilley BC, Strama T, Townsend DE, Hatab P, O'Brien PC. Fertility and outcome of pregnancy in women exposed in utero to diethylstilbestrol. New England Journal of Medicine 1980;302:609-13.

Baulieu 1996

Baulieu EE, Schumacher M, Koenig H, Jung-Testas I, Akwa Y. Progesterone as a neurosteroid: actions within the nervous system. Cellular and Molecular Neurobiology 1996;16:143-54.

Beyer 1999

Beyer C. Estrogen and the developing mammalian brain. Anatomy and Embryology 1999;199:379-90.

Chu 1985

Chu AJ, Rooney SA. Estrogen stimulation of surfactant synthesis. Pediatric Pulmonology 1985;1[suppl]:S110-14.

Downey 1989

Downey J, Ehrhardt AA, Gruen R, Bell JJ, Morishima A. Psychopathology and social functioning in women with Turner syndrome. Journal of Nervous and Mental Disease 1989;177:191-201.

Henderson 1976

Henderson BE, Benton B, Cosgrove M, Baptista J, Aldrich J, Townsend D, Hart W, Mack TM. Urogenital tract abnormalities in sons of women treated with diethylstilbestrol. Pediatrics 1976;58:505-7.

Herbst 1975

Herbst AL, Poskanzer DC, Robboy SJ, Friedlander L, Scully RE. Prenatal exposure to stilbestrol. A prospective comparison of exposed female offspring with unexposed controls. New England Journal of Medicine 1975;292:334-9.

Hercz 1985

Hercz P. Quantitative changes in steroid and peptide hormones in the maternal-fetoplacental system between the 28th - 40th weeks of pregnancy. Acta Medica Hungarica 1985;42:29-39.

Kenny 1973

Kenny FM, Angsusingha K, Stinson D, Hotchkiss J. Unconjugated estrogens in the perinatal period. Pediatric Research 1973;7:826-31.

Khosla 1981

Khosla SS, Walker Smith GJ, Parks PA, Rooney SA. Effects of estrogen on fetal rabbit lung maturation: Morphological and biochemical studies. Pediatric Research 1981;15:1274-81.

Lindsay 1988

Lindsay R. Sex steroids in the pathogenesis and prevention of osteoporosis. In: Melton LJ, Riggs L, editor(s). Osteoporosis: Etiology, Diagnosis and Management. New York: Raven Press, 1988:333-358.

Lyon 1984

Lyon AJ, McIntosh N. Calcium and phosphorus balance in extremely low birthweight infants in the first six weeks of life. Archives of Disease in Childhood 1984;59:1145-50.

Matsumoto 1991

Matsumoto A. Synaptogenic action of sex steroids in developing and adult neuroendocrine brain. Psychoneuroendocrinology 1991;16:25-40.

Melton 2001

Melton L. What can sex hormones do for the damaged brain? Lancet 2001;358:818.

Ross 2000

Ross JL, Roeltgen D, Feuillan P, Kushner H, Cutler GB. Use of estrogen in young girls with Turner syndrome: effects on memory. Neurology 2000;54:164-70.

Siler-Kohr 1992

Siler-Khodr TM. Endocrine and paracrine function of the human placenta. In: Polin RA, Fox WW, editor(s). Fetal and neonatal physiology. Philadelphia, PA: WB Saunders, 1992:74-85.

Singh 2001

Singh K, Caplan M, Moya FR. Effects of antenatal and postnatal steroids on platelet activating factor acetylhydrolase activity in preterm infants. Pediatric Research 2001;49:343A.

Trotter 1999

Trotter A, Maier L, Grill H-J, Wudy SA, Pohlandt F. 17-Beta-estradiol and progesterone supplementation in extremely low-birth-weight infants. Pediatric Research 1999;45:489-93.

Trotter 2000

Trotter A, Pohlandt F. The replacement of oestradiol and progesterone in very premature infants. Annals of Medicine 2000;32:608-14.

Trotter 2001

Trotter A, Bokelmann B, Sorgo W, Bechinger-Kornhuber D, Heinemann H, Schmucker G et al. Follow-up examination at the age of 15 months of extremely preterm infants after postnatal estradiol and progesterone replacement. Journal of Clinical Endocrinology and Metabolism. 2001;86:601-3.

Trotter 2002a

Trotter A, Maier L, Pohlandt F. Calcium and phosphorus balance of extremely preterm infants with estradiol and progesterone replacement. American Journal of Perinatology 2002;19:23-9.

Trotter 2002b

Trotter A, Maier L, Kohn T, Bohm W, Pohlandt F. Growth of the uterus and mammary glands and vaginal cytologic features in extremely premature infants with postnatal replacement of estradiol and progesterone. American Journal of Obstetrics and Gynecology 2002;186:184-8.

Tulchinsky 1994

Tulchinsky D, Little AB. Maternal-Fetal Endocrinology. Second edition edition. Philadelphia, Pensylvania: W B Saunders Company, 1994.

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Data and analyses

01 Estradiol and progesterone replacement versus placebo

Comparison or outcome Studies Participants Statistical method Effect size
01.01 Neonatal mortality (to 28 days of age) 1 30 RR (fixed), 95% CI 2.00 [0.20, 19.78]
01.02 Mortality to hospital discharge 1 30 RR (fixed), 95% CI 0.67 [0.13, 3.44]
01.03 Endotracheal intubation 1 30 RR (fixed), 95% CI 0.92 [0.62, 1.36]
01.04 Chronic lung disease amongst survivors 1 27 RR (fixed), 95% CI 0.12 [0.01, 2.02]
01.05 Necrotising enterocolitis 1 30 RR (fixed), 95% CI 0.33 [0.01, 7.58]

Additional tables

  • None noted.

Amended sections

Cover sheet
Synopsis
Abstract
Objectives
Criteria for considering studies for this review
Search strategy for identification of studies
Methods of the review
Description of studies
Methodological quality of included studies
Results
Discussion
Reviewers' conclusions
References to studies
Other references
Characteristics of Included Studies
Characteristics of excluded studies
Comparisons, data or analyses

Contact details for co-reviewers

Dr Peter G Davis, MD, MBBS

Consultant Paediatrician
Division of Paediatrics
Royal Women's Hospital
132 Grattan St
Melbourne
Victoria AUSTRALIA
3053
Telephone 1: +61 3 93442000 extension: 2130
Facsimile: +61 3 93471761

E-mail: pgd@unimelb.edu.au

A/Prof Terrie E Inder

Peadiatric Neurologist/Neonatologist
Neonatal Services Division
Royal Women's Hospital
132 Grattan Street
Carlton, Melbourne
Victoria AUSTRALIA
3053
Telephone 1: +61 3 93442000 extension: 3178
Facsimile: +61 3 93472731

E-mail: terrie.inder@rch.org.au


This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2004 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and The Cochrane Library should be consulted for the most recent version of the Review.