Maintenance of in utero plasma levels of oestradiol and progesterone was achieved with the ESTRA‐PRO emulsion as in our previous study.10
Surviving infants who received the hormone replacement ATP showed a trend to less BPD (p
0.08), which is in accordance with the result from the pilot study.10
The effect of the hormone replacement was associated with the number of days with hormone replacement (p
0.04). Altogether, the goal of the study was not reached.
Twenty two infants survived but were not treated ATP. The incidence of BPD was higher in this subgroup (five of seven (71%) in the placebo group and nine of 15 (60%) in the ESTRA‐PRO group) compared with 32% and 14%, respectively, in the ATP population. In this subgroup, increased markers of bacterial infection (for definition see table 1) were found postnatally in 91% (71% in the placebo and 100% in the ESTRA‐PRO group) compared with 67% in the ATP group. Infection has been recognised as a risk factor for the development of BPD14
and may have contributed to the high rate of BPD in the non‐ATP subgroup.
In the pilot study,10
there was no difference in plasma triglyceride levels between the replacement (mean 1.3 mmol/l, min–max 0.3–4.8 mmol/l) and the control group (1.47 mmol/l, 0.3–4.9 mmol/l) in the first 28 days after birth, and transient hypertriglyceridaemia (>3.0 mmol/l) was present in 20% of the infants of both groups (unpublished data). In this study, the incidence of hypertriglyceridaemia in the ESTRA‐PRO group was twice as high as in the placebo group (p
0.05). As all other parenteral lipid administration was stopped before withdrawal of the study emulsion, the difference in the incidence of hypertriglyceridaemia between the groups was not explained by a different total lipid supply. For a long time it has been known that plasma triglycerides rise markedly during pregnancy,15
and this was confirmed by more recent investigations.16
Removal of triglycerides may be impaired by diminished activity of lipolytic enzymes. The activity of lipoprotein lipase has been shown to be decreased in pregnant women.17
Oestradiol and progesterone have been shown to decrease the activity of lipoprotein lipase in vitro18
and in vivo.19
Possibly, the response to oestradiol and progesterone is the same in the preterm infant as in the mother, which decreases lipolysis and leads to hypertriglyceridaemia. Sepsis in preterm infants has been associated with reduced ability to use lipids,21
and this effect may be explained by downregulation of lipoprotein lipases.22
In the ESTRA‐PRO group, there was a trend for higher rates of prolonged rupture of membranes (49% v
0.07, table 1) and increased markers of bacterial infections postnatally (81% v
0.14, table 1). This may provide an alternative explanation for the higher incidence of hypertriglyceridaemia. In addition, the higher rate of early‐onset infections in the ESTRA‐PRO group may have diminished the potentially beneficial effects of oestradiol and progesterone replacement on the incidence of BPD.14
Interestingly, none of the surviving infants of the ESTRA‐PRO group treated ATP developed severe retinopathy of prematurity (ROP). This may be an incidental observation and ROP was not a primary outcome variable. However, in vitro and in vivo studies suggest that oestradiol may prevent ROP.23
Preterm birth leads to delayed retinal vascular growth with insufficient vascularisation. This results in hypoxia of the retina, with release of factors stimulating new and abnormal blood vessel growth.25
Vascular endothelial growth factor (VEGF) is an important oxygen‐regulated factor that, if suppressed, inhibits normal vessel growth, but, if in excess, results in retinal neovascularisation. Recently, oestradiol has been shown to function as a significant stimulator of VEGF mRNA expression in retinal endothelial cells.23
In a mouse model of ROP, treatment with oestradiol under different oxygen conditions significantly improved retinopathy by acting on VEGF expression.24
Infants of the ESTRA‐PRO group were discharged home nearly 2 weeks earlier (ITT and ATP population). Early discharge may be a surrogate for achievement of several conditions of preterm infants not further elaborated in this study. A role of oestradiol and progesterone in the prenatal development of the central nervous system is conceivable.26
The follow‐up investigation of the infants of our first pilot study at the corrected age of 15 months showed improved psychomotor development in those infants who had received oestradiol and progesterone replacement after birth.27
Most recently, oestradiol has been recognised as a potentially preventive neuroprotective agent in sick preterm infants who need to be exposed to oxygen or drugs with neurotoxic side effects.28
Several limitations of the study need to be considered. A significant loss of study participants for the ATP analysis was observed because of hypertriglyceridaemia. A major flaw of this study is that we did not compensate for this. The incidence of multiple births in the placebo group was twice as high as found within the verum group (NS), which may have biased the results. On the other hand, no difference was found with regard to birth weight and gestational age between the groups. The protocol violations by hypertriglyceridaemia were seen more often in the replacement group, and this may have biased the results for the ATP analysis. However, the outcome BPD within the surviving dropouts was the same for both groups. Within the ATP population, postnatal dexamethasone was more often used in the ESTRA‐PRO group. During the study period, criteria for use of dexamethasone were not strictly defined. Because the adjusted dose–response relationship between “duration of administration of the study emulsion” and the outcome BPD was virtually unaffected using dexamethasone as a potential confounder, we consider this difference to have occurred by chance. As in our pilot study,10
a trend towards reduced incidence of BPD was seen with the replacement if infants were treated ATP. No obvious serious adverse side effects were observed with the replacement, but lipid metabolism needs to be monitored carefully. Further basic research and sufficiently powered clinical trials are needed to evaluate this new approach in the management of preterm infants.
What is already known on this topic
- From in vitro and animal models, it is known that oestradiol and progesterone may have a major effect on lung development and function.
What this study adds
- This study adds clinical data that preterm infants may benefit in lung development from replacement of oestradiol and progesterone after birth
- A larger better‐powered study will be required to determine this reliably