An investigation of the basis for the male disadvantage in respiratory function and survival following preterm birth
thesisposted on 01.03.2017 by Ishak, Noreen
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Preterm birth accounts for about 8–12% of live births in most developed countries. It is widely known that male preterm infants have a greater risk of respiratory insufficiency than females, which may have long-term consequences. Male preterm infants require more initial respiratory and circulatory support than preterm females. To date, little is known about the causes and basis of this male disadvantage and further investigation is required for a better understanding. The aim of this study was to make an in-depth investigation of the possible causes for the male disadvantage in respiratory function following preterm birth. In one study (fetal study group) we used fetal sheep at 131 days of gestation (d GA; term is 147 days) to provide lung tissue for morphometric analysis and measurement of gene expression of surfactant proteins and tropoelastin in male and female preterm fetuses. In two other groups of sheep (postnatal studies) we used an established model of moderate preterm birth for physiological studies before and after preterm birth. In the postnatal studies, preterm lambs were delivered at 133d GA as lambs born at this age demonstrate lower survival in males than females. The animals in the postnatal study group were grouped into two cohorts; one group was studied for 4 hours (h) after birth and the other group was studied for 8 h to determine whether any differences between the sexes changed with time after birth. Pregnant ewes from both cohorts underwent surgery to chronically implant fetuses with catheters at ~125d GA for the measurement of fetal physiological status at 131 and 132d GA and fluid (plasma, lung liquid and amniotic fluid) sampling and collection from 125–133d GA. A small dose of betamethasone (5.7 mg of Celestone Chronodose) was administered to the ewe at 131d GA. Unanaesthetised lambs were delivered at 133d GA, approximately 14 days before term, and then studied physiologically for 4 h or 8 h after delivery. At the end of the 4 h or 8 h study periods, the lambs were euthanised for measurement of static lung compliance and collection of bronchoalveolar lavage fluid (BALF) and lung tissue. The surfactant phospholipid composition and protein concentration of BALF and the gene expression of surfactant proteins (SP)-A, -B, -C and -D and the protein expression of SP-A and pro-SP-C in lung tissue were also measured. We observed that, at necropsy, lungs excised from fetal sheep at 131d GA were similar in males and females in terms of lung morphology and surfactant protein and tropoelastin gene expression. Our findings indicate that these factors did not contribute to the male disadvantage. Minor differences in surfactant phospholipid composition were observed in the fetal lung liquid collected but it is unknown to what extent they affect respiratory outcome. In the postnatal study where lambs were monitored for 4 h following preterm birth, male lambs demonstrated poorer arterial blood gas parameters (lower pH and higher PaCO₂,) higher arterial glucose and lactate concentrations and had a greater requirement for supplemental oxygen. Arterial cortisol concentration was lower in males than in females before birth. In males we observed altered surfactant phospholipid composition (significantly lower proportions of the molecular species PC 32:0 and higher PC 34:2 and PC 36:2 compared to females) and elevated protein concentration in the BALF, and significantly lower pro-SP-C protein expression in lung tissue; together these alterations could impair surfactant function and contribute to the lower lung volume at necropsy when the lungs were inflated at a pressure of 40 cmH₂0. Overall, the observed sex differences indicate poorer postnatal adaptation in males and could account for the death of 2 males following the first hour of delivery. Consistent with the findings in the fetal sheep, the lung morphology and surfactant protein gene expression were similar in males and females at 4 h after birth, indicating that the male disadvantage in respiratory function following preterm birth is unlikely to be a result of sex differences in lung architecture and surfactant protein gene expression. When another group of lambs was monitored for 8 h after preterm delivery, the findings from the 4 h postnatal study were largely confirmed but there were subtle differences, some of which could be due to the different ventilation technique used in this group of lambs. As in the 4 h study, poorer gas exchange (lower pH and higher PaCO₂) was observed in males. Major findings were a greater inspiratory effort in male lambs than those of female lambs and that male lungs continued to be less compliant than female lungs for up to 8 h after birth. The BALF of males collected at 8 h after birth had significantly lower proportions of the molecular species PC 32:1 and PE 36:2 than in females. In lung tissue, pro-SP-C protein expression was significantly lower in male lambs than in females. We conclude that the male disadvantage in cardio-respiratory adaptation following preterm birth is likely caused by subtle alterations in surfactant phospholipid composition. These may consequently affect lung compliance, thereby altering gas exchange and arterial blood gas parameters. This study provides evidence to support the provision of a targeted intervention in the management of male preterm babies to reduce the RDS incidence and increase the chance of survival.