Sex differences in cardiorespiratory transition and surfactant composition following preterm birth in sheep

Abstract

Male preterm infants are at greater risk of respiratory morbidity and mortality than females but mechanisms are poorly understood. Our objective was to identify the basis for the "male disadvantage" following preterm birth using an ovine model of preterm birth in which survival of females is greater than males. At 0.85 of term, fetal sheep underwent surgery (11 female, 10 male) for the implantation of vascular catheters to monitor blood gases and arterial pressure. After cesarean delivery at 0.90 of term, lambs were monitored for 4 h while spontaneously breathing; lambs were then euthanized and static lung compliance measured. We analyzed surfactant phospholipid composition in amniotic fluid and in bronchoalveolar lavage fluid (BALF) taken at necropsy; we also analyzed surfactant protein (SP) expression in lung tissue. Before delivery male fetuses tended to have lower pH (P = 0.052) compared with females. One hour after delivery, males had significantly lower pH and higher arterial partial pressure of CO(2) (Pa(CO(2))), lactate, glucose, and mean arterial pressure than females. Two males died 1 h after birth. Static lung compliance was 37% lower in males than females (P < 0.05). In BALF, males had significantly more protein, a lower percentage of the phosphatidylcholine (PC) 32:0 (dipalmitoylphosphatidylcholine) and higher percentages of PC34:2 and PC36:2. There were no sex-related differences in lung architecture or expression of SP-A, -B, -C, and -D. The lower lung compliance in male preterm lambs compared with females may be due to altered surfactant phospholipid composition and function. These changes may compromise gas exchange and impair respiratory adaptation after male preterm birth.

Respiratory adaptation and surfactant composition of unanesthetized male and female lambs differ for up to 8 h after preterm birth

“…This finding is consistent with that of our previous study (10) in which we found that male fetuses had a strong tendency (P = 0.052) to have a lower arterial pH compared to female fetuses. We cannot rule out the possibility that these differences are a result of male fetuses being less resilient to surgery than female fetuses, or whether they are indicative of an innate male disadvantage during fetal life with respect to acid-base balance.…”

“…We hypothesized that this initially poorer gas exchange and respiratory adaptation in the male lambs may be overcome with lung recruitment maneuvers such as CPAP; however, the use of CPAP did not improve survival or respiratory dynamics in male preterm lambs. The death of two (out of eight) male lambs within the first hour, in the present study, is a similar survival rate to that seen in our previous studies for preterm lambs (9,10). Two male lambs were killed due to severe hypercapnic acidosis, suggesting impaired pulmonary gas exchange; this indicates that CPAP alone may not be sufficient to improve gas exchange in preterm males.…”

“…*P < 0.05, female vs. male. 128 129 130 131 132 133 5 15 30 45 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 128 129 130 131 132 133 5 15 30 45 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 128 129 130 131 132 133 5 15 30 45 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 128 129 130 131 132 133 5 15 30 45 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 128 129 130 131 132 133 5 15 30 45 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 128 129 130 131 132 133 5 15 30 45 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480 Cesarean Physiological markers of cardiorespiratory adaptation during the first 4 h of the present study, in preterm male and female lambs, were similar to those seen in our previous study at 4 h after birth (10). We can now add that respiratory adaptation in males does not worsen between 4 and 8 h after birth.…”

“…Of note, female lambs reached the target Sao 2 of 80% earlier than males in both the previous 4-h study (10) and the present 8-h study. In agreement with our findings, spontaneously breathing female preterm human neonates (≤32 wk of gestation), receiving CPAP and air, were shown to achieve targeted preductal oxygen saturation levels earlier than males (19).…”

“…We recently reported that the poorer respiratory adaptation in male preterm lambs (born at 0.9 of term) was likely due to lower lung compliance than in females and that this may be a result of sex differences in surfactant phospholipid composition and function (10). As our previous study was terminated at only 4 h after delivery, we wished to extend our observation period up to 8 h after preterm delivery to determine if the sex-related differences in postnatal adaptation worsen with time, which could explain the decreased survival rate that we observed in males after 4 h.…”