Gender differences in perinatal morbidity and long term consequences of preterm birth

Abstract: Newborn male infants have higher morbidity and mortality than female infants. Male fetal gender is associated with an overall increased risk of preterm birth and complications related to pregnancy are overrepresented in women carrying male fetuses. Several studies have shown that being newborn and of male gender are independent risk factors for adverse outcome. Even though experimental data from newborn animals have shown that many gender differences can be explained by differences in hormonal function and stress responses, the specific mechanisms leading to the increased risks for newborn boys have not been clarified. However, several gender specific reactions and physiologic responses have been described in both the fetus and newborn infant, some of these differences persist during childhood; although later other gender specific differences become more important. The aim of this thesis was to further study gender differences in perinatal morbidity and long term consequences of preterm birth. It is important to identify early predicting factors that can help to screen which male preterm infants who face increased mortality and morbidity risks. In an attempt to find such early signs, gender related differences in clinical parameters during the first week of life were assessed in paper I. This paper concludes that there are gender related differences in ventilatory and circulatory support that may contribute to the worse long-term outcome in prematurely born male infants. Two epidemiological studies were carried out (papers III and V) using the Medical Birth Register (MBR) to further elucidate gender differences in morbidity, mortality and long term consequences of preterm birth. The aim of paper III was to investigate if the fetal and newborn gender is associated with the incidence of pregnancy complications and if the gender associated risk changes with gestational age at delivery. The fetal gender affected the occurrence of preeclampsia, woman carrying male infants were subjected to an overall a higher risk of developing preeclampsia. However, the male:female ratio was decreased in preeclampsia associated with preterm delivery. In paper V we investigated if gender mix in twin pairs was related to obstetric and neonatal morbidity and mortality. The results show that male twin gender was significantly associated with respiratory morbidity and increased risk of mortality. Paper II and V were carried out in order to understand if the gender related differences associated with preterm birth can be explained by differences in hormonal and stress responses. Paper II focused on response aspects immediately after birth, whereas paper V focused on long-term response aspects. In paper II we tested the hypothesis that umbilical cord interleukin-1 receptor antagonist (IL-1ra) correlates with infant gender and neonatal outcome in preterm infants. We concluded that umbilical cord IL-1ra was associated with neonatal morbidity, especially postnatal depression after delivery and development of BPD in very preterm female infants. Although there were no gender differences in levels of umbilical cord IL-1ra the concentration of IL-1ra had different implications for neonatal morbidity depending on infant´s gender. The aim of paper IV was to investigate if salivary cortisol and blood pressure responses differed in adolescents born prematurely compared to term born controls, and whether there were gender differences in these responses. Blood pressure was significantly higher and dynamic blood pressure responses differed in prematurely born AGA children as compared to both term controls and preterm SGA children, but there were no gender specific differences in these responses. In conclusion, this thesis contributes to increased understanding of gender-related differences associated with preterm birth. The work highlights gender related differences from both short-term and long-term perspectives. The results show that there are gender related differences with regards to pregnancy complications, the need for ventilatory and circulatory support as well as respiratory morbidity during the neonatal period. It was also confirmed that markers such as IL1-ra, cortisol and blood pressure correlate to neonatal morbidity and preterm birth; however no clear gender-related differences were seen in these responses. Further research on preterm birth with a gender perspective is warranted and will be beneficial for both boys and girls as an increased knowledge and understanding of general disease mechanisms will further improve and personalize the neonatal care