Effect of maternal asthma, inhaled glucocorticoids and cigarette use during pregnancy on the newborn insulin-like growth factor axis
Introduction
Size at birth reflects fetal growth and substrate supply in utero and is associated with neonatal morbidity and mortality and longer term health outcomes [1]. Previously, we have reported that maternal asthma during pregnancy affects fetal growth and development in a sex-specific manner [2]. Female fetal growth was reduced and male growth was normal in the presence of maternal asthma that was not treated with inhaled glucocorticoids [2]. In the presence of a second stressful event such as an acute asthma exacerbation, the mean birthweight of the male fetus was reduced with an increased incidence of IUGR, preterm delivery or still birth in males only [3]. In the presence of an exacerbation of asthma female growth did not change though the fetus was already small due to adjustments in growth in response to the pre-existing complication of asthma [3]. These studies and others [4], [5] suggest that male and female fetuses respond differently to stressful events during pregnancy and these differences lead to alterations in birth weight. The mechanisms contributing to these sex-specific differences in responses to adverse exposures before birth are yet to be examined but may be mediated via changes in placental function [6]. Since the IGF axis is known to be a major contributing factor to fetal and placental development [1] it may contribute to the sex-specific differences in fetal growth observed in pregnancies complicated by asthma.
IGF-1 and IGF-2 are polypeptides with a sequence related to that of insulin [7], which have mitogenic properties, inducing somatic cell growth and proliferation [8], [9]. Knockout and transgenic mice studies have demonstrated that IGF-1 and IGF-2 are required for optimal fetal and placental growth [10], [11], [12], [13]. The actions of IGF-1 and IGF-2 are modulated by insulin-like growth factor binding proteins (IGFBP 1–6) [14]. IGFBP 1, 2, 4, 5 and 6 are present in low concentrations in adult plasma [15]. The predominant form, IGFBP-3 complexes with IGF-1 or 2 and an acid-labile subunit, the complex acting as a reservoir for IGFs in the circulation [14], [16]. IGFBP-1 is dynamically regulated in human plasma, binding IGF-1 and -2 [14], [17] with similar or greater affinity than either of the IGF receptors, thus preventing the IGFs from exerting their mitogenic actions [14]. Over-expression of IGFBP-1 in transgenic mice transiently reduces fetal growth in mid-gestation [18].
Numerous studies have found a positive relationship between circulating levels of IGF-1 in cord plasma and birth weight in normal term singleton infants [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29]. In pregnancies complicated by intrauterine growth restriction (IUGR), umbilical cord blood IGF-1 is reduced compared to pregnancies with normal fetal growth [30], [31], [32], [33], [34]. The relationship between newborn plasma IGF-2 and birth weight is less clear with a positive correlation in term singletons in some [20], [27], but not all studies [19], [21] and no difference between normally grown and growth restricted neonates in another [30]. However, cord blood IGF-2 has been described to be positively correlated with placental weight [24], consistent with an important role in placental growth in a range of studies in other species [11], [12], [13], [35].
The relationship between cord blood IGFBPs and fetal growth has also been examined. IGFBP-3 correlates positively with birth weight [21], [25], [27], [36], while IGFBP-1 is inversely correlated with birth weight in term [22], [29], [37] or preterm infants [38], [39]. Increased cord blood IGFBP-1 [40] and reduced IGFBP-3 have also been observed in IUGR neonates [31], [32], [40] consistent with IGFBP-3 providing a reservoir for IGFs and IGFBP-1 inhibiting IGF actions.
The human placenta produces IGF-1 and IGF-2 which may act as local growth regulators [41] with IGF-2 more highly expressed. IGF-2 is found throughout the chorionic villi, chorionic plate, basal plate and fetal membranes, while all IGFBPs are found in the decidua, with IGFBP-1 in greatest abundance [42], [43]. During human pregnancy, IGFBP-1 may also be a major regulator of IGFs in the fetus and placenta, since it is the main product of the decidua, the main IGFBP in the amniotic fluid and a major binder of IGFs in fetal plasma [44], [45], [46].
Cortisol has been characterised as an important indirect regulator of fetal growth through its actions on IGFs and their binding proteins [1]. Cianfarani et al. [34] found that there was a positive correlation between IGFBP-1 and cortisol in human cord blood from appropriately grown fetuses. However, they could not demonstrate any such relationship in IUGR fetuses suggesting there are other factors influencing fetal growth in IUGR pregnancies [34]. Other studies report that glucocorticoids have varying effects on IGFBP-1 levels. For example, increased plasma IGFBP-1 concentrations have been reported following cortisol infusions in adults [15]. IGFBP-1 was increased in neonates following a stressful labour and delivery [47] and IGFBP-1 production was inhibited following dexamethasone treatment in fetal liver explants [48]. In the sheep fetus, IGF mRNA is decreased with cortisol treatment in the adrenal and liver [49], [50]. These studies have shown IGF-1 and IGF-2 are down regulated by cortisol while IGFBP-1 concentrations are increased. Since we have previously observed sex-specific differences in the placental response to cortisol in pregnancies complicated by asthma, in this study we examined the relationship between maternal asthma, fetal cortisol and the IGF axis.
Fetal sex is known to affect fetal growth, with male fetuses on average being larger than female fetuses [51], [52], [53]. This difference may not be evident until after 30 weeks [51], [54], but increases as gestation progresses [53] with a 150–200 g weight difference apparent by 38 weeks gestation [53], [54]. The mechanisms which contribute to the different growth patterns of male and female fetuses remain unclear. However, differences in growth regulation by the IGF axis may be involved. A recent study of 987 healthy singletons found that IGF-1 and IGFBP-3 concentrations in cord blood were higher in females than males [55]. No difference in cord blood IGF-2 between male and female neonates was reported, while growth hormone concentrations were higher in males than females [55]. Few other studies have examined sexually dimorphic patterns of IGF expression or production in the human fetus [19], [28].
The present study therefore sought to determine the effect of maternal asthma on the IGF axis in relation to fetal sex and growth for the first time. Another common exposure in pregnancy that adversely affects fetal growth is cigarette use. Cigarette use is still common in the Australian community affecting 20–25% of pregnancies [56]. In pregnancy, cigarette use is known to be associated with several adverse outcomes including IUGR [57] and stillbirth [58]. Previous studies have reported that female birth weight relative to male birth weight was reduced in the presence of maternal cigarette use during pregnancy [59]. Pringle et al. [60] has reported decreased cord blood IGF-1 and IGFBP-3 concentrations with cigarette use. Previous studies indicate a combination of adverse factors may be a powerful stimulus for altered growth and development of the fetus during pregnancy and may affect males and females differentially. The present study sought to determine this possibility by examining the effect of maternal asthma on the IGF axis in relation to fetal sex and growth, and to identify whether cigarette smoking compounded this effect.
Section snippets
Experimental subjects
The study was approved by the Hunter Area Health Service and University of Newcastle Human Research Ethics Committees. Pregnant women were recruited at the John Hunter Hospital antenatal clinic during the first trimester (n = 490) and provided written informed consent for participation. The protocol for this study has been described in detail previously [2]. Those women with complications other than asthma such as pre-eclampsia, gestational diabetes, infection or preterm delivery were excluded
Materials and methods
Clinical asthma severity was rated as mild, moderate or severe using the integrated severity score described in the Australian Asthma Management Guidelines [61], which closely approximate the National Heart, Lungs and Blood Institute Guidelines [62]. Proper inhaler use and compliance was assessed in the Asthma Management Service [63]. Cumulative, inhaled glucocorticoid dose was calculated for each trimester, and summarised as the mean daily dose of beclomethasone dipropionate (BDP) or
Maternal characteristics
Maternal characteristics in relation to asthma severity and fetal sex are shown in Table 1. Maternal age was reduced in both asthmatic groups compared to controls [F(2, 139) = 4.907, p = 0.009]. Maternal FEV1 was reduced in women with severe asthma compared to controls [F(2, 112) = 3.290, p = 0.041. post hoc test p < 0.05]. The percent predicted FEV1 was reduced in moderate-severe women, compared to both mild asthmatics and controls [F(2, 71) = 5.664, p = 0.005, post hoc test p < 0.05]. Inhaled glucocorticoid
Discussion
This study has identified sex-specific differences in the IGF axis in the presence of maternal asthma and in the presence of maternal cigarette use during pregnancy. Mild maternal asthma was associated with no change in neonatal birth weight relative to the control population and increased cord plasma IGF-1 in only newborn males. Both male and female birth weights were reduced in the presence of moderate-severe maternal asthma with no significant change in any component of the IGF axis when
Sources of funding
National Health and Medical Research Council (ID 252438), Asthma Foundation of NSW, Hunter Medical Research Institute, NSW Health. Vanessa Murphy was the recipient of a National Health and Medical Research Council Dora Lush (Biomedical) Postgraduate Scholarship and a Hunter Medical Research Institute/Port Waratah Coal Services Postdoctoral Fellowship. A/Prof Vicki Clifton was the recipient of the Arthur Wilson Memorial Scholarship from the Royal Australian College of Obstetricians and
Acknowledgements
There have been numerous collaborators in the asthma and pregnancy study who have contributed in the collection of the data. Professor Peter Gibson supervised the classification of pregnant asthmatic women. Srs. Philippa Talbot and Caroline Kessell were respiratory research nurses involved in the recruitment and care of pregnant women. We thank the staff of the antenatal clinics and delivery suite at John Hunter Hospital for assistance with subject recruitment and the collection of placenta
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