Asthma during pregnancy is associated with a low birth weight, although the mechanisms contributing to this outcome remain unknown. The relationship between maternal asthma and its treatment, placental function, fetal sex, and low birth weight was examined to establish the effect of asthma on fetal growth. Glucocorticoid intake by women with asthma was assessed throughout pregnancy. The placenta was collected after delivery, and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity was measured. Fetal cortisol and estriol were measured in the umbilical vein plasma at delivery. Those with asthma were compared with a nonasthmatic control group. In women with asthma who did not use inhaled steroids and were pregnant with a female fetus, we observed significantly reduced birth weights, whereas male birth weights were unaffected. The presence of a female fetus was associated with significantly increased maternal circulating monocytes, significantly reduced placental 11β-HSD2 activity and fetal estriol, and a trend toward elevated fetal plasma cortisol. This study provides evidence that in pregnancies complicated by asthma there is a fetal sex-specific effect on the maternal immune system with adverse effects on placental function and female fetal growth.
The prevalence of asthma in Western societies is increasing (1, 2). Inflammatory diseases during pregnancy such as asthma (3–8), malaria (9, 10), rheumatoid arthritis (11), inflammatory bowel disease (12, 13) and systemic lupus erythematosis (14) are characterized by poor pregnancy outcomes, including low birth weight. Low birth weight predisposes neonates to an increased risk of developing diseases such as hypertension (15, 16), heart disease (17), and diabetes (18) in adult life. In addition, the maternal–fetal environment during pregnancy may be an important factor in the development of atopy and asthma in childhood (19, 20). The mechanisms causing low birth weight in women with asthma are currently unknown; however, alterations in placental function, asthma severity, or treatment may be contributing factors (21). Inflammation in the mother may also play a role in fetal growth regulation, as elevated maternal serum levels or increased placental gene expression of inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-8 (10, 22, 23), IL-18 (24), and macrophage colony-stimulating factor (25) have previously been associated with intrauterine growth restriction.
The placenta plays an important role in controlling fetal growth by supplying nutrients and oxygen from the mother. The placenta also prevents the transfer of large concentrations of maternal cortisol to the fetus. The placental enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) performs this function, acting as a barrier by metabolizing cortisol to inactive cortisone, thereby preventing excess maternal cortisol from reaching the fetus, where it may inhibit fetal growth. Previous studies have demonstrated reduced 11β-HSD2 enzyme activity in intrauterine growth restriction (26).
This study has been a detailed examination of the relationships between mother, placenta, and fetus in pregnancies complicated by asthma, with the aim of understanding what factors are important for normal fetal growth in this disease state. Some of the results have been previously reported in the form of abstracts (27, 28).
The study was approved by the Hunter Area Health Service and University of Newcastle Human Research Ethics Committees. Pregnant women with and without asthma were recruited in the John Hunter Hospital antenatal clinic during the first trimester after a previously described protocol (21). Clinical asthma severity was rated as mild, moderate, or severe using the integrated severity score described in the Australian Asthma Management Guidelines (29), which closely approximate the National Heart, Lungs, and Blood Institute Guidelines (30). Proper inhaler use and compliance was assessed in the Asthma Management Service. Cumulative, inhaled glucocorticoid dose was calculated for each trimester and summarized as the mean daily dose of beclomethasone dipropionate or equivalent used during pregnancy, where 1 μg of beclomethasone dipropionate was considered equal to 1 μg of budesonide or 0.5 μg of fluticasone propionate (31). Subjects with asthma were grouped based on glucocorticoid dosage: no glucocorticoid use, low-dose glucocorticoid (less than 400 μg/day), moderate-dose glucocorticoid (400–1,500 μg/day), and high-dose glucocorticoid (more than 1,500 μg/day). For most data analysis, the low-, moderate-, and high-dose groups were combined (glucocorticoid). Women with asthma in all groups used the inhaled β2 agonist salbutamol for symptom relief when required.
A full blood count was measured in maternal blood from samples collected in early pregnancy (less than 20 weeks) and late pregnancy (more than 30 weeks).
Fetal biparietal diameter, head circumference, abdominal circumference, and femur length were measured at 18 and 30 weeks of gestation by ultrasound. Birth weight and head circumference were recorded at delivery, and centiles were calculated using John Hunter Hospital intrauterine growth charts (32), based on gestational age determined by the date of the last menstrual period and an 18-week ultrasound. The placenta and cord blood were collected after delivery from a subset of patients.
Placental 11β-HSD2 activity was measured as previously described (33) by the conversion of 3H-cortisol to 3H-cortisone in placental microsomes after a 15-minute incubation at 37°C with a saturating concentration of cortisol (5 μM). Cortisol and unconjugated estriol were measured in umbilical vein plasma using commercial radioimmunoassay kits (Orion Diagnostica, Espoo, Finland; and DSL, Webster, TX, respectively). The sensitivity of the cortisol assay was 5 nM and of the estriol assay was 0.03 ng/ml.
Results are presented as means ± SEM. Statistical analysis was performed using GraphPad Instat version 2.04a (GraphPad Software, Inc., San Diego, CA) and Stata version 7 (Stata Corporation, College Station, TX). Analysis of variance (ANOVA) and the nonparametric equivalent were used where appropriate. Graphical methods were used to test distributional assumptions. When comparing two groups with a normal distribution, the Student's t test was used to compare means, whereas the Mann-Whitney test was used to compare medians of two groups where data were not normally distributed. A p value of less than 0.05 was considered significant. A multivariate analysis was performed using Stata version 7. Generalized linear latent and mixed models and generalized estimating equations were used for repeated-measures data (34, 35). Outcomes were adjusted for asthma severity, cumulative inhaled glucocorticoid intake, fetal sex, and smoking.
Pregnant women with asthma (n = 138) and pregnant women without asthma (control, n = 44) were recruited during the first trimester. Clinical assessment divided the women with asthma into 62 with mild asthma, 28 with moderate asthma, and 48 with severe asthma. Women with asthma were classified based on inhaled glucocorticoid intake during pregnancy as no glucocorticoid or glucocorticoid. Clinical characteristics separate from asthma were similar in all groups (Table 1)
Classification of Inhaled Glucocorticoid Intake During Pregnancy | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Female Fetus | Male Fetus | ||||||||||
Control | No Glucocorticoid | Glucocorticoid | Control | No Glucocorticoid | Glucocorticoid | ||||||
Total number of subjects | 21 | 22 | 47 | 23 | 24 | 45 | |||||
Asthma severity | 18 Mild | 14 Mild | 16 Mild | 14 Mild | |||||||
0 Moderate | 10 Moderate | 5 Moderate | 13 Moderate | ||||||||
4 Severe | 23 Severe | 3 Severe | 18 Severe | ||||||||
Maternal FEV1 (I) | 3.24 ± 0.16 (n = 11)* | 3.20 ± 0.11 (n = 21) | 3.02 ± 0.08 (n = 44) | 3.26 ± 0.13 (n = 13)* | 3.17 ± 0.08 (n = 24) | 3.02 ± 0.07 (n = 45) | |||||
Maternal FEV1:VC | 0.88 ± 0.03 (n = 11) | 0.85 ± 0.01 (n = 20) | 0.79 ± 0.01 (n = 39)† | 0.83 ± 0.01 (n = 13) | 0.82 ± 0.01 (n = 21) | 0.81 ± 0.01 (n = 41) | |||||
Maternal body mass index | 24.6 ± 1.5 (n = 15) | 25.2 ± 1.0 (n = 21) | 27.3 ± 1.1 (n = 40) | 28.1 ± 1.6 (n = 17) | 28.5 ± 2.0 (n = 22) | 28.1 ± 1.1 (n = 40) | |||||
Gravidity | 2.9 ± 0.6 (n = 21) | 2.1 ± 0.3 (n = 22) | 2.6 ± 0.2 (n = 47) | 2.9 ± 0.4 (n = 23) | 2.8 ± 0.4 (n = 24) | 2.1 ± 0.2 (n = 45) | |||||
Parity | 1.3 ± 0.3 (n = 21) | 0.6 ± 0.2 (n = 22) | 1.0 ± 0.2 (n = 47) | 1.5 ± 0.3 (n = 23) | 1.0 ± 0.2 (n = 24) | 0.8 ± 0.1 (n = 45) |
FEV1 was lower in the groups with asthma (no glucocorticoid, 3.19 ± 0.07 L, n = 45; glucocorticoid, 3.02 ± 0.05 l, n = 90) compared with the control group (3.25 ± 0.10 L, n = 24, ANOVA, p = 0.05). The maternal FEV1:VC ratio was significantly lower in women of the glucocorticoid group who were pregnant with a female fetus compared with women in the no-glucocorticoid group who were pregnant with a female fetus (Mann-Whitney test, p = 0.015; Table 1). However, among women pregnant with a male fetus, there was no significant difference in the maternal FEV1:VC between the glucocorticoid and no-glucocorticoid groups (Mann-Whitney test, p = 0.345; Table 1).
There were no significant differences in fetal biparietal diameter, head circumference, abdominal circumference, or femur length between any groups at either 18 or 30 weeks of gestation (ANOVA, p > 0.05).
The birth weight of female neonates in the no-glucocorticoid group was significantly reduced compared with females in the control and glucocorticoid groups (Kruskal-Wallis nonparametric ANOVA, p = 0.027; Table 2)
Classification of Inhaled Glucocorticoid Intake During Pregnancy | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Female Fetus | Male Fetus | ||||||||||
Control | No Glucocorticoid | Glucocorticoid | Control | No Glucocorticoid | Glucocorticoid | ||||||
Gestational age, weeks | 38.9 ± 1.0 (n = 21) | 39.0 ± 0.6 (n = 22) | 39.2 ± 0.2 (n = 47) | 39.6 ± 0.4 (n = 23) | 39.6 ± 0.4 (n = 23) | 38.9 ± 0.4 (n = 45) | |||||
Birth weight, g | 3527.7 ± 85.8 (n = 15) | 3094.5 ± 120.0 (n = 22)* | 3375.5 ± 89.9 (n = 47) | 3601.9 ± 166.2 (n = 16) | 3701.5 ± 88.9 (n = 24) | 3446.5 ± 88.0 (n = 43) | |||||
Head circumference at birth, cm | 34.5 ± 0.3(n = 15) | 33.9 ± 0.3 n = 21 | 34.3 ± 0.2 (n = 46) | 34.8 ± 0.4 (n = 16) | 34.9 ± 0.3 (n = 23) | 34.7 ± 0.3 (n = 43) | |||||
Head circumference centile at birth | 44.0 ± 6.8 (n = 15) | 34.0 ± 5.4 (n = 21) | 44.7 ± 4.2 (n = 46) | 57.2 ± 6.7 (n = 16) | 56.8 ± 5.7 (n = 23) | 55.0 ± 4.1 (n = 43) | |||||
Ponderal index | 2.55 ± 0.06 (n = 14) | 2.51 ± 0.08 (n = 21) | 2.65 ± 0.04 (n = 42) | 2.58 ± 0.05 (n = 15) | 2.49 ± 0.05 (n = 22) | 2.52 ± 0.04 (n = 42) | |||||
Placental weight, g | 641.7 ± 28.6 (n = 12) | 606.4 ± 28.0 (n = 12) | 601.2 ± 36.8 (n = 17) | 610.6 ± 51.4 (n = 11) | 653.6 ± 42.0 (n = 15) | 644.8 ± 31.0 (n = 22) |

Figure 1. Neonatal birth weight centile in pregnancies complicated by asthma. Mean birth weight centile ± SEM for female neonates and for male neonates. *p = 0.047 (analysis of variance [ANOVA]).
[More] [Minimize]No similar effects on growth were observed in male fetuses (Table 2 and Figure 1B). Male birth weight was not significantly different between the control group, the no-glucocorticoid group, or the glucocorticoid group (ANOVA, p = 0.192). Male neonates from those with mild asthma were of similar size regardless of glucocorticoid use (birth weight centile, 66.2 ± 5.9, n = 16, no glucocorticoid versus 64.9 ± 6.9, n = 14, glucocorticoid).
There was a significant positive correlation between maternal lung function, expressed as the FEV1:VC ratio, and neonatal birth weight for females in the no-glucocorticoid group only (r = 0.505, n = 19, p = 0.028, excluding one preterm delivery; Figure 2)

Figure 2. Neonatal birth weight in relationship to maternal lung function in subjects with asthma that did not use inhaled steroids during pregnancy. The correlation between birth weight (g) and maternal FEV1:VC is shown for women with asthma in the no-glucocorticoid group pregnant with a female fetus (r = 0.505, n = 19, p = 0.028).
[More] [Minimize]Some women in our study were smokers (25%), and smoking has been reported to contribute to low birth weight (36). However, we found no significant differences in birth weight between smokers and nonsmokers within any groups. When examining female neonates of smoking mothers, those from the no-glucocorticoid group had a birth weight of 3,033.3 ± 118.6 g (n = 6), whereas female neonates of smoking mothers from the glucocorticoid group had a birth weight of 3,240.0 ± 184.8 g (n = 14). This difference was not significant (Mann-Whitney test, p = 0.444). Female neonates from nonsmoking mothers had a birth weight of 3,117.5 ± 160.7 g (n = 16) in the no-glucocorticoid group and a birth weight of 3,433.0 ± 101.5 g (n = 33) in the glucocorticoid group, indicating that the absence of glucocorticoid use in those with asthma was associated with reduced female birth weight regardless of maternal smoking.
Using multivariate analysis, there was a significant reduction in female fetal growth in women using no glucocorticoids (p = 0.037) and subjects with mild asthma (p = 0.02). There was no significant effect of smoking or asthma severity on birth weight, and sex still remained the determining factor.
There was a significant reduction in placental 11β-HSD2 enzyme activity in placentas from female fetuses in the no-glucocorticoid group (2.60 ± 0.33 nmol cortisone/mg protein/hour, n = 7) compared with placentas from females in the control group (4.96 ± 1.02 nmol/mg/hour, n = 6) or the glucocorticoid group (6.88 ± 0.59 nmol/mg/hour, n = 26, ANOVA, p = 0.002; Figure 3A)

Figure 3. Placental 11β-HSD2 enzyme activity in pregnancies complicated by asthma. Enzyme activity is presented as nmol cortisone formed per mg protein per hour. Values are mean ± SEM for female placentas and for male placentas. *p = 0.002 (ANOVA).
[More] [Minimize]Placental 11β-HSD2 activity was not significantly altered by maternal smoking. 11β-HSD2 activity for smokers was 4.63 ± 0.76 nmol/mg/hour (n = 16) compared with 5.06 ± 0.40 nmol/mg/hour (n = 49) for nonsmokers (Student's t test, p = 0.597). There was no significant difference in placental 11β-HSD2 activity between smokers and nonsmokers within any of the no-glucocorticoid or glucocorticoid male/female subgroups (Student's t test, p > 0.05, data not shown).
Multivariate analysis indicated that 11β-HSD2 activity was associated with sex and glucocorticoid intake (p = 0.008) but was not affected by maternal asthma severity or smoking.
Mean fetal cortisol concentrations in the umbilical vein at delivery were higher in female fetuses from the no-glucocorticoid group (279.8 ± 56.3 nM, n = 13), as expected from reduced placental 11β-HSD2 activity. However, these were not significantly different from values in the control group (214.2 ± 20.2 nM, n = 12) or the glucocorticoid group (224.2 ± 22.9 nM, n = 25, Kruskal-Wallis ANOVA, p = 0.881). Male cortisol concentrations were also not significantly different between the control (193.2 ± 27.7, n = 11), no-glucocorticoid (287.8 ± 59.6, n = 15), or glucocorticoid groups (281.4 ± 41.8, n = 25, Kruskal-Wallis ANOVA, p = 0.624).
Fetal estriol concentrations were significantly reduced in females from the no-glucocorticoid group (417.6 ± 76.2 nM, n = 8) compared with females from the control group (994.2 ± 309.3 nM, n = 7) and the glucocorticoid group (872.1 ± 84.9 nM, n = 20, Figure 4A

Figure 4. Fetal umbilical vein estriol concentrations at delivery. Fetal estriol concentrations (nM) are depicted as mean ± SEM in female cord blood and male cord blood. *p = 0.007 (Kruskal-Wallis nonparametric ANOVA).
[More] [Minimize]To investigate whether changes in placental function and fetal growth may be due to increased maternal inflammation associated with changes in asthma, we examined drug intake by women with asthma who used inhaled glucocorticoids during pregnancy. Women treated with moderate or high doses of inhaled glucocorticoids who were pregnant with a female fetus (n = 41) significantly increased their inhaled glucocorticoid use during pregnancy from 917 ± 99 μg/day in the first trimester to 1,350 ± 111 μg/day in the third trimester (paired nonparametric test, p = 0.0002). However, subjects with asthma using moderate or high doses of inhaled glucocorticoids who were pregnant with a male fetus (n = 30) did not significantly alter their inhaled glucocorticoid use during pregnancy, using 930 ± 106 μg/day in the first trimester and 1,080 ± 103 μg/day in the third trimester (paired nonparametric test, p = 0.176).
To investigate inflammatory pathways in the no-glucocorticoid group, maternal white blood cell counts were examined. The maternal monocyte count significantly increased from early gestation (0.58 ± 0.04 × 109 per L, n = 22) to late gestation (0.80 ± 0.08 × 109 per L, n = 7) in women with asthma in the no-glucocorticoid group who were pregnant with a female fetus (unpaired t test, p = 0.020). In addition, the percentage of white blood cells that were monocytes significantly increased from early to late pregnancy (6.2 ± 0.4%, n = 22, to 7.6 ± 0.4%, n = 7) in the no-glucocorticoid group in women pregnant with a female fetus (Mann-Whitney test, p = 0.020) and in late pregnancy was significantly higher than the other groups (Kruskal-Wallis ANOVA, p = 0.017). There was no significant change during pregnancy in maternal monocyte count in any other group, including the women with asthma who did not use glucocorticoids and were pregnant with a male fetus (0.56 ± 0.05 × 109 per L, n = 14, in early pregnancy to 0.50 ± 0.05 × 109 per, n = 8, in late pregnancy, unpaired t test, p = 0.370). Other white blood cell counts were also examined, including lymphocytes, neutrophils, eosinophils, and basophils. There were no significant differences in any of these parameters between women pregnant with a male or female fetus in the no-glucocorticoid or glucocorticoid groups (p > 0.05, data not shown). Eosinophil counts were significantly higher in all of the groups with asthma compared with the control group (less than 20 weeks, Kruskal-Wallis ANOVA, p < 0.0001). However, there was no significant increase in eosinophil counts as pregnancy progressed or any difference between males and females of the no-glucocorticoid or glucocorticoid groups (p > 0.05, data not shown).
This study examined the effects of asthma on endocrine and immune relationships between the mother, placenta, and fetus and their role in the control of fetal growth during human pregnancy. We have demonstrated that the female fetus has a different effect from the male fetus on the maternal immune system during pregnancy, with an upregulation of inflammatory pathways observed in some women with asthma pregnant with a female fetus. These changes were observed in women with very mild asthma who had been medically advised not to use inhaled glucocorticoids. Alterations observed in maternal asthma in the presence of a female fetus may be directly involved in the changes in placental function, which included a reduction in placental 11β-HSD2 activity and a trend toward increased cord blood cortisol. These changes in placental function were associated with reduced fetal growth and adrenal function in females. We propose that maternal inflammation is the key to alterations in female fetal growth in this setting, as the use of inhaled glucocorticoids by pregnant women with asthma was protective. The male fetus appeared to be insensitive to the effects of inflammation in the mother, with no changes in placental function or growth observed in male fetuses. We conclude that the female fetus has an adverse effect on maternal asthma, which when not treated with inhaled glucocorticoids results in reduced fetal growth.
Recent data in asthmatic pregnancies suggests that women pregnant with a female fetus have increasing asthma severity as gestation progresses (37, 38) and an increase in the incidence of complications such as pre-eclampsia or preterm delivery (39). We found that inhaled glucocorticoid intake by women with asthma using moderate or high doses significantly increased in late pregnancy when women were pregnant with a female fetus, suggesting an upregulation of inflammation associated with asthma as gestation progressed. Such changes in maternal systemic inflammation in the presence of a female fetus may also be involved in the increased risk of developing pre-eclampsia or preterm labor in asthmatic pregnancies. In the women with asthma who were medically advised not to use inhaled steroids because they were assessed as having a very mild disease, we observed a significant rise in the number of circulating monocytes as gestation progressed when they were pregnant with a female fetus. This supports the concept that increased maternal inflammation is associated with reduced female fetal growth in this group.
Monocytes, the precursors to macrophages, are important inflammatory mediators in asthma, via their interactions with Th2 lymphocytes, eosinophils, and mast cells within the asthmatic airway. Alveolar macrophages from patients with mild asthma are highly activated, as demonstrated by the presence of cell wall antigens required for recognition by CD4+ lymphocytes (40). Previous studies have demonstrated that coculture of CD4+ T cells with peripheral blood monocytes from atopic subjects with asthma results in enhanced production of IL-4 and IL-5 (41, 42). In addition, monocytes interact with airway smooth muscle cells in vitro, inducing collagen degradation through the induction of matrix metalloproteinase 1, 2, and 9 (43). Monocytes release numerous cytokines, including tumor necrosis factor-α (44–46), IL-1β (44, 46), IL-6 (46), and granulocyte macrophage colony-stimulating factor (44, 45). In our study, both the number and the percentage of monocytes in the maternal circulation of those with asthma who did not use steroids and had a female fetus increased during gestation, suggesting that there was a specific upregulation of this leukocyte, rather than simply an overall increase in white blood cell numbers. We noted that eosinophil numbers were also higher in early pregnancy in mothers with asthma compared with those without asthma, which is in agreement with previous studies in nonpregnant adults (47). However, unlike monocytes, the eosinophil count did not differ significantly between mothers pregnant with a male and female fetus in the no-glucocorticoid group nor did it increase as gestation progressed. These data suggest that in the absence of inhaled glucocorticoid use and in the presence of a female fetus, cytokines derived from circulating monocytes may be primarily responsible for alterations in placental function, which result in reduced female fetal growth.
Our study indicates that in pregnant women with asthma there is reduced female fetal growth when no inhaled glucocorticoids are used. This occurred regardless of asthma severity or maternal smoking. Female birth weight and head circumference were both reduced to the 34th centile, and ponderal index was normal, suggesting symmetrical growth restriction. Schatz and colleagues have previously demonstrated that poor maternal lung function, indicated by lower maternal FEV1, was associated with a greater incidence of birth weights in the lower quartile and asymmetric growth restriction (48). We also found a relationship between maternal lung function (FEV1:VC) and neonatal birth weight among females from the no-glucocorticoid group, suggesting that reduced lung function may be a contributing factor to reduced birth weight in this group. However, the lung function of mothers in the glucocorticoid group was significantly worse than that in the no-glucocorticoid group (with a female fetus present), and yet no changes in female fetal growth were observed in this group. In addition, the use of glucocorticoids by women with mild asthma was associated with female birth weight centiles comparable to control nonasthmatics. These data suggest that inflammation rather than alterations in lung function itself is a major component of the mechanism contributing to low birth weight in asthmatic pregnancies. Our data indicate that women with asthma with a relatively mild inflammatory disease, who were medically recommended not to use inhaled glucocorticoids, had significant changes in placental function and symmetrically reduced fetal growth.
Changes in female fetal growth may be mediated by decreased placental 11β-HSD2 activity and the antimitogenic effects of cortisol. Fowden and colleagues described that the cortisol surge toward late gestation in sheep was coincident with the slowing down of growth, reflected by a decrease in the increment of crown–rump length growth (49). Significant reductions in placental 11β-HSD2 activity have previously been observed in intrauterine growth restriction placentas (26). Multiple doses of betamethasone, a steroid that is not metabolized by placental 11β-HSD2, administered to women at risk of preterm delivery, resulted in a 9% reduction in neonatal birth weight and 4% reduction in neonatal head circumference (50). In our study, there was a 12% reduction in female birth weight, which equated to an approximately 500-g mean difference in size compared with female neonates from mothers who did not have asthma. This is far greater than fetal growth reductions previously reported for smoking mothers, which average 200 g (36, 51). These data indicate that increased circulating concentrations of bioactive cortisol in the presence of decreased 11β-HSD2 activity results in reduced symmetric growth of the female fetus.
Increased fetal exposure to glucocorticoids in animal models has previously been associated with alterations in fetal hypothalamic–pituitary–adrenal axis development and long term changes into adulthood. Pregnant guinea pigs exposed to synthetic glucocorticoids have altered female fetal hypothalamic–pituitary–adrenal function associated with increased hippocampal mineralocorticoid and glucocorticoid receptor expression (52). In rats, inhibition of placental 11β-HSD2 activity is associated with altered stress responses in offspring (53) and long-term changes such as delays in the development of puberty in females (54). Our human study showed suppression of the female fetal hypothalamic–pituitary–adrenal axis in the presence of maternal asthma and reduced placental 11β-HSD2 activity, as demonstrated by reduced umbilical vein concentrations of estriol, a derivative of fetal adrenal dehydroepiandrosterone sulfate (55). These data suggest that despite similar levels of cortisol in cord blood from males and females of mothers with asthma not treated with steroids, the females of this group are more sensitive to changes in placental cortisol metabolism. This observation supports previous clinical data demonstrating a greater response to synthetic glucocorticoid treatment for lung maturation in female fetuses at risk of preterm delivery (56, 57) and suggests that the female fetus may be more sensitive to changes in cortisol concentration.
In summary, our study of women with asthma during pregnancy has demonstrated that there is a relationship between fetal sex and maternal asthma during pregnancy, with women pregnant with a female fetus showing evidence of increased inflammation in late pregnancy. Figure 5

Figure 5. Proposed mechanisms involved in reducing female fetal growth in pregnancies complicated by asthma. 11β-HSD2 = 11β-hydroxysteroid dehydrogenase type 2.
[More] [Minimize]Our results have several important clinical and scientific implications. We have demonstrated that the use of inhaled steroids by women with mild asthma was beneficial for the growth of female fetuses, by controlling maternal systemic inflammation. In addition, the female fetus itself influenced the course of maternal asthma through pregnancy. Scientifically, this study has contributed to understanding the mechanisms regulating fetal growth in human pregnancy. Placental 11β-HSD2 activity is a key component of this mechanism through its control of cortisol concentrations reaching the fetus. The female fetus was particularly sensitive to alterations in cortisol exposure and the downstream effects of this included reduced fetal adrenal function and reduced growth. These changes in fetal hypothalamic–pituitary–adrenal axis development and growth potentially expose these female neonates to an increased risk of developing diseases in later life through altered fetal programming. By examining the endocrine and immune relationships between mother, placenta, and fetus during asthmatic pregnancies, this study has provided strong evidence for a detrimental effect of maternal inflammation on placental function and female fetal growth and development.
The authors thank the staff of the Antenatal Clinics and Delivery Suite at the John Hunter Hospital for their assistance in subject recruitment and placenta collection.
1. | Varner AE. The increase in allergic respiratory diseases: survival of the fittest? Chest 2002;121:1308–1316. |
2. | Akinbami LJ, Schoendorf KC. Trends in childhood asthma: prevalence, health care utilization, and mortality. Pediatrics 2002;110:315–322. |
3. | Bahna SL, Bjerkedal T. The course and outcome of pregnancy in women with bronchial asthma. Acta Allergol 1972;27:397–406. |
4. | Schatz M, Patterson R, Zeitz S, O'Rourke J, Melam H. Corticosteroid therapy for the pregnant asthmatic patient. JAMA 1975;233:804–807. |
5. | Fitzsimons R, Greenberger PA, Patterson R. Outcome of pregnancy in women requiring corticosteroids for severe asthma. J Allergy Clin Immunol 1986;78:349–353. |
6. | Lao TT, Huengsburg M. Labour and delivery in mothers with asthma. Eur J Obstet Gynecol Reprod Biol 1990;35:183–190. |
7. | Clark SL. Asthma in pregnancy: National Asthma Education Program Working Group on Asthma and Pregnancy: National Institutes of Health, National Heart, Lung and Blood Institute. Obstet Gynecol 1993;82:1036–1040. |
8. | Demissie K, Breckenridge MB, Rhoads GG. Infant and maternal outcomes in the pregnancies of asthmatic women. Am J Respir Crit Care Med 1998;158:1091–1095. |
9. | Brabin BJ. An analysis of malaria in pregnancy in Africa. Bull World Health Organ 1983;61:1005–1016. |
10. | Moormann AM, Sullivan AD, Rochford RA, Chensue SW, Bock PJ, Nyirenda T, Meshnick SR. Malaria and pregnancy: placental cytokine expression and its relationship to intrauterine growth retardation. J Infect Dis 1999;180:1987–1993. |
11. | Skomsvoll JF, Ostensen M, Irgens LM, Baste V. Obstetrical and neonatal outcome in pregnant patients with rheumatic disease. Scand J Rheumatol Suppl 1998;107:109–112. |
12. | Fedorkow DM, Persaud D, Nimrod CA. Inflammatory bowel disease: a controlled study of late pregnancy outcome. Am J Obstet Gynecol 1989;160:998–1001. |
13. | Fonager K, Sorensen HT, Olsen J, Dahlerup JF, Rasmussen SN. Pregnancy outcome for women with Crohn's disease: a follow-up study based on linkage between national registries. Am J Gastroenterol 1998;93:2426–2430. |
14. | Aggarwal N, Sawhney H, Vasishta K, Chopra S, Bambery P. Pregnancy in patients with systemic lupus erythematosus. Aust N Z J Obstet Gynaecol 1999;39:28–30. |
15. | Barker DJ, Osmond C, Golding J, Kuh D, Wadsworth ME. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 1989;298:564–567. |
16. | Barker DJ, Bull AR, Osmond C, Simmonds SJ. Fetal and placental size and risk of hypertension in adult life. BMJ 1990;301:259–262. |
17. | Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet 1989;2:577–580. |
18. | Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 1993;36:62–67. |
19. | Kuehr J, Karmaus W, Forster J, Frischer T, Hendel-Kramer A, Moseler M, Stephan V, Urbanek R, Weiss K. Sensitization to four common inhalant allergens within 302 nuclear families. Clin Exp Allergy 1993;23:600–605. |
20. | Prescott SL, Macaubas C, Holt BJ, Smallacombe TB, Loh R, Sly PD, Holt PG. Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile. J Immunol 1998;160:4730–4737. |
21. | Clifton VL, Giles WB, Smith R, Bisits A, Hempenstall P, Kessell CG, Gibson PG. Alterations of placental vascular function in asthmatic pregnancies. Am J Respir Crit Care Med 2001;164:1–8. |
22. | Fried M, Muga RO, Misore AO, Duffy PE. Malaria elicits type 1 cytokines in the human placenta: IFN-γ and TNF-α associated with pregnancy outcomes. J Immunol 1998;160:2523–2530. |
23. | Hahn-Zoric M, Hagberg H, Kjellmer I, Ellis J, Wennergren M, Hanson LA. Aberrations in placental cytokine mRNA related to intrauterine growth retardation. Pediatr Res 2002;51:201–206. |
24. | Ida A, Tsuji Y, Muranaka J, Kanazawa R, Nakata Y, Adachi S, Okamura H, Koyama K. IL-18 in pregnancy: the elevation of IL-18 in maternal peripheral blood during labour and complicated pregnancies. J Reprod Immunol 2000;47:65–74. |
25. | Hayashi M, Ohkura T. Elevated levels of serum macrophage colony-stimulating factor in normotensive pregnancies complicated by intrauterine fetal growth restriction. Exp Hematol 2002;30:388–393. |
26. | Shams M, Kilby MD, Somerset DA, Howie AJ, Gupta A, Wood PJ, Afnan M, Stewart PM. 11Beta-hydroxysteroid dehydrogenase type 2 in human pregnancy and reduced expression in intrauterine growth restriction. Hum Reprod 1998;13:799–804. |
27. | Murphy VE, Gibson PG, Giles WB, Zakar T, Smith R, Kessell CG, Clifton VL. Inflammatory factors have sex-specific effects on fetal growth in humans [abstract]. Ceska Gynekologie 2002;67(3 Suppl):16. |
28. | Murphy VE, Gibson PG, Giles WB, Smith R, Clifton VL. A novel model for examining fetal growth restriction in human pregnancy [abstract]. J Soc Gynecol Investig 2003;10(2 Suppl):268A. |
29. | National Asthma Campaign. Asthma Management Handbook. Sydney, Australia: National Asthma Council Australia; 1996. |
30. | National Institutes of Health. Guidelines for the diagnosis and management of asthma. Bethesda, MD: National Heart, Lung and Blood Institute; 1997. |
31. | Barnes NC, Marone G, Di Maria GU, Visser S, Utama I, Payne SL. A comparison of fluticasone propionate, 1 mg daily, with beclomethasone dipropionate, 2 mg daily, in the treatment of severe asthma: International Study Group. Eur Respir J 1993;6:877–885. |
32. | Kitchen WH, Robinson HP, Dickinson AJ. Revised intrauterine growth curves for an Australian hospital population. Aust Paediatr J 1983;19:157–161. |
33. | Murphy VE, Zakar T, Smith R, Giles WB, Gibson PG, Clifton VL. Reduced 11beta-hydroxysteroid dehydrogenase type 2 activity is associated with decreased birth weight centile in pregnancies complicated by asthma. J Clin Endocrinol Metab 2002;87:1660–1668. |
34. | Burton P, Gurrin L, Sly P. Extending the simple linear regression model to account for correlated responses: an introduction to generalized estimating equations and multi-level mixed modelling. Stat Med 1998;17:1261–1291. |
35. | Senn S, Stevens L, Chaturvedi N. Repeated measures in clinical trials: simple strategies for analysis using summary measures. Stat Med 2000;19:861–877. |
36. | Andres RL, Day MC. Perinatal complications associated with maternal tobacco use. Semin Neonatol 2000;5:231–241. |
37. | Dodds L, Armson BA, Alexander S. Use of asthma drugs is less among women pregnant with boys rather than girls. BMJ 1999;318:1011. |
38. | Beecroft N, Cochrane GM, Milburn HJ. Effect of sex of fetus on asthma during pregnancy: blind prospective study. BMJ 1998;317:856–857. |
39. | Liu S, Wen SW, Demissie K, Marcoux S, Kramer MS. Maternal asthma and pregnancy outcomes: a retrospective cohort study. Am J Obstet Gynecol 2001;184:90–96. |
40. | Mazzarella G, Grella E, D'Auria D, Paciocco G, Perna F, Petillo O, Peluso G. Phenotypic features of alveolar monocytes/macrophages and IL-8 gene activation by IL-1 and TNF-alpha in asthmatic patients. Allergy 2000;55:36–41. |
41. | Tang C, Rolland JM, Li X, Ward C, Bish R, Walters EH. Alveolar macrophages from atopic asthmatics, but not atopic nonasthmatics, enhance interleukin-5 production by CD4+ T cells. Am J Respir Crit Care Med 1998;157:1120–1126. |
42. | Tang C, Rolland JM, Ward C, Thien F, Li X, Gollant S, Walters EH. Differential regulation of allergen-specific T(H2)- but not T(H1)-type responses by alveolar macrophages in atopic asthma. J Allergy Clin Immunol 1998;102:368–375. |
43. | Zhu YK, Liu X, Wang H, Kohyama T, Wen FQ, Skold CM, Rennard SI. Interactions between monocytes and smooth-muscle cells can lead to extracellular matrix degradation. J Allergy Clin Immunol 2001;108:989–996. |
44. | Ackerman V, Marini M, Vittori E, Bellini A, Vassali G, Mattoli S. Detection of cytokines and their cell sources in bronchial biopsy specimens from asthmatic patients: relationship to atopic status, symptoms, and level of airway hyperresponsiveness. Chest 1994;105:687–696. |
45. | Lim S, John M, Seybold J, Taylor D, Witt C, Barnes PJ, Chung KF. Increased interleukin-10 and macrophage inflammatory protein-1 alpha release from blood monocytes ex vivo during late-phase response to allergen in asthma. Allergy 2000;55:489–495. |
46. | Mathy NL, Scheuer W, Lanzendorfer M, Honold K, Ambrosius D, Norley S, Kurth R. Interleukin-16 stimulates the expression and production of pro-inflammatory cytokines by human monocytes. Immunology 2000;100:63–69. |
47. | Louis R, Bury T, Corhay JL, Radermecker MF. Acute bronchial and hematologic effects following inhalation of a single dose of PAF: comparison between asthmatics and normal subjects. Chest 1994;106:1094–1099. |
48. | Schatz M, Zeiger RS, Hoffman CP. Intrauterine growth is related to gestational pulmonary function in pregnant asthmatic women: Kaiser-Permanente Asthma and Pregnancy Study Group. Chest 1990;98:389–392. |
49. | Fowden AL, Szemere J, Hughes P, Gilmour RS, Forhead AJ. The effects of cortisol on the growth rate of the sheep fetus during late gestation. J Endocrinol 1996;151:97–105. |
50. | French NP, Hagan R, Evans SF, Godfrey M, Newnham JP. Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol 1999;180:114–121. |
51. | United States Department of Health and Human Services. The health benefits of smoking cessation: a report of the Surgeon General. Rockville, MD: Centers for Disease Control; 1990. |
52. | Dean F, Matthews SG. Maternal dexamethasone treatment in late gestation alters glucocorticoid and mineralocorticoid receptor mRNA in the fetal guinea pig brain. Brain Res 1999;846:253–259. |
53. | Welberg LA, Seckl JR, Holmes MC. Inhibition of 11beta-hydroxysteroid dehydrogenase, the foeto-placental barrier to maternal glucocorticoids, permanently programs amygdala GR mRNA expression and anxiety-like behaviour in the offspring. Eur J Neurosci 2000;12:1047–1054. |
54. | Smith JT, Waddell BJ. Increased fetal glucocorticoid exposure delays puberty onset in postnatal life. Endocrinology 2000;141:2422–2428. |
55. | Siiteri PK, MacDonald PC. Placental estrogen biosynthesis during human pregnancy. J Clin Endocrinol Metab 1966;26:751–761. |
56. | Effect of antenatal dexamethasone administration on the prevention of respiratory distress syndrome. Am J Obstet Gynecol 1981;141:276–287. |
57. | Papageorgiou AN, Colle E, Farri-Kostopoulos E, Gelfand MM. Incidence of respiratory distress syndrome following antenatal betamethasone: role of sex, type of delivery, and prolonged rupture of membranes. Pediatrics 1981;67:614–617. |
58. | Chao TC, Van Alten PJ, Greager JA, Walter RJ. Steroid sex hormones regulate the release of tumour necrosis factor by macrophages. Cell Immunol 1995;160:43–49. |