Vicki L. Clifton

Review: Sex and the Human Placenta: Mediating Differential Strategies of Fetal Growth and Survival

There are known sex specific differences in fetal and neonatal morbidity and mortality. There are also known differences in birthweight centile with males generally being larger than females at birth. These differences are generally ignored when studying obstetric complications of pregnancy and the mechanisms that confer these differences between the sexes are unknown. Current evidence suggests sex specific adaptation of the placenta may be central to the differences in fetal growth and survival. Our research examining pregnancies complicated by asthma has reported sexually dimorphic differences in fetal growth and survival with males adapting placental function to allow for continued growth in an adverse maternal environment while females reduce growth in an attempt to survive further maternal insults. We have reported sex differences in placental cytokine expression, insulin-like growth factor pathways and the placental response to cortisol in relation to the complication of asthma during pregnancy. More recently we have identified sex specific alterations in placental function in pregnancies complicated by preterm delivery which were associated with neonatal outcome and survival. We propose the sexually dimorphic differences in growth and survival of the fetus are mediated by the sex specific function of the human placenta. This review will present evidence supporting this hypothesis and will argue that to ignore the sex of the placenta is no longer sound scientific practice.

Asthma exacerbations during pregnancy: incidence and association with adverse pregnancy outcomes

Exacerbations of asthma during pregnancy represent a significant clinical problem and may be related to poor pregnancy outcomes. A systematic review of the literature was conducted for publications related to exacerbations during pregnancy. Four studies with a control group (no asthma) and two groups of women with asthma (exacerbation, no exacerbation) were included in meta-analyses using fixed effects models. During pregnancy, exacerbations of asthma which require medical intervention occur in about 20% of women, with approximately 6% of women being admitted to hospital. Exacerbations during pregnancy occur primarily in the late second trimester; the major triggers are viral infection and non-adherence to inhaled corticosteroid medication. Women who have a severe exacerbation during pregnancy are at a significantly increased risk of having a low birth weight baby compared with women without asthma. No significant associations between exacerbations during pregnancy and preterm delivery or pre-eclampsia were identified. Inhaled corticosteroid use may reduce the risk of exacerbations during pregnancy. Pregnant women may be less likely to receive oral steroids for the emergency management of asthma. The effective management and prevention of asthma exacerbations during pregnancy is important for the health of both the mother and fetus.

Severe asthma exacerbations during pregnancy

OBJECTIVE: To estimate the frequency of severe asthma exacerbations in pregnant women and to estimate whether there is an association with adverse perinatal outcomes. METHODS: Asthma exacerbations were evaluated in 146 women who were enrolled in a prospective cohort study of asthma and pregnancy. A severe exacerbation was defined as a hospital admission, emergency department presentation, or unscheduled doctor visit for asthma or a course of oral corticosteroids. Women were classified as having mild (n = 63), moderate (n = 34), or severe (n = 49) asthma. RESULTS: Severe exacerbations occurred in 8% (95% confidence interval [CI] 1.3–14.6%) of women with mild asthma, 47% (95% CI 30.3–63.8%) of women with moderate asthma, and 65% (95% CI 52–78.6%) of women with severe asthma at a mean gestational age of 25.1 ± 0.9 (range 9–39) weeks of gestation. Among women who had severe exacerbations, there were 2 male stillbirths (P = .102) and a significantly increased rate of male low birth weight (P = .03). Maternal age, lung function, body mass index, gravidity, and parity were not different between women who did or those who did not have a severe exacerbation. Maternal pregnancy weight gain was significantly lower in women who had a severe exacerbation (P = .039). Forty-three percent of severe exacerbations occurred in winter, 34% were associated with self-reported viral infection, and 29% with nonadherence to inhaled corticosteroid medication. CONCLUSION: The exacerbation rate among pregnant women with asthma is high and associated with poor outcomes for the male fetus. Improvements in asthma management to prevent severe exacerbations may lead to a better outcome for both mother and baby. LEVEL OF EVIDENCE: II-2

Asthma and pregnancy: emerging evidence of epigenetic interactions in utero.

Purpose of reviewPregnancy is arguably the most critical period of developmental programming. Here, we particularly focus on the emerging paradigm that disease propensity is epigenetically determined by maternal exposures that have the capacity to activate or silence fetal genes through alterations in DNA and histone methylation, histone acetylation, and chromatin structure. Recent findingsThe most notable recent candidate to emerge in this role has been dietary folate, a methyl donor clearly associated with changes in gene expression and disease susceptibility through gene hypermethylation. Animal studies also provide the first evidence that the allergy protective effects of microbial exposure in pregnancy may be mediated by changes in methylation of Th1 genes of the offspring. There is also emerging evidence that perinatal differences in immune function of allergy-prone newborns extend beyond previously recognized differences in effector T cell (Th1/Th2) function, to also include differences in neonatal regulatory T cell (Treg) and Th17 function, and moreover, that these pathways are also epigenetically regulated. SummaryNew studies reinforce the importance of in-utero exposures (including dietary nutrients, microbial products, cigarette smoking, and certain maternal mediations) in fetal immune development and in programming the susceptibility to asthma and allergic disease.

Asthma during pregnancy: mechanisms and treatment implications

Asthma is becoming increasingly prevalent worldwide. Numerous historical and prospective cohort studies have investigated the effects of maternal asthma on pregnancy outcome; however, the data has been conflicting and many studies have not used standard classifications for asthma severity. Overall, the literature suggests that asthmatic females are more at risk of low birth weight neonates, pre-term delivery and complications such as pre-eclampsia, especially in the absence of actively managed asthma treated with inhaled corticosteroids. Pregnancy with a female foetus may particularly increase the risk of these outcomes. In addition, pregnancy has an effect on the course of asthma. The risk of an exacerbation requiring medical intervention may be as high as 50% in females with severe asthma and this may further increase the risk of poor outcomes, particularly low birth weight and pre-term delivery. The mechanisms responsible for changes in asthma with pregnancy, or alterations in pregnancy outcomes due to asthma have not been thoroughly explored. Maternal inflammatory pathways may contribute to reduced foetal growth through alterations in placental function. Asthma treatment, by reducing maternal inflammation and preventing exacerbations, is safe for use in pregnant females and contributes to improved outcomes for both mother and foetus.

Alterations in Human Placental 11β-hydroxysteroid Dehydrogenase Type 1 and 2 with Gestational Age and Labour

11beta-hydroxysteroid dehydrogenase type 1 and type 2 may be important in the process of human parturition and the regulation of fetal growth, by the modulation of cortisol concentrations in the fetal compartment. Changes in the expression and activity of these enzymes in late gestation have not been well described. This study has examined the gene expression of placental 11beta-HSD1 and 2, activity of 11beta-HSD2 and fetal cortisol concentrations during the final few weeks of human pregnancy and with the onset of labour. Placental 11beta-HSD2 activity decreased significantly between 38 and 40 weeks. There were no significant changes in mRNA abundance or protein expression with gestational age or labour. Placental 11beta-HSD1 mRNA abundance significantly increased with spontaneous labour. Fetal cortisol concentrations increased significantly with spontaneous labour. This study is the first to describe a decrease in 11beta-HSD2 activity in the last few weeks of human gestation. This decrease in type 2 activity, along with an increase in 11beta-HSD1 gene expression may be a mechanism by which cortisol concentrations rise at term to regulate fetal maturation and activate pathways associated with labour.

Sex-specific alterations in placental 11β-hydroxysteroid dehydrogenase 2 activity and early postnatal clinical course following antenatal betamethasone

Placental 11beta-hydroxysteroid dehydrogenase-2 (11betaHSD2) limits fetal glucocorticoid exposure and is associated with physiological stability in the premature newborn infant. Antenatal betamethasone alters 11betaHSD2 activity and confers sex-specific advantages in neonatal outcome. We investigated the influence of betamethasone and sex on 11betaHSD2 activity, neonatal adrenal function and clinical course in 24- to 36-wk gestation neonates from birth to day 5 of life. Univariate analyses demonstrated an interaction between timing of betamethasone exposure and sex for 11betaHSD2 activity rate (P = 0.02) and umbilical arterial cortisol (P = 0.01). For infants born < 72 h following antenatal betamethasone, females had higher 11betaHSD2 activity (P < 0.01) and umbilical arterial cortisol (P = 0.01) than males. Females born < 72 h of betamethasone exposure had higher day 1 urinary cortisol, if exposed to perinatal stress, than males (P < 0.01). For infants born < 72 h after betamethasone exposure, 11betaHSD2 activity was negatively correlated with Clinical Illness Severity Score score (r = -0.79 P = 0.01) and positively correlated with mean arterial blood pressure (r = 0.8 P = 0.01) only in females. Sex-specific placental 11BHSD2 autoregulation following antenatal betamethasone exposure may limit adrenal suppression in females influencing physiological stability following preterm birth. A lack of adjustment in 11betaHSD2 and adrenal response may contribute to the increased incidence of poor outcome observed in preterm males.

Asthma self-management skills and the use of asthma education during pregnancy

During pregnancy, patients with asthma are at risk of poor outcomes, particularly when asthma is poorly controlled. The aim of this study was to determine the level of asthma self-management skills and knowledge among pregnant subjects and describe the implementation of an asthma education programme delivered in an antenatal clinic setting. Pregnant subjects with asthma were assessed by an asthma educator at 20 (n = 211) and 33 weeks gestation (n = 149). Lung function, symptoms, medication use, adherence, knowledge and inhaler technique were assessed. They were asked whether they had a written asthma action plan, or performed peak flow monitoring. Asthma was classified as mild, moderate or severe. At the first visit with the asthma educator, 40% of females reported nonadherence to inhaled corticosteroids, inhaler technique was assessed as inadequate in 16% and 42% had inadequate medication knowledge. Peak flow monitoring was performed by 3% and 15% had a written action plan. There were significant improvements in all aspects of asthma self-management following education. In females with severe asthma, night symptoms and reliever medication use significantly decreased after education. In conclusion, during pregnancy, patients with asthma have poor asthma knowledge and skills, and may benefit from self-management education as part of their obstetric care.

Placental Cytokine Expression Covaries with Maternal Asthma Severity and Fetal Sex

In the presence of maternal asthma, we have previously reported reduced placental blood flow, decreased cortisol metabolism, and reductions in fetal growth in response to maternal asthma and asthma exacerbations. We have proposed that these changes in placental function and fetal development may be related to activation of proinflammatory pathways in the placenta in response to maternal asthma. In the present study, we examined the influence of maternal asthma severity, inhaled glucocorticoid treatment, maternal cigarette use, placental macrophage numbers, and fetal sex on placental cytokine mRNA expression from a prospective cohort study of pregnant women with and without asthma. Placental expression of TNF-α, IL-1β, IL-6, IL-8, and IL-5 mRNA were all increased significantly in placentae of female fetuses whose mothers had mild asthma, but no changes were observed in placentae of male fetuses. The proinflammatory cytokines TNF-α, IL-1β, and IL-6 were negatively correlated with female cord blood cortisol, but there were no such correlations in placentae from males. Multivariate analysis indicated the strongest predictor of both cytokine mRNA expression in the placenta and birth weight was fetal cortisol but only in females. Placental cytokine mRNA levels were not significantly altered by inhaled glucocorticoid use, placental macrophage numbers, cigarette use, moderate-severe asthma, or male sex. These data suggest that placental basal cytokine mRNA expression is sex specifically regulated in pregnancies complicated by asthma, and interestingly these changes are more prevalent in mild rather than severe asthma.

Sexually dimorphic effects of maternal asthma during pregnancy on placental glucocorticoid metabolism and fetal growth

Human pregnancy is associated with sexually dimorphic differences in mortality and morbidity of the fetus with the male fetus experiencing the poorest outcome following complications such as pre-eclampsia, pre-term delivery and infection. The physiological mechanisms that confer these differences have not been well characterised in the human. Work conducted on the effect of maternal asthma during pregnancy, combining data collected from the mother, placenta and fetus has found some significant sex-related mechanistic differences associated with fetal growth in both normal pregnancies and pregnancies complicated by asthma. Specifically, sexually dimorphic differences have been found in placental glucocorticoid metabolism in male and female fetuses of normal pregnancies. In response to the presence of maternal asthma, only the female fetus alters placental glucocorticoid metabolism resulting in decreased growth. The male fetus does not alter placental function or growth in response to maternal asthma. As a result of the alterations in glucocorticoid metabolism in the female, downstream changes occur in pathways regulated by glucocorticoids. These data suggest that the female fetus adjusts placental function and reduces growth to compensate for maternal disease. However, the male fetus continues to grow in response to maternal asthma with no changes in placental function. This response by the male fetus may partially contribute to the increased risk of morbidity and mortality in this sex.