Effect of Maternal Asthma and Gestational Asthma Therapy on Fetal Growth

Asthma is a common chronic condition that might seriously complicate pregnancy and fetal development. This article provides a comprehensive review of the existing literature regarding the effect on fetal growth of maternal asthma and common asthma medications used during pregnancy, including short-and long-acting β ₂-agonists, inhaled and oral corticosteroids, chromones, leukotriene receptor agonists, and theophylline. Evaluated outcomes of fetal growth include low birth weight, mean birth weight, small for gestational age, birth length and head circumference, and measures of asymmetrical growth retardation. Methodological and practical considerations related to safety of asthma medications in pregnancy and management of gestational asthma are discussed.     

Asthma in pregnancy.

Asthma, one of the most common serious medical problems to complicate pregnancy, affects 3-8% of pregnancies in the United States. The goals of therapy in the pregnant asthmatic patient do not differ from those in non-pregnant patients. Inhaled corticosteroids (ICS) are preferred in the management of all levels of persistent asthma in pregnant patients, because these agents have been shown to reduce asthma exacerbations during pregnancy. Asthma in pregnancy is often undertreated due to physician and patient concerns over the effects of asthma medications on the fetus. However, undertreatment leads to loss of asthma control and increases in maternal morbidity, perinatal mortality, preeclampsia, preterm birth, and low birth weight infants. Recent prospective clinical cohort studies with active asthma management by NAEPP guidelines show no evidence of increased maternal or fetal morbidity or mortality. Therefore, it is critical for the mother to understand that failure to control asthma during pregnancy may lead to poor outcomes. A case study follows to highlight clinical pearls and pitfalls in the management of asthma in the pregnant patient.     

Intrauterine growth is related to gestational pulmonary function in pregnant asthmatic women. Kaiser-Permanente Asthma and Pregnancy Study Group

Asthmatic mothers have been reported to deliver infants of lower mean birth weight than nonasthmatic mothers. This study examined the relationship between intrauterine growth and serial gestational spirometry in 352 pregnant asthmatic women who were prospectively treated and observed during pregnancy. A small (r = 0.11) but significant (p less than 0.04) direct correlation was demonstrated between infant birth weight and individual mean percent predicted FEV1 during pregnancy. In addition, lower maternal mean FEV1 during pregnancy was associated with increased incidences of birth weight in the lower quartile of the infant population (p = 0.002) and ponderal indices less than 2.2 (suggestive of asymmetric intrauterine growth retardation) (p less than 0.05), but not with increased incidences of preterm (less than 38 weeks) or low birth weight (less than 2,500 g) infants. Although lower mean birth weight occurred in infants of smoking compared with nonsmoking asthmatic mothers (p less than 0.02), the relationships of lower FEV1 to birth weight in the lower quartile of the population (odds ratio 3.0, p = 0.002) and ponderal indices less than 2.2 (odds ratio 2.8, p less than 0.05) were shown by multivariate analysis to be above and beyond the influence of smoking and also independent of the effects of age, parity, acute asthmatic episodes, and asthma medications. These data support the hypothesis that lower maternal gestational FEV1 during pregnancy is related to intrauterine growth retardation and suggest that the goals of gestational asthma therapy should include optimization of pulmonary function in addition to achievement of symptomatic control.     

Association of birth weight with asthma-related outcomes at age 2 years

BACKGROUND: Although lower birth weight associated with prematurity raises the risk of asthma in childhood, few prospective studies have examined higher birth weight, and few have separated the two components of birth weight, fetal growth and length of gestation. OBJECTIVE: To examine the associations of fetal growth and length of gestation with asthma-related outcomes by age 2 years. METHODS: We studied 1,372 infants and toddlers born after 34 weeks' gestation in Project Viva, a prospective cohort study of pregnant mothers and their children. The main outcome measures were parent report of (1) any wheezing (or whistling in the chest) from birth to age 2 years, (2) recurrent wheezing during the first 2 years of life, and (3) doctor's diagnosis of asthma, wheeze or reactive airway disease ("asthma") by age 2. We calculated gestational age from the last menstrual period or ultrasound examination, and determined birth weight for gestational age z-value ("fetal growth") using US national reference data. RESULTS: Infants' mean birth weight was 3,527 (SD, 517; range, 1,559-5,528) grams. By age 2 years, 34% of children had any wheezing, 14% had recurrent wheezing, and 16% had doctor-diagnosed asthma. After adjusting for several parent, child, and household characteristics in logistic regression models, we found that infants with birth weight > or = 4,000 g were not more likely to have any wheezing (odds ratio (OR), 0.91; 95% confidence interval (CI): 0.62, 1.34) or doctor-diagnosed asthma (OR, 0.80; 95% CI: 0.49, 1.31) than infants with birth weight 3,500-3,999 g. In models examining length of gestation and fetal growth separately, neither the highest nor the lowest groups of either predictor were associated with the three outcomes. Boys had a higher incidence of asthma-related outcomes than girls, and exposure to passive smoking, parental history of asthma, and exposure to older siblings were all associated with greater risk of recurrent wheeze or asthma-related outcomes at age 2 years. CONCLUSION: Although male sex, exposure to smoking, parental history of asthma, and exposure to older siblings were associated with increased risk of wheezing and asthma-related outcomes in this prospective study of children born after 34 weeks gestation, fetal growth and length of gestation were not.     

Asthma in pregnancy

Although about 1% of pregnant women have asthma, it is often underrecognized and suboptimally treated. The course of asthma during pregnancy varies; it improves, remains stable, or worsens in similar proportions of women. The risk of an asthma exacerbation is high immediately postpartum, but the severity of asthma usually returns to the preconception level after delivery and often follows a similar course during subsequent pregnancies. Changes in beta(2)-adrenoceptor responsiveness and changes in airway inflammation induced by high levels of circulating progesterone have been proposed as possible explanations for the effects of pregnancy on asthma. Good control of asthma is essential for maternal and fetal well-being. Acute asthmatic attacks can result in dangerously low fetal oxygenation. Chronically poor control is associated with pregnancy-induced hypertension, preeclampsia, and uterine hemorrhage, as well as greater rates of cesarian section, preterm delivery, intrauterine growth retardation, low birth weight, and congenital malformation. Women with well-controlled asthma during pregnancy, however, have outcomes as good as those in their nonasthmatic counterparts. Inhaled therapies remain the cornerstone of treatment; most appear to be safe in pregnancy.     

Is Fetal Gender Associated with Emergency Department Visits for Asthma During Pregnancy?

Background. To investigate if fetal gender (1) affects the risk of having an emergency department (ED) visit for asthma; and (2) is associated with adverse pregnancy outcomes among women who had at least one visit to the ED for asthma during pregnancy. Methods. We linked two provincial administrative databases containing records on in-patient deliveries and ED visits. The study sample included women who delivered a live singleton baby between April 2003 and March 2004. Pregnant women who made at least one ED visit for asthma were counted as cases and the rest of the women as control subjects. We performed a multivariable analysis using logistic regression to model the risk of having an ED visit for asthma, with fetal gender being one of the predictors. In addition, a series of multivariable logistic regressions were also constructed separately for cases and controls for the following adverse delivery outcomes: low birth weight baby, preterm delivery, and delivery via Caesarian section. Results. Among 109,173 live singleton deliveries, 530 women had visited ED due to asthma during pregnancy. While having an ED visit for asthma was positively associated with teenage pregnancy, low income, and presence of pregnancy-induced hypertension, it was not associated with fetal gender (OR 1.01, 95% CI 0.85-1.19). Fetal gender was not a significant predictor of adverse pregnancy outcomes among women who had an asthma ED visit during pregnancy. Conclusion. Fetal gender does not affect the risk of having an ED visit for asthma during pregnancy, and it is not associated with adverse pregnancy outcomes among women who had an asthma-related ED during pregnancy.     

Costs and Resource Use of Mild Persistent Asthma Patients Initiated on Controller Therapy

Background. To investigate if fetal gender () affects the risk of having an emergency department (ED) visit for asthma; and () is associated with adverse pregnancy outcomes among women who had at least one visit to the ED for asthma during pregnancy. Methods. We linked two provincial administrative databases containing records on in-patient deliveries and ED visits. The study sample included women who delivered a live singleton baby between April 2003 and March 2004. Pregnant women who made at least one ED visit for asthma were counted as cases and the rest of the women as control subjects. We performed a multivariable analysis using logistic regression to model the risk of having an ED visit for asthma, with fetal gender being one of the predictors. In addition, a series of multivariable logistic regressions were also constructed separately for cases and controls for the following adverse delivery outcomes: low birth weight baby, preterm delivery, and delivery via Caesarian section. Results. Among 109,173 live singleton deliveries, 530 women had visited ED due to asthma during pregnancy. While having an ED visit for asthma was positively associated with teenage pregnancy, low income, and presence of pregnancy-induced hypertension, it was not associated with fetal gender (OR 1.01, 95% CI 0.85-1.19). Fetal gender was not a significant predictor of adverse pregnancy outcomes among women who had an asthma ED visit during pregnancy. Conclusion. Fetal gender does not affect the risk of having an ED visit for asthma during pregnancy, and it is not associated with adverse pregnancy outcomes among women who had an asthma-related ED during pregnancy.     

Maternal asthma is associated with reduced female fetal growth

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 11beta-hydroxysteroid dehydrogenase type 2 (11beta-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 11beta-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 Relationship of Asthma-Specific Quality of Life During Pregnancy to Subsequent Asthma and Perinatal Morbidity

Objective. To determine whether asthma-specific quality of life during pregnancy is related to asthma exacerbations and to perinatal outcomes. Methods. This was a secondary analysis of data from a randomized controlled trial of inhaled beclomethasone versus theophylline in the treatment of moderate asthma during pregnancy. The Juniper Asthma Quality of Life Questionnaire (AQLQ) was administered to patients at enrollment. Exacerbations were defined as asthma symptoms requiring a hospitalization, unscheduled medical visit, or oral corticosteroid course. Results. Quality of life assessments were provided by 310 of the 385 participants who completed the study. There was more than a 25% decrease in the odds of a subsequent asthma exacerbation for every 1-point increase in AQLQ score for the overall score (odds ratio [OR] 0.73, 95% confidence interval [CI] 0.55–0.96), emotion domain (OR 0.72, 95% CI 0.59–0.88), and symptoms domain (OR 0.73, 95% CI 0.57–0.94). These relationships were not significantly influenced by initial symptom frequency or forced expiratory volume in 1 s (FEV₁). No significant relationships were demonstrated between enrollment AQLQ scores and preeclampsia, preterm birth, low birth weight, or small for gestational age. Conclusion. Asthma-specific quality of life in early pregnancy is related to subsequent asthma morbidity during pregnancy but not to perinatal outcomes.     

Asthma and pregnancy

Asthma is the most frequent respiratory disorder complicating pregnancy. Diagnosis and evaluation of severity of asthma are unchanged by the presence of pregnancy, but the course of asthma varies: asthma may improve, remain stable, or worsen. Conversely, chronically poor control is associated with pregnancy-induced hypertension, preeclampsia, as well as greater rates of cesarian section, preterm delivery, intrauterine growth retardation, low birth weight, and congenital malformation. Highly-motivated women with well-controlled asthma during pregnancy, can achieve pregnancy outcome as good as their non-asthmatic conterparts. Inhalation therapies remain the cornerstone of treatment; most appear to be safe in pregnancy.     

Managing Asthma in Expectant Mothers

Pregnancy does not appear to have a consistent effect on the frequency or severity of asthma. The most common cause of worsening asthma in pregnancy is likely to be noncompliance with medication. Emphasizing to the patient in advance that fetal well-being is dependent on maternal well-being may help prevent this.In general, well controlled asthma is not associated with a higher risk of adverse pregnancy outcomes. Essential to successful asthma management is patient education that helps to ensure effective medication use, avoidance of triggers, and prompt treatment. This education should include measurement of peak expiratory flow rate and a written asthma action plan. Most of the medications that are used to control asthma in the general population can be safely used in pregnant women. Inhaled beta-adrenoceptor agonists (beta-agonists), cromolyn sodium (sodium cromoglycate), and inhaled and systemic corticosteroids all appear to be very well tolerated by the fetus. Budesonide and beclomethasone should be considered as the preferred inhaled corticosteroids for the treatment of asthma in pregnancy. Use of the leukotriene receptor antagonists zafirlukast and montelukast in pregnancy is probably safe but should be limited to special circumstances, where they are viewed essential for asthma control. Zileuton should not be used in pregnancy.Acute asthma exacerbations in pregnant women should be treated in a similar manner to that in non-pregnant patients. Maternal blood glucose levels should be monitored periodically in pregnant women receiving systemic corticosteroids because of the deleterious effects of hyperglycemia upon embryos and fetuses. During pregnancy, maternal arterial oxygen saturations should be kept above 95% if possible for fetal well-being. Ambulatory oxygenation should be checked prior to discharge to ensure that women do not desaturate with their daily activities.Acute exacerbations of asthma during labor and delivery are rare. Dinoprost, ergometrine, and other ergot derivatives can cause severe bronchospasm, especially when used in combination with general anesthesia, and should be avoided in asthmatic patients. Pregnant women who have been treated with corticosteroids in the past year may require stress-dose corticosteroids during labor and delivery. Most asthma medications, including oral prednisone, are considered compatible with breast-feeding.     

Exposure to second-hand smoke and reproductive outcomes depending on maternal asthma

Tobacco consumption and exposure to second-hand smoke (SHS) are associated with reduced birth weight. One issue that has not been clarified previously is that of the potential higher risk of this outcome in mothers with asthma. We assessed the role of prenatal maternal tobacco use and SHS on reproductive outcomes and assessed the interaction with maternal history of asthma. Data was collected from the INMA study, a maternal birth cohort selected from the general population established in Spain in 2002. We measured cotinine at the 32nd week of pregnancy in 2,219 females. Diagnosed maternal asthma was self-reported during pregnancy. 35% of mothers reported not being exposed to smoking or SHS during pregnancy. Active smoking (i.e. self-reported or cotinine >50 ng·mL(-1)) was related to a 134 g decrease in birth weight and a relative risk of 1.8 for small for gestational age and fetal growth restriction. These results were not modified by maternal asthma. Maternal asthma had a similar frequency in all exposure groups. Non SHS-exposed females had the lowest prevalence of asthma. SHS (i.e. cotinine 20-50 ng·mL(-1)) decreased birth weight by 32 g among those without maternal asthma, but these differences were not statistically significant (95% CI -88.76-24.76). Maternal asthma did not promote these effects. Maternal history of asthma did not modify the effects of smoking on reproductive outcomes in a cohort sampled from the general population.     

Asthma in pregnancy--immunological changes and clinical management

Asthma is one of the most common diseases complicating pregnancy and a risk factor for several maternal and fetal complications, posing a special challenge for physicians treating asthmatic pregnant women. Asthma influences the outcome of pregnancy and - vice versa - pregnancy affects asthma severity with bidirectional immunological interactions that are currently being examined. Supporting pregnancy-induced immunotolerance is the observation that attenuation of allergic responses can be detected in controlled asthmatic pregnant patients. However, uncontrolled asthmatic pregnant women show significant asthma-associated immune reactions, such as diminished pregnancy specific regulatory T cell proliferation, that may - besides other factors - influence fetal growth. Uncontrolled, symptomatic asthma may increase the risk of adverse perinatal outcomes; thus adequate regular anti-asthmatic treatment resulting in optimal asthma control represents a vital need during pregnancy. This review summarizes immunological changes characterizing pregnancy in asthmatic women together with the clinical implications of asthma management during pregnancy.     

Asthma in pregnancy

Worldwide the prevalence of asthma among pregnant women is on the rise, and pregnancy leads to a worsening of asthma for many women. This article examines the changes in asthma that may occur during pregnancy, with particular reference to asthma exacerbations. Asthma affects not only the mother but the baby as well, with potential complications including low birth weight, preterm delivery, perinatal mortality, and preeclampsia. Barriers to effective asthma management and opportunities for optimized care and treatment are discussed, and a summary of the clinical guidelines for the management of asthma during pregnancy is presented.     

Asthma During Pregnancy

Ineffectively controlled asthma during gestation must be avoided to protect the fetus from untoward effects of matenal hypoxemia and hypocarbia. With current therapy and a compliant gravida, the outcome of pregnancy can be similar to the general population. Physician confidence in antiasthma medications is important. Respiratory distress has pregnancy implications by 20-24 weeks gestation and it is important to have fetal assessment documented when the gravida is treated in the emergency room or during hospitalization for status asthmaticus.     

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.     

Reduced 11beta-hydroxysteroid dehydrogenase type 2 activity is associated with decreased birth weight centile in pregnancies complicated by asthma

Pregnancies complicated by asthma are associated with an increased risk of low birth weight. Currently, the mechanisms causing this outcome are unknown. To investigate whether impaired placental function may be a determinant, we measured placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity, protein and mRNA, placental CRH mRNA, fetal cortisol, and fetal estriol concentrations at delivery. Asthmatic subjects were classified according to inhaled glucocorticoid intake during pregnancy and compared with a control nonasthmatic group. There was a 25% reduction in neonatal birth weight centile in asthmatic women who did not use inhaled glucocorticoid treatment. This was accompanied by significantly reduced placental 11beta-HSD2 activity, significantly increased fetal cortisol, and a trend toward increased placental CRH mRNA and reduced fetal estriol concentrations. The use of inhaled glucocorticoids for treatment was associated with birth weight centile, 11beta-HSD2 activity, CRH mRNA, fetal cortisol, and estriol concentrations similar to control levels. There was a significant inverse correlation between fetal cortisol and fetal estriol concentrations across all groups. These studies demonstrate that inhaled glucocorticoid intake for the treatment of asthma is associated with improved placental function and fetal outcome, suggesting that inflammatory factors associated with asthma may be detrimental to fetal growth and development in these pregnancies.     

Fetal growth is not associated with early onset of severe retinopathy in type 1 diabetes mellitus

Reduced fetal growth has been suggested as a possible risk factor for diabetic nephropathy. The aim of the present study was to examine whether there could be an association also with rapidly progressing severe retinopathy in younger type 1 diabetic patients. Maternal pregnancy, as well as birth parameters of 27 type 1 diabetic patients with severe retinopathy diagnosis at a median age of 25 years, were studied retrospectively. The control group consisted of 22 type 1 diabetic patients with mild background retinopathy and with similar age, age at onset, and duration of diabetes. Mothers of the subjects with severe retinopathy had a higher body mass index (P = 0.03) but similar age, blood pressure levels, and weight gain during pregnancy as those of the control group. All but four babies, two in each group, were born after 37 completed gestational weeks. There were no differences regarding birth weight or of relative birth weight corrected for gestational length. Head circumference, birth length, and placenta weight were similar. The results indicate that fetal growth is not a factor of major importance for the development of severe retinopathy in younger type 1 diabetic patients.     

Maternal factors that determine neonatal size and body fat

These data are a review of previously published data. Initially, body composition was estimated in 186 neonates. Fatfree mass (FFM), which constituted 86% of birth weight, accounted for 83% of the variance in birth weight; fat mass (FM), which constituted 14% of birth weight, accounted for 46% of the variance in birth weight. Male neonates were an average of 175 g heavier than females. FFM was greater among males compared with females (P = 0.0001). Using stepwise logistic regression, 29% of the variance in birth weight, 30% in FFM, and 17% in FM was accounted for. Independent variables included maternal height, pregravid weight, weight gain during pregnancy, education, parity, paternal height and weight, neonatal sex, and gestational age. Including maternal insulin sensitivity explained 48% of the variance in birth weight, 53% in FFM, and 46% in FM. There was a positive correlation between weight gain and birth weight in control subjects but a negative correlation in subjects with gestational diabetes mellitus. Lastly, the roles of insulin, insulin-like growth factors, and leptin were examined in relation to fetoplacental growth and body composition. The assessment of fetal/neonatal body composition may improve the understanding of the effect of differential factors on fetal growth. Factors associated with accretion of fetal adipose tissue in late gestation are less well understood compared with birth weight and FFM. Additional studies of maternal glucose and lipid metabolism are needed to better evaluate fetal growth.