Partners Asthma Center Grand Rounds
Lynda M. Cristiano, M.D.
Asthma in Women
This article will focus on three major areas of interest pertaining to asthma among women: the epidemiology of asthma in women; asthma during pregnancy; and the influence of female sex hormones on asthma.
There is increasing evidence that an interplay of gender and age influence the risk of developing asthma and the prognosis of the disease. In a populated-based study of over 9000 persons conducted in Tecumseh, Michigan and reported by Border and colleagues in 1974, almost 50% of all persons with asthma had the onset of their disease before age 10 years. In the youngest age groups, more boys than girls had asthma. Around puberty (ages 12-14) the prevalence of asthma was the same for boys and girls. After puberty and throughout adulthood, asthma was more common among women than among men.
Subsequently, Dodge and Burrows found similar results regarding the age-specific incidence of asthma in their community-based questionnaire survey in Tucson, Arizona. The incidence of new cases of asthma was highest in young children, decreased significantly in adolescence, and then increased again in early adult life. After age 9, the incidence of asthma was at least twice as great among females (0.4 to 0.8% new cases per year) as compared to males (0.2% per year). The gender difference in asthma incidence was most dramatic among persons over age 40: of the 22 new cases identified in this study, 19 were women.
Asthma severity may also differ between the sexes. A retrospective review of hospitalizations for asthma in southeastern Pennsylvania during the years 1986-1989 found significantly different rates of hospitalization depending on age and gender. Under the age of 10 years, boys were admitted to the hospital for asthma care almost twice as often as girls. During the second decade of life, the frequency of male admissions for asthma decreased while that of female admissions increased by the same proportion. Among adults the female-to-male ratio of hospitalizations for asthma rose to nearly 3:1. In addition, the length of hospitalizations increased with advancing age, and beyond age 30 years the duration of hospital stay was greater for women than for men.
Taken together, these studies suggest that after puberty, asthma becomes predominantly a disease of women. New cases of asthma among adults are more common in women, and women may be more severely affected by asthma than men. Table 1 lists some of the potential explanations for these observations. Airway diameter relative to lung size is smaller for young boys than girls, but this relationship reverses after puberty. Also, airway responsiveness (as assessed by methacholine sensitivity) is greater on average among women than among men.
Considering the importance of indoor allergen exposure in asthma (for example, house dust mite antigen), it is possible that in general women experience greater, more sustained exposures than do men. Also, given the dramatic changes in asthma epidemiology around the time of puberty, it is likely that the female sex hormones play an important role in the expression of asthma, either by directly modifying airway responsiveness or perhaps by affecting the immune response to antigen presentation and processing.
Finally, evidence of physician biases in applying a diagnosis of asthma confounds definitive estimates of asthma incidence, especially among older adults. Women over age 60 years presenting to their physician with cough, wheeze, and shortness of breath are more likely to receive a diagnosis of asthma, whereas at this age men with identical symptoms are more likely to be labeled as having emphysema or chronic obstructive pulmonary disease. Furthermore, physicians' concerns specific to women's health, including concerns about medication effects on reproduction, pregnancy, or osteoporosis, may lead to undertreatment of asthma — specifically a delay in the use of systemic steroids — that may contribute to greater asthma severity among older women.
Before considering the impact of asthma on pregnancy and pregnancy on asthma, it is worth reviewing briefly the normal changes in respiratory physiology that occur during pregnancy. Tidal volume increases very early in pregnancy with a resultant increase in minute ventilation by as much as 48% by term. As a result, normal blood gases during pregnancy reveal a respiratory alkalosis with partial or full renal compensation. As the gravid uterus enlarges, lung volumes (specifically, residual volume, functional residual capacity, and, to a lesser extent, total lung capacity) all decrease. Other respiratory parameters do not change significantly throughout normal pregnancy, including respiratory rate, vital capacity, and airway function. Pertinent to asthma, the peak expiratory flow rate (PEFR) and one-second forced expiratory volume (FEV1) remain unchanged during pregnancy.
The physician caring for the pregnant asthmatic also needs to be attentive to the physiologic status of the fetus and to changes that occur during times of maternal illness. Inadequate oxygen delivery to the fetus can cause impaired fetal development and low birth weight infants. Maternal hypoxemia can be tolerated up to a point, but when maternal arterial oxygen tension falls below approximately 60 mm Hg, significant fetal hypoxemia ensues. Adequate uterine arterial blood flow is also crucial to fetal growth. The uterine artery is generally maximally dilated with little capacity for autoregulation of vasomotor tone. Autonomic input is almost exclusively alpha-adrenergic. Decreased uterine blood flow can result from maternal hypotension or compensatory vasodilation, maternal hypocapnia (as can occur during acute asthmatic exacerbations), or exogenously administered vasoconstrictors (e.g., nasal decongestants administered systemically).
Slowing of fetal heart rate is a sensitive indicator of fetal hypoxemia. Monitoring for fetal heart rate decelerations ("fetal monitoring") is often an important part of the care of mother and fetus during labor. Fetal monitoring is also critical during times of significant maternal illness, such as asthmatic exacerbations requiring emergency department treatment or hospitalization. Fetal decelerations may provide an early sign of trouble at a time when maternal vital signs remain normal.
The course of asthma during pregnancy is highly variable and largely unpredictable. Approximately equal percentages of asthmatic women will experience worsening, improvement, or no change in the severity of their asthma during pregnancy. Exacerbations of asthma during pregnancy are most common between weeks 24 and 36; patients are often reassured to learn that asthmatic exacerbations after week 37 (and during labor and delivery) are less common. Although it has been reported that asthma severity tends to be consistent from one pregnancy to the next, in my experience a smooth course to asthma during one pregnancy does not preclude a rocky course during the next, and vice versa. Factors that may contribute to worsening of asthma during pregnancy include: 1) gastroesphageal reflux; 2) rhinitis with post-nasal drip; 3) large hormonal changes; and 4) medication non-compliance. Out of concern for the fetus, some women become particularly compliant with their asthma treatment during pregnancy. Others others avoid all medications, fearful of potential adverse effects. Medication non-compliance in this latter group of pregnant women can be a cause of worsening asthma control.
Two clinical trials in the 1970s compared pregnancy outcomes among women with asthma (approximately 350 asthmatic women total) with data from tens of thousands of pregnancies among healthy women. These studies found that poor asthma control was associated with adverse fetal and maternal outcomes. Women with frequent or severe asthmatic attacks during pregnancy were more likely than women in the control population to have both fetal complications. Fetal complications included growth retardation, pre-term birth, low birth weight infants, neonatal hypoxia, and perinatal mortality. Maternal complications included preeclampsia, gestational hypertension, hyperemeses, vaginal hemorrhage, and induced and complicated labor.
More recently, Dr. Michael Schatz and his colleagues at Kaiser Permanente Medical Center in San Diego reported on the pregnancy outcomes among 486 asthmatic women who received active asthma management compared with a parallel, non-asthmatic control group of 486 healthy pregnant women. The two groups were well matched, including, sadly, for the percentage of cigarette smokers. The asthmatic women received intensive care in accordance with National Institutes of Health asthma guidelines, including home peak flow monitoring, frequent medical follow up, and intensive patient education. Among this relatively large group of asthmatic women receiving good medical care, no significant differences in either maternal or fetal outcomes were found compared to the control group. These investigators concluded that the prognosis for pregnany among women with asthma is no different from that of healthy women when intensive medical care is provided throughout pregnancy. Adverse outcomes appear to result largely from undertreatment of asthma, often resulting from inappropriate patient or physician fear of medication-induced fetal harm.
The safety during pregnancy of medications that might be used to treat asthma and related illnesses are highlighted in Table 2. Inhaled beta-2 selective adrenergic agonists are considered very safe, even when given in large amounts by nebulizer. Orally administered (e.g., albuterol, terbutaline) and systemically administered (e.g., terbutaline) beta agonists tend to have more systemic side effects and may cause fetal tachycardia and jitteriness. They are not, however, thought to be teratogenic. I would recommend against use of epinephrine during the first trimester because of potential adverse effects from its alpha-adrenergic (vasoconstrictor) action.
Beta-adrenergic agonists, especially terbutaline
Of Uncertain Safety:
|Leukotriene modifying drugs
Theophylline has been used for many years to treat asthma and has a good safety profile. Note that because the serum albumin concentration decreases druring pregnancy, the free theophylline concentration is higher at any measured total blood theophylline level. Consequently, a therapeutic target for the theophylline level of 6-10 µg/ml is preferabe during pregnancy.
Among the inhaled anti-inflammatory agents, both cromolyn and inhaled corticosteroids are considered safe for use during pregnancy. Of the inhaled corticosteroids, beclomethasone (Beclovent®, Vanceril®) has been best studied and has the longest track record for safety. Because systemic absorption is low and first-pass hepatic metabolism high, it is likely that at low and moderate doses other steroid preparations are likewise safe, but published experience with the newer preparations such as fluticasone is lacking. Systemically administered corticosteroids such as prednisone and methylprednisolone can also be used with safety in pregnancy. They are the mainstay of therapy for treating and in some instances preventing severe asthmatic attacks. Animal data raising concern over the development of cleft palate and lip in offspring of mothers treated with systemic corticosteroids during pregnancy have never been borne out in human studies.
No published information is available regarding use during pregnancy of the leukotriene modifying drugs (leukotriene receptor antagonists [Accolate® and Singulair®] and lipoxygenase inhibitors [Zyflo®]). Until more experience is gathered regarding these agents, in my opinion they should be avoided during pregnancy and alternative agents used to control asthma.
I encourage my pregnant patients to avoid antihistamines and nasal decongestants if possible. If needed, I favor the antihistamines with which we have the longest experience, such as chlortrimeton, over the newer, non-sedating antihistamines. Pseudoephredine (e.g., Sudafed®) in small doses has not been associated with adverse fetal outcomes, but because of its alpha-adrenergic effect, I tend to avoid its use, especially during the first trimester. Over-the-counter cough syrups (usually containing guaifenesin) are safe when used in moderation, but with those preparations having a high alcohol content, overuse may cause fetal alcohol syndrome.
Medications with known adverse effects if administered during pregnancy include iodides (used in some older cough medications) because of their effect on thyroid development in the fetus; sulfonamides (e.g., sulfamethoxazole-trimethoprim), which if used late in pregnancy can contribute to neonatal jaundice by displacing bilirubin from albumin; tetracycline, which can cause permanent staining of the child's teeth; and quinolone antibiotics, because of their potential teratogenicity.
Overall, the goals of asthma therapy in pregnancy mirror those in the non-pregnant patient: control symptoms, maintain normal activity, maintain normal or near-normal lung function, prevent exacerbations, avoid adverse side effects as much as possible, enable a normal birth experience, and ultimately deliver a healthy baby. Among the most common errors in management is underestimation by patient and physician of the severity of the airways obstruction. Spirometry should be measured at the initial office visit and periodically throughout the pregnancy. Home peak flow monitoring combined with a plan for physician contact when there is a significant deterioration in peak expiratory flow provides the opportunity for the early detection and treatment of deteriorations.
Asthma care should be integrated with obstetrical care. We rely on our obstetrical colleagues to monitor fetal growth, including use of ultrasonography when necessary. Women can be taught to monitor fetal kick counts as a measure to fetal well being. Fetal heart rate monitoring may be indicated during severe maternal asthmatic exacerbations as well as during times of decreased fetal movement in the third trimester and during labor and delivery.
Influence of female sex hormones
We have already alluded to the dramatic increase in asthma incidence among women that occurs after puberty and the changes in asthma severity that may occur during the hormonal fluxes of pregnancy. Two other areas worthy of mention are perimenstrual asthma and the influence of hormone replacement therapy among post-menopausal women.
Many women with asthma — in some reports up to as many as 40% — experience an increase in their asthmatic symptoms just before or during their menstrual periods. Dr. Emil Skobeloff and his colleagues reported on their results of a survey of 182 non-pregnant, adult asthmatic women presenting to one of five participating emergency departments for treatment of asthmatic attacks. Subjects were asked to identify the first day of their last menstrual period and also the onset of their asthmatic exacerbation. (Patients were excluded if they had a history of irregular menses, were using oral contraceptives or were postmenopausal.) The investigators then divided the menstrual cycle into four periods: pre-ovulatory, peri-ovulatory, post-ovulatory, and peri-menstrual. As shown in Figure 1, four times as many women sought emergency department care during the perimenstrual period of their cycle as during the post-ovulatory phase. A disproportionate percentage of the asthmatic attacks in this series, forty-six percent of the total, occurred peri-menstrually. The authors noted that during this time period of the menstrual cycle, serum estradiol levels fall from their peak to their trough values. They speculated that this rapid decline in circulating estrogen hormone may contribute to a predisposition for asthmatic exacerbations.
Case reports have suggested that hormone replacement therapy for post-menopausal women may occasionally worsen — or improve — asthma control. Recently, the results of a large-scale survey of post-menopausal women, conducted by members of the Channing Laboratory as part of the Nurses' Health Study, addressed the impact of hormone replacement therapy on the incidence of adult-onset asthma. Over 93,000 women between the ages of 34 and 68 years were entered into this study, and survey data were collected over a period of 10 years. These researchers found that among women with naturally occurring (non-surgical) menopause, those who reported ever using conjugated estrogens (with or without progesterone) had a 49% greater risk of developing asthma than those who had never used hormone replacement therapy. Similarly, among current users of estrogen supplementation, there was a 50% increased risk of new-onset asthma. Women who had taken hormonal replacement for more than 10 years had twice the age-adjusted risk of developing asthma compared to those who had never used estrogen.
It is probably unwise to extrapolate these epidemiologic data to the management of women with asthma. One would certainly not want to use this information to withhold hormone replacement therapy in an appropriate post-menopausal candidate or to withdraw such therapy from a patient with stable asthma. When initiating estrogen therapy in a patient with asthma, it is reasonable to monitor for any change in clinical status, especially among women with difficult-to-control asthma. Perhaps most importantly, these data lend further support to the concept that asthma is different in women than in men and that female hormones may be a key to at least some of that difference.
1. Schatz M, Zeiger RS, Hoffman CP, et al. Perinatal outcomes in the pregnancies of asthmatic women: a prospective controlled analysis. Am J Respir Crit Care Med 1995; 151:1170-4.
2. Skobeloff EM, Spivey WH, Silverman R, et al. The effect of the menstrual cycle on asthma presentations in the emergency department. Arch Intern Med 1996; 156:1837-40.
3. Troisi RJ, Speizer FE, Willett WC, et al. Menopause, postmenopausal estrogen preparations, and the risk of adult-onset asthma. A prospective cohort study. Am J Respir Crit Care Med 1995; 152 (4 Pt 1):1183-8.
About the author: Dr. Lynda Cristiano is a member of the Pulmonary and Critical Care Division at Brigham and Women's Hospital and Instructor of Medicine at Harvard Medical School. Her primary clinical interests are women's lung health and lung diseases in pregnancy.