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ASTHMA, PROGESTERONE, AND PREGNANCY
204
12. Wroblewski B. Wear and loosening of the socket in the Charnley low-friction arthroplasty of the hip. Orthop Clin N Am 1988; 19: 627-30. 13. Tallroth K, Eskola A, Santavirta S, Konttinen YT, Lindholm TS. Aggressive granulomatous lesions after hip arthroplasty. J Bone Joint Surg 1988; 71B: 571-75.
responsiveness, although a p value of 0-06 was thought to be consistent with a weak association. In some women asthma symptoms improved and they needed less therapy, but again the picture was mixed, with no clear correlations with hormone levels. There was the expected increase in heartburn, but this did not correlate with bronchial hyperresponsiveness as measured by methacholine
challenge. ASTHMA, PROGESTERONE, AND PREGNANCY pregnancy progesterone levels rise steeply; they peak in the third trimester, typically 50-100 times baseline values. These high levels inhibit the formation of gap junctions (pathways of low electrical resistance) in the smooth muscle of the uterus, which remains largely relaxed and poorly contractile. Progesterone levels fall abruptly immediately before parturition, and uterine contractility increases sharply because gap junction formation suddenly increases.1 It has been suggested that this hormonal effect on smooth muscle might apply in other parts of the body, notably the gut, in which relaxation of the oesophageal sphincter is often associated with reflux symptoms that are
During reach
a
troublesome in late pregnancy.2 Bronchial smooth muscle might also be expected to follow the same pattern, with relative relaxation during pregnancy and increased contractility at the onset of labour. If true, clinical implications for patients with asthma, especially those with long-standing disease and associated bronchial smooth muscle hypertrophy, might be dramatic. In reality, there is little consistent evidence that pregnancy profoundly influences the severity of asthma, except in occasional individuals. Many researchers have reported the symptoms of asthma during pregnancy; the consistent finding is that symptoms may worsen, remain unchanged, or improve in variable numbers of individuals. The proportions with such changes have varied considerably, the extremes being reported by Gluck,3who found that 14% of patients improved and 43% worsened, and White et awlwho found that 69% improved and only 6% worsened during pregnancy. Schaefer and Silverman could detect no change in asthma symptoms in 93% of 293 5 pregnant women. Most reports on asthma during pregnancy mention the difficulty of making accurate observations during a time of rapidly changing physiology-the height of the fundus in the third trimester may be a more important cause of breathlessness than is worsening asthma. The frequent sense of wellbeing during pregnancy may mask symptoms and lead to a reduction in therapy, without objective improvement in serial peak flow measurements. Conversely, increased gastro-oesophageal reflux may lead to worsening asthma. Juniper and her colleagues in Hamilton have lately reported a detailed prospective study of asthma during pregnancy.6 They began with careful evaluation of 20 women of child-bearing potential before conception. The 16 who conceived during the study period were then followed throughout pregnancy, with assessment of symptoms, drug requirements, progesterone and oestriol levels, and of bronchial hyperresponsiveness by means of methacholine challenge. Not surprisingly, these women behaved in different ways. Overall, there was a slight but not significant reduction (improvement) in bronchial hyperresponsiveness; 11showed an improvement compared with baseline but 5 a deterioration. There was no clear statistical correlation between progesterone levels and bronchial hypermost
These
mostly negative findings are open to several interpretations. The first is that progesterone does not affect smooth muscle of the bronchial wall in the same way as that of the myometrium and perhaps the gut. The second, favoured by Juniper and her colleagues, is that the effects of progesterone on bronchial smooth muscle are countered by other biological effects during pregnancy--eg, increased free cortisol levels. The third interpretation, for which there is much experimental support, is that measurement of bronchial hyperresponsiveness by methacholine challenge reflects not only smooth muscle contractility but also many complex interactions within the bronchial wall in response to an inflammatory stimulus.8 Nevertheless, occasionally there are compelling clinical reasons to suspect that changing progesterone levels can be important. For example, severe premenstrual asthma can sometimes be completely prevented by injection of progesterone at the appropriate time.9 In such patients there seems little doubt that the sudden fall in progesterone before menstruation is highly associated with clinical asthma and presumably bronchial smooth muscle contractility. All this reinforces conventional clinical wisdom about asthma in pregnancy: namely, that it is impossible to predict hormonal effects on the airways. Most women appear to be little influenced by pregnancy, but there are exceptions in both directions. Previously, asthma could be devastating in its effects on both mother and fetus, but it is now clear that with good management even the most severe types of asthma can be associated with a normal outcome of pregnancy and childbirth.lO Fortunately, none of the usual anti-asthma drugs is harmful in normal doses, to either mother or fetus, and asthma should be managed with the same attention to detail as at any other time. Continuous monitoring of peak flow is strongly recommended in all but the mildest cases.
1. Garfield
RE, Sims S, Daniel EE. Gap junctions: their presence and in myometrium during parturition. Science 1977; 198:
necessity
958-60. 2. Fisher RS, Roberts
GS, Grabowski CJ, Cohen S. Altered lower sphincter function during early pregnancy. Gastroenterology 1978; 74: 1233-37. 3. Gluck JC, Gluck PA. The effects of pregnancy on asthma: a prospective study. Ann Allergy 1976; 37: 164-68. 4. White RJ, Coutts II, Gibbs CJ, MacIntyre C. A prospective study of asthma during pregnancy and the puerperium. Respir Med 1989; 83: oesophageal
103-06. 5. Schaefer G, Silverman F. Pregnancy complicated by asthma. Am J Obstet Gynecol 1961; 82: 182-91. 6. Juniper EF, Daniel EE, Roberts RS, Kline PA, Hargreave FE, Newhouse MT. Improvement in airway responsiveness and asthma severity during pregnancy. Am Rev Respir Dis 1989; 140: 924-31. 7. Nolten WE, Rueckert PA. Elevated free cortisol index in pregnancy possible regulatory mechanisms. Am J Obstet Gynecol 1981; 139: 492-98. 8. Holgate ST, Beasley R, Twentyman OP. The pathogenesis and significance of bronchial hyperresponsiveness in airways disease. Clin Sci 1987; 73: 561-72. 9. Benyon HLC, Garbett ND, Barnes PJ. Severe premenstrual exacerbations of asthma: effect of intramuscular progesterone. Lancet 1988; ii: 370-71. 10. Apter AJ, Greenberger MD, Patterson MD. Outcomes of pregnancy in adolescents with severe asthma. Arch Intern Med 1989; 149: 2571-75.
12. Wroblewski B. Wear and loosening of the socket in the Charnley low-friction arthroplasty of the hip. Orthop Clin N Am 1988; 19: 627-30. 13. Tallroth K, Eskola A, Santavirta S, Konttinen YT, Lindholm TS. Aggressive granulomatous lesions after hip arthroplasty. J Bone Joint Surg 1988; 71B: 571-75.
responsiveness, although a p value of 0-06 was thought to be consistent with a weak association. In some women asthma symptoms improved and they needed less therapy, but again the picture was mixed, with no clear correlations with hormone levels. There was the expected increase in heartburn, but this did not correlate with bronchial hyperresponsiveness as measured by methacholine
challenge. ASTHMA, PROGESTERONE, AND PREGNANCY pregnancy progesterone levels rise steeply; they peak in the third trimester, typically 50-100 times baseline values. These high levels inhibit the formation of gap junctions (pathways of low electrical resistance) in the smooth muscle of the uterus, which remains largely relaxed and poorly contractile. Progesterone levels fall abruptly immediately before parturition, and uterine contractility increases sharply because gap junction formation suddenly increases.1 It has been suggested that this hormonal effect on smooth muscle might apply in other parts of the body, notably the gut, in which relaxation of the oesophageal sphincter is often associated with reflux symptoms that are
During reach
a
troublesome in late pregnancy.2 Bronchial smooth muscle might also be expected to follow the same pattern, with relative relaxation during pregnancy and increased contractility at the onset of labour. If true, clinical implications for patients with asthma, especially those with long-standing disease and associated bronchial smooth muscle hypertrophy, might be dramatic. In reality, there is little consistent evidence that pregnancy profoundly influences the severity of asthma, except in occasional individuals. Many researchers have reported the symptoms of asthma during pregnancy; the consistent finding is that symptoms may worsen, remain unchanged, or improve in variable numbers of individuals. The proportions with such changes have varied considerably, the extremes being reported by Gluck,3who found that 14% of patients improved and 43% worsened, and White et awlwho found that 69% improved and only 6% worsened during pregnancy. Schaefer and Silverman could detect no change in asthma symptoms in 93% of 293 5 pregnant women. Most reports on asthma during pregnancy mention the difficulty of making accurate observations during a time of rapidly changing physiology-the height of the fundus in the third trimester may be a more important cause of breathlessness than is worsening asthma. The frequent sense of wellbeing during pregnancy may mask symptoms and lead to a reduction in therapy, without objective improvement in serial peak flow measurements. Conversely, increased gastro-oesophageal reflux may lead to worsening asthma. Juniper and her colleagues in Hamilton have lately reported a detailed prospective study of asthma during pregnancy.6 They began with careful evaluation of 20 women of child-bearing potential before conception. The 16 who conceived during the study period were then followed throughout pregnancy, with assessment of symptoms, drug requirements, progesterone and oestriol levels, and of bronchial hyperresponsiveness by means of methacholine challenge. Not surprisingly, these women behaved in different ways. Overall, there was a slight but not significant reduction (improvement) in bronchial hyperresponsiveness; 11showed an improvement compared with baseline but 5 a deterioration. There was no clear statistical correlation between progesterone levels and bronchial hypermost
These
mostly negative findings are open to several interpretations. The first is that progesterone does not affect smooth muscle of the bronchial wall in the same way as that of the myometrium and perhaps the gut. The second, favoured by Juniper and her colleagues, is that the effects of progesterone on bronchial smooth muscle are countered by other biological effects during pregnancy--eg, increased free cortisol levels. The third interpretation, for which there is much experimental support, is that measurement of bronchial hyperresponsiveness by methacholine challenge reflects not only smooth muscle contractility but also many complex interactions within the bronchial wall in response to an inflammatory stimulus.8 Nevertheless, occasionally there are compelling clinical reasons to suspect that changing progesterone levels can be important. For example, severe premenstrual asthma can sometimes be completely prevented by injection of progesterone at the appropriate time.9 In such patients there seems little doubt that the sudden fall in progesterone before menstruation is highly associated with clinical asthma and presumably bronchial smooth muscle contractility. All this reinforces conventional clinical wisdom about asthma in pregnancy: namely, that it is impossible to predict hormonal effects on the airways. Most women appear to be little influenced by pregnancy, but there are exceptions in both directions. Previously, asthma could be devastating in its effects on both mother and fetus, but it is now clear that with good management even the most severe types of asthma can be associated with a normal outcome of pregnancy and childbirth.lO Fortunately, none of the usual anti-asthma drugs is harmful in normal doses, to either mother or fetus, and asthma should be managed with the same attention to detail as at any other time. Continuous monitoring of peak flow is strongly recommended in all but the mildest cases.
1. Garfield
RE, Sims S, Daniel EE. Gap junctions: their presence and in myometrium during parturition. Science 1977; 198:
necessity
958-60. 2. Fisher RS, Roberts
GS, Grabowski CJ, Cohen S. Altered lower sphincter function during early pregnancy. Gastroenterology 1978; 74: 1233-37. 3. Gluck JC, Gluck PA. The effects of pregnancy on asthma: a prospective study. Ann Allergy 1976; 37: 164-68. 4. White RJ, Coutts II, Gibbs CJ, MacIntyre C. A prospective study of asthma during pregnancy and the puerperium. Respir Med 1989; 83: oesophageal
103-06. 5. Schaefer G, Silverman F. Pregnancy complicated by asthma. Am J Obstet Gynecol 1961; 82: 182-91. 6. Juniper EF, Daniel EE, Roberts RS, Kline PA, Hargreave FE, Newhouse MT. Improvement in airway responsiveness and asthma severity during pregnancy. Am Rev Respir Dis 1989; 140: 924-31. 7. Nolten WE, Rueckert PA. Elevated free cortisol index in pregnancy possible regulatory mechanisms. Am J Obstet Gynecol 1981; 139: 492-98. 8. Holgate ST, Beasley R, Twentyman OP. The pathogenesis and significance of bronchial hyperresponsiveness in airways disease. Clin Sci 1987; 73: 561-72. 9. Benyon HLC, Garbett ND, Barnes PJ. Severe premenstrual exacerbations of asthma: effect of intramuscular progesterone. Lancet 1988; ii: 370-71. 10. Apter AJ, Greenberger MD, Patterson MD. Outcomes of pregnancy in adolescents with severe asthma. Arch Intern Med 1989; 149: 2571-75.