Cyclical variation in asthma severity with the menstrual cycle (also called catamenial asthma, premenstrual asthma or perimenstrual asthma (PMA) is a poorly understood phenomenon reported to affect between 8.2% and 74% of females with asthma. Deterioration in asthma control during pregnancy or pregnancy associated deterioration (PAD) is similarly a poorly understood phenomenon reported to affect up to 44% of women with asthma during pregnancy.
• To critically appraise the literature describing PMA and PAD.
• To confirm by questionnaire and prospective evaluation the existence of PMA and PAD in an Australian setting.
• To ascertain whether sex hormones influence the course of asthma during
the menstrual cycle and pregnancy.
• To determine what differences exist between subjects with and without PMA and with and without PAD with respect to other variables
including hormone profiles, inflammatory mediators, and airway responsiveness to hypertonic saline.
• To ascertain the determinants of PMA and PAD.
• Integrate the study's findings with the literature review.
• Develop a possible explanation of PMA and PAD integrating the study and literature findings.
1) A modified International Union Against Tuberculosis (lUAT) Bronchial Symptoms Questionnaire was administered to 3892 women attending their first antenatal clinic
appointment at a tertiary teaching hospital in Brisbane.
2) The perimenstrual study evaluated prospectively 51 non-pregnant women with asthma. Data included symptoms of asthma, medication use, peak expiratory flow (PEF), and "premenstrual tension." A subset of 14 volunteers were then evaluated in detail during the menstrual cycle with: hormones, cytokines and inflammatory mediator profiles from blood, urine and induced sputum; lung function; and airway responsiveness to hypertonic saline.
3) The pregnancy study evaluated 10 women with asthma from mid-trimester through to one month post-partum. Subjects prospectively recorded symptoms, medication use, and PEF. In addition, subjects attended during gestational weeks 20, 32, and 4 weeks post-partum for evaluation with: hormones, cytokines and inflammatory mediator profiles from blood, urine and induced sputum; airway responsiveness as measured by hypertonic saline; lung
function; allergy testing; and respiratory quality of life questionnaire.
1) Questionnaire Study of 3892 pregnant women.
• 56.5% of subjects reported one or more asthma symptoms in the last 12 months; 28% reported having ever had asthma; and 15.3%
reported asthma in the last 12 months.
• 55.3% reported smoking for as long as a year. 29% reported smoking during the current pregnancy.
• Smoking was an independent risk factor for reported asthma in the last 12 months
(adjusted odds ratio: 1.48, 95%CI: 1.29-1.70), any asthma symptom in the last 12 months
(adjusted odds ratio: 1.57, 95%
CI: 1.37-1.80), and cough or phlegm first thing in the morning (adjusted odds ratio: 1.64, 95%CI: 1.42-1.88).
• 34% of subjects with asthma who had had a child recalled deterioration in their asthma or breathing during a previous pregnancy.
Deterioration occurred most commonly in the last trimester (68%). In women who recalled deterioration of asthma or breathing
during a previous pregnancy, 71 % reported that the deterioration improved in the first few months after pregnancy.
2) Perimenstrual Study
• 47% (95%CI: 33%-62%) of subjects were determined by prospective
evaluation to have perimenstrual asthma.
• Self reported cyclical deterioration in asthma control (i.e. relying on recall without prospective evaluation) was very unreliable in
identifying or excluding subjects with perimenstrual asthma. Self reported variability had a sensitivity of 33.3%, a specificity of
62%, a positive predictive value of 55%, and a negative predictive value of 39%. Prospective evaluation is required to reliably
diagnose perimenstrual asthma.
• Within the perimenstrual asthma group the following statistically or borderline significant differences existed at the perimenstrual
interval compared to the midcycle interval: higher asthma symptom score; greater reliever medication use; greater preventer
medication use; and lower peak expiratory flows.
• Subjects with PMA were distinguishable from subjects with constant asthma (either with statistical significance p< =0.05 or
borderline significance p > 0.05 and < = 0.08) by virtue of exhibiting: higher perimenstrual asthma scores; greater progesterone
gradient (change in progesterone concentration during the premenstrual week); longer menses; higher premenstrual tension (PMT)
scores; greater proportion of physical type PMT symptoms; deterioration in FEVi during the premenstrual week; lower discomfort
scores to the non-specific stimulus of lamplight 2 days prior to menses; higher blood eosinophil counts at 7 and 2 days prior to
menses; higher serum eosinophil cationic protein (ECP) 7 days and 2 days prior to menses; and higher sputum prostaglandin E2
(PGE2) and higher urinary adrenaline/ creatinine ratio at 7 days prior to menses.
• Within the PMA group the following statistically significant differences existed at 2 days prior to menses compared to 7 days prior to
menses: lower serum progesterone; lower serum oestradiol; lower serum Interleukin 1 beta; lower interferon-gamma; blunted
sensation to lamplight; and lower FEVi.
• The progesterone gradient, premenstrual tension score and age together explain 89.2% of the variability seen in perimenstrual
3) Pregnancy Study
• Three (30%) subjects reported asthma deterioration during pregnancy with subsequently improvement post-partum (95%CI:
6.7% - 65.2%) and 7 (70%) had fairly
constant or stable asthma that did not appear to change during or after pregnancy (95%CI:
34.8% - 93.3%).
• Subjects with PAD were distinguishable from subjects with constant asthma (either with statistical significance p< =0.05 or
borderline significance p > 0.05 and < = 0.08) by virtue of exhibiting: higher (worse) asthma symptom scores at 20 and 32 weeks
gestation; worse QOL score for the breathing domain at week 32; lower morning PEF at week 32; lower serum
aldosterone levels at both 20 and 32 weeks; higher serum ECP level at 20 weeks; and higher serum Interleukin 1 beta level at 32
• Subjects with PAD exhibited trends towards a difference from subjects with constant asthma (magnitude of difference in variable of
interest suggestive but not statistically significant [p >0.08]) in the following variables: higher progesterone and oestradiol levels
at 32 weeks; higher serum ECP at 32 weeks; higher sputum ECP levels at 20 and 32 weeks; higher blood eosinophil count at
32 weeks; higher Interleukin 1 beta level at 20 weeks; higher soluble circulating fragment of the low affinity IgE receptor (sCD23) at
all visits; higher urinary
adrenaline/creatinine ratio at 32 weeks; and an increase in the ratio of the bronchoconstrictor
prostaglandin PGF2a to the bronchodilator prostaglandin PGE2 in sputum at 32 weeks. • 80.3% of the variability seen in asthma
symptom score at 32 weeks could be explained by the serum progesterone concentration, serum aldosterone concentration
and urinary adrenaline/creatinine ratio at 32 weeks.
• Questionnaire and prospective evaluation confirm that both PMA and PAD occur commonly in Australian woman with asthma.
• Subjects with PMA and PAD can be distinguished from those with constant asthma by symptoms, lung function, progesterone levels,
and inflammatory mediators.
• The sex hormone progesterone appears to be the major determinant of PMA, and a major determinant of PAD, while aldosterone plays
an important additional role in PAD.