Vol 44 # 4 December 2012 - Kma.org.kw

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281 Asthma during Pregnancy: An Immunologic Perspective December 2012 Fig. 4: Possible effects of asthma on the outcome of pregnancy asthma symptoms have been reported in association with menstruation [43] and in association with hormone replacement therapy [44,45] . Increased progesterone levels, in both animals [46] and humans [44,45] , have been associated with worsening asthma symptoms in several, but not all studies [47] . Both estrogen and progesterone have been shown to up-regulate Th2 cytokine production both in vitro [48,49] and in vivo [50] . The pregnancy-associated rise in serum-free cortisol may contribute to improvements in asthma during pregnancy [51] , since cortisol has anti-inflammatory properties. In addition, estradiol and progesterone concentrations increase significantly during pregnancy [51] . Progesterone is known to contribute to increased ventilation during normal pregnancy [52] and is also a potent smooth muscle relaxant [53] and may, therefore, be expected to contribute to improved asthma during pregnancy. On the other hand, progesterone has been shown to induce Th2-type reactivity [54-56] and thus pregnancy-associated increase in progesterone levels may be postulated to result in an increased Th2- bias and thus increased severity of asthma. Changes in β2-adrenoreceptor responsiveness and airway inflammation as a result of circulating progesterone may also contribute to worsening asthma during pregnancy [52] . Alterations in asthma associated with changes in sex steroid production during the menstrual cycle have previously been observed [57] , with up to 40% of females experiencing an exacerbation around the time of menstruation when progesterone and estradiol levels are low [58] . The season of pregnancy or delivery was not found to affect asthma progression [38] , suggesting that allergen exposure may not play a role in asthma alterations with pregnancy. Kircher et al [41] suggest that factors, such as IgE, which affect both the upper and lower airways, may be important in changes that occur in asthma during pregnancy. Early studies by Gluck and Gluck [37] also showed a correlation between increased serum IgE and deteriorating asthma during pregnancy. An observation that is worth mentioning here in terms of mechanisms and clinical relevance, is pertinent to the course of asthma during pregnancy. More severe asthma tends to worsen during pregnancy, whereas less severe asthma tends to remain unchanged or tends to improve [38] . The relationship between asthma severity classification and subsequent changes in asthma during pregnancy was assessed in a study on 1,700 pregnant asthmatics [7] . Exacerbations of asthma occurred in over half of all severe asthmatics, while only 12% of patients with mild asthma had exacerbations during pregnancy. It is tempting to suggest that perhaps maternal immune factors, such as the prevailing Th2 versus Th1 cytokine profile, may be one of the determinants of whether an asthmatic woman will get better or worse when she gets pregnant. Is this possibly due to an already heavily Th2-biased immune system tilting towards a stronger Th2 bias during pregnancy? IMPACT OF ASTHMA ON PREGNANCY In addition to the observed effects of pregnancy on asthma, it is also well-recognized that women with asthma are at increased risk of poor pregnancy outcomes [59] . Cases of severe life-threatening asthma requiring first trimester termination of pregnancy have been reported and an improvement in maternal asthma within 24 hours of termination has been observed [60] . Epidemiological studies have demonstrated that asthmatic females are at increased risk of many poor outcomes of pregnancy. Uncontrolled asthma in pregnant women can result in perinatal complications and exacerbations which can be life-threatening for the mother and fetus [37] . Increased maternal complications, including pre-eclampsia [61] , gestational diabetes [62] , preterm labor [63] , intrauterine growth restriction [59] , vaginal hemorrhage [64] , placenta previa [65] and cesarean delivery [65] have been described. Adverse fetal outcomes include increased risk of perinatal mortality [66] , intrauterine growth restriction [59] and low birth weight [62] . As early as in 1970, Gordon et al [66] reported a relatively large number of maternal or perinatal deaths in asthmatic patients, which were more likely to occur in severe asthmatics. A Californian perinatal database study comparing asthmatics to controls showed that asthmatics were more at risk of cesarean section, pre-term labour or delivery and pre-term premature rupture of the membranes. A cohort of almost 25,000 pregnant females in Canada found a significant association between pre-eclampsia and asthma [67] . Greenberger and Patterson [68] found
December 2012 KUWAIT MEDICAL JOURNAL 282 that those who had been hospitalized with status asthmaticus delivered neonates of reduced birth weight compared with those who were not hospitalized for asthma, suggesting that an acute attack of asthma may put the fetus at additional risk, particularly of intrauterine growth restriction (IUGR). However, it must be conceded that a few studies have not found such correlations. Apter et al [69] found no evidence of an increased rate of pre-eclampsia, pre-term delivery or IUGR in asthmatic adolescents compared with general estimates for adolescent pregnancies. However, these researchers did report that IUGR was significantly more likely in females with moderate or severe asthma, who required hospitalization during pregnancy, compared to subjects with mild asthma, who were not hospitalized for asthma during pregnancy. Similarly, Mabie et al [70] reported no increased rate of pre-term delivery or low birth weight among asthmatic females compared with general population rates, which were very high (17.7 and 6.3%, respectively). Likewise, Tata et al [71] reported an increase in risks of miscarriage and cesarean section in women with more severe asthma and previous asthma exacerbation, but not other complications. Despite the few studies showing a lack of adverse consequences, a majority of the studies have demonstrated associations between asthma and preeclampsia, and asthma and low birth weight by both historical or prospective cohort and case-control studies. A meta-analysis of the association between asthma in pregnancy and low birth weight babies showed that there was a significantly increased risk of low birth-weight babies in asthmatic pregnancies and that there was no significant increase in the risk of low birth weight with asthma when inhaled corticosteroids (ICS) were used [59] . There is therefore, a general agreement that severe asthma requiring corticosteroid therapy is associated with an increased incidence of low birth-weight babies and of preterm births [72-74] . Asthma, when not treated with inhaled steroids during pregnancy was associated with changes in placental function that affect fetal development which includes the hypothalamic-pituitary axis and growth [16] . In general, published data suggest that asthma severity, especially with suboptimal control, is associated with adverse pregnancy outcomes (Fig. 4) [74] . PREGNANCY: A Th2-TYPE SITUATION The fetus can be viewed as a sort of a semiallogeneic allograft that expresses paternally-derived antigens, which under non-pregnant circumstances would result in the activation of a “rejection reaction”. However, it is postulated that a number of processes are activated in concert to protect the fetus and thus ensure its survival. These include the separation of the maternal and fetal circulations, masking of paternal antigens on the trophoblast, endocrinological inhibition of adverse maternal immune reactions and production of immunomodulatory factors by both the mother and fetus. In 1993, Wegmann et al proposed that a shift towards Th2-mediated immunity particularly at uterine sites during pregnancy inhibits Th1 immune responses and prevents the rejection of the fetus by the maternal immune system [75] . Humoral immune responses are enhanced during pregnancy, while cell-mediated immune responses and the course of cell-mediated autoimmune disorders are down-regulated. Clinical evidence indicates that pregnant women undergo immunological changes consistent with a weakening of Th1 responses and strengthening of Th2 responses [75,76] leading to the contention that successful pregnancy probably depends on preferential stimulation of Th2 cytokineproducing cells. Experiments on mice and evidence in humans indicate that humoral responses are enhanced during pregnancy, but that there is a down-regulation of cell-mediated reactivity, responses to intracellular infections and the course of cell-mediated autoimmune disorders. These observations are consistent with a dampening of pro-inflammatory or Th1 reactivity and augmentation of anti-inflammatory or Th2 immunity during pregnancy. Dudley et al [77] found that cytokine responses by activated lymphocytes from pregnant mice are marked by a progressive decline in the production of the Th1 cytokine IL-2 and a concomitant increase in the levels of the Th2 cytokine IL-4. In humans, there are reports of significantly higher production of IL-10 (a Th2 cytokine) by mitogen-activated PBMC in pregnant women as compared with non-pregnant women [78] . Kruse et al [79] reported significantly reduced IL-2 and IFNγ mRNA expression during normal human pregnancy and a shift to a pronounced Th2 status. Using flow cytometric techniques on a single cell, significantly increased IL-4-producing CD4 + and CD8 + T cells were demonstrated in normal pregnant women as compared to non-pregnant women. In contrast, IFNγ- and IL-2-producing CD4 + and CD8 + T cells were significantly reduced in pregnancy, which is suggestive of a Th2 shift in pregnancy [80] . Thus, pregnancy is indeed a Th2-type phenomenon as proposed by Wegmann et al [75] and pregnancy seems to engender a shift towards Th2 bias [76] . Thus, the two broad lines of evidence described above show that both asthma and pregnancy are indeed Th2-type situations. Th2 cells and cytokines stimulate IgE production and are responsible for the activation of mast cells and inflammatory responses in asthma [17-21,23-26] . Likewise, pregnancy is associated with a dominance of Th2 reactivity and at the same time Th2 reactivity is conducive to successful pregnancy [75,76] .
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