General search strategy

You begin to address the topic of asthma during pregnancy by searching for evidence in electronic databases looking for cohort studies prospective or retrospective in design addressing perinatal outcomes. Randomized controlled trials with pregnant asthmatic subjects are rarely performed but can be searched for as well.

1. In pregnant women with asthma (population), is there a higher risk of adverse perinatal outcomes such as low birth weight, preterm birth, congenital malformations, perinatal mortality, and pre‐eclampsia (outcomes)?

A recent meta‐analysis from Murphy et al., derived from a substantial body of literature spanning several decades and including very large numbers of pregnant women, (over 1 000 000 for low birth weight and over 250 000 for preterm labor), indicates that pregnant women with asthma are at a significantly increased risk of a range of adverse perinatal outcomes including low birth weight and preterm birth [2] (Table 24.1).

Low birth weight, independent of prematurity, is a significant contributor to neonatal morbidity and mortality and therefore represents a significant public health issue. Recent interest in the developmental origins of adult disease has revealed that small size at birth is also a predictor for the development of and/or death from diseases in adult life, including diabetes, cardiovascular disease, atherosclerosis, hypertension, stroke, and coronary heart disease [3–5]. In their meta‐analysis, data were reported in 13 publications with over one million subjects, and this meta‐analysis indicated that maternal asthma reduces fetal growth, with statistically increased risks of low birth weight and small for gestational age. The risk of having a low birth weight baby was increased by 46% in women with asthma compared to women without asthma (relative risk [RR] 1.46, 95% confidence interval [CI] 1.22, 1.75). The mean birth weight of infants of mothers with asthma was 93 g lower (95% CI 160, 25 g) than that of infants of control mothers [2].

Preterm birth is the leading cause of neonatal mortality in developed countries and is associated with significant neonatal morbidity from diseases such as cerebral palsy. The meta‐analysis of 18 publications reported that maternal asthma significantly increases the risk of preterm delivery prior to 37 weeks (RR 1.41, 95% CI 1.23, 1.62) [2]. In contrast, recent data from a retrospective examination of a database which included over 17 000 births, demonstrated no significant increase in preterm delivery in pregnancies complicated by asthma (n = 1944) when compared with the normal population [6].

The meta‐analysis by Murphy et al. found that the risk of congenital anomalies in women with asthma was not significantly increased compared to control women without asthma (R 1.08, 95% CI 1.00, 1.16) [2]. However, a recent retrospective study, which included a cohort of 41 637 pregnancies of women with and without asthma, found that maternal asthma was associated with an increased risk of any congenital malformation. (OR = 1.30; 95% CI: 1.20–1.40) [7].

Murphy et al. found the risk of perinatal mortality (a combination of still births and neonatal deaths) in infants of asthmatic mothers to be significantly increased compared to control mothers (RR 1.25, 95% CI 1.05, 1.50), with the overall effect size being intermediate between that observed for still birth and neonatal death [2]. This result was largely driven by a recent large Canadian database study with over 13 000 women with asthma and 28 000 controls, which reported a significantly increased risk of perinatal mortality in women with asthma [8].

Pre‐eclampsia, a multi‐organ disease that is characterized by the presence of both hypertension and proteinuria in later pregnancy, is the leading cause of maternal mortality during pregnancy, and in severe cases is associated with significant morbidity for both the mother and the neonate. Recent work suggests that the development of any type of hypertension in pregnancy is predictive for future cardiovascular and cerebrovascular disease later in life in the mother [9]. Murphy et al. found that maternal asthma significantly increases the risk of pre‐eclampsia, by at least 50% [2].

1. 2. In pregnant women with asthma (population), does asthma control (risk factor) influence the occurrence of outcomes such as low birth weight, preterm birth, congenital malformations, perinatal mortality, and pre‐eclampsia (outcomes)?

Uncontrolled asthma can lead to hypoxia and other physiologic abnormalities that could lead to decreased fetal blood oxygen and resulting abnormal growth and development of the fetus. Another recent meta‐analysis sought to investigate if asthma exacerbations, oral corticosteroid use, or asthma severity, all components of poor asthma control, are associated with prematurity and intrauterine growth restriction (IUGR).

Data from this meta‐analysis found a significantly increased risk of low birth weight infants of those subjects experiencing asthma exacerbation during pregnancy (RR 3.02 [1.87, 4.89]) and using oral corticosteroids during pregnancy (RR 1.41, 95% CI [1.04, 1.93]). Overall, the risk of early low birth weight or preterm delivery was not increased in women with moderate/severe asthma compared to women with mild asthma (in publication). Murphy et al., reported in a recent meta‐analysis an increased risk of low birth weight in women who had an asthma exacerbation during pregnancy (RR 2.54, 95% CI 1.52–4.25) compared with women without asthma. This meta‐analysis also reported a non‐significant trend of increased preterm delivery in asthmatics with exacerbations during pregnancy (RR 1.54 [0.89, 2.69]) and an increased relative risk of preterm delivery (RR 1.51, 95% CI [1.15, 1.98]) in those asthmatic women using oral corticosteroids during pregnancy [10]. Firoozi et al., investigated the effect of the severity of asthma during pregnancy on the risk of a small for gestational infants, low birth weight and preterm birth. Their retrospective cohort study included over 13 000 subjects and demonstrated an increased risk of small for gestational age infants in the moderate and severe asthmatic groups. There was no increased risk of low birth weight or preterm delivery in these groups [11].

Dombrowski et al. found no significant effect of mild asthma or moderate‐severe asthma on preterm delivery (at either <32 weeks or <37 weeks gestation), compared to controls without asthma. However, when the sub‐group of women with severe asthma (FEV₁ < 60% predicted and/or used oral steroids in the four weeks prior to study enrolment) was compared with controls, there was a significantly increased risk of preterm delivery (adjusted OR 2.2, 95% CI 1.2, 4.2) [12].

Stenius‐Aarniala et al. compared data from 47 patients with an attack of asthma during pregnancy to data from 457 asthmatics with no recorded acute exacerbation and 237 healthy subjects. The authors found no increased incidence of congenital malformations in the infants of asthma women with exacerbations during pregnancy. [13]. However, a more recent cohort of over 4000 pregnancies found an increased risk of total congenital malformations in the infants of pregnant asthmatic women who had an asthma exacerbation during pregnancy (1.48, 95% CI, 1.04–2.09) compared to infants of women who did not experience an exacerbation [14].

Stenius Aarniala et al. did not find any increased risk of perinatal death in those women with an attack of asthma during pregnancy [13]. Similarly, a more recent study of 146 pregnant women with asthma exacerbations during pregnancy found that there was no increased risk of stillbirth in those women with severe exacerbations during pregnancy [15]. Two smaller retrospective studies also found that severe asthma was not associated with an increased risk of perinatal death compared with mild asthmatics and controls [16, 17]. This was supported by a more recent prospective study conducted at 16 centers of the Maternal‐Fetal Medicine Units Network of the National Institute of Child Health and Human Development in over 2000 pregnant asthmatics. The authors found no increased risk of perinatal mortality when comparing moderate to severe asthmatics to those with milder disease [12]

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