TABLE II.

Human pregnancy summary safety data for selected asthma medications

Medication	Major birth defects	Other birth outcomes	Evidence gaps and recommendations	Lactation
Short-acting beta agonists (any, primarily albuterol)	No increase in major birth defects over expected among 1090 albuterol-exposed pregnancies in a claims database.14 No increase in major birth defects in 1753 albuterol-exposed pregnancies compared with other asthmatic pregnancies.15	No increase in preterm delivery, low birth weight, or small-for- gestational-age infants in 1828 pregnancies exposed to short-acting beta agonists compared with other asthmatic pregnancies15	First patented in 1972, albuterol is one of the most commonly used asthma medications. Despite this, there is still a lack of evidence regarding its safety when used during pregnancy. There have been reports of associations with specific congenital defects. These observations may be a result of uncontrolled confounding by indication	No published data. Poor bioavailability and low serum levels expected to produce low levels in milk
	Modest increased risk in isolated cleft lip or cleft palate (odds ratios from 1.65 to 1.79) in albuterol-exposed pregnancies in case-control study of 2711 cases of oral clefts and 6482 controls.16
	Several additional studies have suggested modest increased risks (odds ratios, <3) for specific birth defects such as any cardiac or gastroschisis, esophageal atresia, or omphalocele17–19
Any inhaled corticosteroid (ICS) including beclomethasone, budesonide, flunisolide, fluticasone, triamcinolone	No increased risk for major birth defects in 396 exposed compared with the general population.20 A meta-analysis of studies of inhaled steroids did not find increased risk of major birth defects overall21	No increased risks for preterm delivery, low birth weight, or pregnancy-induced hypertension in 396 exposed or in metaanalysis.22,23 Higher doses of ICSs may be associated with an increased risk of low birth weight, preterm delivery, and small-for- gestational-age infants21	Budesonide and fluticasone may be preferred if starting ICS during pregnancy. Other ICSs may be continued in patients who were well controlled by these agents before pregnancy, especially if it is thought that changing formulations may jeopardize asthma control. Adverse outcomes associated with higher doses of ICSs need further study because confounding by severity may explain this association
Budesonide	No increased risk for major birth defects overall or oral clefts among 2014 exposed in population-based Scandinavian register24	No increased risks for preterm birth, reduced birth weight or length, or stillbirths in 2968 exposed in population-based Scandinavian register25		Small amounts excreted in 8 women with asthma using inhaled budesonide26
Fluticasone	No increased risk of major congenital malformations overall in a cohort study of 1602 mother-infant pairs exposed to fluticasone compared with 3678 exposed to other ICSs, stratified by severity27	No increased risk of low birth weight, preterm birth, or small-for- gestational-age infants in retrospective database study of infants of 3190 mothers exposed to fluticasone compared with 608 mothers exposed to budesonide28		No published data. Poor bioavailability and low serum levels expected to produce low levels in milk
Long-acting beta agonists (LABAs)	No evidence of increased risk in major birth defects in 65 salmeterol-exposed pregnancies.29 In an analysis of a database, increased risks for major cardiac and major l to produce low levels in milk pairs expo- trimester exposure in 165 pregnancies.30 However, in a later study from the same database, 841 pregnancies exposed to LABAs with low- or medium-dose ICSs showed no increased risk of major birth defects overall compared with pregnancies exposed to medium- to high-dose ICSs alone31	No difference in low birth weight, preterm birth, or small-for-gestational-age infants was noted in infants of mothers exposed to salmeterol vs formoterol in a retrospective database study28	Limited observational data are available regarding the safety of LABA use during pregnancy. The benefits of the use of LABA appear to outweigh the risks as long as they are used concurrently with ICSs	Salmeterol: No published data. Poor bioavailability and low serum levels expected to produce low levels in milk
Montelukast/leukotriene receptor antagonist (LTRA)	No increased risk of major birth defects overall in 74 and 180 exposed pregnancies.32,33 No increased risk in major birth defects overall or specific birth defects in 1164 exposed pregnancies in claims study.34 No increased risk in major birth defects in 1827 exposed pregnancies in Danish register study35	No increased risk for reduced birth weight or shortened gestational age in 180 exposed when compared with other asthmatic patients.32 No increased risk for preterm delivery, low birth weight, or preeclampsia in 1827 exposed compared with other treated asthmatic 35 patients	Data on the use of LTRA during human pregnancy are limited	Very low levels in breast milk of 7 women given 10 mg dose—0.68% of weight-adjusted maternal dose36
Systemic corticosteroids	Meta-analysis of cohort studies showed no overall increased risk of major birth defects in pooled 535 exposed pregnancies; meta-analysis of 4 case-control studies showed an increased risk of ~3-fold for oral clefts.37 However, most recent and largest case-control study from US National Birth Defects Prevention Study showed no increased risk for oral clefts with first-trimester systemic steroid use for any indication in 2372 cases and 5922 controls38	Preterm delivery, low birth weight or reduced birth weight, preeclampsia, and gestational diabetes have all been reported to occur more frequently in women treated with systemic steroids in pregnancy; however, studies that attempted to control for underlying maternal disease and disease activity typically find the associated risks for these outcomes reduced or eliminated39	Adverse outcomes seen may be a result of severe asthma or the medication itself. These outcomes would be outweighed by the potential risks of a severe asthma exacerbation, which include maternal or fetal mortality. Oral corticosteroids are recommended when indicated for the management of severe asthma during pregnancy	Prednisone: Amounts very low in breast milk; no adverse effects noted in breast-fed infants.40,41 High doses may cause temporary loss of milk supply42,43
Tiotropium			No published human data	No published data. Poor bioavailability and low serum levels expected to produce low levels in milk
Biologics			Continue biologics in patients who are responding to them before pregnancy. Consider starting biologics during pregnancy in women who (1) are candidates for the therapy, and (2) who have severe asthma and are at risk of asthma exacerbations or oral corticosteroid use. Data are needed
Omalizumab/anti-IgE	No increased risk compared with general population for major birth defects overall in 169 exposed pregnancies enrolled in a registry.44 Also when compared with a disease-matched unexposed cohort45	The rates of prematurity (<37 wk’ gestation) and small for gestational age were not unlike those seen in other studies of severe pregnant asthmatic patients	Continue omalizumab in patients who are responding to it before pregnancy. Consider starting omalizumab during pregnancy in patients who (1) are candidates for this therapy and (2) have severe asthma and are at risk of asthma exacerbations or oral corticosteroid use. Consider omalizumab over other biologics in women who are candidates for more than 1 biologic due to some available human data. More data are needed	No published data. Large protein is likely destroyed in infant gastrointestinal tract
Mepolizumab/anti–IL-5			No published human data/Pregnancy registry through mothertobaby.org	No published data. Large protein is likely destroyed in infant gastrointestinal tract
Reslizumab/anti–IL-5			No published human data	No published data. Large protein is likely destroyed in infant gastrointestinal tract
Benralizumab/anti–IL-5 receptor			No published human data/Pregnancy registry through mothertobaby.org ongoing	No published data. Large protein is likely destroyed in infant gastrointestinal tract
Dupilmuab/anti–IL-4 receptor			No published human data/Pregnancy registry through mothertobaby.org ongoing	No published data. Large protein is likely destroyed in infant gastrointestinal tract

Adapted from Namazy et al.⁴⁶