Respiratory Agent (Corticosteroid)
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
The animal data suggest risk, but the limited human pregnancy experience prevents a complete assessment of the embryo–fetal risk. Moreover, human pregnancy data exist only for inhaled flunisolide. Inhaled corticosteroids play an important role in preventing acute exacerbations of asthma. In a position statement from a joint committee of the American College of Obstetricians and Gynecologists (ACOG) and the American College of Allergy, Asthma, and Immunology (ACAAI) published in 2000, either beclomethasone or budesonide were considered the inhaled steroids of choice for use during pregnancy (1).
FETAL RISK SUMMARY
The oral inhaled formulation of the corticosteroid flunisolide is indicated for the maintenance treatment of asthma as prophylactic therapy (2). The nasal spray product is indicated for the management of the nasal symptoms of seasonal or perennial rhinitis (3). Flunisolide has potent anti-inflammatory and antiallergic activity, but it is not a bronchodilator and is not indicated for the relief of bronchospasm. Total systemic bioavailability of inhaled flunisolide is 40%. The agent is rapidly metabolized by the liver to low potency or inactive metabolites; the plasma half-life of flunisolide is about 1.8 hours. Plasma accumulation has not been observed after 2 weeks of therapy with 2 mg/day (2). After use of the nasal spray, 50% of the dose reaches the systemic circulation as unmetabolized flunisolide with a plasma half-life of 1–3 hours (3).
Reproduction studies have been conducted with oral flunisolide in rats and rabbits. As with other corticosteroids, flunisolide was teratogenic and fetotoxic at daily oral doses of 1180 mcg/m2and 480 mcg/m2, respectively (2,3). A reproduction study in pregnant mice observed dose-related teratogenicity (cleft palate) and reduced fetal weight, but the SC doses also caused maternal toxicity (reduced body weight) (4). Another study used pregnant rats and observed dose-related growth restriction, multiple congenital defects, and increased mortality (5).
The maximum recommended daily human dose (MRDHD) for the inhaled and nasal formulations are 2000 mcg and 464 mcg, respectively (2,3). If the systemic bioavailability of the two formulations are 40% (800 mcg) and 50% (232 mcg), respectively, and if a typical patient has a BSA of about 1.8 m2, then the systemic bioavailable doses are about 444 and 129 mcg/m2, respectively. Thus, based on systemic bioavailability, the dose in rats causing developmental toxicity was about 3 and 9 times the MRDHD, respectively, and in rabbits, about 1 and 4 times the MRDHD, respectively.
It is not known if flunisolide crosses the human placenta. The molecular weights of the formulations (about 434 and 444) are low enough to cross the placenta, but the short elimination half-lives and extensive metabolism should limit the amount reaching the embryo or fetus.
A 2004 study examined the effect of inhaled corticosteroids on low birth weight, preterm births, and congenital malformations in pregnant asthmatic patients (6). The inhaled steroids and the number of patients were beclomethasone (N = 277), fluticasone (N = 132), triamcinolone (N = 81), budesonide (N = 43), and flunisolide (N = 25). Compared with the general population, the study found no increased incidence of small-for-gestational-age infants (less than 10th percentile for gestational age), low birth weight (<2500 g), preterm births, and congenital malformations (6).
In another 2004 study, 722 asthmatic women used inhaled corticosteroids during pregnancy (7). Although the number of subjects using flunisolide was not mentioned, there were no significant relationships between the inhaled steroid users and low birth weight, small for gestational age, major malformations, gestational hypertension, or preterm birth (7).
The two studies cited above suggest that the embryo–fetal risk is low. However, the one study (7) examining perinatal outcomes was too small to have identified an association with oral clefts, if it had existed.Systemic corticosteroids are known to be associated with a low risk for isolated, nonsyndromic oral clefts (cleft lip and/or palate) when used in the 1st trimester, as well as fetal growth restriction when used for long periods later in gestation. (See Hydrocortisone.).
A 2006 meta-analysis on the use of inhaled corticosteroids during pregnancy was published in 2006 (8). The analysis included five agents: beclomethasone, budesonide, flunisolide, fluticasone, and triamcinolone. The results showed that these agents do not increase the risk of major congenital defects, preterm delivery, low birth weight, and pregnancy-induced hypertension. Thus, they could be used during pregnancy (8).
BREASTFEEDING SUMMARY
No reports describing the use of flunisolide during human lactation have been located. The molecular weights of the inhaled and nasal spray formulations (about 434 and 444) are low enough for excretion into breast milk, but the short elimination half-lives and extensive metabolism should limit the amount. Other corticosteroids are excreted into milk in low concentrations (see Prednisone), and the passage of flunisolide into milk should be expected. The effects of this exposure on a nursing infant are unknown, but the amounts excreted into milk should be low. Therefore, use of flunisolide during breastfeeding probably is compatible.
References
1.Joint Committee of the American College of Obstetricians and Gynecologists (ACOG) and the American College of Allergy, Asthma, and Immunology (ACAAI). Position statement. The use of newer asthma and allergy medications during pregnancy. Ann Allergy Asthma Immunol 2000;84:475–80.
2.Product information. Aerobid. Forest Pharmaceuticals, 2006.
3.Product information. Nasarel. IVAX Laboratories, 2006.
4.Tamagawa M, Hatori M, Ooi A, Nishioeda R, Tanaka N. Comparative teratological study of flunisolide in mice. Oyo Yakuri (Pharmacometrics) 1982;24:741–50.
5.Itabashi M, Inoue T, Yokota M, Takehara K, Tajima M. Reproductive studies on flunisolide in rats: oral administration during the period of organogenesis. Oyo Yakuri (Pharmacometrics) 1982;24:643–59.
6.Namazy J, Schatz M, Long L, Lipkowitz M, Lillie MA, Voss M, Deitz RJ, Petitti D. Use of inhaled steroids by pregnant asthmatic women does not reduce intrauterine growth. J Allergy Clin Immunol 2004;113:427–32.
7.Schatz M, Dombrowski M, Wise R, Momirova V, Landon M, Mabie W, Newman RB, Hauth JC, Lindheimer M, Caritis SN, Leveno KJ, Meis P, Miodovnik M, Wapner RJ, Paul RH, Varner MW, O’Sullivan MJ, Thurnau GR, Conway DL, for The National Institute of Child Health and Development Maternal-Fetal Medicine Units Network and The National Heart, Lung, and Blood Institute. The relationship of asthma medication use to perinatal outcomes. J Allergy Clin Immunol 2004;113:1040–5.
8.Rahimi R, Nikfar S, Abdollahi M. Meta-analysis finds use of inhaled corticosteroids during pregnancy safe: a systematic meta-analysis review. Hum Exp Toxicol 2006;25:447–52.