A is for Asthma and Autism, B is for Beta-agonist

Is there a link between asthma and autism? A recent study supports this idea. More precisely the link appears to be between the prenatal use of beta-agonists and autism. The beta-agonists include both the short- and long-acting forms.

The use of medication to control asthma during pregnancy is essential. Pregnant women are advised to be careful in their the choice of medications and to avoid
∙    tetracycline, sulfonamides and ciprofloxacin
∙    decongestants, aspirin, NSAIDs and over-the-counter-medications
∙    herbal medications and teas (red raspberry leaf tea can induce uterine contractions)

Asthma Medications during Pregnancy

It is essential that asthma be well controlled through pregnancy, and the asthma medications prescribed are usually in either Category B or Category C. The Food and Drug Administration has defined a scale of medication safety during pregnancy that ranges from “A” where the possibility of harm is remote to “X” where medications are contraindicated due to teratogenic risks.

Because there is no evidence of risk, Category B is considered safe for pregnancy. These medications include prednisone and prednisolone (despite the risk of both low birth weight and cleft palate); budesonide; and the leukotriene-receptor antagonists (LTRAs) montelukast and zafirlukast. Budesonide is the preferred choice of inhaled corticosteroid (ICS) but if the mother is already using another ICS, then it is advisable to stay with the ICS being used and not switch. Similarly, if already on an LTRA, then it may be continued but it should not be introduced during pregnancy.

Category C medications are those essential for the control of asthma for which the benefits are believed to outweigh the risks. These include the short- and long-acting beta agonists (SABA and LABA); beclomethasone dipropionate; foradil; triamcinalone; theophylline and zileuton.

Caution; the minimization of medication; andcontrol of the environment are the watchwords for pregnant women. It should be noted that the SABAs and LABAs cross the placenta and likely have neurodevelopmental effects.1,2

The primary action of beta-agonists is to relax airway smooth muscle by stimulating beta2 receptors. While this reduces bronchoconstriction, this medication also acts to relax the uterine muscles. To date, only two studies have reported on the use of SABA’s transient cardiovascular effect on the fetus due to a SABA overdose in a 24-hour period.3 SABA are not associated with major congenital malformations or adverse perinatal outcomes.

A comparison of two studies in England on the LABAs salmeterol (Serevent) and formoterol (Foradil) found that there were slightly more abnormalities with formoterolbut because the numbers of pregnant women involved in both studies were small, no definite conclusions could be made.3

Autism and Beta-agonists

In the USA, autism spectrum disorder (ASD) affects one in 68 children. While its precise cause is unclear, autism is seen as the result of genetic vulnerability combined with certain environmental exposures. Oxygen deprivation, birth complications, pre-term delivery, low birth weight, prenatal exposure to particular infections, air pollution and some medications have all been linked to autism.

A recent study4, that did not differentiate between SABA and LABA, showed that their use increased the risk of ASD by 30% (OR 1.3), no matter the trimester of usage. While the risk varied both during pre-conception ( 90 days before the determined start of pregnancy; OR 1.3) and through the three trimesters, (OR 1.3; 1.5 and 1.4 respectively), it remained significant throughout the pregnancy. The researchers found that lengthier exposure (more than 45 days) increased the risk.

This study involved a nine–year comparisonin Denmark of 5,200 children withASD against an equal number of children without ASD. Matched by month and year of birth, 3.7% of children with ASD and 2.9% of children without ASD had been exposed to beta-agonists prior to birth. Results were adjusted for possible confounders such as the mother’s asthma, birth complications and parents’ age.

While this is the first study that links use of beta-agonists with ASD, more research will be needed to replicate and confirm these findings. The study did not prove causation and it should be remembered that uncontrolled asthma in pregnancy results in poor birth outcomes including pre-term birth, low birth weight, below-average gestational size, and increased hospital stay. Acute exacerbations during the first trimester increase the risk for congenital anomalies.5 The risk of adverse pregnancy outcomes with poorly controlled asthma also include perinatal loss, prematurity, possibility of stillbirth; particularly with moderate to severe persistent asthma. Hence, the use of asthma medications should be considered carefully with the specific objective of keeping the asthma well controlled with the minimum use of medication.

References

  1. Dombrowski MP, Schatz M et al. Asthma during pregnancy. Obstet Gynecol. 2004 Jan;103(1):5-12.
  2. Dombrowski MP.  Asthma and Pregnancy. Obstet Gynecol. 2006 Sep;108(3 Pt 1):667-81.
  3. National Asthma Education and Prevention Program. Working Group Report on Managing asthma during pregnancy: recommendations for pharmacologic treatment. Update 2004. NIH Publication No. 05-5236. http://www.nhlbi.nih.gov/files/docs/ resources/lung/astpreg_full.pdf.
  4. Gidaya NB, Lee BK, et al. In utero exposure to beta-2-adrenergic receptor agonist drugs and risk for autism spectrum disorders. Pediatrics, 2016; DOI: 10.1542/peds.2015-1316
  5. Vatti RR, Teuber SS. Asthma and pregnancy. Clin Rev Allergy Immunol. 2012 ;43(1-2): 45-56. doi: 10.1007/s12016-011-8277-8.