Betamimetics in Pregnancy Related to Autism: Really?

Abstract & Commentary

By John C. Hobbins, MD, Professor and Chief of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Denver, is Associate Editor for OB/GYN Clinical Alert.

Synopsis: A recent review addresses the potential link between beta 2-adrenergic agonists in pregnancy and autism.

Source: Witter FR, et al. In utero beta 2 adrenergic agonist exposure and adverse neurophysiologic and behavioral outcomes. Am J Obstet Gynecol 2009;201:553-559.

In the last two months, there were four articles in the American Journal of Obstetrics & Gynecology and Obstetrics & Gynecology dealing with drugs that are commonly used in pregnancy and their possible contribution to adverse outcomes. One of these articles was particularly attention-getting.

Witter et al reviewed the literature regarding possible adverse effects of beta 2-adrenergic receptor (B2AR) agents in pregnancy. This group of drugs can cause an overstimulation of these receptors, resulting in a disruption of the delicate balance between sympathetic and parasympathetic systems. By dampening the latter, mellowing mechanism, the sympathetic system is given free rein. Stimulation of B2AR has been shown in rats to have an effect on cells in the fetal cortex, cerebellum, and hippocampus that are similar to those found in humans with autism.1

The authors reviewed what data are available regarding a possible link between B2AR agents and autism:

  • Some human studies have suggested an increased incidence of autism in children exposed to B2AR agents in utero.2,3
  • One study linked maternal asthma with autism4 (perhaps relating more to the treatment for asthma, rather than the condition itself).
  • Some data have suggested a possible linkage between subnormal cognitive and motor performance in children and maternal exposure to B2AR agents, along with poor school performance in association with ritodrine, in particular.5
  • A greater tendency toward adolescent hypertension in those whose mothers were given ritodrine for preterm labor.6
  • As to how much B2AR exposure would be needed to cause a possible problem, this can be difficult to assess, since some fetuses harboring a known B2AR polymorphism are likely to be more sensitive to the effects of these agents than others exposed to the same dose.

Commentary

Current figures indicate that 1 in 110 children in the United States have some form of autism. Although some have interpreted this to suggest an alarming increase in the prevalence of this condition, this could be also due to a recent increased focus on documenting this condition. Whether this is new or old news, any condition that affects 1% of children is very concerning and has generated a search for a reason(s).

The above review has shed some light on one possible in utero mechanism, but there is obviously more to this story, especially since not all follow-up studies have shown an association between B2AR agents and autism. Nevertheless, we have to ask ourselves how necessary it is to use various forms of B2AR agents in pregnancy. The two most common reasons this type of medication has been used are for asthma and to stop labor.

Asthma. Here, B2AR agents are used primarily as bronchodilators. Since there is no doubt that unabated asthma is far worse for the fetus (and mother) than any current therapy, it is clear that some type of treatment is essential. In most cases, to limit fetal exposure time, one can preferably treat this condition with the shortest acting medications such as albuterol (which has a reasonable safety record), or to substitute a corticosteroid inhaler for treatment of mild intermittent asthma. Also, extrapolating from the rat model, the most vulnerable time in the neural development of the fetus is the last part of the second trimester and early third trimester.

Preterm labor. Beta 2-adrenergic agonists have been used as tocolytics for years. Interestingly, ritodrine is the only medication approved by the FDA for this purpose, yet terbutaline has been by far the most commonly used. Now, after many randomized trials, no B2AR has been shown to be beneficial in preventing preterm birth, although one study did show that ritodrine was better than placebo in prolonging pregnancy for 48 hours — long enough to get steroids on board. Terbutaline, administered in any form, has not been shown to lengthen pregnancy. However, anecdotally, oral terbutaline does seem to decrease the number of Braxton-Hicks contractions (thereby blunting patient anxiety and diminishing the number of telephone calls to providers).

So, based on current information, there seems to be no reason to use B2AR agents for tocolysis. Unfortunately, the labor-stopping track record of other drugs is not stellar, and virtually every substitute has its own possible maternal/fetal side effects. Our "go-to" drug now is a calcium channel blocker (nifedipine) or, in some cases, a prostaglandin synthetase inhibitor such as indomethacin (while watching for early signs of ductal closure).

In summary, as yet there has been no concrete evidence to directly blame autism on B2AR agents, since this unfortunately common condition undoubtedly evolves through many pathways. However, if one of these pathways can be avoided, why not err on the side of caution and use B2AR agents judiciously in asthma, and not at all in preterm labor.

References

  1. Rhoades MC, et al. Terbutaline is a developmental neurotoxicant: Effects on neuroproteins and morphology in cerebellum, hippocampus, and somatosensory cortex. J Pharmacol Exp Ther 2004;308:529-537.
  2. Connors SL, et al. Beta2-adrenergic receptor activation and genetic polymorphisms in autism: Data from dizygotic twins. J Child Neurol 2005;20:876-884.
  3. Thrasher JD, et al. Autism, terbutaline and neurologic impairment: Ramazzi Days 2007: 25th Anniversary Jubilee, Capri Italy. Available at: www.collegiumramazzini.org. Accessed Jan. 24, 2009.
  4. Croen LA, et al. Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders. Arch Pediatr Adolesc Med 2005;159:151-157.
  5. Hadders-Algra M, et al. Long-term follow-up of children prenatally exposed to ritodrine. BJOG 1986;93:156-161.
  6. Alvarez M, et al. Long term effects of ritodrine on blood pressure and heart rate of adolescents exposed during the prenatal stage. Eur J Obstet Gynecol Reprod Biol 1995;59:137-141.