Risk of childhood cerebral palsy following prenatal exposure to ß2-adrenergic receptor agonist: A nationwide cohort study

PLoS One. 2018 Aug 16;13(8):e0202078. doi: 10.1371/journal.pone.0202078. eCollection 2018.


Background: Cerebral palsy (CP) is the most common physical developmental disability in childhood with a prevalence of 2 to 3 per 1000 live births. β2-adrenoreceptor agonist (β2AA) are widely used for the treatment of asthma. Maternal use of β2AAs may increase the risk of adverse neuro-psychiatric health outcomes in the offspring. No study, however, has evaluated the effect of prenatal exposure to β2AAs on the risk of CP.

Objective: To examine the association between prenatal exposure to β2AAs and the risk of childhood cerebral palsy.

Methods: This population-based cohort study included all live singleton births in Denmark from January 1, 1997 to December 31, 2003. The information on outpatient prescriptions of β2AAs was extracted from Danish National Prescription Registry. Children born to mothers who used β2AAs from 30 days before pregnancy until delivery were categorized as the exposed. To differentiate the effect of β2AAs from the underlying indications, the exposure window was further extended to 2 years before pregnancy and the exposed groups were re-defined to represent different periods of exposure to maternal use of β2AAs (use only before pregnancy, use only during pregnancy, and use both before and during pregnancy). Cases of CP were identified from the Danish Cerebral Palsy Register. Logistic regression was used to estimate incidence odds ratio (OR) of CP.

Results: Among all the 442,278 singletons, 19,616 (4.44%) were exposed to β2AAs in utero (from 30 days before pregnancy until delivery). The risk of childhood CP was 0.21% in exposed and 0.19% in unexposed group, yielding an adjusted OR (aOR) 1.12 (95% confidence interval (CI): 0.82, 1.53). When extending the exposure time window to 2 years prior to pregnancy, no overall significant association was observed regardless of the exposure period. However, an increased risk of CP (aOR = 1.41, 95%CI: 0.92, 2.18) for maternal β2AAs use during pregnancy was observed in female offspring, especially in those born at term (aOR = 1.65, 95%CI: 1.02, 2.67). This increase was mainly attributed to an increased risk in those born to mothers who used β2AAs both before and during pregnancy (aOR = 1.81, 95%CI: 0.99, 3.33).

Conclusions: We observed an association between maternal β2AAs use during pregnancy and an increased risk of CP in female offspring, but we could not rule out confounding by the underlying indications for β2AAs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-2 Receptor Agonists / adverse effects*
  • Age Factors
  • Cerebral Palsy / epidemiology*
  • Cerebral Palsy / etiology*
  • Child
  • Child, Preschool
  • Cohort Studies
  • Denmark / epidemiology
  • Female
  • Humans
  • Odds Ratio
  • Population Surveillance
  • Pregnancy
  • Prenatal Exposure Delayed Effects*
  • Registries
  • Risk Assessment
  • Risk Factors


  • Adrenergic beta-2 Receptor Agonists

Grant support

The study was supported by the National key research and development program (2016YFC1000505), the National Natural Science Foundation of China (81428011), the Innovation-oriented Science and Technology Grant from NPFPC Key Laboratory of Reproduction Regulation (CX2017-0X), the European Research Council (ERC-2010-StG-260242-PROGEURO), Nordic Cancer Union (176673, 186200), Danish Council for Independent Research(DFF-6110-00019), Karen Elise Jensens Fond (2016), and Program for Clinical Research Infrastructure (PROCRIN) established by the Lundbeck Foundation and the Novo Nordisk Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.