Association of Intraventricular Hemorrhage and Death With Tocolytic Exposure in Preterm Infants

JAMA Netw Open. 2018 Sep 7;1(5):e182355. doi: 10.1001/jamanetworkopen.2018.2355.


Importance: No trials to date have demonstrated the benefits of tocolysis on death and/or neonatal morbidity in preterm infants; tocolytics may affect the fetal blood-brain barrier.

Objectives: To assess the risks associated with tocolysis in women delivering prematurely as measured by death and/or intraventricular hemorrhage (IVH) in preterm infants and to compare the association of calcium channel blockers (CCBs) nifedipine and nicardipine hydrochloride vs atosiban used for tocolysis with death and/or IVH.

Design, settings, and participants: The French 2011 EPIPAGE-2 (Enquête Épidémiologique sur les Petits Âges Gestationnels) cohort was limited to mothers admitted for preterm labor without fever, who delivered from 24 to 31 weeks of gestation from April 1 through December 31, 2011. Groups of preterm infants with vs without tocolytic exposure and groups with atosiban vs CCB exposure were compared. Data analysis was performed from June 7, 2014, through September 3, 2017.

Exposures: Tocolytics.

Main outcomes and measures: The primary outcome was a composite of death and/or IVH in preterm infants. Secondary outcomes included death, IVH, and a composite of death and/or grades III to IV IVH.

Results: A total of 1127 mothers (mean [SD] age, 25.5 [6.0] years) experienced preterm labor and gave birth to 1343 preterm infants with a male to female ratio of 1.23 and mean (SD) gestational age of 27 (2.5) weeks. Of these, 789 mothers (70.0%) received tocolytics; 314 (39.8%) received only atosiban, and 118 (15.0%) received only a CCB. In the first analysis, the primary outcome (death and/or IVH) was not significantly different in preterm infants with vs without tocolytic exposure (183 of 363 [50.4%] vs 207 of 363 [57.0%]; relative risk [RR], 0.88; 95% CI, 0.77-1.01; P = .07). The secondary outcome (death and/or grades III-IV IVH) was significantly lower in preterm infants with vs without tocolytic exposure (92 of 363 [25.3%] vs 118 of 363 [32.5%]; RR, 0.78; 95% CI, 0.62-0.98; P = .03). Other outcomes did not differ significantly. In the secondary analysis, death and/or IVH was not significantly different in preterm infants with atosiban vs CCB exposure (96 of 214 [44.9%] vs 62 of 121 [51.2%]; RR, 0.88; 95% CI, 0.70-1.10; P = .26), nor was IVH (77 of 197 [39.1%] vs 48 of 106 [45.3%]; RR, 0.86; 95% CI, 0.66-1.13; P = .29).

Conclusions and relevance: In this population-based study, findings suggest that tocolytics were associated with a reduction of death and severe IVH. Other studies are necessary to compare perinatal outcomes after use of atosiban vs CCBs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cerebral Intraventricular Hemorrhage / complications
  • Cerebral Intraventricular Hemorrhage / epidemiology
  • Cerebral Intraventricular Hemorrhage / etiology*
  • Death*
  • Female
  • Humans
  • Infant, Newborn
  • Infant, Premature / metabolism*
  • Male
  • Pregnancy
  • Pregnancy Complications / epidemiology
  • Pregnancy Complications / etiology
  • Tocolytic Agents / adverse effects*
  • Tocolytic Agents / therapeutic use
  • Vasotocin / adverse effects
  • Vasotocin / analogs & derivatives
  • Vasotocin / therapeutic use


  • Tocolytic Agents
  • atosiban
  • Vasotocin