Affect, Social Behavior and Communication Among Children Prenatally Exposed to Oxytocin Receptor Antagonists

Background: Prematurity is the major cause of neonatal death and morbidity in the developed world. Therefore, measures are taken to delay preterm labor as long as possible. These measures generally include pharmacological inhibition of uterine contractility to allow the administration of corticosteroids to enhance fetal lung maturation. Different agents including calcium channel blocker (e.g. Nifedipine) and oxytocin receptors (OTR) antagonists such as tractocile (Atosiban) can inhibit myometrial contractions. These drugs were recommended as first line of treatment. Atosiban is considered to have minimal adverse effects. However, recent evidence shows that Atosiban had similar tocolytic efficacy as betamimetics and placebo, and more maternal side-effects requiring cessation of treatment. In randomized control trials comparing Atosiban and Nifedipine for treatment of preterm labor, women who were treated with Nifedipine had a lower rate of preterm deliveries and delivered a week later than women treated with Atosiban. More neonates in the Atosiban group were hospitalized at the neonatal intensive care units and for a longer time than those from the Nifedipine group.

A large body of evidence shows oxytocin modulate behavior and cognition across species as well as social memory. Moreover, oxytocin partially mediates the risk of perinatal risk factors in Autism. Although Atosiban crosses the placental barrier and the blood brain barrier rather freely, its long-term effect on brain development has not been examined yet.

Objectives: We hypothesize that we will observe deficits in affect, social behavior and communication even in the absence of autism spectrum disorder (ASD) or social communication disorders in children prenatally exposed to OTR antagonists.

Methods: 162 children between the age of 3:0 and 7:6 (years: months) participated in the current study. The Atosiban group consisted of 71 children prenatally exposed to Atosiban as well as Nifedipine to inhibit premature labor, whereas the comparison group consisted of 91 children who were exposed only to Nifedipine. All children were born between 2003 and 2010 at the Hadassah Medical Centers in Jerusalem to Hebrew-speaking mothers and were assessed between 2009 and 2013. The developmental assessment consisted of state of the art developmental assessment tools: The Mullen Scales of Early Learning, The Vineland Adaptive Behavior Scales and the Autism Diagnostic Observation Scale (ADOS).

Results: The cognitive and the adaptive behavior and daily functioning of the Atosiban group were similar to those of the comparison group. However, there were significantly more social communication abnormalities in the Atosiban group than in the comparison group (F (1,142) = 6.29, p = .013).

Conclusions: The current findings suggest that OTR antagonists may hold additional risk for deficits in affect, social behavior and communication even in the absence of ASD, in comparison to Nifedipine treatment. Therefore, the use of Atosiban to delay labor may have subtle effects on brain development which cannot be detected in the neonatal period, and clinically manifest only later in life. More research, including randomized control studies is needed to further examine these initial findings.