Long‐term follow‐up of children prenatally exposed to ritodrine

Hadders‐Algra, Mijna; Touwen, B. C. L.; Huisjes, H.J.

doi:10.1111/j.1471-0528.1986.tb07880.x

Cited by 53 publications

(17 citation statements)

References 10 publications

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“…Nevertheless, these morphological changes are likely to underlie many of the synaptic deficits evoked by terbutaline in animal studies (Slotkin et al, 1989(Slotkin et al, , 1990Garofolo et al, 2003). In turn, our results point to a causative link between ␤AR tocolytic treatment for preterm labor and subsequent adverse neurobehavioral outcomes in the offspring (Hadders-Algra et al, 1986;Feenstra, 1992;Pitzer et al, 2001).…”

Section: Discussionmentioning

confidence: 62%

“…In addition to blocking uterine contractions, terbutaline penetrates the placenta to activate fetal ␤ARs, eliciting a number of adverse neonatal effects, including alterations in glucose metabolism and tachycardia (for review, see Slotkin et al, 2003). In the long-term, offspring of women treated with terbutaline may show impaired school performance (Hadders-Algra et al, 1986;Feenstra, 1992), cognitive dysfunction, and increased incidence of psychiatric disorders (Pitzer et al, 2001). The neurobehavioral consequences of fetal exposure to terbutaline are obviously a major biomedical and societal concern and set the stage for the current study.…”

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confidence: 99%

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Terbutaline Is a Developmental Neurotoxicant: Effects on Neuroproteins and Morphology in Cerebellum, Hippocampus, and Somatosensory Cortex

Rhodes

Seidler²,

Abdel-Rahman³

et al. 2003

J Pharmacol Exp Ther

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␤ 2 -Adrenoceptor agonists, especially terbutaline, are widely used to arrest preterm labor, but they also cross the placenta to stimulate fetal ␤-adrenoceptors that control neural cell differentiation. We evaluated the effects of terbutaline administration in neonatal rats, a stage of neurodevelopment corresponding to human fetal development. Terbutaline administered on postnatal days PN2 to 5 elicited neurochemical changes indicative of neuronal injury and reactive gliosis: immediate increases in glial fibrillary acidic protein and subsequent induction of the 68-kDa neurofilament protein. Quantitative morphological evaluations carried out on PN30 indicated structural abnormalities in the cerebellum, hippocampus, and somatosensory cortex. In the cerebellum, PN2 to 5 terbutaline treatment reduced the number of Purkinje cells and elicited thinning of the granular and molecular layers. The hippocampal CA3 region also displayed thinning, along with marked gliosis, effects that were restricted to females. In the somatosensory cortex, terbutaline evoked a reduction in the proportion of pyramidal cells and an increase in smaller, nonpyramidal cells; again, females were affected more than males. Although abnormalities were obtained with later terbutaline treatment (PN11 to 14), in general the effects were smaller than those seen with PN2 to 5 exposure. Our results indicate that terbutaline is a neurotoxicant that elicits biochemical alterations and structural damage in the immature brain during a critical period. These effects point to a causal relationship between fetal terbutaline exposure and the higher incidence of cognitive and neuropsychiatric disorders reported for the offspring of women receiving terbutaline therapy for preterm labor.

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Section: Discussionmentioning

confidence: 62%

mentioning

confidence: 99%

Terbutaline Is a Developmental Neurotoxicant: Effects on Neuroproteins and Morphology in Cerebellum, Hippocampus, and Somatosensory Cortex

Rhodes

Seidler²,

Abdel-Rahman³

et al. 2003

J Pharmacol Exp Ther

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“…Terbutaline crosses the placenta (Bergman et al, 1984) and, by overstimulating ␤2ARs in the fetal brain, can disrupt the replication and differentiation of developing neurons (Slotkin et al, 2001). Studies of offspring of women treated with terbutaline dur-ing pregnancy showed impaired school performance, cognitive dysfunction, and an increased incidence of psychiatric disorders (Hadders-Algra et al, 1986;Feenstra, 1992;Pitzer et al, 2001). Notably, the use of terbutaline in pregnancy has also been linked to increased concordance for autism in dizygotic twins (Connors et al, 2005).…”

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confidence: 99%

Neuroinflammation and Behavioral Abnormalities after Neonatal Terbutaline Treatment in Rats: Implications for Autism

Zerrate¹,

Pletnikov²,

Connors

et al. 2007

J Pharmacol Exp Ther

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Autism is a neurodevelopmental disorder presenting before 3 years of age with deficits in communication and social skills and repetitive behaviors. In addition to genetic influences, recent studies suggest that prenatal drug or chemical exposures are risk factors for autism. Terbutaline, a ␤2-adrenoceptor agonist used to arrest preterm labor, has been associated with increased concordance for autism in dizygotic twins. We studied the effects of terbutaline on microglial activation in different brain regions and behavioral outcomes in developing rats. Newborn rats were given terbutaline (10 mg/kg) daily on postnatal days (PN) 2 to 5 or PN 11 to 14 and examined 24 h after the last dose and at PN 30. Immunohistochemical studies showed that administration of terbutaline on PN 2 to 5 produced a robust increase in microglial activation on PN 30 in the cerebral cortex, as well as in cerebellar and cerebrocortical white matter. None of these effects occurred in animals given terbutaline on PN 11 to 14. In behavioral tests, animals treated with terbutaline on PN 2 to 5 showed consistent patterns of hyper-reactivity to novelty and aversive stimuli when assessed in a novel open field, as well as in the acoustic startle response test. Our findings indicate that ␤2-adrenoceptor overstimulation during an early critical period results in microglial activation associated with innate neuroinflammatory pathways and behavioral abnormalities, similar to those described in autism. This study provides a useful animal model for understanding the neuropathological processes underlying autism spectrum disorders.

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“…For example, Hadders-Algra et al [14] found that some children exposed to tocolytics in utero later evidenced impaired school performance. Other investigations discovered higher prevalence of motor developmental delays, cognitive dysfunction, and psychiatric diagnoses in children with a history of intrauterine terbutaline exposure [9].…”

Section: Introductionmentioning

confidence: 99%

Terbutaline and Associated Risks for Neurodevelopmental Disorders

Perna

Loughan

Perkey

et al. 2014

Child Development Research

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Preterm labor often leads to a preterm birth and has been shown to be the most important determinant of risk for perinatal morbidity and mortality. While medication management has been utilized by physicians to delay preterm labor, the results these medications achieve remain inconsistent, in addition to increasing the risk to the developing fetus. Terbutaline has been among the most commonly used 2 -adrenoreceptor ( 2 AR) agonists in the management of preterm labor. The research suggests that tocolytic terbutaline therapy carries a significant risk for the mother and the child, which can be magnified by extended exposure, sex of the fetus, and administration during critical fetal developmental periods. This paper highlights the research on terbutaline in treatment of preterm labor, along with the possible associated cognitive deficits in adolescents who were treated with terbutaline in utero. Two case summaries are presented to illustrate the potential deficits in clinical presentations of adolescents with history of intrauterine exposure to terbutaline. Publicizing the association between terbutaline and these deficits can not only assist obstetricians and expectant mothers in making a more informed choice in the treatment of preterm labor but also provide neuropsychologists and pediatricians with information helpful in understanding the etiology of these impairments.

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Long‐term follow‐up of children prenatally exposed to ritodrine

Cited by 53 publications

References 10 publications

Terbutaline Is a Developmental Neurotoxicant: Effects on Neuroproteins and Morphology in Cerebellum, Hippocampus, and Somatosensory Cortex

Terbutaline Is a Developmental Neurotoxicant: Effects on Neuroproteins and Morphology in Cerebellum, Hippocampus, and Somatosensory Cortex

Neuroinflammation and Behavioral Abnormalities after Neonatal Terbutaline Treatment in Rats: Implications for Autism

Terbutaline and Associated Risks for Neurodevelopmental Disorders

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