Child neurodevelopment unaffected by exposure to multiple course of antenatal steroids

SAN FRANCISCO – Giving more than one course of antenatal corticosteroids to prevent preterm birth does not appear to benefit or harm offspring in the longer term, according to a follow-up analysis of the randomized MACS trial.

In the trial, 1,724 pregnant women at high risk for preterm birth were given either a single course of antenatal steroids or multiple courses every 14 days on a double-blind basis.

Results reported at the Pregnancy Meeting, the annual meeting of the Society for Maternal-Fetal Medicine, showed that one-fourth of the infants had died or were severely neurodevelopmentally impaired at the age of 5 years, with no significant difference between groups.

"Multiple courses of antenatal corticosteroids given every 14 days does not increase nor does it decrease the risk of death or neurodevelopmental difficulties by 5 years of age compared to a single course," commented lead author Dr. Elizabeth Asztalos of the department of pediatrics and ob.gyn. at the University of Toronto and director and scientist at the Centre for Mother, Infant and Child Research at Sunnybrook Health Sciences Centre, also in Toronto. "Because we could not identify short-term neonatal or long-term neurodevelopmental benefits, we conclude that multiple courses of antenatal steroids given every 14 days are not recommended for the woman at risk of preterm birth."

"We emphasize that continued follow-up of this cohort is needed to rule out the possibility of long-term neurobehavioral and neurosensory function [differences], as well as disabilities and metabolic and cardiovascular disease that could not be detected at this early age," she added. "Additional analyses will be conducted that will try to evaluate the interaction between multiple courses and outcomes as it relates to prolonged rupture of membranes, term versus preterm birth, and infant sex."

One attendee noted that a previous study did find a difference in developmental disability after three or four courses of antenatal steroids. "So I’m wondering whether you have a subanalysis of outcomes by number of courses," he said.

"We have not specifically done that from the neurocognitive perspective," Dr. Asztalos replied. "That is something that we will start to look at."

Another attendee commented, "It appears that the measures you looked at [at] this young age are of fairly significant impacts; yet, in human studies, there is some suggestion of behavioral abnormalities induced by steroids including anxiety and stress responses, and clearly in animal studies – particularly those done in Australia – of programming of offspring HPA [hypothalamic-pituitary-adrenal] axis that’s in a sex-specific manner. Do you plan to look at any of those factors in the future?"

"We do. We are hoping that the Canadian government will allow us to continue to follow these children [until] 12 [years of age], and we will definitely look at these measures," Dr. Asztalos replied.

Pregnant women were eligible for the MACS (Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study) trial if they were at 26-30 weeks’ gestation and were at risk for early birth and had not delivered 14 or more days after an initial course of antenatal corticosteroids.

They were assigned to receive study medication, either betamethasone or placebo, every 14 days until 33 completed weeks or delivery.

Initial trial results, previously published (Lancet 2008;372:2143-51), showed that the multicourse group did not have a lower rate of perinatal or neonatal mortality or neonatal morbidity. Birth weight and length were less, and head circumference was smaller in the multicourse group.

In addition, at the age of 18-24 months, offspring in the multicourse group did not have a lower rate of death or neurologic impairment such as cerebral palsy or cognitive delay (Pediatrics 2010;126:1045-55). They still weighed less, but appeared to be catching up.

The latest results, now at a median age of 5.2 years, showed that children in the multicourse group did not have a significantly different rate of the composite outcome of death or neurodevelopmental impairment relative to their counterparts in the single-course group (24.9% vs. 24.6%), according to data reported at the meeting.

The findings were similar for the individual components of death, neuromotor impairment (defined as nonambulatory cerebral palsy), neurosensory impairment (blindness in at least one eye, deafness, or need for visual or hearing aid), and neurocognitive impairment (abnormal attention, memory, or behavior).

At this time point, children in the two groups were statistically indistinguishable with respect to weight, height, and head circumference; systolic and diastolic blood pressure; and various measures of intelligence and specific cognitive skills, according to Dr. Asztalos.

Dr. Asztalos disclosed no conflicts of interest related to the research.

SAN FRANCISCO – Giving more than one course of antenatal corticosteroids to prevent preterm birth does not appear to benefit or harm offspring in the longer term, according to a follow-up analysis of the randomized MACS trial.

In the trial, 1,724 pregnant women at high risk for preterm birth were given either a single course of antenatal steroids or multiple courses every 14 days on a double-blind basis.

Results reported at the Pregnancy Meeting, the annual meeting of the Society for Maternal-Fetal Medicine, showed that one-fourth of the infants had died or were severely neurodevelopmentally impaired at the age of 5 years, with no significant difference between groups.

"Multiple courses of antenatal corticosteroids given every 14 days does not increase nor does it decrease the risk of death or neurodevelopmental difficulties by 5 years of age compared to a single course," commented lead author Dr. Elizabeth Asztalos of the department of pediatrics and ob.gyn. at the University of Toronto and director and scientist at the Centre for Mother, Infant and Child Research at Sunnybrook Health Sciences Centre, also in Toronto. "Because we could not identify short-term neonatal or long-term neurodevelopmental benefits, we conclude that multiple courses of antenatal steroids given every 14 days are not recommended for the woman at risk of preterm birth."

"We emphasize that continued follow-up of this cohort is needed to rule out the possibility of long-term neurobehavioral and neurosensory function [differences], as well as disabilities and metabolic and cardiovascular disease that could not be detected at this early age," she added. "Additional analyses will be conducted that will try to evaluate the interaction between multiple courses and outcomes as it relates to prolonged rupture of membranes, term versus preterm birth, and infant sex."

One attendee noted that a previous study did find a difference in developmental disability after three or four courses of antenatal steroids. "So I’m wondering whether you have a subanalysis of outcomes by number of courses," he said.

"We have not specifically done that from the neurocognitive perspective," Dr. Asztalos replied. "That is something that we will start to look at."

Another attendee commented, "It appears that the measures you looked at [at] this young age are of fairly significant impacts; yet, in human studies, there is some suggestion of behavioral abnormalities induced by steroids including anxiety and stress responses, and clearly in animal studies – particularly those done in Australia – of programming of offspring HPA [hypothalamic-pituitary-adrenal] axis that’s in a sex-specific manner. Do you plan to look at any of those factors in the future?"

"We do. We are hoping that the Canadian government will allow us to continue to follow these children [until] 12 [years of age], and we will definitely look at these measures," Dr. Asztalos replied.

Pregnant women were eligible for the MACS (Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study) trial if they were at 26-30 weeks’ gestation and were at risk for early birth and had not delivered 14 or more days after an initial course of antenatal corticosteroids.

They were assigned to receive study medication, either betamethasone or placebo, every 14 days until 33 completed weeks or delivery.

Initial trial results, previously published (Lancet 2008;372:2143-51), showed that the multicourse group did not have a lower rate of perinatal or neonatal mortality or neonatal morbidity. Birth weight and length were less, and head circumference was smaller in the multicourse group.

In addition, at the age of 18-24 months, offspring in the multicourse group did not have a lower rate of death or neurologic impairment such as cerebral palsy or cognitive delay (Pediatrics 2010;126:1045-55). They still weighed less, but appeared to be catching up.

The latest results, now at a median age of 5.2 years, showed that children in the multicourse group did not have a significantly different rate of the composite outcome of death or neurodevelopmental impairment relative to their counterparts in the single-course group (24.9% vs. 24.6%), according to data reported at the meeting.

The findings were similar for the individual components of death, neuromotor impairment (defined as nonambulatory cerebral palsy), neurosensory impairment (blindness in at least one eye, deafness, or need for visual or hearing aid), and neurocognitive impairment (abnormal attention, memory, or behavior).

At this time point, children in the two groups were statistically indistinguishable with respect to weight, height, and head circumference; systolic and diastolic blood pressure; and various measures of intelligence and specific cognitive skills, according to Dr. Asztalos.

Dr. Asztalos disclosed no conflicts of interest related to the research.

SAN FRANCISCO – Giving more than one course of antenatal corticosteroids to prevent preterm birth does not appear to benefit or harm offspring in the longer term, according to a follow-up analysis of the randomized MACS trial.

In the trial, 1,724 pregnant women at high risk for preterm birth were given either a single course of antenatal steroids or multiple courses every 14 days on a double-blind basis.

Results reported at the Pregnancy Meeting, the annual meeting of the Society for Maternal-Fetal Medicine, showed that one-fourth of the infants had died or were severely neurodevelopmentally impaired at the age of 5 years, with no significant difference between groups.

"Multiple courses of antenatal corticosteroids given every 14 days does not increase nor does it decrease the risk of death or neurodevelopmental difficulties by 5 years of age compared to a single course," commented lead author Dr. Elizabeth Asztalos of the department of pediatrics and ob.gyn. at the University of Toronto and director and scientist at the Centre for Mother, Infant and Child Research at Sunnybrook Health Sciences Centre, also in Toronto. "Because we could not identify short-term neonatal or long-term neurodevelopmental benefits, we conclude that multiple courses of antenatal steroids given every 14 days are not recommended for the woman at risk of preterm birth."

"We emphasize that continued follow-up of this cohort is needed to rule out the possibility of long-term neurobehavioral and neurosensory function [differences], as well as disabilities and metabolic and cardiovascular disease that could not be detected at this early age," she added. "Additional analyses will be conducted that will try to evaluate the interaction between multiple courses and outcomes as it relates to prolonged rupture of membranes, term versus preterm birth, and infant sex."

One attendee noted that a previous study did find a difference in developmental disability after three or four courses of antenatal steroids. "So I’m wondering whether you have a subanalysis of outcomes by number of courses," he said.

"We have not specifically done that from the neurocognitive perspective," Dr. Asztalos replied. "That is something that we will start to look at."

Another attendee commented, "It appears that the measures you looked at [at] this young age are of fairly significant impacts; yet, in human studies, there is some suggestion of behavioral abnormalities induced by steroids including anxiety and stress responses, and clearly in animal studies – particularly those done in Australia – of programming of offspring HPA [hypothalamic-pituitary-adrenal] axis that’s in a sex-specific manner. Do you plan to look at any of those factors in the future?"

"We do. We are hoping that the Canadian government will allow us to continue to follow these children [until] 12 [years of age], and we will definitely look at these measures," Dr. Asztalos replied.

Pregnant women were eligible for the MACS (Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study) trial if they were at 26-30 weeks’ gestation and were at risk for early birth and had not delivered 14 or more days after an initial course of antenatal corticosteroids.

They were assigned to receive study medication, either betamethasone or placebo, every 14 days until 33 completed weeks or delivery.

Initial trial results, previously published (Lancet 2008;372:2143-51), showed that the multicourse group did not have a lower rate of perinatal or neonatal mortality or neonatal morbidity. Birth weight and length were less, and head circumference was smaller in the multicourse group.

In addition, at the age of 18-24 months, offspring in the multicourse group did not have a lower rate of death or neurologic impairment such as cerebral palsy or cognitive delay (Pediatrics 2010;126:1045-55). They still weighed less, but appeared to be catching up.

The latest results, now at a median age of 5.2 years, showed that children in the multicourse group did not have a significantly different rate of the composite outcome of death or neurodevelopmental impairment relative to their counterparts in the single-course group (24.9% vs. 24.6%), according to data reported at the meeting.

The findings were similar for the individual components of death, neuromotor impairment (defined as nonambulatory cerebral palsy), neurosensory impairment (blindness in at least one eye, deafness, or need for visual or hearing aid), and neurocognitive impairment (abnormal attention, memory, or behavior).

At this time point, children in the two groups were statistically indistinguishable with respect to weight, height, and head circumference; systolic and diastolic blood pressure; and various measures of intelligence and specific cognitive skills, according to Dr. Asztalos.

Dr. Asztalos disclosed no conflicts of interest related to the research.