Children exposed to maternal antenatal corticosteroids have higher rates of emotional – behavioral – psychological disorders

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Maternal antenatal corticosteroid treatment is standard care when there is a risk for preterm delivery.

The treatment improves the prognosis of babies born preterm. However, a new study conducted by experts from the University of Helsinki, University of Oulu and THL Finnish Institute for Health and Welfare shows that children exposed to maternal antenatal corticosteroid treatment have higher rates of emotional, behavioral and psychological development disorders than nonexposed children.

The difference in the rates of these disorders was most evident in children born at term after maternal antenatal corticosteroid treatment exposure, as reported in the study published in JAMA.

Of the term-born children who were exposed to this maternal treatment, 8.9% had been diagnosed with an emotional, behavioral or psychological development disorder. Of the nonexposed term-born children, the rate was 6.3%.

In high-income countries, antenatal corticosteroid treatment has been in routine use for over 30 years. Recommendations and clinical care guidelines for maternal antenatal corticosteroid treatment differ between continents and countries.

In Finland the treatment is currently recommended when the risk for preterm delivery is at 34 gestational weeks or less. In select cases, the treatment is recommended even later in gestation.

Corticosteroids accelerate fetal maturation, especially in the lungs, and increase the child’s resilience to the stress that results from being born preterm.

The population-based register study used records from the Finnish Medical Birth Register and the Care Register for Health Care. The registers are kept at the THL Finnish Institute for Health and Welfare, which is the statutory statistical authority for social and healthcare data in Finland.

The researchers followed up with over 670 000 singleton children born between 2006 and 2017. Of the pregnant mothers, 2.2% were treated with corticosteroids when preterm birth was imminent.

Maternal corticosteroid treatment is an effective treatment – but the long-term benefits and harms should still be weighed

The researchers emphasize that maternal corticosteroid treatment is an effective treatment and can be life-saving for babies who are born extremely or very preterm. However, in recent years, there has been considerable debate on whether to expand the treatment indications beyond 34 gestational weeks.

In Finland, this treatment is recommended, for instance, in the case of elective caesarean section, until 36 gestational weeks. Gestational week 36 refers to a pregnancy that has lasted for 36 weeks and 6 days.

“This is an observational study, and the results do not prove that antenatal corticosteroids are the cause of the increased risks found in the study. However, we conclude that it is important to weigh the balance between the long-term benefits and harms, in particular when considering whether to expand the treatment indications to later gestational weeks.

The prognosis of babies who are born preterm at later gestational weeks is very good in high-income countries,” says Professor Eero Kajantie from the University of Oulu and THL Finnish Institute for Health and Welfare.

“Of the mothers who were treated with antenatal corticosteroids, 45% went on to deliver a term baby. This means that prediction of preterm birth is often very difficult,” he adds.

Finding not explained by genes, smoking or other factors

The study took into account a number of factors that increase the risk of preterm birth, including maternal pregnancy disorders and smoking during pregnancy.

The study also compared term-born maternal sibling pairs, of which one sibling was exposed to maternal antenatal corticosteroid treatment and the other sibling was not.

Also in these sibling comparisons, the treatment-exposed children had higher rates of emotional, behavioral and psychological development disorders, suggesting that shared genetic or familial factors do not explain these associations.

In term-born children, the findings could not be attributed to a single, specific disorder. However, in preterm children whose mothers had received corticosteroid treatment, the rate of mild intellectual disability was lower than in preterm children whose mothers had not received the treatment. This finding is in line with those showing that maternal antenatal corticosteroid treatment improves the prognosis of the children born preterm.

“Even though experimental studies in animals have shown that antenatal corticosteroid treatment has harmful effects on the neurodevelopment of the offspring, population-based cohort studies, like ours, cannot verify if any of the harmful effects on child disorders are accounted for by maternal corticosteroid treatment or if some other factor explains these associations. We tested for several candidates, but none of these factors explained the associations,” says Professor Katri Raikkonen from the University of Helsinki.


Antenatal corticosteroids (ACS), which have been clearly shown to decrease neonatal mortality and short-term morbidity when administered to women at risk of preterm birth before 340/7 weeks,1–5 are a common obstetrical intervention.

Nearly 10% of fetuses in some centres are exposed to ACS,6 a proportion that has been increasing over the last two decades6 7 Still, the long-term safety of ACS has been an ongoing source of concern given the presence of glucocorticoid receptors in the developing fetal brain which might thus be particularly vulnerable to ACS.8–10

In animal studies, exposure to ACS has been associated with delay in brain growth and development11–14 and with persistent changes in the hypothalamic–pituitary–adrenal (HPA) axis.15–20 Data regarding the long-term effects of ACS on human fetuses are less clear.

Several randomised controlled trials have found that newborns exposed in utero to multiple courses of ACS have lower birth weight, length and head circumference compared with those exposed to only a single course of ACS.21–23

Although follow-up of these infants to the age of 2–3 years did not reveal a long-term effect on growth and composite neurodevelopmental outcome,24–26 one of these studies reported a non-significant but concerning increase in the risk of cerebral palsy.25

In addition, there are observational data linking exposure to multiple courses of ACS to increased rates of aggressive, destructive, distractible and hyperkinetic behaviour at both ages of 3 and 6 years.27

Finally, postnatal treatment of preterm infants with corticosteroids has been associated with increased risk of neurological impairment.12 28 29 However, interpretation of human data is limited by insufficient power to detect differences in uncommon neurodevelopmental abnormalities and lack of a control group of infants not exposed to ACS.24–26

Another important factor that should be considered when interpreting available human studies on the long-term effects of ACS is that many of the infants who were included in these studies were born prematurely.24–26 30–33 It is likely that in this population of preterm infants, the immediate benefits of ACS compensate for the potential long-term adverse effects of ACS described above.34–36

However, it is possible that in the subgroup of fetuses that were at risk of preterm birth but were eventually born at term (≥370/7 weeks), in whom the short-term benefits of ACS are minimal or absent, any potential adverse long-term effects of ACS are more likely to be evident.

This question, which is the focus of the current study, is highly relevant given that more than one-third of fetuses exposed to ACS are born at term.22 23

Even more importantly, the recent recommendation to extend the use of ACS to the late preterm period (340/7 to 365/7 weeks)37 38 might lead to a dramatic increase in the number of infants exposed in utero to ACS and an even greater increase in the proportion of fetuses exposed to ACS which will eventually be born at term.

However, despite the importance and relevance of this question, data on the long-term outcomes in this subgroup of term infants who were exposed to ACS are scarce.39–43 Currently available human data raise concerns that prior exposure to ACS, in term infants, might increase the risk of adverse neurodevelopmental outcome, specifically neurosensory disability.39 44

These concerns are supported by animal studies demonstrating neurosensory susceptibility to ACS in the form of delayed optic and auditory nerve myelination,14 45 decreased eye growth,46 decreased retinal thickness and maturation46 47 and abnormal auditory function.48

Other concerning long-term observations in term infants exposed to ACS include lower academic ability at school age,49 long-term dysfunction of the HPA axis42 43 and abnormal brain anatomical findings such as cortical thinning which persist to early childhood.41

In the current study, we assessed the likelihood of neurodevelopmental problems among term infants exposed to ACS compared with term infants without such exposure.

Exposures and outcomes
The primary exposure was administration of ACS during pregnancy and was ascertained from the BORN database. Although information about the preparation, dose and timing of exposure are not recorded in the BORN database, the Society of Obstetricians and Gynaecologists of Canada recommend administration of either betamethasone (2 doses of 12 mg intramuscularly, 24 hours apart) or dexamethasone (4 doses of 6 mg intramuscularly, 12 hours apart) between 24 and 34 weeks of gestation.52 The majority of women would have received betamethasone, as it is the most common type of ACS used in Canada.

The primary outcome was a composite of any of the following that reflect proven or suspected neurodevelopmental problems: (1) audiometry testing—physician service claim for this testing outside the routine provincial infant screening programme for hearing deficits; (2) visual testing —any consultations or assessments from an ophthalmologist or optometrist; the follow-up period for this outcome was limited to the age of 5 years to exclude visual testing done as part of the routine screening initiated at school age or (3) suspected neurocognitive disorder—any physician service claim with a diagnosis code related to a suspected neurocognitive disorder. The codes used to define these outcomes are presented in online supplemental table S1. While service claims with these diagnostic codes do not necessarily prove that individuals have the corresponding diagnosis, a physician claim bearing one of these codes (particularly in infants and young children) suggests at minimum a concern about neurocognitive or neurosensory development that warranted clinical evaluation, although it is acknowledged that these outcomes are different from measured neurodevelopmental impairment. Secondary outcomes were each of the individual components of the primary outcome. While the follow-up period for visual testing was restricted to 5 years of age for the reasons discussed above, we did not restrict the follow-up period for the other outcomes since we do not anticipate that routine screening for visual impairment at the age of 5 years would impact the rate of audiometry testing or neurocognitive assessment.

Supplementary data : [bmjopen-2019-031197supp001.pdf]

Results
Characteristics of the study population
A total of 738 377 live singleton infants were born in Ontario during the study period. Of the 529 205 infants who met the study criteria, 5432 (1.02%) were exposed to ACS during pregnancy and were compared with 523 782 (98.98%) infants not exposed to ACS (figure 1).

Maternal baseline characteristics are presented in table 1. There were significant differences between the groups in maternal age, parity, income, medical disorders, induction of labour and mode of delivery.

However, for many of these characteristics the absolute differences between the groups were very small (table 1). Infants in the ACS group were born at an earlier gestational age, had a lower mean birth weight, were more likely to have a birth weight below the 10th percentile for gestational age and were slightly more likely to require resuscitation at birth and admission to the NICU compared with infants not exposed to ACS (table 1).

Table 1

Maternal and neonatal baseline characteristics of the study and control groups

CharacteristicTerm infants exposed to ACS
n=5423
Term infants
NOT exposed to ACS
n=523 782
P value
Maternal age (years)29.50±5.8729.97±5.48< 0.001
 >35 years847 (15.6%)82 860 (15.8%)0.69
Parity0.002
 0 (nulliparity)2298 (42.4%)226 739 (43.3%)
 11927 (35.5%)190 250 (36.3%)
 2777 (14.3%)72 454 (13.8%)
 ≥3421 (7.8%)34 339 (6.6%)
Income quintile*0.02
 Q1 (lowest)1308 (24.1%)117 423 (22.4%)
 Q21059 (19.5%)105 093 (20.1%)
 Q31110 (20.5%)107 509 (20.5%)
 Q41104 (20.4%)109 147 (20.8%)
 Q5 (highest)842 (15.5%)84 610 (16.2%)
Chronic hypertension60 (1.1%)3317 (0.6%)< 0.001
Pregestational diabetes126 (2.3%)7467 (1.4%)< 0.001
Hypertensive complications298 (5.5%)22 552 (4.3%)< 0.001
Gestational diabetes345 (6.4%)23 961 (4.6%)< 0.001
Gestational age at birth< 0.001
 370/7 to 386/7 weeks2598 (47.9%)148 843 (28.4%)
 390/7 to 406/7 weeks2396 (44.2%)301 183 (57.5%)
 ≥410/7 weeks429 (7.9%)73 756 (14.1%)
Induction of labour1596 (29.4%)126 925 (24.2%)< 0.001
Caesarean delivery1501 (27.7%)139 062 (26.5%)0.06
Forceps/vacuum delivery621 (11.5%)64 800 (12.4%)0.04
Neonatal characteristics
Birth weight (g)3315±4963447±468< 0.001
Birth weight <10th percentile‡656 (12.1%)45 989 (8.8%)< 0.001
Male sex2738 (50.5%)265 003 (50.6%)0.88
5 min Apgar<742 (0.8%)3714 (0.7%)0.57
Resuscitation at birth856 (15.8%)75 305 (14.4%)0.003
NICU admission179 (3.3%)10 121 (1.9%)< 0.001
  • Data are presented as mean±SD or n (%).
  • *Measured ecologically as the neighbourhood household income, divided into quintiles.
  • †Refers to gestational hypertension or pre-eclampsia.
  • ‡Based on the national reference charts by Kramer et al.57
  • ACS, antenatal corticosteroids; NICU, neonatal intensive care unit

Exposure to ACS and outcomes: unadjusted analysis
The median duration of follow-up for the entire cohort was 7.8 (IQR 6.4–9.2) years. At 5 years of age, term infants exposed to ACS were significantly more likely to have the primary composite outcome (61.7% vs 57.8%), due to a higher rate of audiometry testing (15.3% vs 12.7%), visual testing (45.4% vs 43.5%) and suspected neurocognitive disorder (25.8% vs 21.6%) compared with term infants not exposed to ACS (table 2). The NNH was lowest for suspected neurocognitive disorder (NNH=24, 95% CI 19 to 33), followed by the composite outcome (NNH=25, 95% CI 19 to 38) and audiometry testing (NNH=39, 95% CI 29 to 63).

Table 2

Unadjusted rates of the primary and secondary outcomes at 5 years of age in the antenatal corticosteroids and control groups

OutcomeCumulative rate of outcome at a fixed time point of 5 years of age
Term infants exposed to ACS
n=5423
Term infants
NOT exposed to ACS
n=523 782
P valueNNH
(95% CI)
Composite long-term outcome3346 (61.7%)302 520 (57.8%)< 0.00125 (19 to 38)
Audiometry testing827 (15.3%)66 555 (12.7%)< 0.00139 (29 to 63)
Visual testing2461 (45.4%)227 948 (43.5%)0.00654 (31 to 200)
Suspected neurocognitive disorder1397 (25.8%)113 181 (21.6%)< 0.00124 (19 to 33)
  • Significant p values are emphasized in bold font.
  • ACS, antenatal corticosteroids; NNH, number needed to harm.

Exposure to ACS and outcomes: adjusted analysis
Given the differences in baseline characteristics, we assessed the association between exposure to ACS and the primary and secondary outcomes while adjusting for potential confounding variables using Cox proportional hazards analysis (table 3). Exposure to ACS was associated with an increased risk of the primary composite outcome (aHR 1.12, 95% CI 1.08 to 1.16), audiometry testing (aHR 1.18, 95% CI 1.11 to 1.25), visual testing (aHR 1.08, 95% CI 1.04 to 1.12), suspected neurocognitive disorder (aHR 1.16, 95% CI 1.10 to 1.21) and combination of both audiometry testing and suspected neurocognitive disorder (aHR 1.23, 95% CI 1.14 to 1.43) (table 3, overall cohort). Findings remained unchanged when infants who were either admitted to the NICU or had a birth weight <10th percentile were excluded from the analysis (table 3).

Table 3

Risk of adverse long-term outcome by exposure to antenatal corticosteroids: time-to-event analysis

OutcomeRisk of the corresponding outcome in term infants exposed to ACS (using non-exposed infants as reference)
(Hazard ratio (95% CI))
Overall cohort*Cohort after exclusion of infants with either NICU admission or birth weight <10th percentile†
Composite long-term outcome1.12 (1.08 to 1.16)1.12 (1.08 to 1.16)
Audiometry testing1.18 (1.11 to 1.25)1.18 (1.11 to 1.26)
Visual testing1.08 (1.04 to 1.12)1.03 (1.03 to 1.12)
Suspected neurocognitive disorder1.16 (1.10 to 1.21)1.17 (1.11 to 1.23)
Audiometry testing AND suspected neurocognitive disorder1.23 (1.14 to 1.34)1.26 (1.15 to 1.38)
  • Values reflect the results of Cox proportional hazards model.
  • *Model adjusted for the following variable: maternal age (as a continuous variable), week of gestation, parity, income, chronic hypertension, pregestational diabetes, hypertensive complications, gestational diabetes, preterm premature rupture of membranes, induction of labour, mode of delivery, infant sex, birth weight <10th percentile, 5 min Apgar <7, resuscitation at birth and admission to NICU.
  • †Model adjusted for the following variable: maternal age (as a continuous variable), week of gestation, parity, income, chronic hypertension, pregestational diabetes, hypertensive complications, gestational diabetes, preterm premature rupture of membranes, induction of labour, mode of delivery, infant sex, 5 min Apgar <7 and resuscitation at birth.
  • ACS, antenatal corticosteroids; NICU, neonatal intensive care unit.

Finally, to determine the timing during childhood at which these differences between term infants exposed versus not exposed to ACS were most pronounced, we compared the rates of each of the outcomes of interest between the two groups stratified by age (figures 2–4). For audiometry testing, visual testing and suspected neurocognitive disorders, the differences between the groups emerged early in life and persisted up to the age of 6, 3 and 7 years, respectively.

Rate of audiometry testing by exposure to antenatal corticosteroids stratified by age. Unadjusted rate of outcome (expressed as number of events per 1000 person years) is compared between term infants exposed (red bars) versus non exposed (green bars) to antenatal corticosteroids stratified by child age. P values are presented for statistically significant differences (defined as p<0.05).
RFigure 3Rate of visual testing by exposure to antenatal corticosteroids stratified by age. Unadjusted rate of outcome (expressed as number of events per 1000 person years) is compared between term infants exposed (red bars) versus non exposed (green bars) to antenatal corticosteroids stratified by child age. P values are presented for statistically significant differences (defined as p<0.05).
Figure 4Rate of suspected neurocognitive disorder by exposure to antenatal corticosteroids stratified by age. Unadjusted rate of outcome (expressed as number of events per 1000 person years) is compared between term infants exposed (red bars) versus non exposed (green bars) to antenatal corticosteroids stratified by child age. P values are presented for statistically significant differences (defined as p<0.05).

Conclusion
Our findings support the increasing concerns regarding the potential adverse long-term effects of fetal exposure to ACS. This question is highly relevant given the considerable proportion of ACS-exposed fetuses who subsequently are born at term, a proportion that is likely to increase given the recent recommendations to administer ACS to all women at risk of preterm birth during the late-preterm period.38

When women present in preterm labour, we appreciate that sometimes it is difficult to predict who will actually give birth preterm and may thus benefit from ACS. Still, by not recognising that there is a potential for long-term risk from ACS exposure, clinicians may be too liberal with the use of ACS.53 54

We believe that greater awareness regarding the potential long-term adverse effects of ACS, along with the development of better tools for the prediction of preterm birth,55 56 may assist clinicians in decision-making regarding administration of ACS in those cases where the likelihood of imminent preterm birth is relatively low.

Finally, this information, if confirmed by additional prospective studies, may be important for guideline writers when deciding on the risk–benefit ratio of a policy of routine administration of ACS during the late-preterm period.

Still, it should be emphasised that the findings described above merely represent an association rather than causation, and the interpretation of these findings is limited by the limitations described above.


Source:
University of Helsinki

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