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Antenatal corticosteroids beyond 34 weeks gestation: What do we do now?

American Journal of Obstetrics and Gynecology, Volume 215, Issue 4, October 2016, Pages 423 - 430

The practice of antenatal corticosteroid administration in pregnancies of 24–34 weeks of gestation that are at risk of preterm delivery was adopted over 20 years after the first randomized clinical trial in humans. It is biologically plausible that antenatal corticosteroid in pregnancies beyond 34 weeks of gestation would reduce rates of respiratory morbidity and neonatal intensive care admission. Mostly guided by the results of a large multicenter randomized trial of antenatal corticosteroid in late preterm infants, the Antenatal Late Preterm Steroids Trial, the American Congress of Obstetricians and Gynecologists has released a practice advisory that the “administration of betamethasone may be considered in women with a singleton pregnancy between 34 0/7 and 36 6/7 weeks of gestation at imminent risk of preterm birth within 7 days.” However, many unanswered questions about the risks and benefits of antenatal corticosteroids in this population remain and should be considered with the adoption of this treatment recommendation. This review of the literature indicates that the greatest effect is in the reduction of transient tachypnea of the newborn infant, which is a mostly self-limited condition. This benefit must be weighed against unanticipated outcomes, such as neonatal hypoglycemia, and unknowns about long-term neurodevelopmental follow up and metabolic risks. Amelioration of respiratory morbidity in late preterm infants does not preclude these infants from having other complications that are related to prematurity that require intensive care. Other possible morbidities of prematurity may be magnified if these babies no longer have respiratory symptoms. Conversely, if these late preterm babies no longer exhibit respiratory symptoms and “look good,” they may be discharged before other morbidities of prematurity have resolved and be at risk for readmission. Furthermore, it is also important to ensure that unintended consequences are avoided to achieve a minor benefit. Some of these consequences may include treatment with multiple steroid courses or “treatment creep” in women at 34 to <37 weeks of gestation who do not meet the inclusion/exclusion criteria of the Antenatal Late Preterm Steroids Trial, particularly when a high percentage of women do not receive antenatal corticosteroid within 7 days of delivery. Finally, we believe that caution should be exercised before wide-scale universal adoption of antenatal corticosteroid for pregnancies that are at risk of preterm birth at 34 to <37 weeks of gestation, when it is unclear whether there are long-term effects. For a more balanced rationale for the decision to use antenatal corticosteroid treatment in pregnancies at >34 weeks of gestation, we urge for ongoing research into the risks and benefits of antenatal corticosteroid use in preterm infants overall, for better prediction of preterm birth so that antenatal corticosteroid can be administered within the ideal time frame, and for long-term neurodevelopmental follow-up of the participants in the large randomized Antenatal Late Preterm Steroids Trial.

Key words: antenatal corticosteroid, betamethasone, dexamethasone, hypoglycemia, late preterm infant, respiratory distress syndrome.

Liggins and Howie1 published the first randomized controlled trial of antenatal corticosteroids (ANCS) in Pediatrics in 1972 that demonstrated a reduction in respiratory distress syndrome (RDS) in infants <32 weeks of gestation from 69.6–11.8%. Fourteen more randomized controlled trials were reported before 1995, but the use of ANCS to reduce neonatal morbidity after preterm birth remained approximately 20-40%, primarily because of concerns about adverse effects of ANCS on the fetal brain.2 and 3 A 1995 meta-analysis demonstrated an approximately 50% reduction in RDS in infants whose mothers were treated with ANCS, with the best treatment-to-delivery interval of 24 hours to 1 week after ANCS treatment.3 Sinclair then calculated a number-needed-to-treat with ANCS of 4 for preterm deliveries at <31 weeks of gestation and 15 for deliveries at 31–34 weeks of gestation to prevent 1 case of RDS.4 In 1995, over 20 years after the original randomized trial, a multidisciplinary National Institutes of Health panel concluded in a consensus statement that ANCS for fetal maturation reduced neonatal mortality rates, RDS, and intraventricular hemorrhage in preterm infants and should be used for pregnancies likely to deliver at 24–34 weeks of gestation.5 and 6

Until the recent release of the practice advisory in April 2016,7 the most up-to-date guideline was the 2011 American Congress of Obstetricians and Gynecologists practice bulletin regarding ANCS that recommended a single course of ANCS for pregnant women who were at 24–34 weeks of gestation and at risk of preterm delivery.8 However, contentious issues regarding the use of ANCS still remain. Should the treatment be extended to infants at >34 weeks of gestation, when the risks of RDS and other problems of prematurity are less significant? What do we know about the longer term effects of ANCS in the late preterm population?

With biologic plausibility that ANCS administration would benefit older fetuses, some obstetricians have given corticosteroids outside this recommended gestational window.9 Therefore, it is instructive to analyze the various studies in which ANCS were given at >34 weeks of gestation, the clinical situations of use, and the neonatal outcomes. Given recent publications that have addressed some of these unanswered questions about ANCS treatment, we will review the evidence regarding ANCS use at >34 weeks of gestation in different clinical scenarios and possible long-term consequences.

Use of ANCS at >34 weeks of gestation

ANCS after immature fetal lung indices

A retrospective cohort study by Kamath-Rayne et al9 followed the different clinical treatments of women ≥34 weeks of gestation who had an amniocentesis for fetal lung maturity testing. One hundred two women whose fetal lung indices were immature were given ANCS before delivery. The ANCS-exposed infants (delivered at a mean gestation of 36 weeks) had higher rates of a composite adverse respiratory outcome, neonatal intensive care admission, hypoglycemia, and sepsis evaluation, compared with 76 infants who delivered expectantly (mean, 38 weeks of gestation) after immature fetal lung indices, and a third group of 184 infants who delivered after mature fetal lung indices (mean, 37 weeks of gestation). A second retrospective cohort study by Yinon et al10 evaluated 83 infants of women with immature fetal lung indices from 34–37 weeks of gestation who subsequently received betamethasone treatment vs 84 infants whose mothers did not, based on provider preference. There were no differences in RDS, transient tachypnea of the newborn infant (TTN), hypoglycemia, admission to a special care unit, or length of hospitalization between groups.10 The rates of respiratory support (continuous positive airway pressure or oxygen supplementation) and a composite respiratory outcome (RDS, TTN, or respiratory support) were lower in the treated group (8.4% vs 20% [P=.03], 8.4% vs 21% [P=.02], respectively). It is important to note that, for the study by Yinon et al, the average gestational age at delivery in the ANCS-exposed infants was later (37 vs 36 weeks of gestation) and the time between amniocentesis and delivery was slightly longer (5 days vs 4.6 days) than the Kamath-Rayne study.9 and 10

A 2015 survey of 312 obstetricians and maternal-fetal medicine specialists showed that 44% of respondents use ANCS in patients >34 weeks of gestation. Many were using steroids in both late preterm and early term periods after immature fetal lung indices and waiting on the basis of the lung maturity test result and its expected rate of rise over time (unpublished data). Indeed, in a study by Shanks et al,11 ANCS administration after 34 weeks of gestation was associated with a higher mean weekly increase in a fluorescence polarization fetal lung maturity test than was no treatment, although the study was stopped early because of difficulty in patient recruitment and insufficient power to examine neonatal outcomes.

ANCS before elective cesarean delivery at term

Three studies have evaluated the use of ANCS before elective cesarean delivery at term. The Antenatal Steroids for Term Elective Cesarean Section (ASTECS) study, by Stutchfield et al,12 evaluated ANCS for 998 women who planned an elective cesarean delivery at ≥37 weeks of gestation. The primary outcome was admission to the special care unit with respiratory distress. The authors described the study as a multicenter pragmatic randomized trial; it was not blinded, and the criteria for admission to the different levels of intensive care were not clearly defined. Despite these weaknesses in study design, admission to the special care unit for respiratory distress decreased from 5.4% (24 patients) in the control group to 2.9% (11 patients) in the treatment group (P=.02), and RDS was reduced between control and treatment groups (1.1% vs 0.2%), which was not statistically significant. Despite a decrease in admissions for respiratory distress in the ANCS-exposed group, there were similar numbers of admissions to the special care nursery in both groups (26 in treatment group; 32 in control group), although the authors note that the level of intensive care was less in the treatment group (Table 1).12

Table 1

Studies that have compared the use of antenatal corticosteroids for elective cesarean delivery at term

 

Study Treatment, n Control, n Antenatal corticosteroid used Deaths, % NICU
Admission, %
Respiratory distress syndrome, % Transient tachypnea of newborn
Infant, %
Respiratory morbidity, % Hypoglycemia
Stutchfield et al (2005)12 373 446 Betamethasone: 12 mg × 2 doses, 24 hr apart None reported 6.9 vs 7.1
(not significant)a
0.2 vs 1.1
(RR, 0.21; 95% CI, 0.03–1.32)
2.1 vs 4.0
(RR, 0.54; 95% CI, 0.26–1.12)
Defined as respiratory distress with admission to NICU
2.4 vs 5.1
(RR, 0.46; 95% CI, 0.23–0.93)
Did not report
Ahmed et al (2015)13 228 224 Dexamethasone: 12 mg × 2 doses, 24 hr apart None in either group 0.9 vs 6.3
(P=.07)
0.9 vs 3.6 (P=.4) 7 vs 19.6 (P<.01) “Respiratory distress morbidity”
7.9 vs 23.2 (P<.01)
Did not report
Nada et al (2016)14 616 611 Dexamethasone: 8 mg, 12 hours apart × 4 doses, 48 hr before delivery 0.2 vs 0.3 (P=.99) 3.1 vs 6.7 (P<.01) 0.6 vs 1.6
(P=.10)
1.3 vs 3.4 (P=.01) Defined as NICU admission with respiratory morbidity
1.6 vs 3.9 (P=.01)
Did not report

a No probability value reported.

CI, confidence interval; NICU, neonatal intensive care unit; RR, relative risk.

Kamath-Rayne. Antenatal corticosteroids beyond 34 weeks. Am J Obstet Gynecol 2016.

A nonblinded randomized trial by Ahmed et al13 analyzed the effect of 2 doses of antenatal dexamethasone given to a group of pregnant women at ≥37 weeks of gestation before elective cesarean delivery (Table 1). Although the rates of respiratory distress overall were decreased in the treatment group (7.9% vs 23.2%; P<.01), the decrease was primarily from TTN (7% vs 19.6%).13 Similar to the study of Stutchfield et al,12 there were large absolute differences in rates of RDS (0.9% vs 3.6%; P=.40) and admission to the neonatal intensive care unit (NICU; 0.9% vs 6.3%; P=.07) that were associated with ANCS that were not statistically significant. The duration of admission to NICU was shorter in the treatment group (1.1 days compared with 3.8 days; P<.01).13

Finally, Nada et al14 performed a randomized placebo-controlled trial of 3 doses of dexamethasone 48 hours before elective cesarean delivery at 38 to <39 weeks of gestation. In contrast to the other 2 studies, the treatment group had significantly decreased rates of admission to NICU overall. Similar to the study by Stutchfield et al,12 there was a significant decrease in NICU admission because of respiratory distress, likely mediated by the decrease in TTN in the treatment group compared with the control group (1.3% vs 3.4%; P=.01).

In summary, these 3 trials demonstrate a low incidence of respiratory-related adverse outcomes such as RDS after cesarean delivery at term, and the greatest effect of ANCS exposure in reduction of respiratory morbidity is related to TTN. Although not statistically significant, all 3 trials show a directionally similar reduction in RDS and NICU admission.

Antenatal corticosteroids in the late preterm period

Older studies that included small numbers of infants at >34 weeks of gestation did not show a benefit of ANCS. Crowley’s3 meta-analysis in 1995 included 29 cases of RDS in 886 infants at >34 weeks of gestation, with no significant improvement in the incidence of RDS. Based on these numbers, Sinclair4 calculated a number-needed-to-treat of 145 to prevent 1 case of RDS. The Roberts and Dalziel15 meta-analysis included 189 infants treated from 35 to <37 weeks of gestation with the first dose of ANCS and showed no difference in rates of RDS. Since that meta-analysis was updated in 2010, further studies that have analyzed the use of ANCS in pregnancies at >34 weeks of gestation are discussed here. In 2010, Balci et al16 published a prospective clinical trial of 100 women at 34–36 weeks of gestation, one-half of whom were assigned randomly to receive a single dose of betamethasone at least 24 hours before delivery. Rates of RDS with admission to NICU were reported to be 4% in the treatment group vs 16% in the control group (P=.046; odds ratio, 0.21 [95% confidence interval, 0.04–1.08]). TTN was not discussed.

Porto et al17 performed a randomized triple-blinded controlled trial of ANCS in Brazil that included 320 women at 34-36 weeks of gestation who were at risk of imminent premature delivery who were assigned randomly to a course of betamethasone vs placebo (Table 2). The average gestational age of both groups at delivery was the same. When the treatment and control groups were compared, there were no differences in rates of neonatal intensive care admission, respiratory morbidity, RDS, TTN, hypoglycemia, or length of NICU stay.

Table 2

Studies comparing the use of antenatal corticosteroids for late preterm infants at risk of preterm delivery

 

Authors Treatment, n Control, n Antenatal corticosteroid used Deaths, % Neonatal intensive care
admission, %
Respiratory distress syndrome, % Transient tachypnea of newborn infant, % Respiratory morbidity, % Hypoglycemia, %
Balci, et al (2010)16 50 50 Betamethasone: 12 mg × 1 dose
24 hr before delivery
None reported Only reported as respiratory distress syndrome with admission 4% vs 16% (P=.046) Did not report Did not report Did not report
Porto et al (2011)17 143 130 Betamethasone: 12 mg × 2 doses, 24 hr apart 0 vs 2a 33 vs 33a 1 vs 1
(P=.54)
24 vs 22 (P=.77) 25 vs 23 (P=.69) 11 vs 7a
Ramadan et al (2016)18 74 221 Betamethasone: 12 mg × 2 doses, 24 hr apart 0 vs 1a 27 vs 19 (P=.14) 8.1 vs 6.8 (P=.70) 8.1 vs 6.8 (P=.70) 17.6 vs 15.4 (P=.66) 20.3 vs 10.9 (P=.04)
Gyamfi-Bannerman (2016)19 1427 1400 Betamethasone: 12 mg × 2 doses, 24 hr apart 0.1 vs 0
(P=.50)
41.8 vs 44.9
(P=.09)
5.5 vs 6.4
(P=.36)
6.7 vs 9.9 (P<.01) 11.6 vs 14.4
(P=.02)b
24.0 vs 15.0 (P<.01)

a Not significant; no probability value reported

b Primary outcome for this study was defined by any of the following occurrences within 72 hours after birth: continuous positive airway pressure or high-flow nasal cannula for at least 2 continuous hours, supplemental oxygen with a fraction of inspired oxygen of ≥0.30 for at least 4 continuous hours, mechanical ventilation, stillbirth or neonatal death, or the need for extracorporeal membrane oxygenation.

Kamath-Rayne. Antenatal corticosteroids beyond 34 weeks. Am J Obstet Gynecol 2016.

A nonrandomized prospective cohort study in Lebanon by Ramadan et al18 compared the infants of women from 34 to <37 weeks of gestation who were at risk of imminent preterm delivery whose providers treated with antenatal betamethasone with a group whose providers did not (Table 2). Of note, the control group had a higher number of babies at 36 to <37 weeks of gestation, and the treatment group had higher numbers of babies at 34 to <35 weeks of gestation. Similar to the Porto et al17 study, Ramadan et al noted no differences in rates of RDS, TTN, respiratory morbidity, NICU admission, or NICU stay. As opposed to the study of Porto et al, however, they detected statistically increased rates of hypoglycemia and suspected sepsis in the treated group.18

In February 2016, the results of the large randomized controlled double-blind Antenatal Late Preterm Steroids Trial (ALPS) were published.19 Women with a singleton pregnancy and without previous exposure to ANCS who were at high risk of imminent delivery in the late preterm period (34–36 weeks 6 days) were assigned randomly to betamethasone 12 mg for 2 doses that were given 24 hours apart vs placebo.19High risk of imminent delivery was defined strictly as preterm labor with intact membranes and at least 3 cm dilation or 75% cervical effacement or spontaneous rupture of membranes. There was no statistical difference in rates of RDS, the need for mechanical ventilation, or NICU admission between groups (Table 2), although these were notably higher than rates seen in term infants (Table 1). There was a statistical difference in the primary outcome, a composite endpoint that occurred within 72 hours of birth and consisted of 1 of the following events: the use of continuous positive airway pressure or high-flow nasal cannula for at least 2 consecutive hours, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least 4 continuous hours, extracorporeal membrane oxygenation, or mechanical ventilation. Rates of the primary outcome were 11.6% in the treatment group compared with 14.4% in the control group (relative risk, 0.80; 95% confidence interval, 0.66–0.97; P=.02).19 There was also a decreased need for surfactant in the ANCS group (1.8% vs 3.1%; P=.03). An unanticipated finding was an increased incidence of hypoglycemia, defined as a glucose level <40 mg/dL, in the ANCS group compared with the control group (24.0% vs 15.0%; relative risk, 1.60; 95% confidence interval, 1.37–1.87; P<.01).19 Although there was no discussion of number of blood glucose measurement, the nadir of these levels, maternal blood glucoses, nor interventions that were required for hypoglycemia, the infants with hypoglycemia were discharged an average of 2 days earlier than those without hypoglycemia, which suggests that the condition was “self-limiting.”19 The composite outcome of severe respiratory morbidity (continuous positive airway pressure or high-flow nasal cannula for at least 12 continuous hours, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least 24 continuous hours, extracorporeal membrane oxygenation, or mechanical ventilation, stillbirth, or neonatal death within 72 hours after delivery) was lower in the treatment group compared with the control group (8.1% vs 12.1%; relative risk, 0.67; 95% confidence interval, 0.53–0.84; P<.01), and the number-needed-to treat to prevent 1 case of the primary outcome was 35.19 No long-term follow-up data were presented.

The Society of Maternal-Fetal Medicine and American Congress of Obstetricians and Gynecologists have now recommended guidelines to adopt and implement the findings of the ALPS study into clinical practice.7 and 20 The recommendations include an adherence to the criteria for preterm labor to decrease the potential risk for overtreatment of women who ultimately would deliver at term.20 They acknowledge a lack of long-term neonatal outcome data and recommend standard guidelines for the assessment of monitoring of neonatal hypoglycemia in late preterm infants.20

Challenges and consequences to antenatal corticosteroid use in late preterm infants

Neonatologists have long struggled to understand the complex relationship between glucocorticoids and neurodevelopmental impairment.21, 22, 23, and 24 Glucocorticoids can have beneficial effects on the developing brain.21 However, the gestational age at the time of the exposure, the duration of the exposure, the pharmacodynamics of the steroid, and genetic variation in glucocorticoid receptors in the brain all may modulate how the effects are manifested in the short and long term.21 and 25 There are steroid treatments with betamethasone and dexamethasone that are effective for the preterm infant, but the minimal doses have not been evaluated adequately.26 and 27

Although a single course of ANCS appears to improve neurodevelopmental outcomes in infants born at <34 weeks of gestation,28 little is known about the long-term effects of exposure to ANCS after 34 weeks of gestation. This time period is critical for brain development because, at 34 weeks, the brain weight is only 65% of the term brain, and gyral and sulcal formation are still incomplete.29 From 34–40 weeks of gestation, cortical volume increases by 50% and 25% of the cerebellar development occurs.29 Stutchfield et al30 performed a follow-up assessment to the Antenatal Steroids for Term Elective Cesarean Section trial of betamethasone before an elective cesarean delivery at term; 93% of the original cohort could be contacted, but only 51% of them completed the questionnaires that served as the basis for the assessment.30 Although there were no differences in behavior and health for the subjects at 8–15 years of age, a higher incidence of being in the lowest quarter of academic ability was noted in the betamethasone group (17.7% vs 8.5%).30

Several studies have examined the metabolic and hormonal effects of ANCS that were administered in the late preterm period. Hypoglycemia was noted in late preterm infants whose mothers were treated with ANCS in several studies.9, 18, and 19 In a retrospective cohort study of 6675 preterm deliveries at 32–37 weeks of gestation at a single university hospital, the odds ratio of hypoglycemia in corticosteroid-exposed infants, after adjustment of gestational age, was 1.60 (95% confidence interval, 1.24–2.07). The hypoglycemia was increased in infants whose mothers had pregestational diabetes mellitus (adjusted odds ratio, 5.65; 95% confidence interval, 3.84–8.33).31 However, there were no statistically significant differences between groups when stratified by gestational age. A limitation of the study was the lack of maternal blood glucose levels.31 Sifianou et al32 analyzed cord blood in a convenience sample of 32 singleton newborn infants at >35 weeks of gestation whose mothers received a single 12-mg dose of betamethasone approximately 24 hours before planned cesarean delivery.32 This group was compared with 44 babies of comparable gestational age, sex, and nutritional status who were not exposed to ANCS. None of the mothers had pregestational or gestational diabetes mellitus. Cord blood levels of C-peptide and glucose were higher in ANCS-exposed fetuses, which indicates that these fetuses were hyperinsulinemic and thus at higher risk for neonatal hypoglycemia.32

Finally, ANCS therapy in preterm infants may lead to cardiovascular and metabolic health problems in later life, although the reports, which were derived mostly from observational studies, are conflicting.27 and 33 For example, a cohort of 210 preterm survivors who were observed until age 14 years had higher systolic and diastolic blood pressures in adolescence, which could lead to clinical hypertension later in life.34 Potential mechanisms that were responsible for this observation have been identified in animal studies.35 A different cohort of 209 term born children who were exposed to ANCS in approximately week 30 of gestation had significantly increased cortisol reactivity to psychosocial stress when evaluated at 6–11 years of age, which suggests longer term effects of ANCS on the hypothalamus-pituitary-adrenal axis than previously thought.36 However, it is important to note that there are no data on long-term cardiovascular or metabolic data on late preterm or term infants.

Challenges for administration of ANCS

There are clear benefits to the administration of ANCS in preterm gestation when delivery occurs 24 hours to 7 days after treatment.15 However, ensuring that ANCS are given at the correct time, without adequate methods to predict the timing of preterm birth, is an ongoing challenge. Many perinatal collaboratives use treatment with ANCS as a marker of quality, and rates of ANCS have increased to approximately 90% for deliveries at 24–34 weeks of gestation.37 and 38 However, of concern, there has been a subsequent increase in suboptimal treatment <24 hours or >7 days before delivery) and questionably appropriate treatment (≥35 weeks exposed to ANCS). In all live births in Nova Scotia from 1998–2012, the rates of suboptimal treatment were 34% (odds ratio, 6.7; 95% confidence interval, 3.9–11.6) and questionably appropriate treatment of 1.7% (odds ratio, 7.5; 95% confidence interval, 4.9–11.3).39 In fact, in 2012, more than one-half the newborn infants whose mothers received ANCS were born at 35 weeks of gestation and thus were exposed unnecessarily.39 Another study demonstrated that, of 692 women who received ANCS at a single institution, 35.7% delivered at ≥34 weeks of gestation, and 17.9% remained pregnant beyond a week after ANCS and were still <34 weeks of gestation.40 A rescue dose of steroids is often used in these situations; however, multiple courses of ANCS are not recommended because of poor fetal head growth and increased risk of neurodevelopmental impairment by 5 years.41, 42, and 43 To fully implement ANCS to the greatest benefit of the preterm pregnancies that are at risk of imminent delivery, improved methods of preterm birth prediction are needed.44 and 45 Furthermore, if ANCS treatment is extended from 34 to <37 weeks of gestation and many of these fetuses deliver at term, the effects are unknown.

Comment

ANCS are an important evidence-based practice for reduction of mortality rates and for a decrease in the rates of RDS, intraventricular hemorrhage, and necrotizing enterocolitis in premature infants; the benefits of treatment in the <34 week gestation time period clearly outweigh the risks. At early gestational ages, ANCS may prevent significant short-term neonatal morbidity that could impact future neurodevelopmental outcome greatly. In the late preterm and term period, these effects are much less clear. We believed that it was important to separate the situations in which ANCS are used; giving steroids before a planned cesarean delivery at term without labor may have a different risk/benefit ratio than ANCS given to a woman who is at risk of delivery in the late preterm period.

For ANCS given before an elective cesarean delivery at term, the 3 studies described showed decreased rates of NICU admission for respiratory morbidity, likely related to decreased incidence of TTN.12, 13, and 14 However, there was no decrease in rates of RDS nor in NICU admission overall, except in the Nada et al study.12, 13, and 14 Thus, in the term period, the greatest effect of ANCS is a decrease in the rate of TTN, which is normally a self-limiting process. We must weigh this relatively small benefit with a lack of follow-up information for term infants who were exposed to ANCS, with a concern for longer term effects on academic performance in the Antenatal Steroids for Term Elective Cesarean Section follow up.12, 13, 14, and 46

Even before the publication of the ALPS trial for ANCS use at >34 weeks of gestation, there has been treatment creep of this practice outside of current practice recommendations.9 and 31 Although the ALPS trial supports improvements in respiratory morbidity after infants are exposed during late preterm gestation, it is important to note that there were no significant differences in rates of RDS nor NICU admission.19 The rationale for how the authors derived their primary composite outcome measure and whether this composite outcome is of clinical significance is unclear. Most babies who had the primary composite outcome had respiratory morbidity related to TTN. Given the predisposition for treatment creep, it is of concern that obstetricians may not adhere to the inclusion/exclusion criteria of the ALPS study and that more late preterm infants will be exposed to ANCS, when we do not fully understand the long-term implications.

An unintended consequence of the use of ANCS to improve respiratory symptoms in late preterm infants is that it may unmask other morbidities, such as hypoglycemia. It should be noted that the risk of hypoglycemia in the late preterm infants in the ALPS study was higher than the benefit that was derived from decreased respiratory morbidity.19 Although the authors speculate that the hypoglycemia was a mild and self-limited condition, the nadir of the infants’ blood glucose levels and treatments have not been reported.19 We presented 1 explanation for the hypoglycemia, a transient neonatal hyperinsulinism that is related to elevated maternal blood glucose levels. Another possible explanation is that the infants who were not exposed to ANCS were indeed sicker, as demonstrated by their increased incidence of respiratory symptoms, need for resuscitation, and longer duration of NICU stay.19 These sicker infants were likely admitted to the NICU and started on intravenous fluids, thus preventing possible hypoglycemia.

Although the hypoglycemia appears to have been self-limiting, the longer term effects of the hypoglycemia in conjunction with ANCS exposure are unknown. Although RDS in the late preterm and term period can be a serious condition, it is not associated with poor neurodevelopmental outcome. On the other hand, although the critical threshold glucose concentration below which neurologic injury occurs has not been identified, significant hypoglycemia has been associated with poor outcomes in moderately born preterm infants (32-36 weeks of gestation).47, 48, and 49 Although the incidence of respiratory morbidity of late preterm infants who were exposed antenatally to ANCS is slightly decreased, rates of NICU admission were not, and it may just be that we are trading 1 morbidity for another. Further details on the hypoglycemia and a cost analysis of the use of NICU resources would be helpful to further elucidate these issues.

Although ANCS exposure may decrease respiratory symptoms, these babies still require close observation for other preterm morbidities that include hypoglycemia, jaundice, hypothermia, and feeding difficulties.50 Providers should not be fooled into thinking these infants “look good” and discharge them earlier than the recommended guidelines, which could increase rates of later morbidity or readmission. In addition, long-term follow-up data from the ALPS trial would be invaluable to understanding how ANCS exposure (with and without hypoglycemia) affects the late preterm brain.

With so many unknowns, the question facing all of us is whether the benefits of less short-term, potentially self-limited, respiratory morbidity outweighs unclear and unknown longer term neurodevelopmental and metabolic risks for the late preterm or term infant who is exposed to ANCS. When the rapid development of recommendations to treat with ANCS in the late preterm period is juxtaposed over the 20 years that it took to adopt ANCS into obstetric practice in the first place, we strongly urge for a more thoughtful and balanced approach and a greater understanding of the long-term outcomes before quickly changing clinical practice when so many unknowns still exist.

References

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Footnotes

a Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

b Division of Neonatology, University of Colorado School of Medicine, Aurora, CO

c Department of Obstetrics/Gynecology, Columbia University Medical Center, New York, NY

Corresponding author: Beena D. Kamath-Rayne, MD, MPH.

A.H.J. has a grant from the Bill and Melinda Gates Foundation to study corticosteroids for fetal maturation in monkey and sheep models, is a collaborator on a grant from Glaxo-Smith-Kline to study betamethasone pharmacokinetics in maternal and fetal sheep, and is the Chair of the National Institute of Child and Human Development Global Network; A.H.J. and R.L.G. were co-investigators in the Antenatal Corticosteroid Trial (ACT) trial published in Lancet in 2015. The other authors report no conflict of interest.