This study aimed to compare perinatal outcomes, including nonreassuring fetal
status, according to antenatal corticosteroid therapy (ACT) use during
late-preterm and early-term pregnancies. This was a retrospective cohort study of
women with singleton pregnancies who were at risk of late-preterm (34-36
Since its first description by Liggins and Howie in 1972 [1], antenatal corticosteroid therapy (ACT) in pregnant women at risk of preterm birth has been an important and standard obstetric intervention to reduce neonatal mortality and morbidity, especially respiratory complications. Recently, ACT has been reported to significantly reduce the neonatal respiratory morbidity rate even among those at high risk of late-preterm birth, who are between 34 + 0/7 weeks and 36 + 6/7 weeks of gestation [2]. Accordingly, the American College of Obstetricians and Gynecologists (ACOG) recommends ACT for women with imminent late-preterm birth after 34 weeks of gestation as well as imminent preterm birth before 34 weeks of gestation [3]. Selective cesarean section is also considered an important cause of neonatal respiratory morbidity. In particular, the risk of respiratory distress syndrome (RDS) and transient tachypnea of the newborn (TTN) increases at the time of elective cesarean section before 39 weeks. The Royal College of Obstetricians and Gynecologists recommends that all women planning to undergo elective cesarean delivery before 39 weeks of gestation be given antenatal corticosteroids [4].
However, whether the benefits of the use of standardized ACT in late-preterm or early-term pregnancy outweigh the side effects remains unknown. A high incidence of hypoglycemia has been reported in neonates whose mothers received ACT [2], and an association between ACT and reduced fetal thymic growth has also been reported [5]. Studies on the long-term effects of exposure to antenatal corticosteroid use are lacking. In addition, there is a lack of discriminatory results on the role of antenatal corticosteroids in special populations, such as women with diabetes or multiple pregnancies.
It has been reported that the administration of antenatal corticosteroids is associated with temporal suppression of indicators of fetal wellbeing, including fetal heart rate acceleration, heart rate variability, breathing and response to vibroacoustic stimulation [6, 7]. There is concern that antenatal corticosteroid use may lead to a misdiagnosis of fetal distress and the unnecessary delivery of premature neonates. However, to the best of our knowledge, there have been no studies on differences in perinatal outcomes, including indicators for evaluating fetal wellbeing, other than neonatal respiratory morbidity according to antenatal corticosteroid use in late-preterm and early-term pregnancy.
At the study institution, antenatal corticosteroids were administered to women at risk of late-preterm birth or who were planning to undergo early-term scheduled cesarean section without labor. One case of intrauterine fetal death occurred after two doses of betamethasone in a woman who had no underlying disease or other obstetric risk factors and was admitted for the administration of antenatal corticosteroids in early-term pregnancy, with the intent to undergo scheduled cesarean section. Based on that experience, our institution changed its policy to not use ACT in cases of late-preterm birth or of women who were planning to undergo early-term scheduled cesarean sections without labor.
The purpose of this study was to investigate differences in perinatal outcomes according to the use of antenatal corticosteroids in late-preterm and early-term pregnancy.
This was a retrospective cohort study of women with singleton pregnancies who
were at risk of late-preterm (34-36
During the study period, betamethasone was administered to the cohort of women until June 2018. The women received the contents of the two syringes intramuscularly 24 hours apart, each containing betamethasone 12 mg (as betamethasone sodium phosphate 15.7 mg). Since June 2018, a policy not to use betamethasone has been implemented for pregnant women in the above situation.
Women at risk for late-preterm delivery who were at 34 + 0/7 weeks to 36 + 6/7
weeks of gestation were enrolled. The risk for late-preterm delivery included
preterm labor with cervical change, preterm premature rupture of membranes, or
maternal-fetal indications that require preterm delivery (maternal: hypertensive
disorder, placenta previa bleeding, and maternal underlying diseases; fetal:
oligohydramnios). Women with early-term scheduled cesarean section, birth between
37
Maternal charts were reviewed, and the following data were collected: maternal
age, height, time of steroid administration, gestational age at delivery, method
of delivery, diabetes, reasons for late-preterm birth or early-term scheduled
cesarean birth, and antepartum complications, including nonreassuring fetal
status on cardiotocography (CTG) and meconium staining. Nonreassuring fetal
status was based on abnormal fetal heart rate tracing. Fetal heart monitoring was
carried out, and tracings were classified as normal, suspicious, or pathologic,
according to 1) the presence, type, and length of decelerations, 2) the presence
of bradycardia, and 3) the assessment of variability, as reported by the
International Federation of Gynecology and Obstetrics (FIGO) in 2015 [8].
According to this criterion, pathological patterns were either baseline heart
rate below 100 bpm or reduced variability; increased variability; sinusoidal
pattern or repetitive late or prolonged decelerations during
Neonatal charts were linked to maternal charts. Neonatal charts were reviewed
for the following data: birth weight, one-minute and five-minute Apgar scores,
umbilical artery pH, blood glucose concentration within the first 24 hours of
life, neonatal hypoglycemia (
The primary outcome was to compare the differences in perinatal outcomes according to ACT use, namely, nonreassuring fetal status, NICU admission, and the presence of TTN. Furthermore, the outcomes of the newborns were suspected to be influenced by the number of gestational weeks, so the outcomes were stratified by late-preterm and early-term birth. In addition, in the clinical situation, factors affecting nonreassuring fetal status were identified to further explore the circumstances in which predelivery attention should be paid for favorable newborn outcomes.
The included women were grouped for analysis according to whether they delivered
before or after the antenatal corticosteroid use policy change that occurred in
June 2018. Differences in maternal characteristics and neonatal outcomes were
compared according to the use of antenatal corticosteroids and late-preterm or
early-term birth. In the statistical analysis, the chi-squared test or Fisher’s
exact test was used for categorical variables, and Student’s t-test or the
Wilcoxon rank-sum test was used for continuous variables. To evaluate the
associations between perinatal outcomes and the use of ACT, odds ratios (ORs) and
the corresponding 95% confidence intervals (CIs) were calculated. A logistic
regression model with Firth’s penalized likelihood approach was carried out to
identify the mutually adjusted effects among outcomes and the independent
variables chosen on the basis of statistical significance (univariate analysis,
P-value
The study protocol was approved by the Institutional Review Board (IRB) of Gyeongsang National University Changwon Hospital, and the requirement for informed consent was waived (serial number: GNUCH 2020-07-017). All methods were performed in accordance with the relevant guidelines and regulations of the institution.
A total of 216 women (215 with live newborns, 1 with a stillbirth) were included
in the study. In our hospital, the policy for ACT was changed in June 2018; 103
women (47%) were included before the discontinuation of ACT and 113 women (53%)
were included after the discontinuation of ACT. The mean gestational age was 36.7
(
Gestational age at delivery (weeks) | Late preterm | Early term | ||||
Antenatal corticosteroid | Steroids (N |
No steroids (N |
P | Steroids (N |
No steroids (N |
P |
Maternal age (years) | 32.6 |
33.6 |
0.260 | 34.6 |
34.4 |
0.874 |
Height (cm) | 161.7 |
160.6 |
0.234 | 161.5 |
160.7 |
0.406 |
BMI (kg/m |
24.9 |
28.7 |
22.4 |
26.9 |
||
Normal weight (18.5-24.9) | 35 (58.3%) | 15 (30.0%) | 0.005 | 35 (83.3%) | 20 (31.7%) | |
Overweight (25.0-29.9) | 16 (26.7%) | 16 (32.0%) | 6 (14.3%) | 31 (49.2%) | ||
Obese ( |
9 (15.0%) | 19 (38.0%) | 1 (2.4%) | 12 (19.0%) | ||
Gestational diabetes | 7 (11.7%) | 14 (28.0%) | 0.054 | 9 (20.9%) | 5 (7.9%) | 0.099 |
Gestational age at delivery (weeks) | 35.6 |
35.9 |
0.113 | 37.5 |
37.9 |
|
Major indication for antenatal corticosteroids | ||||||
Scheduled cesarean delivery | 4 (6.7%) | 4 (8.0%) | 1.000 | 43 (100%) | 63 (100.0%) | |
Placenta previa | 4 (6.7%) | 3 (6.0%) | 1.000 | 8 (18.6%) | 1 (1.6%) | 0.006 |
Preeclampsia | 3 (5.0%) | 7 (14.0%) | 0.193 | 2 (4.7%) | 0 (0.0%) | 0.317 |
Oligohydramnios | 22 (36.7%) | 14 (28.0%) | 0.447 | 16 (37.2%) | 0 (0.0%) | |
Preterm labor | 22 (36.7%) | 12 (24.0%) | 0.221 | 0 (0.0%) | 0 (0.0%) | |
Preterm PROM | 8 (13.3%) | 13 (26.0%) | 0.150 | 1 (2.3%) | 0 (0.0%) | 0.847 |
Perinatal events | ||||||
Nonreassuring fetal status | 20 (33.3%) | 6 (12.0%) | 0.017 | 8 (19.0%) | 4 (6.3%) | 0.091 |
Meconium stained AF | 1 (1.7%) | 0 (0.0%) | 1.000 | 1 (1.7%) | 0 (0.0%) | 0.704 |
Stillbirth | 0 (0.0%) | 0 (0.0%) | 1 (2.3%) | 0 (0.0%) | 0.847 | |
Neonatal outcome | ||||||
pHUA | 7.3 |
7.3 |
0.675 | 7.3 |
7.3 |
0.093 |
Birth weight (g) | 2623.4 |
2681.8 |
0.516 | 2875.7 |
3087.9 |
0.006 |
NICU admission | 41 (68.3%) | 33 (66.0%) | 0.956 | 8 (19.0%) | 13 (20.6%) | 1.000 |
Duration of admission (days) | 7.7 |
8.2 |
0.728 | 2.6 |
1.4 |
0.325 |
Glucose | 72.6 |
72.6 |
0.995 | 70.9 |
68.3 |
0.395 |
Hypoglycemia ( |
3 (5.3%) | 2 (4.0%) | 1.000 | 2 (5.4%) | 1 (1.8%) | 0.725 |
Respiratory distress syndrome | 5 (8.3%) | 1 (2.0%) | 0.301 | 1 (2.4%) | 0 (0.0%) | 0.837 |
Transient tachypnea of the newborn | 19 (31.7%) | 21 (42.0%) | 0.356 | 0 (0.0%) | 7 (11.1%) | 0.066 |
Meconium aspiration syndrome | 0 (0.0%) | 0 (0.0%) | 1 (2.4%) | 0 (0.0%) | 0.837 | |
Surfactant use | 5 (8.3%) | 2 (4.0%) | 0.593 | 1 (2.4%) | 1 (1.6%) | 1.000 |
Apgar score at 1 min | 6.9 |
6.8 |
0.779 | 7.3 |
7.5 |
0.112 |
Apgar score at 5 min | 8.2 |
8.1 |
0.729 | 8.4 |
8.7 |
0.008 |
Data are shown as the mean |
The overall outcomes are shown in Table 2. After multivariable logistic regression, exposure to antenatal corticosteroids was associated with an increased risk of nonreassuring fetal status (adjusted OR 2.61, 95% CI 1.13-6.04) and a reduced incidence of TTN (adjusted OR 0.36, 95% CI 0.16-0.79). Antenatal corticosteroids were not associated with the need for NICU admission (adjusted OR 1.02, 95% CI 0.45-2.30).
Variable | Steroids (n |
No steroids (n |
Adjusted |
P |
Nonreassuring fetal status | 28 (73.7%) | 10 (26.3%) | 2.61 (1.13-6.04) | 0.025 |
NICU admission | 49 (51.6%) | 46 (48.4%) | 1.02 (0.45-2.30) | 0.965 |
Transient tachypnea of the newborn | 19 (40.4%) | 28 (59.6%) | 0.36 (0.16-0.79) | 0.011 |
CI, confidence interval; NICU, neonatal intensive care unit.
oligohydramnios, preterm labor, and preterm premature rupture of membranes. |
We performed a categorized analysis to detect any differences in the effect of corticosteroid use according to gestational age at delivery. The results are depicted in Table 3. In the late-preterm birth group, exposure to antenatal corticosteroids was associated with an increased risk of nonreassuring fetal status (adjusted OR 3.29, 95% CI 1.20-8.99), but there was no significantly increased risk in the early-term birth group. In a categorized analysis to detect differences in antenatal corticosteroid effects by gestational age at delivery, ACT did not significantly reduce the incidence of TTN (adjusted OR 0.15, 95% CI 0.01-2.75) or the need for NICU admission.
Gestational age at delivery (weeks) | Late preterm | Early term | ||
Adjusted |
P | Adjusted |
P | |
Nonreassuring fetal status | 3.29 (1.20-8.99) | 0.017 | 1.86 (0.40-8.61) | 0.185 |
NICU admission | 1.53 (0.62-3.76) | 0.332 | 1.53 (0.62-3.76) | 0.424 |
Transient tachypnea of the newborn | 0.55 (0.24-1.27) | 0.146 | 0.15 (0.01-2.75) | 0.996 |
CI, confidence interval; NICU, neonatal intensive care unit.
oligohydramnios, preterm labor, and preterm premature rupture of membranes. |
Factors found to affect nonreassuring fetal status in the logistic multivariate analysis were the presence of preeclampsia (adjusted OR 4.72, 95% CI 1.22-18.33), oligohydramnios (adjusted OR 3.90, 95% CI 1.74-8.75) and ACT (adjusted OR 2.96, 95% CI 1.29-6.79), as shown in Fig. 1.
Plot of odds ratios of factors associated with nonreassuring fetal status. Factors found to affect the nonreassuring fetal status in the multivariate stepwise backward logistic regression model were preeclampsia, oligohydramnios and antenatal corticosteroid use. The increased odds of the presence of nonreassuring fetal status were significantly associated with preeclampsia (adjusted OR 4.72, 95% CI 1.22-18.33), oligohydramnios (adjusted OR 3.90, 95% CI 1.74-8.75) and ACT (adjusted OR 2.96, 95% CI 1.29-6.79).
In this study, ACT in late-preterm and early-term pregnancy was associated with an increased risk of perinatal nonreassuring fetal status and a decreased prevalence of TTN in neonates. A decreased prevalence of TTN in neonates after antenatal corticosteroid use has already been demonstrated in a large randomized controlled trial [2]. However, to the best of our knowledge, this is the first study on the relationship between the use of antenatal corticosteroids in late-preterm or early-term pregnancy and negative perinatal outcomes, such as nonreassuring fetal status. Furthermore, our study suggests that in addition to antenatal corticosteroid use, the presence of preeclampsia and oligohydramnios also increases the risk of nonreassuring fetal status. There is a common consensus that preeclampsia and oligohydramnios are associated with perinatal morbidity [9]. Therefore, antenatal corticosteroid administration in the presence of preeclampsia and oligohydramnios should be decided cautiously, and additional attention should be given to interpreting reassuring signs of fetal wellbeing.
In our study, there was a statistically significant difference in the rate of TTN between the group treated with antenatal corticosteroids and the control group. This is in accordance with a study published by Gyamfi-Bannerman et al. [2]. When the incidence rate of TTN was divided by 37 weeks of gestation to reduce the differences in neonatal outcomes according to variations in gestational age, there was no significant reduction in either group. Porto et al. [10] also found that antenatal corticosteroid use did not reduce respiratory morbidity among late-preterm newborns. Furthermore, in our study, the use of antenatal corticosteroids was not associated with NICU admission rates, and neonatal prognoses, such as Apgar scores, did not differ between the antenatal corticosteroid groups.
In our study, the birth weight of newborns was lower in the steroid group than
in the nonsteroid group (2875
Our finding is consistent with a recent population cohort study that showed that neonates who were exposed to antenatal corticosteroids were smaller in size at birth than unexposed neonates [11]. In addition, the study reported an increased rate of medical interventions in neonates exposed to antenatal corticosteroids. The growth and wellbeing of the fetus is multifactorial, and the degree to which antenatal corticosteroid use affects the fetus is unknown. However, these findings should be considered when administering antenatal corticosteroids in clinical practice.
Mouse studies have suggested that exogenous steroids may have different effects, particularly with regard to brain development, at different gestational ages and according to glucocorticoid receptor-mediated responses [12]. In this regard, few studies have been conducted on the long-term effects of antenatal corticosteroid exposure in late-preterm or term newborns, so the effects on neurodevelopment in newborns are uncertain to date.
There are limitations to this study. First, because not all suspected nonreassuring fetal status cases resulted in birth asphyxia, low pH on umbilical cord blood gas analysis or low Apgar scores, it is difficult to conclude that ACT is a decisive factor in a poor outcome of an actual newborn. However, our results showing that the use of antenatal corticosteroids in late-preterm pregnancy is associated with an abnormal fetal heart rate parameter, which may mimic fetal distress, is worth considering in clinical practice. Second, the effects of tocolytics for antenatal corticosteroid administration in late preterm pregnancy and medication for maternal comorbidities were not considered. Third, since this study is a retrospective study conducted by a single institution, influencing variables other than the use of antenatal steroids may not be the same.
Nevertheless, this study is the first report of a case of stillbirth after antenatal corticosteroid administration in a low-risk term pregnancy without other obstetrical risk factors. Furthermore, the results of this study are important in raising the possibility of negative effects associated with the universal adoption of antenatal corticosteroids in pregnant women at risk of late-preterm birth or early-term birth, despite the lack of research on the negative short- and long-term outcomes.
Our study showed that ACT in late-preterm pregnancy was associated with nonreassuring fetal status and that the use of ACT in late-preterm and early-term pregnancy resulted in a decreased incidence of TTN. Among the perinatal outcomes examined in this study, except for TTN, there was no benefit from the use of antenatal corticosteroids. In addition, the factors that increase the likelihood of a nonreassuring fetal heart rate were preeclampsia and oligohydramnios, as well as antenatal corticosteroid use. Additional attention should be given to the use of antenatal steroids to identify benefits in these clinical situations.
ACT, antenatal corticosteroid therapy; CI, confidence intervals; OR, odds ratio; RDS, respiratory distress syndrome; TTN, transient tachypnea of the newborn.
JEP contributed to the conception and design of the study, the acquisition, analysis, and interpretation of the data, review of the literature, and writing and revision of the manuscript. JKP contributed to the conception and design of the study, the acquisition, analysis, and interpretation of the data, and writing and revision of the manuscript. HCJ, IAC and JCB contributed to the acquisition of the data and revision of the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.
The study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board (IRB) of Gyeongsang National University Changwon Hospital, and the requirement for informed consent was waived (approval number: GNUCH 2020-07-017). All methods were performed in accordance with the relevant guidelines and regulations of the institution.
Thanks to all the peer reviewers and editors for their opinions and suggestions.
The authors declare that they have no competing interests.