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Optimal time interval between a single course of antenatal corticosteroids and delivery for reduction of respiratory distress syndrome in preterm twins

      Objective

      The objective of the study was to investigate the effect of a single course of antenatal corticosteroid (ACS) therapy on the incidence of respiratory distress syndrome (RDS) in preterm twins according to the time interval between ACS administration and delivery.

      Study Design

      We performed a retrospective cohort study of twins born between 24 and 34 weeks of gestation from November 1995 to May 2011. Subjects were grouped on the basis of the time interval between the first ACS dose and delivery: the ACS-to-delivery interval of less than 2 days (n = 166), 2-7 days (n = 114), and more than 7 days (n = 66). Pregnancy and neonatal outcomes of each group were compared with a control group of twins who were not exposed to ACS (n = 122). Multiple logistic regression analysis was used to examine the association between the ACS-to-delivery interval and the incidence of RDS after adjusting for potential confounding variables.

      Results

      Compared with the ACS nonexposure group, the incidence of RDS in the group with an ACS-to-delivery interval of less than 2 days was not significantly different (adjusted odds ratio [aOR], 1.089; 95% confidence interval [CI], 0.524–2.262; P = .819). RDS occurred significantly less frequently when the ACS-to-delivery interval was between 2 and 7 days (aOR, 0.419; 95% CI, 0.181–0.968; P = .042). However, there was no significant reduction in the incidence of RDS when the ACS-to-delivery interval exceeded 7 days (aOR, 2.205; 95% CI, 0.773–6.292; P = .139).

      Conclusion

      In twin pregnancies, a single course of ACS treatment was associated with a decreased rate of RDS only when the ACS-to-delivery interval was between 2 and 7 days.

      Key words

      For Editors' Commentary, see Contents
      The incidence of twin and higher-order multiple pregnancies has significantly increased over the past few decades worldwide,
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      they are based mainly on the extrapolation of data from singleton pregnancies and randomized trials in which twin pregnancies represent a small subpopulation. The safety and efficacy of ACS treatment in twin pregnancies has not been sufficiently studied, and the current available data in the literature present inconsistent findings.
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      Another important issue in the use of ACS is the optimal time interval for ACS to become beneficial. The effect of a single course of ACS appeared to be most beneficial when delivery occurs between 24 hours and 7 days after a complete course of treatment, and its benefit was decreased when the ACS-to-delivery interval exceeded 7 days.
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      Comparison of interval duration between single course antenatal corticosteroid administration and delivery on neonatal outcomes.
      It is not well understood whether the optimal ACS-to-delivery interval seen in singleton pregnancies can be applied to twin pregnancies.
      Therefore, we conducted this study to determine whether ACS therapy has an effect on reducing RDS in preterm twins born between 24 and 34 weeks of gestation and whether its beneficial effect is related to the time interval between ACS administration and delivery.

      Materials and Methods

      We performed a retrospective cohort study of twins born between 24 and 34 weeks of gestation from January 1996 to May 2011 in Samsung Medical Center, a tertiary-care referral hospital in Seoul, Korea. Subjects were grouped on the basis of the time interval between administration of the first ACS dose and delivery (ACS-to-delivery interval): less than 2 days, 2-7 days, and more than 7 days. A single complete course of ACS therapy constituted four 6 mg doses of intramuscular dexamethasone at 12 hour intervals or two 12 mg doses of intramuscular betamethasone at 24 hour intervals. The decision about to whom and when to give ACS was made at the discretion of the attending physicians.
      The group of ACS-to-delivery interval of less than 2 days consisted of patients who delivered within less than 48 hours of administration of the first dose. Twin pregnancies that were not exposed to ACS comprised the control group (nonuser group). Twin pregnancies complicated by twin-to-twin transfusion syndrome, 1 or more fetal deaths, fetal chromosomal or nonchromosomal major anomalies, placenta previa, placental abruption, serious maternal medical diseases, and usage of multiple-course ACS were excluded from this study.
      Medical records of both mothers and their twins were examined independently, with the researcher reviewing the neonatal data for outcome blinded to maternal data including the exposure to ACS and the ACS-to-delivery interval. This was a retrospective study and was approved to be exempt from full institutional review board review in the Samsung Medical Center.
      Maternal data recorded included age, parity, history of previous preterm delivery, type of twin pregnancy, gestational age at admission, indications for admission, type of ACS used, tocolytic treatment, ACS-to-delivery interval, mode of delivery, occurrence of chorioamnionitis, placental chorionicity, and intertwin birthweight discordance. Gestational age was estimated based on the last menstrual period, when reliable, or on ultrasonography performed during the first trimester. Placental chorionicity was determined by sonographic findings and/or by pathological examination of the placenta after delivery. Histological chorioamnionitis was defined as the presence of acute inflammatory change in 1 or more placentas. Intertwin birthweight discordance was defined as a difference of more than 20% in birthweight between a twin pair calculated as 100 × (birthweight of the larger twin – birthweight of the smaller twin)/birthweight of the larger twin. Tocolytic treatment was defined as any use of tocolytics, regardless of timing of initiation, type, dose, duration, multiple drugs, maintenance, or repeat therapy.
      We compared the outcomes of twin neonates in each ACS-to-delivery interval group with those of the control group. The primary outcome was the incidence of RDS, which was diagnosed as the presence of diagnostic radiographic chest findings plus 1 or more clinical signs of respiratory distress including respiratory grunting, retracting, and increased oxygen requirement (fraction of inspired oxygen of greater than 0.4) or the administration of exogenous pulmonary surfactant.
      Other secondary neonatal outcomes analyzed were sex; birthweight; the Apgar scores; small for gestational age; necessity and duration of ventilator therapy; necessity and duration of neonatal intensive care unit stay; mortality and morbidities including bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), periventricular leukomalacia (PVL), grade 3-4 intraventricular hemorrhage (IVH), grade 3-4 retinopathy of prematurity (ROP), stage 2-3 necrotizing enterocolitis (NEC), suspected or proven early and late neonatal sepsis, and mortality. BPD was defined as the need for supplementary oxygen for 28 days or more or by diagnostic radiographic or histological findings. IVH and PVL were diagnosed and graded by ultrasonographic examination of the neonatal brain. IVH was defined as intraventricular bleeding without ventricular dilatation (grade 2) or with ventricular dilatation (grade 3) or with parenchymal involvement (grade 4). PVL was defined as the presence of an obvious hypoechoic cyst in the periventricular white matter. ROP was diagnosed by ophthalmologists, and its grading was based on the International Classification of Retinopathy of Prematurity.
      An international classification of retinopathy of prematurity. Prepared by an international committee.
      NEC was defined in the presence of abdominal distention and feeding intolerance for more than 24 hours with radiological evidence of intramural air, perforation, meconium plug syndrome, or definitive surgical findings. The diagnosis of neonatal sepsis was based on the presence of a positive blood culture (proven sepsis) or positive laboratory evidences in clinically suspected neonates (suspected sepsis).
      The unit of analysis for neonatal outcomes was the individual infant in a twin pair, and each of the maternal exposure variables was counted twice. For the comparison of multiple means, analysis of variance or the Kruskal-Wallis test was used, as appropriate, and the Jonckheere-Terpstra test was used to identify trends. Proportions were compared using the χ2 test or Fisher exact test, as appropriate, and linear-by-linear association was used to identify trends. The Bonferroni test was used for post hoc analysis to correct for multiple comparisons. Multiple logistic regression analysis was performed to evaluate the effects of potential confounding variables such as gestational age at delivery, indication for preterm birth at admission, chorionicity, gestational diabetes, hypertension, mode of delivery, fetal sex, and birth order on the incidence of RDS. The results were considered statistically significant when values of P were < .05. For multiple comparisons, P value was adjusted to .0083 (0.05/6) by Bonferroni correction.

      Results

      During the 16 year period of review, 1483 twin births (3.4%) were identified from a total of 43,227 deliveries. Nine hundred nine of all twin pregnancies (61.3%) were delivered preterm (less than 37 weeks of gestation), and 374 of them (25.2%) were delivered between 24 and 34 weeks of gestation. One hundred forty cases were excluded by the aforementioned exclusion criteria. Finally, 234 twin pregnancies (468 twin neonates) were included in the study: 61 in the ACS nonuser group (control group), 83 in the group of ACS-to-delivery interval of less than 2 days, 57 in the group of ACS-to-delivery interval of 2-7 days, and 33 in the group of ACS-to-delivery interval of more than 7 days.
      The 4 groups were similar with respect to baseline maternal characteristics except for a higher proportion of hypertension in women in the group of ACS-to-delivery interval of 2-7 days compared with the control group (Table 1). The mean gestational age at admission, indications for admission, and type of ACS used were similar in the 4 groups. Among the 61 patients in the control group, 50 patients were delivered on the day of admission and 11 patients were delivered beyond 1 day after admission. The reasons for the emergent preterm delivery without having a chance to receive ACS treatment were mostly advanced preterm labor at admission or rapid progression of preterm labor, nonreassuring fetal status, or preeclampsia after admission. Women in the control group were significantly less likely to receive any tocolytic treatment compared with those in the other 3 groups.
      Table 1Baseline maternal characteristics
      CharacterisitcNonuser (n = 61)ACS-to-delivery intervalP value
      Intergroup difference by analysis of variance or the χ2 test
      <2 d (n = 83)2-7 d (n = 57)>7 d (n = 33)
      Age (y, mean ± SD)31.0 ± 4.130.7 ± 3.931.2 ± 4.931.2 ± 3.2.898
      Nulliparity46 (75.4%)63 (75.9%)49 (86.0%)26 (78.8%).463
      History of preterm delivery5 (8.2%)3 (3.6%)2 (3.5%)3 (9.1%).449
      Type of pregnancy.762
       Spontaneous21 (34.4%)34 (41.0%)23 (40.4%)12 (36.4%)
       Ovulation induction2 (3.3%)4 (4.8%)1 (1.8%)2 (6.1%)
       IUI5 (8.2%)2 (2.4%)3 (5.3%)1 (3.0%)
       IVF
      Intergroup difference by analysis of variance or the χ2 test
      26 (42.6%)34 (41.0%)28 (49.1%)16 (48.5%)
       Unknown7 (11.5%)9 (10.8%)2 (3.5%)2 (6.1%)
      Chorionicity.924
       Monochorionic9 (14.8%)12 (14.5%)9 (15.8%)7 (21.2%)
       Dichorionic50 (82.0%)69 (83.1%)47 (82.5%)26 (78.8%)
       Unknown2 (3.3%)2 (2.4%)1 (1.8%)0 (0%)
      Gestational diabetes7 (11.5%)2 (2.4%)3 (5.3%)2 (6.1%).157
      Hypertension
      Significantly different compared with the nonuser group
      2 (3.3%)1 (1.2%)11 (19.3%)
      Includes preeclampsia, gestational hypertension, and chronic hypertension.
      2 (6.1%)< .001
      ACS, antenatal corticosteroids; IUI, intrauterine insemination, IVF, in vitro fertilization.
      Kuk. Optimal antenatal corticosteroids-to-delivery interval in preterm twins. Am J Obstet Gynecol 2013.
      a Intergroup difference by analysis of variance or the χ2 test
      b Significantly different compared with the nonuser group
      c Includes preeclampsia, gestational hypertension, and chronic hypertension.
      The median interval between admission and delivery and mean gestational age at delivery of the group of ACS-delivery interval of more than 7 days was significantly higher than that of the control group. Other pregnancy outcomes including occurrence of clinical or histological chorioamnionitis, mode of delivery, and intertwin birthweight discordance were not significantly different among the 4 groups (Table 2).
      Table 2Pregnancy outcome
      VariableNonuser (n = 61)ACS-to-delivery intervalP value
      Intergroup difference by analysis of variance or the χ2 test
      <2 d (n = 83)2-7 d (n = 57)>7 d (n = 33)
      Gestational age at admission (wks), mean ± SD29.9 ± 2.829.7 ± 2.629.8 ± 2.529.3 ± 2.6.767
      Indication for preterm birth at admission.095
       Preterm labor36 (59.0%)53 (63.9%)31 (54.4%)23 (69.7%)
       PPROM24 (39.3%)29 (34.9%)20 (35.1%)9 (27.3%)
       Preeclampsia1 (1.6%)1 (1.2%)6 (10.5%)1 (3.0%)
      Type of ACS used.379
       Dexamethasone26 (31.3%)12 (21.1%)8 (24.2%)
       Betamethasone57 (68.7%)45 (78.9%)25 (75.8%)
      ACS-to-delivery interval (d), median (range)
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      0 (0–2)3 (2–7)17 (8–54)< .001
      Use of any tocolytics25 (41.0%)73 (88.0%)
      Significantly different compared with the nonuser group
      54 (94.7%)
      Significantly different compared with the nonuser group
      32 (97.0%)
      Significantly different compared with the nonuser group
      < .001
      Admission-to-delivery interval (d), median (range)
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      0 (0–29)1 (0–34)4 (2–22)16 (8–55)
      Significantly different compared with the nonuser group
      < .001
      Gestational age at delivery (wks), mean ± SD
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      30.1 ± 2.829.9 ± 2.730.5 ± 2.532.0 ± 1.7
      Significantly different compared with the nonuser group
      .001
       <28 wks
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      14 (23.0%)20 (24.1%)10 (17.5%)1 (3.0%).058
       <32 wks
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      38 (62.3%)55 (66.3%)34 (59.6%)13 (39.4%).062
      Clinical chorioamnionitis1 (1.6%)4 (4.8%)2 (3.5%)3 (9.1%).384
      Histological chorioamnionitis
      Denominators are the numbers of cases with available placental pathology results.
      11/52 (21.2%)22/84 (29.7%)15/55 (27.3%)11/31 (34.5%).532
      Cesarean delivery54 (88.5%)70 (84.3%)49 (86.0%)25 (75.8%).425
      Intertwin birthweight discordance12 (19.7%)11 (13.3%)11 (19.3%)8 (24.2%).508
      ACS, antenatal corticosteroids; PPROM, preterm premature rupture of membranes.
      Kuk. Optimal antenatal corticosteroids-to-delivery interval in preterm twins. Am J Obstet Gynecol 2013.
      a Intergroup difference by analysis of variance or the χ2 test
      b Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      c Significantly different compared with the nonuser group
      d Denominators are the numbers of cases with available placental pathology results.
      The mean birthweight of twins in the group of ACS-to-delivery interval of more than 7 days was higher than that in the control group (Table 3). Twins born at an ACS-to-delivery interval of 2-7 days were less likely to have a low 1 minute Apgar score at birth compared with twins in the control group.
      Table 3Neonatal outcome
      VariableNonuser (n = 122)ACS-to-delivery intervalP value
      Intergroup difference by analysis of variance or the χ2 test
      <2 d (n = 166)2-7 d (n = 114)>7 d (n = 66)
      Sex (male)61 (50.0%)78 (47.0%)61 (53.5%)40 (60.6%).281
      Birthweight (g), mean ± SD1461.2 ± 455.81417.4 ± 445.21484.4 ± 424.21712.0 ± 364.9
      Significantly different compared with the nonuser group
      < .001
      SGA11 (9.0%)10 (6.0%)8 (7.0%)4 (6.1%).781
      1 minute Apgar score <4
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      25 (20.5%)29 (17.5%)7 (6.1%)
      Significantly different compared with the nonuser group
      5 (7.6%).003
      5 minute Apgar score <7
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      21 (17.2%)23 (13.9%)9 (7.9%)3 (4.5%).029
      NICU admission
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      122 (100%)166 (100%)110 (96.5%)65 (98.5%).022
      Duration of NICU stay (d), median (range)
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      Analyzed with neonates who were admitted to NICU only
      37.5 [4-131]39.5 [3-142]36 [2-161]23 [3-80]
      Significantly different compared with the nonuser group
      < .001
      Ventilator treatment
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      74 (60.7%)104 (62.7%)55 (48.2%)30 (45.5%).020
      Duration of assisted ventilation (d), median (range)
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      Analyzed with neonates who were treated with assisted ventilation only
      10 [1-69]7 [1-94]6.5 [1-89]2 [6-36]
      Significantly different compared with the nonuser group
      .023
      Neonatal mortality
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      7 (5.7%)7 (4.2%)1 (1.1%)0 (0%).064
      Neonatal morbidity
       RDS
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      62 (50.8%)86 (51.8%)38 (33.3%)
      Significantly different compared with the nonuser group
      26 (39.4%).008
       BPD
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      29 (23.8%)35 (21.1%)23 (20.2%)1 (1.5%)
      Significantly different compared with the nonuser group
      .001
       IVH (grade 3 or higher)
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      7 (5.7%)3 (1.8%)3 (2.6%)0 (0%).092
       PVL4 (3.3%)7 (4.2%)4 (3.5%)2 (3.0%).964
       PDA
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      56 (45.9%)70 (42.2%)42 (36.8%)20 (30.3%).162
       ROP (grade 3 or higher)
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      14 (11.5%)17 (10.2%)10 (8.8%)1 (1.5%).124
       NEC (stage 2 or higher)4 (3.3%)5 (3.0%)3 (2.6%)1 (1.5%).909
       Early sepsis16 (13.1%)16 (9.6%)20 (17.5%)11 (16.7%).230
       Late sepsis
      Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      21 (17.2%)21 (12.7%)13 (11.4%)2 (3.0%)
      Significantly different compared with the nonuser group
      .043
      Composite morbidity
      Defined as having more than 1 of the following: death, RDS, BPD, IVH (grade 3 or higher), PVL, PDA, ROP (grade 3 or higher), NEC (stage 2 or higher), or suspected or proven early and late neonatal sepsis.
      71 (58.2%)99 (59.6%)61 (53.5%)33 (50.0%).502
      ACS, antenatal corticosteroids; BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; PDA, patent ductus arteriosus; PVL, periventricular leukomalacia; RDS, respiratory distress syndrome; ROP, retinopathy of prematurity; SGA, small-for-gestational age.
      Kuk. Optimal antenatal corticosteroids-to-delivery interval in preterm twins. Am J Obstet Gynecol 2013.
      a Intergroup difference by analysis of variance or the χ2 test
      b Significantly different compared with the nonuser group
      c Significant trend by the Jonckheere-Terpstra test for continuous variables and linear by linear association for categorical variables
      d Analyzed with neonates who were admitted to NICU only
      e Analyzed with neonates who were treated with assisted ventilation only
      f Defined as having more than 1 of the following: death, RDS, BPD, IVH (grade 3 or higher), PVL, PDA, ROP (grade 3 or higher), NEC (stage 2 or higher), or suspected or proven early and late neonatal sepsis.
      The median duration of stay in the neonatal intensive care unit (NICU) of the group of ACS-to-delivery interval of more than 7 days was shorter than the other 3 groups. The overall neonatal mortality and morbidity rate in twins born at an ACS-to-delivery interval of less than 2 days was not significantly different compared with that in the control group.
      No reduction of RDS in the twins in the group of ACS-to-delivery interval of less than 2 days was confirmed by multivariable analysis (adjusted odds ratio [aOR], 1.089; 95% confidence interval [CI], 0.524–2.262; P = .819) (Table 4). Compared with the control group, RDS occurred significantly less frequently in twins born at an ACS-delivery interval of 2-7 days (33.3% vs 50.8%; aOR, 0.419; 95% CI, 0.181–0.968; P = .042) (Table 4). Twins in the group of ACS-delivery interval of more than 7 days (39.4%) had a lower incidence of RDS than those in the control group (50.8%), but the difference was not statistically significant (aOR, 2.205; 95% CI, 0.773–6.292; P = .139) (Table 4). Twins in the group of ACS-delivery interval of more than 7 days had a lower incidence of BPD and late sepsis (Table 3), but the differences were not statistically significant in the multivariable analysis (data not shown).
      Table 4Multiple logistic regression analyses of neonatal respiratory distress syndrome controlling for potential confounding variables
      VariablesAdjusted odds ratio (95% CI)P value
      Gestational age at delivery, wks0.452 (0.393–0.521)< .001
      Indication for preterm birth at admission
      Preterm labor was used as the reference
       PPROM1.139 (0.657–1.974).643
       Preeclampsia2.902 (0.801–10.514).105
      Gestational diabetes3.264 (1.159–9.197).025
      Dichorionic twin0.994 (0.503–1.965).987
      Use of any tocolytics0.735 (0.347–1.560).423
      Admission-to-delivery interval, d1.010 (0.976–1.046).572
      Cesarean section1.565 (0.760–3.222).224
      Female neonate0.864 (0.518–1.439).573
      Second twin1.902 (1.145–3.159).013
      ACS-to-delivery interval
      ACS nonusers were used as the reference group.
       <2 d1.089 (0.524–2.262).819
       2-7 d0.419 (0.181–0.968).042
       >7 d2.205 (0.773–6.292).139
      ACS, antenatal corticosteroids; CI, confidence interval; PPROM, preterm premature rupture of membranes.
      Kuk. Optimal antenatal corticosteroids-to-delivery interval in preterm twins. Am J Obstet Gynecol 2013.
      a Preterm labor was used as the reference
      b ACS nonusers were used as the reference group.
      We performed a subgroup analysis of women whose indications for admission were preterm labor or preterm premature rupture of membranes, but the results were not significantly different from those from the total study population (data not shown).

      Comment

      In this study, we evaluated the effect of ACS on the incidence of RDS in preterm twins according to the time interval between ACS administration and delivery. Our data showed that the administration of a single complete course of ACS was associated with a significantly reduced incidence of RDS in preterm twins born between 24 and 34 weeks of gestation when the time interval between the first steroid dose and delivery was between 2 and 7 days. However, there was no significant reduction in the incidence of RDS when twins were born before the completion of the steroid course or delivered within less than 2 days or beyond 7 days of administration of the first dose of steroids.
      The twin birth rate and preterm delivery of twins before 37 weeks of gestation in our study population is comparable with other population-based studies,
      • Ananth C.V.
      • Chauhan S.P.
      Epidemiology of twinning in developed countries.
      • Refuerzo J.S.
      • Momirova V.
      • Peaceman A.M.
      • et al.
      Neonatal outcomes in twin pregnancies delivered moderately preterm, late preterm, and term.
      • Martin J.A.
      • Hamilton B.E.
      • Ventura S.J.
      • et al.
      Births: final data for 2009.
      but the rate of early preterm delivery before 34 weeks of gestation (25.2%) was higher than reported. This may be due to the high proportion of twin pregnancies presenting with threatened preterm delivery referred to our tertiary care hospital from the community. Given the rising twin birth, the issue of reducing complications associated with preterm birth in these high-risk pregnancies is acquiring greater importance.
      Among the available interventions for reducing the perinatal complications of preterm birth, ACS treatment is the most established method with a proven reduction in the rate of RDS, IVH, and mortality.
      American College of Obstetricians and Gynecologists. ACOG committee opinion no. 147, December 1994. Antenatal corticosteroid therapy for fetal maturation. Committee on Obstetric Practice.
      Antenatal corticosteroids revisited: repeat courses.
      However, the effectiveness of ACS therapy in improving neonatal outcomes in twin pregnancies is still unproven.
      • Turrentine M.A.
      • Wilson P.D.
      • Wilkins I.A.
      A retrospective analysis of the effect of antenatal steroid administration on the incidence of respiratory distress syndrome in preterm twin pregnancies.
      • Quist-Therson E.C.
      • Myhr T.L.
      • Ohlsson A.
      Antenatal steroids to prevent respiratory distress syndrome: multiple gestation as an effect modifier.
      • Al-Yatama M.K.
      • Al Essa M.
      • Omu A.E.
      • Al-Shamali I.
      • Egbase P.
      • Rashwan N.
      Effect of repeated doses of dexamethasone on the incidence and severity of respiratory distress syndrome in multifetal gestation between 24 and 34 weeks.
      • Blickstein I.
      • Shinwell E.S.
      • Lusky A.
      • Reichman B.
      Plurality-dependent risk of respiratory distress syndrome among very-low-birth-weight infants and antepartum corticosteroid treatment.
      • Murphy D.J.
      • Caukwell S.
      • Joels L.A.
      • Wardle P.
      Cohort study of the neonatal outcome of twin pregnancies that were treated with prophylactic or rescue antenatal corticosteroids.
      • Choi S.J.
      • Song S.E.
      • Seo E.S.
      • Oh S.Y.
      • Kim J.H.
      • Roh C.R.
      The effect of single or multiple courses of antenatal corticosteroid therapy on neonatal respiratory distress syndrome in singleton versus twin pregnancies.
      • Roberts D.
      • Dalziel S.
      Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.
      It has been hypothesized that the suboptimal benefits of ACS treatment in twin pregnancies may be attributable to the greater degree of maternal physiological changes in twin pregnancies compared with singleton pregnancies, such as greater maternal blood volume expansion, a shorter half-life, and greater clearance of betamethasone.
      • Ballabh P.
      • Lo E.S.
      • Kumari J.
      • et al.
      Pharmacokinetics of betamethasone in twin and singleton pregnancy.
      However, this hypothesis was challenged by recent studies that demonstrated no difference in maternal pharmacokinetics of betamethasone
      • Della Torre M.
      • Hibbard J.U.
      • Jeong H.
      • Fischer J.H.
      Betamethasone in pregnancy: influence of maternal body weight and multiple gestation on pharmacokinetics.
      and no differences in betamethasone concentrations in maternal serum or cord blood
      • Gyamfi C.
      • Mele L.
      • Wapner R.J.
      • et al.
      The effect of plurality and obesity on betamethasone concentrations in women at risk for preterm delivery.
      between singleton and twin pregnancies.
      In our previous retrospective cohort study of 117 twin pregnancies, we found that ACS administration, either as a single course or as multiple courses, did not reduce the incidence of RDS of twins born between 24 and 34 weeks of gestation.
      • Choi S.J.
      • Song S.E.
      • Seo E.S.
      • Oh S.Y.
      • Kim J.H.
      • Roh C.R.
      The effect of single or multiple courses of antenatal corticosteroid therapy on neonatal respiratory distress syndrome in singleton versus twin pregnancies.
      However, the study had limitations in that the number of twin pregnancies was small and did not take account of the time interval from ACS administration to delivery. Therefore, we were not able to evaluate whether the lack of benefit of ACS treatment in twins was due to the diminished effect of ACS in twins born more than 7 days after the ACS exposure. In the current study, in which the sample size was doubled and the ACS-to-delivery interval was considered in the analysis, we found that a single course of ACS treatment was beneficial in reducing the incidence of RDS in twin pregnancies when the interval was between 2 and 7 days.
      The optimal time period between ACS administration and delivery in twin pregnancies has not been sufficiently studied. Most of the studies that evaluated the effect of ACS on neonatal RDS in twin pregnancies included only twins born within 7 days after the ACS dose.
      • Turrentine M.A.
      • Wilson P.D.
      • Wilkins I.A.
      A retrospective analysis of the effect of antenatal steroid administration on the incidence of respiratory distress syndrome in preterm twin pregnancies.
      • Quist-Therson E.C.
      • Myhr T.L.
      • Ohlsson A.
      Antenatal steroids to prevent respiratory distress syndrome: multiple gestation as an effect modifier.
      • Al-Yatama M.K.
      • Al Essa M.
      • Omu A.E.
      • Al-Shamali I.
      • Egbase P.
      • Rashwan N.
      Effect of repeated doses of dexamethasone on the incidence and severity of respiratory distress syndrome in multifetal gestation between 24 and 34 weeks.
      In a large population-based cohort study, Blickstein et al
      • Blickstein I.
      • Shinwell E.S.
      • Lusky A.
      • Reichman B.
      Plurality-dependent risk of respiratory distress syndrome among very-low-birth-weight infants and antepartum corticosteroid treatment.
      found that a complete course of ACS significantly reduced the incidence of RDS in singletons as well as in twins and triplets. However, partial corticosteroid treatment, defined as a delivery occurring less than 24 hours after the first dose or more than 7 days after the last dose, was shown to have the same effect on the incidence of RDS as no treatment at all, irrespective of plurality.
      Similar to Blickstein et al,
      • Blickstein I.
      • Shinwell E.S.
      • Lusky A.
      • Reichman B.
      Plurality-dependent risk of respiratory distress syndrome among very-low-birth-weight infants and antepartum corticosteroid treatment.
      we found that there was no significant reduction in the incidence of RDS when twins were delivered at an ACS-to-delivery interval of less than 2 days or more than 7 days. In a study by Gyamfi et al,
      • Gyamfi C.
      • Mele L.
      • Wapner R.J.
      • et al.
      The effect of plurality and obesity on betamethasone concentrations in women at risk for preterm delivery.
      the concentrations of betamethasone in cord blood decreased over time (from 0 days to 6 days of last dose) for both singletons and twins. Although the data beyond 7 days after the steroid dose were not available, the levels of betamethasone in cord blood after 7 days presumably would never increase unless an additional course of ACS is given.
      These results, taken together with our current study, may suggest that the effects of ACS decrease after 7 days of the treatment and may give rise to a concern of a repeated or rescue course of ACS in women who still confer a risk of preterm birth after the first course of ACS.
      The efficacy and safety of repeated or multiple courses of ACS are still debated, and the issue is even more controversial in twin pregnancies because it has been assessed in only a few studies with conflicting results.
      • Al-Yatama M.K.
      • Al Essa M.
      • Omu A.E.
      • Al-Shamali I.
      • Egbase P.
      • Rashwan N.
      Effect of repeated doses of dexamethasone on the incidence and severity of respiratory distress syndrome in multifetal gestation between 24 and 34 weeks.
      • Murphy D.J.
      • Caukwell S.
      • Joels L.A.
      • Wardle P.
      Cohort study of the neonatal outcome of twin pregnancies that were treated with prophylactic or rescue antenatal corticosteroids.
      • Murphy K.E.
      • Hannah M.E.
      • Willan A.R.
      • et al.
      Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial.
      Regularly scheduled repeated courses or multiple courses (more than 2) of ACS are not recommended because of insufficient data regarding the benefit and concern for the potential adverse impact on fetal growth and brain development.
      Antenatal corticosteroids revisited: repeat courses. National Institutes of Health Consensus Development Conference Statement, August 17-18, 2000.
      Instead, a recent American College of Obstetricians and Gynecologists Committee Opinion stated that a single rescue course could be considered if the previous ACS treatment was given more than 2 weeks previously.
      American College of Obstetricians and Gynecologists
      ACOG Committee Opinion no. 475: antenatal corticosteroid therapy for fetal maturation.
      The efficacy of a rescue course of ACS in twin pregnancies was investigated in a recent retrospective cohort study, which failed to find any benefit of rescue ACS in reducing the incidence of RDS.
      • Bibbo C.
      • Deluca L.
      • Gibbs K.A.
      • et al.
      Rescue corticosteroids in twin pregnancies and short-term neonatal outcomes.
      However, a rescue course of ACS was associated with fewer severe respiratory morbidities and a lower incidence of retinopathy of prematurity.
      Most patients who were not exposed to ACS in our study were in advanced preterm labor or had a rapid progression of preterm labor. This might influence the results of our study because these women had a shorter admission-to-delivery interval and they might be more likely to be associated with intrauterine infection. However, we were not able to control for this possibility because this study was a retrospective data review. The only variables that indicate the evidence of intrauterine infection were the occurrence of clinical and histological chorioamnionitis, but their incidence was similar in the 4 groups. And the admission-to-delivery interval was not shown to be associated with the incidence of RDS in the multivariable analysis.
      There are several limitations of our study. First, as a retrospective chart review, our study has potential biases including misclassification bias. In addition, maternal steroid exposure and the ACS-to-delivery interval may have been biased by unidentifiable confounding factors such as practice changes over a long study period of 16 years (eg, regimens for tocolytics used to control preterm labor and antibiotics used in women with preterm premature rupture of membranes [PPROM]) and other maternal or fetal conditions not controlled for the multivariable analysis.
      The study is further limited by the sample size. Our study may be underpowered because the sample size was not enough to show a difference in the neonatal outcome, especially between the group with ACS-to-delivery interval of more than 7 days and the nonuser group. However, because this was a retrospective cohort analysis, we were not able to calculate the sample size before commencing this study. Therefore, well-designed prospective studies with adequate sample sizes are needed to confirm our findings and to determine the effectiveness of ACS treatment and the optimal ACS-to-delivery interval in twin pregnancies.
      In conclusion, the administration of a single complete course of ACS significantly reduced the incidence of RDS in preterm twins born between 24 and 34 weeks of gestation. However, the ACS treatment was associated with a decreased risk of RDS only when the ACS-delivery interval was between 2 and 7 days. Because there is no evidence identified for the efficacy and safety of a rescue course of ACS in twins, careful consideration must be given to predict the risk of delivery within 7 days in twin pregnancies with threatened preterm delivery to administer ACS within an optimal time interval.

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