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.
For Editors’ Commentary, see Contents
The incidence of twin and higher-order multiple pregnancies has significantly increased over the past few decades worldwide, mainly because of the widespread use of assisted reproductive technologies (ART) and increasing maternal age. Among infants conceived with ART, nearly half are born as multiple-birth infants and they account for 20% of all multiple-birth infants. The most significant and common complication of twin pregnancy is preterm delivery. Nearly 60% of twins are born preterm (<37 weeks of gestation), and 12-14.5% of twins are born before 34 weeks of gestation. This higher risk of preterm delivery, especially before 34 weeks of gestation, in twin gestations is associated with an increased risk of neonatal mortality and morbidities including respiratory distress syndrome (RDS).
It is well established that administration of antenatal corticosteroid (ACS) to women with threatened preterm delivery enhances fetal lung maturation and reduces the incidence of RDS and its complications in babies born between 24 and 34 weeks of gestation. Although current guidelines recommend the administration of ACS to women with a twin pregnancy who are at risk of preterm delivery using the same protocol applied for singleton pregnancies, 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.
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. However, the existing evidence of the optimal time period between ACS administration and delivery is based mainly on studies of singleton pregnancies. 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. 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 χ 2 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.
| Characterisitc | Nonuser (n = 61) | ACS-to-delivery interval | P value a | ||
|---|---|---|---|---|---|
| <2 d (n = 83) | 2-7 d (n = 57) | >7 d (n = 33) | |||
| Age (y, mean ± SD) | 31.0 ± 4.1 | 30.7 ± 3.9 | 31.2 ± 4.9 | 31.2 ± 3.2 | .898 |
| Nulliparity | 46 (75.4%) | 63 (75.9%) | 49 (86.0%) | 26 (78.8%) | .463 |
| History of preterm delivery | 5 (8.2%) | 3 (3.6%) | 2 (3.5%) | 3 (9.1%) | .449 |
| Type of pregnancy | .762 | ||||
| Spontaneous | 21 (34.4%) | 34 (41.0%) | 23 (40.4%) | 12 (36.4%) | |
| Ovulation induction | 2 (3.3%) | 4 (4.8%) | 1 (1.8%) | 2 (6.1%) | |
| IUI | 5 (8.2%) | 2 (2.4%) | 3 (5.3%) | 1 (3.0%) | |
| IVF a | 26 (42.6%) | 34 (41.0%) | 28 (49.1%) | 16 (48.5%) | |
| Unknown | 7 (11.5%) | 9 (10.8%) | 2 (3.5%) | 2 (6.1%) | |
| Chorionicity | .924 | ||||
| Monochorionic | 9 (14.8%) | 12 (14.5%) | 9 (15.8%) | 7 (21.2%) | |
| Dichorionic | 50 (82.0%) | 69 (83.1%) | 47 (82.5%) | 26 (78.8%) | |
| Unknown | 2 (3.3%) | 2 (2.4%) | 1 (1.8%) | 0 (0%) | |
| Gestational diabetes | 7 (11.5%) | 2 (2.4%) | 3 (5.3%) | 2 (6.1%) | .157 |
| Hypertension b | 2 (3.3%) | 1 (1.2%) | 11 (19.3%) c | 2 (6.1%) | < .001 |
a Intergroup difference by analysis of variance or the χ 2 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 ).
| Variable | Nonuser (n = 61) | ACS-to-delivery interval | P value a | ||
|---|---|---|---|---|---|
| <2 d (n = 83) | 2-7 d (n = 57) | >7 d (n = 33) | |||
| Gestational age at admission (wks), mean ± SD | 29.9 ± 2.8 | 29.7 ± 2.6 | 29.8 ± 2.5 | 29.3 ± 2.6 | .767 |
| Indication for preterm birth at admission | .095 | ||||
| Preterm labor | 36 (59.0%) | 53 (63.9%) | 31 (54.4%) | 23 (69.7%) | |
| PPROM | 24 (39.3%) | 29 (34.9%) | 20 (35.1%) | 9 (27.3%) | |
| Preeclampsia | 1 (1.6%) | 1 (1.2%) | 6 (10.5%) | 1 (3.0%) | |
| Type of ACS used | .379 | ||||
| Dexamethasone | 26 (31.3%) | 12 (21.1%) | 8 (24.2%) | ||
| Betamethasone | 57 (68.7%) | 45 (78.9%) | 25 (75.8%) | ||
| ACS-to-delivery interval (d), median (range) b | 0 (0–2) | 3 (2–7) | 17 (8–54) | < .001 | |
| Use of any tocolytics | 25 (41.0%) | 73 (88.0%) c | 54 (94.7%) c | 32 (97.0%) c | < .001 |
| Admission-to-delivery interval (d), median (range) b | 0 (0–29) | 1 (0–34) | 4 (2–22) | 16 (8–55) c | < .001 |
| Gestational age at delivery (wks), mean ± SD b | 30.1 ± 2.8 | 29.9 ± 2.7 | 30.5 ± 2.5 | 32.0 ± 1.7 c | .001 |
| <28 wks b | 14 (23.0%) | 20 (24.1%) | 10 (17.5%) | 1 (3.0%) | .058 |
| <32 wks b | 38 (62.3%) | 55 (66.3%) | 34 (59.6%) | 13 (39.4%) | .062 |
| Clinical chorioamnionitis | 1 (1.6%) | 4 (4.8%) | 2 (3.5%) | 3 (9.1%) | .384 |
| Histological chorioamnionitis d | 11/52 (21.2%) | 22/84 (29.7%) | 15/55 (27.3%) | 11/31 (34.5%) | .532 |
| Cesarean delivery | 54 (88.5%) | 70 (84.3%) | 49 (86.0%) | 25 (75.8%) | .425 |
| Intertwin birthweight discordance | 12 (19.7%) | 11 (13.3%) | 11 (19.3%) | 8 (24.2%) | .508 |
a Intergroup difference by analysis of variance or the χ 2 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.
| Variable | Nonuser (n = 122) | ACS-to-delivery interval | P value a | ||
|---|---|---|---|---|---|
| <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 ± SD | 1461.2 ± 455.8 | 1417.4 ± 445.2 | 1484.4 ± 424.2 | 1712.0 ± 364.9 b | < .001 |
| SGA | 11 (9.0%) | 10 (6.0%) | 8 (7.0%) | 4 (6.1%) | .781 |
| 1 minute Apgar score <4 c | 25 (20.5%) | 29 (17.5%) | 7 (6.1%) b | 5 (7.6%) | .003 |
| 5 minute Apgar score <7 c | 21 (17.2%) | 23 (13.9%) | 9 (7.9%) | 3 (4.5%) | .029 |
| NICU admission c | 122 (100%) | 166 (100%) | 110 (96.5%) | 65 (98.5%) | .022 |
| Duration of NICU stay (d), median (range) c,d | 37.5 [4-131] | 39.5 [3-142] | 36 [2-161] | 23 [3-80] b | < .001 |
| Ventilator treatment c | 74 (60.7%) | 104 (62.7%) | 55 (48.2%) | 30 (45.5%) | .020 |
| Duration of assisted ventilation (d), median (range) c,e | 10 [1-69] | 7 [1-94] | 6.5 [1-89] | 2 [6-36] b | .023 |
| Neonatal mortality c | 7 (5.7%) | 7 (4.2%) | 1 (1.1%) | 0 (0%) | .064 |
| Neonatal morbidity | |||||
| RDS c | 62 (50.8%) | 86 (51.8%) | 38 (33.3%) b | 26 (39.4%) | .008 |
| BPD c | 29 (23.8%) | 35 (21.1%) | 23 (20.2%) | 1 (1.5%) b | .001 |
| IVH (grade 3 or higher) c | 7 (5.7%) | 3 (1.8%) | 3 (2.6%) | 0 (0%) | .092 |
| PVL | 4 (3.3%) | 7 (4.2%) | 4 (3.5%) | 2 (3.0%) | .964 |
| PDA c | 56 (45.9%) | 70 (42.2%) | 42 (36.8%) | 20 (30.3%) | .162 |
| ROP (grade 3 or higher) c | 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 sepsis | 16 (13.1%) | 16 (9.6%) | 20 (17.5%) | 11 (16.7%) | .230 |
| Late sepsis c | 21 (17.2%) | 21 (12.7%) | 13 (11.4%) | 2 (3.0%) b | .043 |
| Composite morbidity f | 71 (58.2%) | 99 (59.6%) | 61 (53.5%) | 33 (50.0%) | .502 |
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