The rate of late-preterm births (34 0/7 to 36 6/7 weeks of gestation) has been gradually increasing, accounting for 60–70% of preterm deliveries.1,2 The evidence regarding the risk of mortality and short- and long-term morbidity related to late prematurity1,3,4 has led to major efforts to promote research on the prevention and management of late-preterm neonates.5 As part of these efforts, a recent randomized controlled trial by Gyamfi-Bannerman et al6 provided evidence that the administration of antenatal corticosteroids to women with a singleton pregnancy at risk of late-preterm birth decreases the rate of neonatal respiratory morbidity.
Among twin gestations, which represent 2–3% of overall pregnancies,2,7 the rate of late-preterm birth approaches 50%.2,8 Furthermore, twins account for approximately one third of neonates born at 34–35 weeks of gestation.9 Thus, the question of whether the findings of Gyamfi-Bannerman et al can be extrapolated to twin pregnancies is of major importance. The answer to this question is yet unclear and would depend in part on whether late-preterm twins face the same risks as late-preterm singletons. However, although data on the short- and long-term complications associated with late prematurity are widely available for singletons,1,3,5,10–13 similar data on the outcome of late-preterm twins are limited and conflicting.8,9,14–17
The aim of the current study was to test the hypothesis that the risk of neonatal morbidity among low-risk, late-preterm twins is similar to that of low-risk, late-preterm singletons. For this comparison to be more relevant to the potential role of antenatal corticosteroids in late-preterm twins, we chose to use the same primary outcome of composite respiratory morbidity that was used in the study of Gyamfi-Bannerman et al6 described previously.
MATERIALS AND METHODS
We conducted a retrospective cohort study of all women with a twin or singleton pregnancy who gave birth during the late-preterm period (defined as 34 0/7 to 36 6/7 weeks of gestation) in a single tertiary referral center between January 2008 and September 2015.
In the current study, neonatal outcomes of late-preterm twins (twins group) were compared with those of late-preterm singletons (singletons group). To try to isolate the effect of late prematurity on neonatal outcomes, we excluded pregnancies complicated by conditions that may affect neonatal morbidity, including gestational or pre-existing diabetes, placental abruption, chorioamnionitis, umbilical artery pH less than 7.1, intrauterine fetal death or selective reduction of one or both fetuses, major congenital anomalies, birth weight below the third percentile,18,19 monoamniotic twins, and complicated monochorionic diamniotic twins (including twin-to-twin transfusion syndrome, twin-anemia-polycythemia syndrome, or selective fetal growth restriction). The rationale for not excluding women with hypertensive disorders was our assumption that hypertensive disorders, in the absence of associated complications such as severe fetal growth restriction or placental abruption, are less likely to have an independent effect on neonatal morbidity. The study protocol was approved by the Sunnybrook Health Sciences Center Research Ethics Board.
Cases were identified using the comprehensive institutional perinatal database. This database is maintained by the institutional information services and has been found to be extremely reliable based on comparisons with data extracted from the medical charts on multiple chart-based studies that were conducted in our department in the past. Maternal and neonatal charts were then reviewed for the following information: demographic information, medical and obstetric history, pregnancy-related complications, labor and delivery complications, and short-term neonatal outcomes.
To make the comparison of the outcomes of late-preterm twins and late-preterm singletons more relevant to the potential role of antenatal corticosteroids in late-preterm twins, we chose to use the same primary outcome that was used in the recent randomized controlled trial of Gyamfi-Bannerman et al6 on antenatal betamethasone for women at risk for late-preterm delivery. Thus, the primary outcome was a composite respiratory morbidity, which was defined as need for respiratory support within 72 hours after birth and consisted of one or more of the following: 1) use of continuous positive airway pressure or high-flow nasal cannula (greater than 1 L/min) for at least 2 consecutive hours, 2) supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least 4 continuous hours, 3) extracorporeal membrane oxygenation, 4) mechanical ventilation, or 5) stillbirth and neonatal death within 72 hours after delivery. Severe respiratory morbidity was defined as one or more of the following: 1) need for respiratory support in the form of continuous positive airway pressure or high-flow nasal cannula for at least 12 continuous hours, 2) supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least at least 24 continuous hours, 3) extracorporeal membrane oxygenation, 4) mechanical ventilation, or 5) stillbirth or neonatal death within 72 hours after delivery.
Bronchopulmonary dysplasia was defined as the requirement for oxygen at a postmenstrual age of 36 weeks of gestation or at the time of transfer to a level II facility.20 Severe neurologic injury was defined as grade 3 or 4 intraventricular hemorrhage according to the criteria of Papile et al21 or periventricular leukomalacia, diagnosed by cranial ultrasonography or magnetic resonance imaging. Severe retinopathy of prematurity (ROP) was defined as stage 3 or higher according to the International Classification of ROP or ROP requiring treatment.22 Necrotizing enterocolitis was defined according to Bell's criteria.23
Baseline characteristics and neonatal outcomes were compared between the twins and singleton groups. Student t test and the Mann-Whitney U test were used for continuous variables with and without normal distribution, respectively. χ2 and Fisher exact tests were used for categorical variables, as appropriate. Multivariable logistic regression analysis was used to assess the association between twin pregnancies (using singleton pregnancies as a reference) with respiratory morbidity after adjustment for the characteristics that differed between the twins and singleton groups in the bivariate analysis. These models were fitted with the generalized estimating equation to account for the correlation within a pair of twins from the same mother. Data analysis was performed with SPSS 24.0. Differences were considered significant when P value was <.05.
A total of 26,124 singleton and twin neonates were born during the study period (Fig. 1). The proportion of late-preterm neonates in the overall cohort was 7.8% (n=2,040) and was higher among twins (33.9%) than in singletons (5.0%). A total of 1,643 late-preterm neonates (922 singletons and 721 twins) met the inclusion criteria (Fig. 1).
The characteristics of the singletons and twins group are presented in Table 1. Women in the twins group were more likely to be nulliparous, to give birth before 36 weeks of gestation, to receive antenatal corticosteroids for fetal lung maturation, and to give birth by cesarean delivery. The proportion of women with preterm prelabor rupture of membranes was lower in the twins group (Table 1).
The unadjusted rates of neonatal respiratory morbidity and severe respiratory morbidity were similar in the singletons and twins groups (7.4% [n=68] compared with 8.3% [n=60], P=.5 and 6.0% [n=55] compared with 6.8% [n=49], P=.5, respectively; Table 2). When stratified by gestational week at birth, the rates of respiratory morbidity were highest among twins and singleton neonates born at 34 weeks of gestation (19.4% [n=31] compared with 22.6% [n=28], respectively, P=.5) and decreased considerably with each successive week, but remained similar in the twins and singleton groups (35 weeks of gestation: 8.6% [n=23] compared with 8.1% [n=22], respectively, P=.9; 36 weeks of gestation: 2.1% [n=6] compared with 3.4% [n=18], respectively, P=.3; Fig. 2). The rates of respiratory morbidity were not different between twins and singletons when stratified by mode of delivery (Table 3) or by exposure to antenatal corticosteroids (Table 4).
Multivariable logistic regression analysis was used to assess the association between plurality (using singletons as a reference) and respiratory morbidity while adjusting for parity, gestational age at birth, exposure to antenatal corticosteroids, preterm prelabor rupture of membranes, and fetal sex (Table 5). There was no significant association between plurality and the risk of respiratory morbidity (adjusted odds ratio [OR] 0.73, 95% CI 0.48–1.12) or severe respiratory morbidity (adjusted OR 0.79, 95% CI 0.50–1.24) (Table 5).
Secondary neonatal outcomes are presented in Table 6. Twin neonates had a lower birth weight (2,323±383 compared with 2,676±403 g, P<.001) and were more likely to require resuscitation at birth (17.1% compared with 11.7%, P=.002) and admission to the neonatal intensive care unit (43.6% compared with 30.7%, P<.001). The rates of other measures of neonatal respiratory and nonrespiratory morbidity were similar between the twins and singleton groups (Table 6). The rates of the most common types of neonatal morbidity (transient tachypnea of the newborn, hypoglycemia, jaundice requiring phototherapy, and feeding difficulties) remained similar in both groups even when stratified by gestational week at birth (Fig. 3). The rate of respiratory distress syndrome was low in both groups (1.8% and 1.9% in singletons and twins, respectively) and there were no cases of neonatal death, severe neurologic injury, or ROP (Table 6).
The aim of the current study was to test the hypothesis that the risk of neonatal morbidity among late-preterm twins is similar to that of late-preterm singletons. Our main findings were as follows: 1) late prematurity is associated with neonatal morbidity in both singletons and twins, and the risk drops abruptly in both groups with each additional week of gestation; 2) the risk of respiratory morbidity among late-preterm twins is similar to that of late-preterm singletons; and 3) we found no differences in the rate of nonrespiratory morbidity between late-preterm twins and late-preterm singletons.
Based on the results of the randomized controlled trial by Gyamfi-Bannerman et al6 described previously, the Society for Maternal-Fetal Medicine and the American College of Obstetricians and Gynecologists have now recommended that women at high risk of preterm birth during the late-preterm period should receive a course of betamethasone, a recommendation that applies only to singleton pregnancies.24,25 Given that the proportion of twins born during the late-preterm period approaches 50%2,8 and that twins account for approximately one third of neonates born at 34–35 weeks of gestation,9 it would be highly relevant to determine whether these beneficial effects of antenatal corticosteroids during the late-preterm period also apply to twin pregnancies. However, two questions need to be addressed to determine whether the findings of the study of Gyamfi-Bannerman et al can be extrapolated to twins. The first is whether the biological effects of antenatal corticosteroids during the late-preterm period are similar for singletons and twins. We have recently reported that the beneficial effects of antenatal corticosteroids in twins are similar in magnitude to those observed in singletons when administrated between 24 and 34 weeks of gestation.26 It is therefore not unreasonable to assume that the effects of antenatal corticosteroids will be similar in twins and singletons during the late-preterm period as well, although this has not been tested. The second question, which is the focus of the current study, is whether the risk of respiratory morbidity among late-preterm twins is similar to that observed in late-preterm singletons; ideally, this question should be addressed by using the same composite primary outcome that was used in the study of Gyamfi-Bannerman et al and that was found to be reduced by administration of antenatal corticosteroids. The answer to this latter question is less clear because available data are limited and conflicting.9,14–17,27,28 In the current study, we have found that the rates of the composite respiratory morbidity and severe respiratory morbidity variables among late-preterm twins were similar to those of late-preterm singletons.
In the current study, we chose to use the same composite respiratory outcomes that were used by Gyamfi-Bannerman et al6 to facilitate comparison of the respiratory outcomes of late-preterm twins and late-preterm singletons in a context that is relevant to the potential role of antenatal corticosteroids in late-preterm twins. The importance of using a standardized outcome variable has been highlighted by the CROWN Initiative.29 It should be noted that the overall rate of the composite respiratory outcome in our study (7.4% and 8.3% in late-preterm singletons and twins, respectively) was lower than that observed by Gyamfi-Bannerman et al in the placebo group (14.4%) and was even lower than that observed by the authors in the betamethasone group (11.6%). These differences in the rate of the primary outcome are even more notable considering the fact that although all the neonates in our study were born during the late-preterm period, approximately 16% of the neonates in the study of Gyamfi-Bannerman et al6 were born at term. These differences may be attributed to the fact that in contrast to our study, the population in the study Gyamfi-Bannerman et al included pregnancies complicated by conditions such as fetal growth restriction and gestational diabetes, which may increase the risk of neonatal morbidity. However, this discrepancy may also be the result of variation in diagnostic and management protocols between centers as well as ascertainment bias in the setting of a randomized controlled trial. The observation that the rate of the primary outcome was highest among twins and singleton neonates born at 34 weeks of gestation (19.2% and 22.6%, respectively) and decreased abruptly afterward may suggest that the risk:benefit ratio for this intervention would be highest among those born closer to 34 weeks of gestation.
The current study has several limitations including its retrospective nature and the differences in the characteristics of the twin and singleton groups. Although we have tried to adjust the risk of respiratory morbidity for multiple confounding variables, residual confounding cannot be ruled out. For example, data on the use of infertility treatments were not available for our cohort. Another limitation relates to the sample size. It should be noted that our study was not powered to detect differences between the twins and singleton groups with respect to the risk of the individual components of the composite variables as well as with respect to the risk of some of the other nonrespiratory neonatal outcomes given the low event rate for these outcomes. In addition, the sample size did not allow us to conduct the multivariable analysis within a subgroup of potential confounding variables such as gestational age at birth and mode of delivery or exposure to antenatal corticosteroids.
We have found that the risk of respiratory morbidity among late-preterm twins is similar to that observed among late-preterm singletons. This finding, along with data suggesting that the effect of antenatal corticosteroids in twins is similar to that observed in singletons,26 provides indirect support to the hypothesis that the beneficial effects of antenatal corticosteroids observed in late-preterm singletons may be extrapolated to late-preterm twins at risk of imminent delivery. These findings may have important implications given the high proportion of twins born during the late-preterm period. Still, the overall low absolute rates of the composite respiratory morbidity in our population and the potential concerns regarding long-term effects of antenatal corticosteroids30,31 suggest that this intervention may be mostly justified among those born closer to 34 weeks of gestation. Further studies are required to better understand the benefit of antenatal corticosteroids during the late-preterm period in twin pregnancies.
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