Discussion
In this nationwide cohort study, we demonstrated that effects of ACS therapy administered before preterm birth on neonatal outcomes were not significantly different by plurality. Mortality and surfactant use were reduced by ACS exposure in both gestational age groups. ACS exposure was associated with decreased risks of high-grade IVH and PVL in infants born at 23–28 weeks of gestation, but increased the risk of sepsis in infants born at 29–33 weeks of gestation.
ACS therapy for mothers at risk of impending preterm delivery is the most effective evidence-based strategy to reduce the mortality and morbidity of their preterm offspring. However, previous studies that investigated the association between ACS therapy and neonatal outcomes in twin pregnancies not only reported conflicting results but also lacked quantity.
A recent meta-analysis has reported that ACS therapy is associated with decreased neonatal death, respiratory distress syndrome (RDS) and IVH in singleton pregnancies, but not in multiple pregnancies.4 Furthermore, a randomised controlled trial on 311 twin infants who were delivered before 34 weeks of gestation showed that ACS therapy had no association with RDS or composite neonatal morbidity.23 However, large population-based cohort studies from the mid-2000s reported positive ACS effects in multiple pregnancies.24–26 A study of 750 twin infants from France has reported that a complete course of ACS therapy administered within 7 days before birth is associated with decreased rates of brain injury and mortality.24 Another study of 8274 multiplets from Italian Neonatal Network reported that ACS therapy reduced the risk of severe IVH and mortality, although it was less effective in multiple pregnancies than in singleton pregnancies.25 A study of 2516 twin infants from Canadian Neonatal Network has reported that twins can benefit from a complete course of ACS therapy as good as singletons in short-term respiratory morbidity, severe brain injury and mortality.26 Consistent with results of these large cohort studies, our study, using the latest data from KNN, revealed that the effectiveness of ACS therapy in twins was comparable with that of singletons. Moreover, its benefits on mortality and morbidity were shown to be different by gestational age groups.
Additionally, we found that twins had a higher rate of morbidity than singletons in this study. Twins were associated with higher risks of high-grade IVH and advanced ROP in infants born at 23–28 weeks of gestation and PVL in infants born at 29–33 weeks of gestation than singletons. Although twins are more likely to be delivered preterm than singletons, whether twin pregnancy alone has such adverse effects on neonatal outcomes in preterm infants remains unknown.27 In a large study of infants born between 23 and 35 weeks of gestation, twins and singletons had comparable average birth weights up to 32 weeks of gestation and similar neonatal outcomes.28 One study from Australian and New Zealand Neonatal Network has found higher mortality, but not morbidities, in twins than in singletons.12 Furthermore, two national cohort studies have reported comparable risks for neonatal outcomes except for RDS between twins and singletons.29 30 However, a population-based European cohort study showed that twins had higher risk of mortality and high-grade IVH in infants born at 24–27 weeks of gestation.14 Other studies have revealed disparities in the rate of morbidity such as BPD and ROP between twins and singletons.8 31
Possible reasons for conflicting findings in twins include study design and changes in population characteristics over time.32 We found that twins had lower rates of antenatal complications such as maternal hypertension and chorioamnionitis, and higher rates of obstetric interventions, including IVF, ACS and caesarean section than singletons in both gestational age groups (online supplemental file 2). This trend has also been observed across other recent studies.12 33 The higher rate of IVF in twins reflects the current trend of childbirth in Korea.5 The reason for higher ACS exposure in twins is currently unclear. However, more medical attention for twin pregnancies might be one possible cause.34 One noteworthy result was that the caesarean section rate for twins born between 23 and 28 weeks of gestation was 87.2% in our study, which was higher than that in other countries. For similar gestational age, the caesarean section rate for twins was 74.4% in the USA and 61.8% in Australia and New Zealand.12 15
Despite the fact that these differences in characteristics between twins and singletons are observed in other studies, an increase in the proportion of the population exposed to ACS along with variation in practice of neonatal care in each country might have complexly contributed to the interaction between ACS and plurality as well as the inherent risk of a twin pregnancy.35 Although we adjusted potential confounders which were different between twins and singletons in the analyses, different population characteristics between twins and singletons and/or between studies should be considered when interpreting our results.
Our study has several limitations. First, the KNN registry had no information about chorionicity in multiple pregnancies. Thus, we were unable to investigate the difference in the effect of ACS therapy on neonatal outcomes according to chorionicity in twins. Second, although we used prospective cohort data of preterm infants with VLBW for this study, antenatal information including ACS administration was collected retrospectively because preterm infants were enrolled after they were born. Therefore, it was unknown why ACS was not or incompletely administered in infants who did not receive a complete course of ACS therapy. Notably, the percentage of singletons without exposure to ACS was higher in this study than in other studies.36 37 Moreover, information on the total amount of ACS administered was not available in the KNN registry database. Information on total amount of ACS administered will enable a more quantitative analysis of effects of ACS therapy on neonatal outcomes. Lastly, in our cohort, 56.6% of twins were conceived via IVF whereas only 7.1% of singletons were conceived via IVF. Although preterm infants conceived via IVF are known to have comparable morbidity and mortality with their peers conceived via natural pregnancy,38 higher proportion of IVF cases among twins should be taken into account when interpreting our results.