In this retrospective cohort analysis of ELBW infants, we showed that the risk of death or NDI in triplet or higher-order multiples is higher compared with both twins and singletons. We also showed that the risk of neurodevelopmental handicap among survivors was similarly higher. To our knowledge, this is the first report of a large cohort of ELBW multiples evaluating their outcomes at 18 to 22 months' corrected age.
Previous population-based studies of very low birth weight infants have shown varying results. Shinwell et al4
analyzed a large Israeli very low birth weight registry and showed that triplets have a higher death rate compared with twins and singleton-gestation infants, after controlling for several confounding variables. They also showed a higher risk of respiratory distress syndrome in both twins and triplets compared with singletons. However, they did not show any difference in chronic lung disease or adverse neurologic findings. Adverse neurologic findings were defined as short-term outcomes of intracranial hemorrhage, periventricular leukomalacia, and posthemorrhagic hydrocephalus instead of the longer-term outcomes that we analyzed in our study. Ziadeh et al9
compared short-term outcomes of triplet pregnancies with twin pregnancies and showed a higher mortality rate in triplets. They did not show any difference in any other short-term outcomes evaluated. This study included more mature infants, however, with a mean birth weight of 1600 g in triplets and 2320 g in twins. Other studies10–15
have evaluated outcomes of triplet or higher-gestation infants in comparison to twins, but they had small sample sizes and none of them had evaluated ELBW infants exclusively. Russell et al,5
using National Center for Health Statistics data, showed that the mortality rate for very low birth weight and moderately low birth weight multiple-gestation infants was lower than for singletons in similar birth-weight categories. However, they did not evaluate ELBW infants separately. Kaufman et al16
reported experience with outcomes of multiple births from a single center. They did not show any differences in outcomes of triplets compared with twins and singletons, except for a higher incidence of retinopathy of prematurity in triplets. Their study cohort, however, was smaller than the current study, and the infants were more mature and of a higher birth weight. Sutcliffe et al17
found a higher risk of cerebral palsy and speech and language delays in multiple-birth infants compared with singletons, but their study was not restricted to ELBW infants. Similarly, Petterson et al18
showed a 47-fold-higher risk of cerebral palsy after triplet births compared with singleton infants, when using a population-based sample from western Australia that included infants of all birth-weight categories. They proposed that most of this increased risk of cerebral palsy was attributed to the tendency of multiple pregnancies to result in very low birth weight. Unlike our study, this study did not evaluate ELBW infants exclusively and did not control for factors other than multiple gestation that may impact neurodevelopmental outcomes in these infants.
In our study, we found that higher-order ELBW multiple births were more likely to be born to women who were older, of white race, and had private insurance. Mothers of these infants also were more likely to have received prenatal care and prenatal steroids. Others also have shown similar trends of higher maternal age and greater use of prenatal care and prenatal steroids in mothers with multiple pregnancies compared with singleton pregnancies.5
The reasons for these differences are not clear and may be related to multiple factors, including a higher use of artificial reproductive technologies in the triplet or higher-order multiple-birth population.
Mothers of multiples were less likely to have preeclampsia or hypertension. This may be related to hypertension or preeclampsia being the reason for an indicated extreme preterm delivery in singleton infants. Both twins and triplets or higher were more likely to receive surfactant compared with singleton ELBW infants. This finding is in agreement with the findings of Shinwell et al,4
who showed a higher incidence of respiratory distress syndrome in multiple-gestation infants despite a higher exposure to prenatal steroids in that group.
The follow-up rate of infants who were eligible for follow-up was 79% (). The percentage of infants lost to follow-up or with incomplete follow-up was similar in the 3 categories (data not shown). We also contrasted the short-term in-hospital outcomes of infants with follow-up with those with missing or incomplete follow-up. Infants with follow-up had a higher rate of severe intraventricular hemorrhage, late-onset sepsis, and necrotizing enterocolitis compared with infants who were either lost to follow-up or had incomplete follow-up. The bronchopulmonary dysplasia rates in the 2 groups were similar (data not shown).
Our study had several limitations. We did not have data on the use of artificial reproductive technology. It is likely that the rate of use of artificial reproductive technology was significantly different in the groups. Some studies19,20
have shown outcomes to be worse in infants conceived with artificial reproductive technology compared with spontaneously conceived multiple births, whereas others21,22
have shown the opposite to be true. This may have had an influence on outcomes of these infants. We similarly did not have the data on the birth order of these infants, which has been proposed by some to have an influence on outcomes in multiple births.23
We also did not have data on zygosity of the multiple birth infants, which has been proposed to have an effect on outcomes.10,20,24
The strengths of the study are the large cohort of ELBW patients and the availability of follow-up data at 18 to 22 months of age. Although ~21% of the eligible infants had either missing or incomplete follow-up data, the percentage of infants with missing or incomplete data were similar in the 3 categories.