OBJECTIVE. The purpose of this work was to compare the risk-adjusted incidence of death or neurodevelopmental impairment at 18 to 22 months’ corrected age between twin and singleton extremely low birth weight infants. We hypothesized that twin gestation is independently associated with increased risk of death or adverse neurodevelopmental outcomes at 18 to 22 months’ corrected age in these infants.
METHODS. We conducted a retrospective study of inborn extremely low birth weight infants admitted to Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network units between 1997 and 2005, who either died or had follow-up data available at 18 to 22 months’ corrected age. Neurodevelopmental impairment, the primary outcome variable, was defined as the presence of any 1 of the following: moderate or severe cerebral palsy, severe bilateral hearing loss, bilateral blindness, Bayley Mental Developmental Index or Psychomotor Developmental Index of <70. Death was included with neurodevelopmental impairment as a composite outcome. Results were compared for both twins, twin A, twin B, same-gender twins, unlike-gender twins, and singleton infants. Logistic regression analysis was performed to control for demographic and clinical factors that were different among the groups.
RESULTS. The cohort of infants who either died or were assessed for neurodevelopmental impairment consisted of 7630 singleton infants and 1376 twins. Logistic regression adjusting for clinical and sociodemographic risk factors showed an increased risk of death or neurodevelopmental impairment for twins as a group when compared with the singletons. On analyzing twin A and B separately as well, risk of death or neurodevelopmental impairment was increased in both twin A and twin B.
CONCLUSIONS. Twin gestation in extremely low birth weight infants is associated with an independent increased risk of death or neurodevelopmental impairment at 18 to 22 months’ corrected age compared with singleton-gestation infants. Both first- and second-born twins are at increased risk.
Population-based studies from large databases have shown a fivefold higher risk of cerebral palsy (CP) in twins as compared with CP rates in singletons.1 Comparison of term twins with singleton pregnancies has been shown to be associated with a higher perinatal mortality and morbidity.2 The relationship between birth order of twins and adverse outcomes, with more adverse outcomes among second-born twins, has been proposed by some authors3 but refuted by others.4–6 Previous studies have proposed that there is a slowing of in utero growth in twins after 30 weeks’ gestation, and the increased rate of CP in twins may apply only to infants closer to term gestation.7 A Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) network study reported that the short-term neonatal outcomes of very low birth weight twins (birth weight: <1500 g) are similar to singleton infants in the same birth weight category.8 Wolf et al9 showed similar results for short-term morbidities in very low birth weight twins and singletons. Others have studied growth-restricted twins and singletons and shown that the neonatal outcomes, although worse as compared with nongrowth-restricted infants, were similar in the 2 groups.10 To our knowledge, there has been no report on the neurodevelopmental outcome of extremely low birth weight (ELBW) infants with reference to twin pregnancy. This retrospective cohort study was designed to compare the short-term neonatal outcomes during hospital stay and 18- to 22-month neurodevelopmental outcomes of twin in comparison with the singleton ELBW infants.
This is a retrospective cohort study of ELBW infants admitted to 16 NICUs in the NICHD Neonatal Research Network during calendar years 1997–2005. The primary hypothesis was that, in ELBW infants, twin gestation is associated with an increased risk of death or adverse neurodevelopmental outcome at 18 to 22 months’ corrected age.
Infants with a birth weight between 401 and 1000 g were included in the study. The cohort consisted of 10 559 singleton and twin infants admitted to the network centers during the study period, who were inborn, met the weight criteria, and survived beyond 12 hours after birth. Of these, 9006 infants had data on survival and follow-up at 18 to 22 months’ corrected age available for analysis (Fig 1). A total of 1859 infants were excluded from the study because of death before 12 hours of life. Of these, 1493 were singletons and 360 were twins. If 1 of the set of twins died before 12 hours of age, both twins were excluded from analysis. Triplets and higher-order multiple births were excluded from the study.
Infants were analyzed as twin and singleton cohorts. Within the twin category, the infants were further analyzed as firstborn twins (twin A) versus singletons and second-born twins (twin B) versus singletons. Separate analyses were also conducted on same-gender twins and unlike-gender twins. Data on maternal and infant demographic and clinical characteristics were abstracted from medical charts. All of the centers participating in the Neonatal Research Network received local institutional review board approval for data collection. Trained research coordinators obtained the data based on pre-specified definitions listed in the manual of operations.
A comprehensive 18- to 22-months’ corrected age evaluation for survivors consisted of the following evaluations: neurologic, hearing, vision, and development. A neurologic examination based on the Amiel-Tison assessment was administered.11 The assessment was performed by certified examiners and included an evaluation of tone, strength, reflexes, angles, and posture. CP was defined as a nonprogressive central nervous system disorder characterized by abnormal muscle tone in ≥1 extremity and abnormal control of movement and posture.
Hearing status was obtained by parental history or from audiologic test results, when available. Deafness was defined as the need for bilateral amplification. A history of eye examinations and procedures since initial discharge was obtained, and a standard eye examination was completed. Blindness was defined as bilateral corrected vision of <20/200.
The Bayley Scales of Infant Development-II was administered, and the Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) were derived. Scores of 100 ± 15 represent the mean ± 1 SD, with a score <70 (≥2 SDs below the mean) indicating significant delay. Children who could not be assessed because of severe developmental delay were assigned MDI and PDI scores of 49.
Outcomes were analyzed in relation to specific maternal and neonatal demographic and clinical variables. The primary outcome was death or neurodevelopmental impairment (NDI) at 18 to 22 months’ corrected age. NDI was defined as the presence of any 1 of the following: CP, bilateral blindness, bilateral hearing loss needing amplification, MDI <70, or PDI <70. Death occurring after 12 hours of age and before follow-up assessment was included in our composite primary outcome measure because it is a competing outcome for NDI in this high-risk ELBW population.
The rates of death or NDI, death, and NDI among survivors were compared among singletons, twins as a group, twin A, twin B, same-gender twins, and unlike-gender twins. Maternal and infant demographic and clinical characteristics were similarly compared between these groups. Logistic regressions were used to test for risk-adjusted differences between these groups. For our primary hypothesis, we performed adjusted logistic regression to determine the association of twin status with death or NDI, controlling for maternal and neonatal factors and short-term outcomes that were significantly different between the 2 groups. Birth weight, gestation, small for gestation status (weight <10th percentile for gestation), male gender, race, antenatal steroids, early or late onset sepsis, respiratory distress, early indomethacin therapy, bronchopulmonary dysplasia, steroids for bronchopulmonary dysplasia, and severe intraventricular hemorrhage (IVH grade 3 or 4)/periventricular leukomalacia (PVL) were included in the model. Birth weight in grams was divided by 100, so the odds ratio (OR) represents a 100-g increase in birth weight. Similar analysis was done for twin A and B status and same and unlike gender in separate logistic regression models. All of the other variables included were the same. The data were analyzed in clusters to account for correlated outcomes from the same-twin pair, using generalized estimating equations. These adjusted logistic regression analyses, presented in Figs 2 through 4, were performed by using SUDAAN software 9.0.3 (RTI International, Research Triangle Park, NC). RTI International performed the statistical analyses. A P value of <.05 was considered significant.
A total of 9006 infants had data on survival or follow-up available and were enrolled in the study (Fig 1). The cohort consisted of 7630 singleton infants and 1376 twins, of whom 686 were twin A and 690 were twin B. Survival to hospital discharge was higher for singleton infants as compared with twins. A total of 7068 (78.8%) of 8965 singletons as compared with 584 (73.3%) of 797 twin A subjects and 561 (70.4%) of 797 twin B subjects survived to hospital discharge (Fig 1). Compliance rates for those available for follow-up were 87% for singleton subjects and 89% and 87% for twins A and B, respectively. Table 1 depicts the clinical and demographic characteristics of the study groups. There were approximately twice as many same-gender twins as compared with unlike-gender twins. A greater proportion of twins analyzed as the twin, twin A or twin B, and same-gender twin were male as compared with singleton infants. The mean birth weight and gestational age for twins (including same gender or unlike gender) were lower than for singleton infants. Twins were less likely to be small for gestation as compared with singleton infants. A higher proportion of white infants were likely to be born as a result of twin gestation as compared with black or Hispanic infants. Preeclampsia/hypertension was more common as a pregnancy complication in mothers of singletons. As compared with singletons, twins were more likely to develop sepsis, respiratory distress syndrome, and patent ductus arteriosus. They were more likely to receive surfactant and early indomethacin therapy. There was no difference in the administration of antenatal steroids. Mothers of twins were more likely to have received less than high school education.
Table 2 depicts short-term outcomes of the study infants. The incidence of bronchopulmonary dysplasia, defined as the need for supplemental oxygen at 36 postconceptional weeks of gestation, was higher in twins (P < .001). Similarly, the incidence of grade 3 or 4 IVH and PVL was higher in twins (P < .001) as compared with singleton infants. The incidence of severe retinopathy of prematurity was also higher among twins (P < .001). Twins had a higher rate of these morbidities as compared with singleton infants, even when they were analyzed separately as twin A, twin B, same-gender twin, or unlike-gender twin.
Table 3 shows the 18- to 22-month follow-up outcomes of study infants. The incidence rates for death or NDI and NDI among survivors were higher in twins as compared with singleton infants. The rates of low MDI and PDI were also higher in twins. The rate of moderate-to-severe CP was, however, higher in twin B but did not attain a statistically significant difference in twin A as compared with singletons.
On adjusted logistic regression analysis (Fig 2), the risk for death or NDI in twins was increased as compared with singleton infants (OR: 1.39 [95% confidence interval (CI): 1.19–1.63]). When twins were analyzed separately as twin A or twin B (Fig 3), the risk of death or NDI was increased in both twin A (OR: 1.32 [95% CI: 1.09–1.59]) and twin B (OR: 1.47 [95% CI: 1.21–1.78]). On analyzing twins separately as same-gender (OR: 1.41 [95% CI: 1.17–1.71]) or unlike-gender twins (OR: 1.36 [95% CI: 1.06–1.74]), risk for death or NDI was similarly increased in twins (Fig 4). Other variables found to be significant were higher birth weight and antenatal steroids, which reduced the risk of death or NDI, whereas male gender, early or late-onset sepsis, and the presence of grade 3 or 4 IVH or PVL increased the risk of death or NDI.
There has been a large increase in the number of multiple births over the past 2 decades.12 This is associated with an increasing concern that twin gestation may be associated with a higher long-term morbidity rate. Multiple gestation is associated with a higher prematurity rate and a higher incidence of low birth weight. Infants born as a result of multiple gestation have been shown to have a higher incidence of adverse outcomes, including a higher mortality rate.13,14 Other studies have shown an increase in the prevalence of CP in twins, as compared with the overall population rate.15 This is consistent with our data, which identified a higher rate of moderate-to-severe CP in twin B survivors. Whether this increased adverse outcome rate is simply a result of prematurity and a lower birth weight or a result of an independent influence of multiple gestation or being the second-born twin is not clear. The fact that our association was adjusted for gestation and birth weight suggests that this association is more likely a result of being born in multiple gestation rather than because of prematurity alone. Luke et al16 performed a case-control study comparing twins with gestation-matched controls. They showed no difference in morbidity, length of stay, or cost of care between twins and gestation-matched singletons of <34 weeks’ gestation. However, their study evaluated a more mature cohort of infants as compared with our study, which included only ELBW infants.
A higher neonatal adverse outcome rate was not seen when very low birth weight twin and singleton infants were studied adjusting for birth weight using the NICHD database.8 In our study, however, we did find a higher rate of grade 3 or 4 IVH and PVL in twins compared with ELBW singletons. The 2 studies differ in population (birth weight <1000 g for our series and <1500 g for the study by Donovan et al8) and time era (1997–2005 in ours and 1991–1993 in the study by Donovan et al8), which may account for the discrepancy in findings.
In this retrospective study, we compared the incidence of death or NDI between ELBW twins and singletons and found a higher risk of this composite outcome in twin ELBW infants. Analyses of twins A and B separately showed that there was a higher risk of the composite outcome of death or NDI in both twins as compared with singleton infants. This finding adds to the controversy regarding the outcomes of twins with reference to birth order.3–6 In our study, twin B survivors had the highest rates of low PDI and moderate-to-severe CP. Twin A survivors, on the other hand, did not have a higher incidence of moderate-to-severe CP when compared with ELBW singleton infants. These differences may be explained by the differences in the characteristics of infants, because the combined risk of death or NDI after controlling for confounding factors was higher in twins overall as compared with singleton infants.
We restricted our analysis to only inborn ELBW infants to achieve a more homogenous group of study infants and to exclude the possible influence of varying resuscitation practices in referring institutions of outborn infants. There were, however, differences in several characteristics among the study groups. We controlled for these differences by adjusting for these factors in the logistic regression analysis. The retrospective nature of this study does not allow further exploration of this issue.
Infants included in this analysis had a good follow-up rate. Of the infants who were eligible for follow-up, ∼87% were followed up at 18 to 22 months’ corrected age. We also compared short-term morbidities of infants who were followed up and those who were lost to follow-up. There were no consistent differences in these short-term morbidities in the 2 groups, which makes it unlikely that the results of this study were influenced by the infants who were lost to follow-up (data not shown).
Using the Israeli national very low birth weight registry, Shinwell et al17 reported an increased rate of adverse neonatal neurologic outcomes in twins compared with singletons. They defined adverse neurologic outcome as severe IVH, periventricular leukomalacia, and posthemorrhagic hydrocephalus; they did not report postdischarge neurodevelopmental outcomes. Our study finding of higher rates of IVH grades 3 to 4 and PVL is in agreement with their results. In addition, we found higher rates of death or NDI in ELBW twins compared with ELBW singletons. We also found a higher survival to discharge for ELBW singletons as compared with twins. Infants dying within the first 12 hours of birth were excluded to control for the possible influence of varying attitudes toward resuscitation among different centers.
Fetal zygosity has been proposed to have an influence on outcomes of twins, with monozygous twins suffering more adverse outcomes. Of the monozygous twins, monochorionic twins are proposed to have outcomes that are worse than dichorionic twins.18 Because this is a retrospective study, the information on chorionicity of twins is lacking. However, we did compare same-gender with unlike-gender twins as a surrogate of chorionicity, based on the premise that a significant percentage of same-gender twins may have had monochorionic placentation, whereas that will never be the case in unlike-gender twins. We found that the risk of death or NDI was increased in both same-gender twins and unlike-gender twins when compared with singleton infants in our study (Fig 4). Thus, although using our surrogate parameter is not ideal to indicate chorionicity, the lack of difference may suggest that chorionicity is not a factor in the neurodevelopmental outcome in ELBW twins.
Preterm higher-order multiples have been shown to have short-term outcomes that are worse than preterm twins.17,19 However, we excluded triplets and higher-order multiples form our study because of the potential of making the study very confusing with multiple comparisons.
Our study has the following limitations: it is a retrospective analysis, and important variables that might affect outcomes, such as zygosity, mode of conception,7,20,21 and twin-twin transfusion syndrome,22,23 were not available. Although some studies have shown a higher incidence of NDI in twins conceived by assisted reproductive technology as compared with naturally conceived twins,24 others have shown the opposite to be true.25 There were no data available on the acuity of illness of these infants that may have had an impact on their long-term outcomes. The strength of this study is a large cohort of ELBW infants with both neonatal and 18- to 22-month follow-up data.
Our data indicate a higher risk of death or NDI in ELBW twin infants, independent of the influence of prematurity and birth weight. This fact should be included in discussions when counseling families of multiple-gestation ELBW infants about long-term outcomes.
This work was supported by grants from the NICHD (U10 HD53124, U10 HD53119, U10 HD53109, U10 HD53089, U10 HD40689, U10 HD40521, U10 HD40498, U10 HD40492, U10 HD40461, U10 HD34216, U10 HD34167, U10 HD27904, U10 HD27881, U10 HD27880, U10 HD27871, U10 HD27856, U10 HD27853, U10 HD27851, U10 HD21415, U10 HD21397, U10 HD21385, U10 HD21373, U10 HD21364, and U01 HD36790) and the National Institutes of Health (CCTS UL1 RR24128, CCTS UL1 RR24148, GCRC M01 RR30, GCRC M01 RR32, GCRC M01 RR39, GCRC M01 RR44, GCRC M01 RR54, GCRC M01 RR59, GCRC M01 RR64, GCRC M01 RR70, GCRC M01 RR80, GCRC M01 RR633, GCRC M01 RR750, GCRC M01 RR997, GCRC M01 RR1032, GCRC M01 RR2172, GCRC M01 RR2588, GCRC M01 RR2635, GCRC M01 RR6022, GCRC M01 RR7122, GCRC M01 RR8084, and GCRC M01 RR16587).
The following investigators participated in the NICHD Neonatal Research Network's Generic Database (1997–2001) and Follow-up Studies (1998–2003): Chair: Alan Jobe, MD, PhD, University of Cincinnati; Brown University, Women and Infants Hospital of Rhode Island: William Oh, MD; Betty R. Vohr, MD; Angelita Hensman, BSN, RNC; Lucy Noel RN; Case Western Reserve University, Rainbow Babies and Children's Hospital: Avroy A. Fanaroff, MB, BCh; Deanne Wilson-Costello, MD; Nancy S. Newman, BA, RN; Bonnie S. Siner, RN; Duke University, University Hospital, Alamance Regional Medical Center, Duke Raleigh Hospital, and Durham Regional Hospital: Ronald N. Goldberg, MD; Ricki Goldstein, MD; Kathy Auten, BS; Melody Lohmeyer, RN; Emory University, Grady Memorial Hospital, Emory Crawford Long Hospital, and Children's Healthcare of Atlanta: Barbara J. Stoll, MD; Ira Adams-Chapman, MD; Ellen Hale, RN, BS; Harvard Medical School, Brigham and Women's Hospital: Ann R. Stark, MD; Kimberly Gronsman Lee, MD; Kerri Fournier, RN; Colleen Driscoll; Indiana University, Indiana University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services: James A. Lemons, MD; Anna M. Dusick, MD; Diana D. Appel, RN, BSN; Dianne Herron, RN; Lucy Miller, RN, BSN, CCRC; Leslie Dawn Wilson, RN, BSN; NICHD: Linda L. Wright, MD; Elizabeth M. McClure, Med; Research Triangle Institute: W. Kenneth Poole, PhD; Betty Hastings; Stanford University, Dominican Hospital, El Camino Hospital, and Lucile Packard Children's Hospital: David K. Stevenson, MD; Susan R. Hintz, MD, MS; Barry E. Fleisher, MD; M. Bethany Ball, BS, CCRC; University of Alabama at Birmingham, Health System and Children's Hospital of Alabama: Waldemar A. Carlo, MD; Myriam Peralta-Carcelen, MD; Monica V. Collins, RN, BSN; Shirley S. Cosby, RN, BSN; Vivien Phillips, RN, BSN; University of California, San Diego, Medical Center and Sharp Mary Birch Hospital for Women: Neil N. Finer, MD; Yvonne E. Vaucher, MD, MPH; Maynard R. Rasmussen MD; Kathy Arnell, RN; Clarence Demetrio, RN; Martha G. Fuller, RN, MSN; Chris Henderson, RCP, CRTT; University of Cincinnati, University Hospital, Cincinnati Children's Hospital Medical Center, and Good Samaritan Hospital: Edward F. Donovan, MD; Jean Steichen, MD; Barb Alexander, RN; Cathy Grisby, BSN, CCRC; Marcia Mersmann, RN; Holly Mincey, RN; Jody Shively, RN; Teresa Gratton, PA; University of Miami, Holtz Children's Hospital: Shahnaz Duara, MD; Charles R. Bauer, MD; Ruth Everett, RN, BSN; University of New Mexico Health Sciences Center: Lu-Ann Papile, MD; Conra Backstrom Lacy, RN; University of Rochester, Golisano Children's Hospital at Strong: Dale L. Phelps, MD; Gary Myers, MD; Linda Reubens, RN; Diane Hust, RN, PNP; Rosemary Jensen; Erica Burnell, RN; University of Tennessee: Sheldon B. Korones, MD; Henrietta S. Bada, MD; Tina Hudson, RN, BSN; Kim Yolton, PhD; Marilyn Williams, LCSW; University of Texas Southwestern Medical Center at Dallas, Parkland Health and Hospital System, and Children's Medical Center Dallas: Abbot R. Laptook, MD; R. Sue Broyles, MD; Roy J. Heyne, MD; Susie Madison, RN; Jackie Hickman, RN; Sally Adams, PNP; Linda Madden, PNP; Elizabeth Heyne, PA; University of Texas at Houston, Health Science Center, and Children's Memorial Hermann Hospital: Jon E. Tyson, MD, MPH; Brenda H. Morris, MD; Pamela J. Bradt, MD, MPH; Esther G. Akpa, RN, BSN; Patty A. Cluff, RN; Anna E. Lis, RN, BSN; Georgia McDavid, RN; Wake Forest University, Baptist Medical Center, Forsyth Medical Center, and Brenner Children's Hospital: T. Michael O'Shea, MD, MPH; Robert Dillard, MD; Nancy Peters, RN; Barbara Jackson, RN, BSN; Wayne State University, Hutzel Women's Hospital, and Children's Hospital of Michigan: Seetha Shankaran, MD; Yvette Johnson, MD; Rebecca Bara, RN, BSN; Geraldine Muran, RN, BSN; Debbie Kennedy, RN; Yale University, Yale-New Haven Children's Hospital: Richard A. Ehrenkranz, MD; Patricia Gettner, RN; Monica Konstantino, RN; Elaine Romano, RN.
We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study.
- Accepted October 8, 2008.
- Address correspondence to Rajan Wadhawan, MD, All Children's Hospital, 880 Sixth St South, Suite 470, St Petersburg, FL 33701. E-mail:
The authors have indicated they have no financial relationships relevant to this article to disclose.
What's Known on This Subject
Short-term outcomes of very low birth weight twins are known to be worse than those of very low birth weight singletons.
What This Study Adds
This study adds to the literature on long-term outcomes of twins compared with singleton infants in the ELBW category. This is a study of a large cohort of infants in this birth weight category.
- ↵Doyle P. The outcome of multiple pregnancy. Hum Reprod.1996;11 (suppl 4):110– 117; discussion 8–20
- ↵Shinwell ES, Blickstein I, Lusky A, Reichman B. Excess risk of mortality in very low birthweight triplets: a national, population based study. Arch Dis Child Fetal Neonatal Ed.2003;88 (1):F36– F40
- ↵Minakami H, Sayama M, Honma Y, et al. Lower risks of adverse outcome in twins conceived by artificial reproductive techniques compared with spontaneously conceived twins. Hum Reprod.1998;13 (7):2005– 2008
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