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1.  Twin Gestation and Neuro-developmental Outcome in Extremely Low Birth Weight Infants 
Pediatrics  2009;123(2):e220-e227.
To compare the risk-adjusted incidence of death or neuro-developmental impairment at 18–22 months corrected age, between twin and singleton extremely low birth weight infants.
Twin gestation is independently associated with increased risk of death or adverse neuro-developmental outcomes at 18–22 months corrected age in extremely low birth weight infants.
Retrospective study of inborn extremely low birth weight infants (BW 401– 1000g) admitted to NICHD Neonatal Research Network units between 1997 and 2005, who either died or had follow-up data available at 18–22 months corrected age. Neuro-developmental impairment (NDI), the primary outcome variable, was defined as the presence of any one of the following: moderate or severe cerebral palsy, severe bilateral hearing loss needing amplification, bilateral blindness, Bayley Mental Developmental Index or Psychomotor Developmental Index of less than 70. Death was included with NDI as a composite outcome since it is a competing variable. Results were compared for both twins, twin A, twin B, same sex twins, unlike sex twins and singleton infants. Logistic regression analysis was done to control for demographic and clinical factors that were different among the groups.
The cohort of infants who either died or were assessed for NDI consisted of 7,630 singleton infants and 1,376 twins. Logistic regression adjusting for clinical and socio-demographic risk factors showed an increased risk of death or NDI for twins as a group when compared with the singletons (OR-1.39, 95% CI- 1.19–1.63). On analyzing twin A and B separately as well, risk of death or NDI was increased in both twin A (OR-1.32, 95% CI- 1.09–1.59) and for twin B (OR-1.47, 95% CI- 1.21–1.78), when compared with singleton infants.
Twin gestation in ELBW infants is associated with an independent increased risk of death or NDI at 18–22 months corrected age, compared to ELBW singleton gestation infants. Both first and second born twins are at increased risk of death or NDI when compared to singleton ELBW infants.
PMCID: PMC2842087  PMID: 19139085
twins; neuro-developmental impairment; extremely low birth weight infants
2.  Twins, triplets, and cerebral palsy in births in Western Australia in the 1980s. 
BMJ : British Medical Journal  1993;307(6914):1239-1243.
OBJECTIVES--To examine the rate of cerebral palsy in twins and triplets in births from 1980 to 1989 in Western Australia and to identify factors associated with increase in risk. DESIGN--Pluralities for all births in Western Australia were identified through the standardised midwives' notification system, and cases of cerebral palsy were identified from the Western Australian cerebral palsy register. MAIN OUTCOME MEASURES--Multiple births, cerebral palsy, excluding postneonatal cause. RESULTS--The prevalence of cerebral palsy in triplets, of 28 per 1000 survivors to 1 year (95% confidence interval 11 to 63) exceeded that in twins (7.3; 5.2 to 10) and singletons (1.6; 1.4 to 1.8). Although twins and triples were more likely than singletons to be low in birth weight, their risks of cerebral palsy if low in birth weight were similar. In contrast, in normal birthweight categories twins had a higher rate of cerebral palsy (4.2; 2.2 to 7.7) than singletons (1.1; 1.0 to 1.3). The prevalence of cerebral palsy was similar in twins of unlike sex pairs, all of whom are dizygotic, and in like sex pairs. A twin pair in which one member died in utero was at higher risk of cerebral palsy: 96 per 1000 twin pairs (36 to 218) compared with 12 (8.2 to 17) for twin pregnancies in which both survived. There was a similar but non-significant trend for death of one triplet to be associated with increased risk of cerebral palsy in the survivors of the set. CONCLUSION--Triplet pregnancies produced a child with cerebral palsy 47 times more often than singleton pregnancies did and twin pregnancies eight times more often. Eighty six per cent of cerebral palsy in multiple births was in twins. As multiple births are increasing mainly because of personal and medical decisions the increased risk of cerebral palsy in multiple births is of concern.
PMCID: PMC1679356  PMID: 8281055
3.  Perinatal Outcomes of Multiple Births in Southwest Nigeria 
Compared to singletons, multiple births are associated with a substantially-higher risk of maternal and perinatal mortality worldwide. However, little evidence exists on the perinatal profile and risk of neurodevelopmental disabilities among the survivors, especially in developing countries. This cross-sectional study, therefore, set out to determine the adverse perinatal outcomes that are potential markers for neurodevelopmental disabilities in infants with multiple gestations in a developing country. In total, 4,573 mothers, and their 4,718 surviving offspring in an inner-city maternity hospital in Lagos, Nigeria, from May 2005 to December 2007, were recruited. Comparisons of maternal and infant outcomes between single and multiple births were performed using multivariable logistic regression and generalized estimation equation analyses. Odds ratio (OR) and the corresponding 95% confidence interval (CI) for each marker were estimated. Of the 4,573 deliveries, there were 4,416 (96.6%) singletons and 157 (3.4%) multiples, comprising 296 twins and six triplets together (6.4% of all live 4,718 infants). After adjusting for maternal age, ethnicity, occupation, parity, and antenatal care, multiple gestations were associated with increased risks of hypertensive disorders and caesarean delivery. Similarly, after adjusting for potential maternal confounders, multiple births were associated with low five-minute Apgar score (OR: 1.47, 95% CI 1.13-1.93), neonatal sepsis (OR: 2.16, 95% CI 1.28-3.65), severe hyperbilirubinaemia (OR: 1.60, 95% CI 1.00-2.56), and admission to a special-care baby unit (OR: 1.56, 95% CI 1.12-2.17) underpinned by preterm delivery before 34 weeks (OR: 1.91, 95% CI 1.14-3.19), birthweight of less than 2,500 g (OR: 6.45, 95% CI 4.80-8.66), and intrauterine growth restriction (OR: 9.04, 95% CI 6.62-12.34). Overall, the results suggest that, in resource-poor settings, infants of multiple gestations are associated with a significantly-elevated risk of adverse perinatal outcomes. Since these perinatal outcomes are related to the increased risk of later neurodevelopmental disabilities, multiple-birth infants merit close developmental surveillance for timely intervention.
PMCID: PMC3259727  PMID: 22283038
Cross-sectional studies; Multiple gestations; Perinatal outcomes; Retrospective studies; Twins; Nigeria
4.  The Changing Risk of Infant Mortality by Gestation, Plurality, and Race: 1989–1991 Versus 1999–2001 
Pediatrics  2006;118(6):2488-2497.
Our aim was to quantify contemporary infant mortality risks and to evaluate the change by plurality, gestation, and race during the most recent decade.
The study population included live births of 20 to 43 weeks’ gestation from the 1989–1991 and 1999–2001 US Birth Cohort Linked Birth/ Infant Death Data Sets, including 11 317 895 and 11 181 095 live births and 89 823 and 67 129 infant deaths, respectively. Adjusted odds ratios and 95% confidence intervals were calculated to evaluate the change in risk by plurality and gestation and to compare the change with that for singletons.
Overall, the infant mortality risk decreased significantly for singletons, twins, and triplets but nonsignificantly for quadruplets and quintuplets. Compared with singletons, significantly greater reductions were experienced by twins overall and at <37 weeks and triplets at <29 weeks. The largest reduction was for triplets at 20 to 24 weeks and for quadruplets and quintuplets at 25 to 28 weeks. For white infants, significant reductions were achieved overall for singletons, twins, and triplets and at every gestation. For black infants, significant reductions occurred for singletons overall and at every gestation, for twins at <37 weeks, and for triplets at 25 to 28 weeks. Compared with white infants, black infants had significantly lower risks before and higher risks after 33 weeks, although between 1989–1991 and 1999–2001 this survival advantage at earlier ages diminished, and the risk at later gestations increased.
The improvements in survival were greater for multiples versus singletons and for white versus black infants. Within each plurality, at each gestation the racial disparity in mortality has widened.
PMCID: PMC3623686  PMID: 17142535
infant mortality; birth weight; gestation; plurality; racial disparities
5.  Neurodevelopmental Outcomes of Extremely Low Birth Weight Infants with Spontaneous Intestinal Perforation or Surgical Necrotizing Enterocolitis 
To determine if extremely low birth weight infants with surgical necrotizing enterocolitis have a higher risk of death or neurodevelopmental impairment and neurodevelopmental impairment among survivors (secondary outcome) at 18–22 months corrected age compared to infants with spontaneous intestinal perforation and infants without necrotizing enterocolitis or spontaneous intestinal perforation.
Study Design
Retrospective analysis of the Neonatal Research Network very low birth weight registry, evaluating extremely low birth weight infants born between 2000–2005. The study infants were designated into 3 groups: 1) Spontaneous intestinal perforation without necrotizing enterocolitis; 2) Surgical necrotizing enterocolitis (Bell's stage III); and 3) Neither spontaneous intestinal perforation nor necrotizing enterocolitis. Multivariate logistic regression analysis was performed to evaluate the association between the clinical group and death or neurodevelopmental impairment, controlling for multiple confounding factors including center.
Infants with surgical necrotizing enterocolitis had the highest rate of death prior to hospital discharge (53.5%) and death or neurodevelopmental impairment (82.3%) compared to infants in the spontaneous intestinal perforation group (39.1% and 79.3%) and no necrotizing enterocolitis/no spontaneous intestinal perforation group (22.1% and 53.3%; p<0.001). Similar results were observed for neurodevelopmental impairment among survivors. On logistic regression analysis, both spontaneous intestinal perforation and surgical necrotizing enterocolitis were associated with increased risk of death or neurodevelopmental impairment (adjusted OR 2.21, 95% CI: 1.5, 3.2 and adjusted OR 2.11, 95% CI: 1.5, 2.9 respectively) and neurodevelopmental impairment among survivors (adjusted OR 2.17, 95% CI: 1.4, 3.2 and adjusted OR 1.70, 95% CI: 1.2, 2.4 respectively).
Spontaneous intestinal perforation and surgical necrotizing enterocolitis are associated with a similar increase in the risk of death or neurodevelopmental impairment and neurodevelopmental impairment among extremely low birth weight survivors at 18–22 months corrected age.
PMCID: PMC3877158  PMID: 24135709
spontaneous intestinal perforation; necrotizing enterocolitis; extremely low birth weight; neurodevelopmental impairment
6.  Excess risk of mortality in very low birthweight triplets: a national, population based study 
Background: Neonatal morbidity and mortality differ between singletons, twins, and triplets.
Objective: To evaluate whether plurality is associated with excess risk of neonatal morbidity and poor outcome (death, chronic lung disease, or adverse neurological findings) in very low birthweight (VLBW) infants from a national, population based cohort.
Methods: The Israel national VLBW infant database has prospectively collected extensive perinatal and neonatal data on all liveborn VLBW infants since 1995. The study sample (n = 5594) consisted of all singletons (n = 3717) and all complete sets of twins (n = 1394) and triplets (n = 483) born during 1995–1999. To account for differences in case-mix, both univariate and multivariate comparisons that included confounding variables such as antenatal steroid treatment and mode of delivery were performed for each of the outcome variables.
Results: There was a small inverse correlation between gestational age (GA) and birth weight (BW) and the number of fetuses (singletons: GA 28.9 (2.6) weeks, BW 1096 (269) g; twins: GA 28.4 (2.3) weeks, BW 1062 (271) g; triplets: GA 28.5 (2.4) weeks, BW 1049 (259) g). Triplets were significantly more likely to have been conceived following fertility treatments, to have received antenatal steroids, and to be delivered by caesarean section. Respiratory distress syndrome was significantly more common in twins and triplets in spite of the increased exposure to antenatal steroids. Multivariate logistic regression analysis using all significant perinatal covariates showed that triplets were at increased risk of death (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.13 to 2.11), but not of adverse neurological outcome (OR 1.29, 95% CI 0.91 to 1.85) or chronic lung disease (OR 0.69, 95% CI 0.46 to 1.02).
Conclusion: Despite considerable differences in the incidence of confounding variables between the groups, VLBW triplets are at increased risk of death compared with twins and singletons. In addition, VLBW twins and triplets more often have respiratory distress syndrome but not chronic lung disease or adverse neurological findings.
PMCID: PMC1756005  PMID: 12496224
7.  Influence of Clinical Status on the Association Between Plasma Total and Unbound Bilirubin and Death or Adverse Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants 
To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18–22 months corrected age in extremely low birth weight infants.
Total plasma biirubin and unbound biirubin were measured in 1,101 extremely low birth weight infants at 5±1 day of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18–22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors.
Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants.
In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma and unbound bilirubin and death or adverse neurodevelopmental outcomes at 18–22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.
PMCID: PMC2875328  PMID: 20105142
Plasma bilirubin; unbound bilirubin; Extremely low birth weight infants; Neurodevelopmental outcomes
8.  Long-Term Neurodevelopmental Outcome of Monochorionic and Matched Dichorionic Twins 
PLoS ONE  2009;4(8):e6815.
Monochorionic (MC) twins are at increased risk for perinatal mortality and serious morbidity due to the presence of placental vascular anastomoses. Cerebral injury can be secondary to haemodynamic and hematological disorders during pregnancy (especially twin-to-twin transfusion syndrome (TTTS) or intrauterine co-twin death) or from postnatal injury associated with prematurity and low birth weight, common complications in twin pregnancies. We investigated neurodevelopmental outcome in MC and dichorionic (DC) twins at the age of two years.
This was a prospective cohort study. Cerebral palsy (CP) was studied in 182 MC infants and 189 DC infants matched for weight and age at delivery, gender, ethnicity of the mother and study center. After losses to follow-up, 282 of the 366 infants without CP were available to be tested with the Griffiths Mental Developmental Scales at 22 months corrected age, all born between January 2005 and January 2006 in nine perinatal centers in The Netherlands. Due to phenotypic (un)alikeness in mono-or dizygosity, the principal investigator was not blinded to chorionic status; perinatal outcome, with exception of co-twin death, was not known to the examiner.
Four out of 182 MC infants had CP (2.2%) - two of the four CP-cases were due to complications specific to MC twin pregnancies (TTTS and co-twin death) and the other two cases of CP were the result of cystic PVL after preterm birth - compared to one sibling of a DC twin (0.5%; OR 4.2, 95% CI 0.5–38.2) of unknown origin. Follow-up rate of neurodevelopmental outcome by Griffith's test was 76%. The majority of 2-year-old twins had normal developmental status. There were no significant differences between MC and DC twins. One MC infant (0.7%) had a developmental delay compared to 6 DC infants (4.2%; OR 0.2, 95% 0.0–1.4). Birth weight discordancy did not influence long-term outcome, though the smaller twin had slightly lower developmental scores than its larger co-twin.
There were no significant differences in occurrence of cerebral palsy as well as neurodevelopmental outcome between MC and DC twins. Outcome of MC twins seems favourable in the absence of TTTS or co-twin death.
PMCID: PMC2728837  PMID: 19714240
9.  Contemporary Risks of Maternal Morbidity and Adverse Outcomes With Increasing Maternal Age and Plurality 
Fertility and sterility  2007;88(2):283-293.
To evaluate the risks of pregnancy complications and adverse outcomes associated with increasing maternal age and higher plurality.
Population-based, historical cohort study.
US birth certificates and infant death certificates.
Live births of ≥20 weeks gestation between 1995-2000: 22,991,306 singleton, 316,696 twin, and 12,193 triplet pregnancies.
Main Outcome Measures:
Pregnancy-associated hypertension, incompetent cervix, tocolysis, premature rupture of membranes, excessive bleeding at delivery, delivery <29 weeks, and infant death.
Compared to singletons, the risks for all adverse outcomes among multiple pregnancies were significantly elevated and were highest for tocolysis, delivery <29 weeks, and infant mortality. Within pluralities, increasing maternal age was associated with significantly higher risks of pregnancy-associated hypertension, excessive bleeding, and incompetent cervix, but for twin and triplet pregnancies, significantly lower risks for tocolysis (ages ≥40, singleton AOR 0.97, twin AOR 0.67, triplet AOR 0.72), delivery <29 weeks (ages ≥40, singleton AOR 1.55, twin AOR 0.72, triplet AOR 0.52), and infant mortality (ages ≥40, singleton AOR 1.34, twin AOR 0.71, triplet AOR 0.42).
Older maternal age and higher plurality are each associated with increasing risks for many pregnancy complications, but with significantly lower risks of tocolysis, early preterm birth, and infant mortality.
PMCID: PMC1955760  PMID: 17258214
Maternal age; multiple pregnancy; pregnancy complications; early preterm birth; infant mortality
10.  Chorioamnionitis and Early Childhood Outcomes among Extremely Low-Gestational-Age Neonates 
JAMA pediatrics  2014;168(2):137-147.
Chorioamnionitis is strongly linked to preterm birth and to neonatal infection. The association between histological and clinical chorioamnionitis and cognitive, behavioral and neurodevelopmental outcomes among extremely preterm neonates is less clear. We evaluated the impact of chorioamnionitis on 18-22 month neurodevelopmental outcomes in a contemporary cohort of extremely preterm neonates.
To compare the neonatal and neurodevelopmental outcomes of three groups of extremely-low-gestational-age infants with increasing exposure to perinatal inflammation: no chorioamnionitis, histological chorioamnionitis alone, or histological plus clinical chorioamnionitis.
Longitudinal observational study.
Sixteen centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.
2390 extremely preterm infants born <27 weeks' gestational age between January 1, 2006 and December 31, 2008 with placental histopathology and 18-22 months' corrected age follow-up data were eligible.
Main exposure
Main Outcome Measures
Outcomes included cerebral palsy, gross motor functional limitation, behavioral scores (according to the Brief Infant-Toddler Social and Emotional Assessment), cognitive and language scores (according to the Bayley Scales of Infant Development, 3rd-Edition) and composite measures of death/neurodevelopmental impairment. Multivariable logistic and linear regression models were developed to assess the association between chorioamnionitis and outcomes while controlling for important variables known at birth.
Neonates exposed to chorioamnionitis had a lower gestational age (GA) and had higher rates of early-onset sepsis and severe periventricular-intraventricular hemorrhage as compared with unexposed neonates. In multivariable models evaluating death and neurodevelopmental outcomes, inclusion of gestational age in the model diminished the association between chorioamnionitis and adverse outcomes. Still, histological+clinical chorioamnionitis was associated with increased risk of cognitive impairment as compared with no chorioamnionitis (Adjusted OR 2.4, [1.3- 4.3] without GA; Adjusted OR 2.0, [1.1-3.6] with GA as a covariate). Histological chorioamnionitis alone was associated with lower odds of death/neurodevelopmental impairment as compared with histological+clinical chorioamnionitis (Adjusted OR 0.68, [0.52-0.89] without GA; 0.66, [0.49-0.89] with GA). Risk of behavioral problems did not differ statistically between groups.
Conclusions and Relevance
Antenatal exposure to chorioamnionitis is associated with altered odds of cognitive impairment and death/neurodevelopmental impairment in extremely preterm infants.
PMCID: PMC4219500  PMID: 24378638
chorioamnionitis; preterm; neurodevelopmental impairment; outcome
11.  The epidemiology of sudden infant death syndrome 
Background: Twins compared to singletons are at increased risk of sudden infant death syndrome (SIDS).
Aims: To compare the epidemiology of SIDS in twins and singletons and to test the hypothesis that monozygous (MZ) were at greater risk of SIDS than dizygous (DZ) twins.
Methods: Data from the Office for National Statistics on all registered live births and infant deaths with registered cause of death "sudden unexpected death in infancy" in England and Wales from 1993 to 1998 were obtained, together with the registered birth weight and, for twins, whether they were of like or unlike sex.
Results: The crude relative risk of SIDS in twins is twice that in singletons. There has been a significant temporal decline in SIDS mortality. There is also a significant increase in risk with decreasing birth weight for both twins and singletons. The birth weight specific risk of SIDS in all except for those ≥3000 g is greater in singletons than in twins. There is no significant difference in risk of SIDS in like compared with unlike sex twins.
Conclusions: In spite of a lower risk of SIDS in twins compared with singletons for each birth weight group <3000 g, one component of the higher crude relative risk of SIDS in twins is attributable to the higher proportion of twins that are of low birth weight. A second component is the higher risk in twins compared with singletons for those of birth weight ≥3000 g. Like sex are at no greater risk than unlike sex twins, which suggests that zygosity is not a significant factor in SIDS.
PMCID: PMC1719293  PMID: 12495955
12.  Hospital and neurodevelopmental outcomes of extremely low-birth-weight infants with necrotizing enterocolitis and spontaneous intestinal perforation 
We sought to determine the incidence of necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) in surviving extremely low-birth-weight (ELBW, <1000 g birth weight) infants and to establish the impact of NEC on outcomes by hospital discharge and at 18 to 22 months adjusted age in a large, contemporary, population-based practice.
Study Design
Hospital outcome data for all ELBW infants born in the greater Cincinnati region from 1998 to 2009 were extracted from the National Institute of Child Health Neonatal Research Network Database. Neurodevelopmental outcome at 18 to 22 months was assessed using Bayley Scales of Infant Development-II scores for Mental Developmental Index and Psychomotor Developmental Index. Multivariable logistic regression was used and adjusted odds ratios reported to control for confounders.
From 1998 to 2009, ELBW infants accounted for 0.5% of the 352 176 live-born infants in greater Cincinnati. The incidence of NEC was 12%, with a 50% case-fatality rate. Death before discharge, morbid complications of prematurity and neurodevelopmental impairment were all increased among infants diagnosed with NEC. Infants with surgical NEC and SIP had a higher incidence of death, but long-term neurodevelopmental outcomes were not different comparing surviving ELBW infants with medical NEC, surgical NEC and SIP.
Although ELBW infants comprise a very small proportion of live-born infants, those who develop NEC and SIP are at an increased risk for death, morbid complications of prematurity and neurodevelopmental impairment. No significant differences in neurodevelopmental outcomes were observed between the medical and surgical NEC and SIP groups.
PMCID: PMC3496418  PMID: 22157625
necrotizing enterocolitis; extremely low-birth-weight; neurodevelopmental outcome; Bayley scales of infant development
13.  Intensive Care for Extreme Prematurity — Moving Beyond Gestational Age 
The New England journal of medicine  2008;358(16):1672-1681.
Decisions regarding whether to administer intensive care to extremely premature infants are often based on gestational age alone. However, other factors also affect the prognosis for these patients.
We prospectively studied a cohort of 4446 infants born at 22 to 25 weeks' gestation (determined on the basis of the best obstetrical estimate) in the Neonatal Research Network of the National Institute of Child Health and Human Development to relate risk factors assessable at or before birth to the likelihood of survival, survival without profound neurodevelopmental impairment, and survival without neurodevelopmental impairment at a corrected age of 18 to 22 months.
Among study infants, 3702 (83%) received intensive care in the form of mechanical ventilation. Among the 4192 study infants (94%) for whom outcomes were determined at 18 to 22 months, 49% died, 61% died or had profound impairment, and 73% died or had impairment. In multivariable analyses of infants who received intensive care, exposure to antenatal corticosteroids, female sex, singleton birth, and higher birth weight (per each 100-g increment) were each associated with reductions in the risk of death and the risk of death or profound or any neurodevelopmental impairment; these reductions were similar to those associated with a 1-week increase in gestational age. At the same estimated likelihood of a favorable outcome, girls were less likely than boys to receive intensive care. The outcomes for infants who underwent ventilation were better predicted with the use of the above factors than with use of gestational age alone.
The likelihood of a favorable outcome with intensive care can be better estimated by consideration of four factors in addition to gestational age: sex, exposure or nonexposure to antenatal corticosteroids, whether single or multiple birth, and birth weight. ( numbers, NCT00063063 and NCT00009633.)
PMCID: PMC2597069  PMID: 18420500
14.  Cerebral palsy in the surviving twin associated with infant death of the co-twin 
BACKGROUND—Monozygotic twins are at greater risk of dying and of serious morbidity than dizygotic twins, and both are at greater risk than singletons. This is only partly explained by the higher proportion of low birthweight infants among twins.
AIM—To compare, in same sex and different sex twins, birth weight specific neonatal death rates and cerebral palsy prevalence rates in the surviving twin when the co-twin has died in infancy.
METHODS—Analysis of birth and death registration data for same sex and different sex twins for England and Wales 1993-1995 where both were live births. Death certificates of all liveborn twins who died were obtained from the Office for National Statistics. A questionnaire was sent to the general practitioners of all surviving co-twins to determine if the child had any disability.
RESULTS—The neonatal death rate in same sex twins was 25.4 and in different sex twins 18.0 per 1000 live births (death rate difference 7.4; 95% confidence interval 4.7 to 10.1; p < 0.001). The higher neonatal death rate in same sex compared with different sex twins is attributable to the higher proportion of same sex twins with low birth weight. Prevalence of cerebral palsy in the low birthweight group (< 1000 g) was marginally higher in same sex (224 per 1000) than different sex (200 per 1000) twin survivors. In the birth weight group 1000-1999 g, same sex twin survivors were at a significantly higher risk of cerebral palsy than those of different sex: 167v 21 per 1000; difference 145 (95% confidence interval 44 to 231; p < 0.01) per 1000 infant survivors.
CONCLUSION—There are two components to the cause of cerebral palsy in twins. Immaturity per se predisposes to cerebral damage. Also, same sex twins may sustain cerebral damage that is in excess of that due to immaturity.

PMCID: PMC1721231  PMID: 11207227
15.  Unimpaired Outcome in Extremely Low Birth Weight Infants at 18–22 Months 
Pediatrics  2009;124(1):112-121.
To identify among extremely low birth weight (≤ 1000 grams) live births, the percent of infants who are unimpaired at 18–22 months corrected age.
Unimpaired outcome was defined as both Bayley-II MDI and PDI Scores ≥ 85, a normal neurological exam, normal vision, normal hearing and normal swallowing and ambulating. Outcomes at 18–22 months were determined for 5250 (86%) of 6090 ELBW inborn infants. Group comparisons were made and regression models were developed to identify factors associated with unimpaired outcome.
Of the 5250 infants whose outcome was known at 18 months, 850 (16%) were unimpaired, 1153 (22%) had mild impairments, 1147 (22%) had moderate to severe neurodevelopmental impairments and 2100 (40%) had died. Unimpaired survival rates varied by birth weight from <1% for infants ≤ 500 grams to 24% for infants 901–1000 grams for all live births. The regression model to predict unimpaired survival versus death or impairment for live births ( n=5250) identified that 25.3% of the variance was derived from infant factors present at birth including female gender, higher birth weight, singleton, and small for gestation, and less than 2% was explained either by maternal demographic factors or selected obstetric interventions. For the 3232 infants discharged from the NICU, the unimpaired survival rate was 26%. The regression model to predict unimpaired survival for discharged infants identified that most of the variance was derived from combined effects of major neonatal morbidities, neonatal interventions, and maternal demographics (15.7%) and only 8.5% was derived from infant factors present at birth.
Although <1% of ELBW live births ≤ 500 grams survive free of impairment at 18 months this increases to almost 24% for infants 901–1000 grams. Female gender, singleton, higher birth weight, absence of neonatal morbidities, private health insurance and White race increase the likelihood of unimpaired status.
PMCID: PMC2856069  PMID: 19564290
Extremely low birth weight; outcomes; neurodevelopmental impairment
16.  Outcomes Following Candiduria in Extremely Low Birth Weight Infants 
Extremely low birth weight (ELBW) infants with candiduria are at substantial risk for death or neurodevelopmental impairment. Therefore, identification of candiduria should prompt a systemic evaluation for disseminated Candida infection and initiation of treatment in all ELBW infants.
Background. Candidiasis carries a significant risk of death or neurodevelopmental impairment (NDI) in extremely low birth weight infants (ELBW; <1000 g). We sought to determine the impact of candiduria in ELBW preterm infants.
Methods. Our study was a secondary analysis of the Neonatal Research Network study Early Diagnosis of Nosocomial Candidiasis. Follow-up assessments included Bayley Scales of Infant Development examinations at 18–22 months of corrected age. Risk factors were compared between groups using exact tests and general linear modeling. Death, NDI, and death or NDI were compared using generalized linear mixed modeling.
Results. Of 1515 infants enrolled, 34 (2.2%) had candiduria only. Candida was isolated from blood only (69 of 1515 [4.6%]), cerebrospinal fluid (CSF) only (2 of 1515 [0.1%]), other sterile site only (not urine, blood, or CSF; 4 of 1515 [0.3%]), or multiple sources (28 of 1515 [2%]). Eleven infants had the same Candida species isolated in blood and urine within 3 days; 3 (27%) had a positive urine culture result first. Most urine isolates were Candida albicans (21 of 34 [62%]) or Candida parapsilosis (7 of 34 [29%]). Rate of death or NDI was greater among those with candiduria (50%) than among those with suspected but not proven infection (32%; odds ratio, 2.5 [95% confidence interval, 1.2–5.3]) after adjustment. No difference in death and death or NDI was noted between infants with candiduria and those with candidemia.
Conclusions. These findings provide compelling evidence that ELBW infants with candiduria are at substantial risk of death or NDI. Candiduria in ELBW preterm infants should prompt a systemic evaluation (blood, CSF, and abdominal ultrasound) for disseminated Candida infection and warrants treatment.
PMCID: PMC3258271  PMID: 22144537
17.  The Effect of Plurality and Gestation on the Prevention or Postponement of Infant Mortality: 1989–1991 Versus 1999–2001 
Advances in perinatal technology that improved survival may have also resulted in prolonged death from the neonatal to the postneonatal period for some infants. The objectives of this study were to determine if the medical advances that occurred in the 1990s benefited infants of multiple births more than their singleton counterparts, and if these changes prevented or postponed mortality for the smallest and most immature infants. The study population included live births of 22 to 43 weeks’ gestation from the 1989–1991 and 1999–2001 US Birth Cohort Linked Birth/Infant Death Data Sets. Odds ratios were calculated to evaluate the change in risk by plurality, gestation, and to compare the change to that for singletons. Neonatal and infant mortality rates declined for all pluralities; postneonatal mortality increased for births at less than 26 weeks, but declined at later gestations. In general, the risk of death for twins and triplets compared to singletons decreased, and the improvement in survival was greater for multiples during the early neonatal period and overall. Infant mortality rates improved by 28% for singletons, 32% for twins and triplets during the 1990s, although for the most premature infants, some deaths were postponed from the early to the late neonatal period.
PMCID: PMC3623673  PMID: 17564510
18.  Birth Outcome in Women with Previously Treated Breast Cancer—A Population-Based Cohort Study from Sweden 
PLoS Medicine  2006;3(9):e336.
Data on birth outcome and offspring health after the appearance of breast cancer are limited. The aim of this study was to assess the risk of adverse birth outcomes in women previously treated for invasive breast cancer compared with the general population of mothers.
Methods and Findings
Of all 2,870,932 singleton births registered in the Swedish Medical Birth Registry during 1973–2002, 331 first births following breast cancer surgery—with a mean time to pregnancy of 37 mo (range 7–163)—were identified using linkage with the Swedish Cancer Registry.
Logistic regression analysis was used. The estimates were adjusted for maternal age, parity, and year of delivery. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate infant health and mortality, delivery complications, the risk of preterm birth, and the rates of instrumental delivery and cesarean section.
The large majority of births from women previously treated for breast cancer had no adverse events. However, births by women exposed to breast cancer were associated with an increased risk of delivery complications (OR 1.5, 95% CI 1.2–1.9), cesarean section (OR 1.3, 95% CI 1.0–1.7), very preterm birth (<32 wk) (OR 3.2, 95% CI 1.7–6.0), and low birth weight (<1500 g) (OR 2.9, 95% CI 1.4–5.8). A tendency towards an increased risk of malformations among the infants was seen especially in the later time period (1988–2002) (OR 2.1, 95% CI 1.2–3.7).
It is reassuring that births overall were without adverse events, but our findings indicate that pregnancies in previously treated breast cancer patients should possibly be regarded as higher risk pregnancies, with consequences for their surveillance and management.
The large majority of births from women previously treated for breast cancer had no adverse events, but such pregnancies might benefit from increased surveillance and management.
Editors' Summary
More women of all ages are developing breast cancer than ever before. In the US, one woman in eight will now develop this disease during her lifetime. For most of these women, their breast cancer diagnosis will come late in life, but a fifth of breast cancers are diagnosed before the age of 50. These days, the long-term outlook for women with breast cancer is quite good; 80% of women who receive a diagnosis of breast cancer survive more than five years. These figures, together with a trend towards starting families later in life—since the late 1970s birth rates for women in their late 30s and 40s have more than doubled in the US, and in Sweden the average age for having a first baby is now 29 years—mean that many women who have had breast cancer want to have children. One estimate is that up to 7% of women who are fertile after treatment for breast cancer will later have children.
Why Was This Study Done?
Pregnancy seems to have no adverse affects on women who have had breast cancer—there is no evidence that pregnancy can trigger a relapse. However, little is known about whether the chemotherapy and radiotherapy used to treat breast cancer have any long-lasting effects that might result in a poor birth outcome such as stillbirth, low birth weight, premature delivery, or abnormalities in the baby (congenital abnormalities). In this study, the researchers assessed the risk of adverse birth outcomes in women previously treated for breast cancer in Sweden.
What Did the Researchers Do and Find?
Nearly three million singleton births that occurred between 1973 and 2002 are recorded in the Swedish Medical Birth Registry. The researchers linked this information with that in the Swedish Cancer Registry to identify 331 first births after treatment for invasive breast cancer (cancer that has spread from where it started to grow in the breast). The birth registry includes details on maternal age and health, child's birth weight, whether the delivery was preterm, and whether the child had any congenital abnormalities, so the researchers were able to compare birth outcomes in these 331 births with those in the general population. They discovered that most births after breast cancer treatment went smoothly. There was no increase in stillbirths, but there were slightly more delivery complications in the women who had had breast cancer than in the general population, and a slight increase in babies born prematurely or with low birth weight. Finally, a few more babies with congenital abnormalities were born to women after breast cancer treatment than to women in the general population.
What Do These Findings Mean?
Overall, these results should reassure women who are thinking about having children after breast cancer about the health of their future offspring. However, they do suggest that these women may need careful monitoring during late pregnancy and delivery. This result was not predicted by the researchers who performed the study. Before starting the study, they thought that there would be no difference in birth outcomes between patients previously treated for breast cancer and the general population. Furthermore, a recently published similar study in Denmark found no increased risk of preterm birth, low birth weight, or congenital abnormalities after breast cancer. Differences between the two countries in the accuracy of their registries or in the use of chemotherapy and radiotherapy treatments may account for this difference in results. Additional studies are now needed in other populations to resolve this discrepancy and to provide more information about how breast cancer treatment might affect birth outcomes. For example, the current study did not provide any information about whether specific chemotherapy regimens or different types of breast cancer might put women at a higher risk of adverse birth outcomes, or whether the time between the cancer diagnosis and treatment and the pregnancy made a difference.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus encyclopedia entry on breast cancer
National Cancer Institute information for patients and physicians on breast cancer, including links to pages on breast cancer and pregnancy
Cancer Research UK's information on breast cancer for patients, and statistics on breast cancer in the UK
• Wikipedia page on breast cancer (note: Wikipedia is a free online encyclopedia that anyone can edit)
Royal College of Obstetricians and Gynaecologists guidelines for physicians on pregnancy and breast cancer
PMCID: PMC1564170  PMID: 16968117
19.  Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight 
It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less).
We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments.
Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 μmol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P = 0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g.
Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials. gov number, NCT00114543.)
PMCID: PMC2821221  PMID: 18971491
20.  Outcomes of Small for Gestational Age Infants < 27 Weeks’ Gestation 
The Journal of pediatrics  2013;163(1):55-60.e1-3.
To determine whether small for gestational age (SGA) infants <27 weeks gestation is associated with mortality, morbidity, growth and neurodevelopmental impairment at 18–22 months’ corrected age (CA).
Study design
This was a retrospective cohort study from National Institute of Child Health and Human Development Neonatal Research Network’s Generic Database and Follow-up Studies. Infants born at <27 weeks’ gestation from January 2006 to July 2008 were included. SGA was defined as birth weight <10th percentile for gestational age by the Olsen growth curves. Infants with birth weight ≥10th percentile for gestational age were classified as non-SGA. Maternal and infant characteristics, neonatal outcomes and neurodevelopmental data were compared between the groups. Neurodevelopmental impairment was defined as any of the following: cognitive score <70 on BSID III, moderate or severe cerebral palsy, bilateral hearing loss (+/− amplification) or blindness (vision <20/200). Logistic regression analysis evaluated the association between SGA status and death or neurodevelopmental impairment.
There were 385 SGA and 2586 non-SGA infants. Compared with the non-SGA group, mothers of SGA infants were more likely to have higher level of education, prenatal care, cesarean delivery, pregnancy-induced hypertension and antenatal corticosteroid exposure. SGA infants were more likely to have postnatal growth failure, a higher mortality and to have received prolonged mechanical ventilation and postnatal steroids. SGA status was associated with higher odds of death or neurodevelopmental impairment [OR 3.91 (95% CI: 2.91–5.25), P<0.001].
SGA status among infants <27 weeks’ gestation was associated with an increased risk for postnatal steroid use, mortality, growth failure and neurodevelopmental impairment at 18–22 months’ CA.
PMCID: PMC3947828  PMID: 23415614
extremely preterm infants; neurodevelopmental follow-up
21.  Fetal and infant death in mono- and dizygotic twins in England and Wales 1982-91 
AIM—To quantify the level of risk for stillbirth and infant death in singleton compared with twin pregnancies, using national data; to determine the independent effects of zygosity, sex, and birthweight on these risks in twin pregnancies.
METHODS—A retrospective national study was carried out of all singleton and twin birth and death registrations in England and Wales 1982-91, according to sex and birthweight group. Weinberg's rule was applied to the twin pairs to differentiate mono- from dizygotic twins. Relative risks for mono- compared with dizygous twins for both twins being stillbirths and for one of the pair being a stillbirth were determined. For twins where one was stillborn and the other live born, the relative risk of neonatal and infant mortality in the surviving co-twin was determined.
RESULTS—There were 6 563 834 registered singletons and 70772 registered twin pairs for the period under study. Monozygotic twins had a relative risk of: 18.91 (95% CI 12.48-28.64) for both twins being stillborn; 1.63 (95% CI 1.48-1.79) for one twin being a stillbirth; and 2.26 (95% CI 1.45-3.52) for the live born co-twin dying as a neonate. When both twins were live born and among singletons, the odds ratio for neonatal mortality of being male was 1.41 (95% CI 1.37-1.45) and there was a highly significant negative association with birthweight. After adjusting for birthweight group and sex, twins had a reduced neonatal mortality compared with singletons: odds ratio 0.91 (95% CI 0.85-0.96).
CONCLUSIONS—Fetal death in one of monozygotic twins has serious implications for survival of the co-twin. Monochorionicity is probably the essential feature of the increased risk to the co-twin. It is imperative that all fetal deaths in multiple pregnancies are recorded and chorionicity determined if parents are to be adequately counselled.

PMCID: PMC1720930  PMID: 10212085
22.  Retinopathy of Prematurity: Single versus Multiple-Birth Pregnancies 
To compare the frequency and severity of retinopathy of prematurity (ROP) among singleton and multiple-birth neonates referred to Farabi Eye Hospital, Tehran- Iran.
In this retrospective study, records of 99 consecutive neonates from multiplegestation pregnancies including 68 twins, 26 triplets and 5 quadruplets who were screened for ROP from 2002 to 2004 were reviewed. The frequency, severity and risk factors for ROP were determined and compared to a group of singletons who were matched in terms of gender, birth weight (BW), gestational age (GA), oxygen therapy, respiratory distress syndrome, blood transfusion, sepsis and phototherapy.
ROP was present in 12.1% of multiple-birth neonates as compared to 15.1% of singletons (P=0.53). Threshold ROP was present in 6.1% of multiple-birth neonates versus 7.1% of singletons (P=0.62). ROP was detected in 60% of quadruplets versus 9.6% of twins and triplets; threshold disease was observed in 40% of quadruplets as compared to 4.2% of twins and triplets (P<0.03). However, considering the effect of BW and GA, logistic regression analysis revealed no statistically significant difference in the frequency and severity of ROP among subgroups of multiple-gestation pregnancies.
There was no significant difference between multiple-birth neonates and matched singletons in terms of frequency and severity of ROP. Any apparent higher rate may be due to independent risk factors such as low birth weight and gestational age rather than multiple pregnancies per se. Screening for ROP in multiple gestation births may be conducted according to standard protocols applied for singletons.
PMCID: PMC3589219  PMID: 23479522
23.  Estimation of optimal birth weights and gestational ages for twin births in Japan 
BMC Public Health  2006;6:45.
As multiple pregnancies show a higher incidence of complications than singletons and carry a higher perinatal risk, the calculation of birth weight – and gestational age (GA)-specific perinatal mortality rates (PMR) for multiple births is necessary in order to estimate the lowest PMR for these groups.
Details of all reported twins (192,987 live births, 5,539 stillbirths and 1,830 early neonatal deaths) in Japan between 1990 and 1999 were analyzed and compared with singletons (10,021,275 live births, 63,972 fetal deaths and 16,862 early neonatal deaths) in the annual report of vital statistics of Japan. The fetal death rate (FDR) and PMR were calculated for each category of birth weight at 500-gram intervals and GA at four-week intervals. The FDR according to birth weight and GA category was calculated as fetal deaths/(fetal deaths + live births) × 1000. The perinatal mortality rate (PMR) according to birth weight and GA category, was calculated as (fetal deaths + early neonatal deaths)/(fetal deaths + live births) × 1000. Within each category, the lowest FDR and PMR were assigned with a relative risk (RR) of 1.0 as a reference and all other rates within each category were compared to this lowest rate.
The overall PMR per 1,000 births for singletons was 6.9, and the lowest PMR was 1.1 for birth weight (3.5–4.0 kg) and GA (40- weeks). For twins, the overall PMR per 1,000 births was 36.8, and the lowest PMR was 3.9 for birth weight (2.5–3.0 kg) and GA (36–39 weeks). At optimal birth weight and GA, the PMR was reduced to 15.9 percent for singletons, and 10.6 percent for twins, compared to the overall PMR. The risk of perinatal mortality was greater in twins than in singletons at the same deviation from the ideal category of each plurality.
PMRs are potentially reduced by attaining the ideal birth weight and GA. More than 90 percent of mortality could be reduced by attaining the optimal GA and birth weight in twins by taking particular care to ensure appropriate pregnancy weight gain, as well as adequate control for obstetric complications.
PMCID: PMC1402276  PMID: 16504133
24.  Maternal Age, Multiple Birth and Extremely Low Birth Weight Infants 
The Journal of pediatrics  2008;154(4):498-503.e2.
To compare the rates of adverse neurodevelopmental outcome or death at 18 to 22 months among extremely low birth weight (ELBW) infants born to mothers ≥ 40 years to the corresponding rates among infants of younger mothers.
Study Design
Prospective evaluation of ELBW infants to quantify the relative risks of maternal age and multiple birth for death or adverse neurodevelopmental outcome.
The sample consisted of 14,671 live ELBW births divided into maternal age groups: <20; 20–29; 30–39; and ≥ 40 years. Of infants born to mothers ≥ 40 years, 20% were multiples. Mothers ≥ 40 years had high rates of obstetrical interventions and medical morbidities compared to mothers < 40 years. ELBW live births of mothers ≥ 40 years were 22 % more likely to survive and had a 13% decreased risk of neurodevelopmental impairment or death compared to mothers< 20. Multiple birth, however, was associated with a 10 % greater risk or neurodevelopmental impairment or death.
Although mothers ≥ 40 years had high pregnancy related morbidities, we found no overall increased risk of the composite outcome of death or NDI. Multiple birth, however, was a predictor of all adverse outcomes examined, regardless of maternal age.
PMCID: PMC2834530  PMID: 19111322
outcomes; neurodevelopmental impairment; death
25.  A parsimonious explanation for intersecting perinatal mortality curves: understanding the effect of plurality and of parity 
Birth weight- and gestational age-specific perinatal mortality curves intersect when compared across categories of maternal smoking, plurality, race and other factors. No simple explanation exists for this paradoxical observation.
We used data on all live births, stillbirths and infant deaths in Canada (1991–1997) to compare perinatal mortality rates among singleton and twin births, and among singleton births to nulliparous and parous women. Birth weight- and gestational age-specific perinatal mortality rates were first calculated by dividing the number of perinatal deaths at any given birth weight or gestational age by the number of total births at that birth weight or gestational age (conventional calculation). Gestational age-specific perinatal mortality rates were also calculated using the number of fetuses at risk of perinatal death at any given gestational age.
Conventional perinatal mortality rates among twin births were lower than those among singletons at lower birth weights and earlier gestation ages, while the reverse was true at higher birth weights and later gestational ages. When perinatal mortality rates were based on fetuses at risk, however, twin births had consistently higher mortality rates than singletons at all gestational ages. A similar pattern emerged in contrasts of gestational age-specific perinatal mortality among singleton births to nulliparous and parous women. Increases in gestational age-specific rates of growth-restriction with advancing gestational age presaged rising rates of gestational age-specific perinatal mortality in both contrasts.
The proper conceptualization of perinatal risk eliminates the mortality crossover paradox and provides new insights into perinatal health issues.
PMCID: PMC166132  PMID: 12780942

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