Prophylactic indomethacin in extremely premature infants between 23 and 24 weeks gestation

Background: In extremely premature infants, the presence of a left‐to‐right shunt through a patent ductus arteriosus (PDA) increases the risks of pulmonary hemorrhage, intraventricular hemorrhage, necrotizing enterocolitis, renal failure, and chronic lung disease. Conservative management induces spontaneous ductus closure in <20% of extremely premature infants (infants born at <25 weeks of gestation). The aim of the present study was to determine the efficacy and safety of prophylactic indomethacin (INDO) administration for PDA closure in extremely premature infants born between 23 and 24 weeks of gestation. Methods: A historical case–control study of 30 infants born between 23 and 24 weeks of gestation was carried out. In the prophylactic INDO group, a 12 h‐long, 0.01 mg/kg per h dose of INDO was administered within 6 h of life. During the historical control period, only infants with symptomatic PDA were treated with INDO for 1 h. The incidence of symptomatic PDA, mortality and early neonatal morbidity was compared between the two groups on Fisher's exact test and Mann–Whitney rank–sum test. Results: None of the infants in the prophylactic INDO group had symptomatic PDA, while 11 of the 15 infants in the control group showed symptomatic PDA (P < 0.001). There were no significant differences between the mortality rates and the early neonatal morbidities in the two groups. Conclusions: Prophylactic INDO administration to extremely premature infants born between 23 and 24 weeks of gestation decreased the incidence of symptomatic PDA without increasing the incidence of adverse effects.     

Incidence of and risk factors for neonatal morbidity after active perinatal care: extremely preterm infants study in Sweden (EXPRESS)

Aims: The aim of this study was to determine the incidence of neonatal morbidity in extremely preterm infants and to identify associated risk factors. Methods: Population based study of infants born before 27 gestational weeks and admitted for neonatal intensive care in Sweden during 2004–2007. Results: Of 638 admitted infants, 141 died. Among these, life support was withdrawn in 55 infants because of anticipation of poor long‐term outcome. Of 497 surviving infants, 10% developed severe intraventricular haemorrhage (IVH), 5.7% cystic periventricular leucomalacia (cPVL), 41% septicaemia and 5.8% necrotizing enterocolitis (NEC); 61% had patent ductus arteriosus (PDA) and 34% developed retinopathy of prematurity (ROP) stage ≥3. Eighty‐five per cent needed mechanical ventilation and 25% developed severe bronchopulmonary dysplasia (BPD). Forty‐seven per cent survived to one year of age without any severe IVH, cPVL, severe ROP, severe BPD or NEC. Tocolysis increased and prolonged mechanical ventilation decreased the chances of survival without these morbidities. Maternal smoking and higher gestational duration were associated with lower risk of severe ROP, whereas PDA and poor growth increased this risk. Conclusion: Half of the infants surviving extremely preterm birth suffered from severe neonatal morbidities. Studies on how to reduce these morbidities and on the long‐term health of survivors are warranted.     

Neonatal antecedents for cerebral palsy in extremely preterm babies and interaction with maternal factors

BACKGROUND: Preterm delivery is associated with an increased risk of cerebral palsy (CP). The greatest risk is for infants born <28 weeks' gestation. AIMS: To identify significant neonatal risk factors for CP and explore the interactions between antenatal and neonatal risk factors, among extremely preterm infants of 27 weeks' gestation or less. STUDY DESIGN: Nested case control design. METHODS: Infants born between 1989 and 1996, at 24-27 weeks' gestation, were evaluated: 30 with CP at 2 years corrected age and 120 control infants matched for gestation age. Neonatal variables were compared using matched analyses with the interaction between antenatal and neonatal factors being examined using logistic regression analyses. RESULTS: Risk factors for CP on matched analyses included patent ductus arteriosus requiring surgical ligation, peri-intraventricular haemorrhage, moderate to severe ventricular dilatation, periventricular leukomalacia (PVL) and need for home oxygen. Independent neonatal predictors were ventricular dilatation (OR 7.3; 95% CI 1.6, 32.3), PVL (OR 29.8; 95% CI 5.6, 159.1) and home oxygen use (OR 3.4; 95% CI 1.2, 9.4). No interaction terms in the logistic models were significant between the previously identified pregnancy risk factors of absence of antenatal steroids and intrauterine growth restriction and the neonatal risk factors. CONCLUSIONS: PVL is the most powerful independent predictor of CP in extremely preterm infants of 27 weeks' gestation or less and appears to be uninfluenced by antenatal factors.     

Patent ductus arteriosus and retinopathy of prematurity in infants below 27 weeks gestation

Retrospective study of infants who survived the neonatal period after delivery at 24–26 weeks gestation revealed patency of the ductus arteriosus (PDA) in 44%. The mean birthweight of infants who developed PDA was lower. Retinopathy of prematurity (ROP) was seen in 79% of survivors with 24% having grade III or IV involvement. All but one of the more severe grades of ROP occurred among infants with PDA. Infants with PDA required more prolonged ventilatory support. Perinatal factors did not have a significant role in the development of these complications.     

Patent ductus arteriosus and retinopathy of prematurity in infants below 27 weeks gestation

Retrospective study of infants who survived the neonatal period after delivery at 24-26 weeks gestation revealed patency of the ductus arteriosus (PDA) in 44%. The mean birthweight of infants who developed PDA was lower. Retinopathy of prematurity (ROP) was seen in 79% of survivors with 24% having grade III or IV involvement. All but one of the more severe grades of ROP occurred among infants with PDA. Infants with PDA required more prolonged ventilatory support. Perinatal factors did not have a significant role in the development of these complications.     

Variation in mortality and intraventricular haemorrhage in occupants of Pacific Rim nurseries

OBJECTIVE: A network of neonatal intensive care units in Pacific Rim countries was formed to compare infant risk factors, clinical practices, and outcomes for very low birthweight infants. METHODOLOGY: A multicentre, prospective study compared outcomes for infants born smaller than 1501 g or at less than 31 weeks gestation. RESULTS: Gestational age-specific survival and incidence of intracranial haemorrhage varied for infants born in these nurseries. We found differences in infant risk factors among the nurseries. There were also significant differences in the use of antenatal steroids, but similar rates for Caesarean section and surfactant treatment. The factor most predictive of neonatal death and severe intracranial abnormality was an elevated Clinical Risk Index for Babies (CRIB) score. Antenatal steroid treatment (>24 h prior to delivery) was associated with improved survival and decreased incidence of severe intracranial abnormalities. Antenatal steroid treatment for less than 24 h prior to delivery was not associated with improved survival. Caesarean delivery was associated with improved survival, but showed no benefit regarding the incidence of severe intracranial abnormality. CONCLUSIONS: Our Pacific Rim nursery network found differences in neonatal outcomes that correlated best with measures of neonatal risk at birth, antenatal steroid treatment, and Caesarean delivery. These data emphasize the importance of obstetric care to improve postnatal outcomes in premature infants, and highlight the usefulness of CRIB scores in these patients.     

Prenatal predictors of mortality in very preterm infants cared for in the Australian and New Zealand Neonatal Network

AIM: To identify antenatal and perinatal risk factors for in-hospital mortality of babies born within the Australian and New Zealand Neonatal Network (ANZNN). METHODS: Data were collected prospectively as part of the ongoing audit of high-risk infants (birth weight <1500 g or gestation <32 weeks) admitted to all level III neonatal units in Australia and New Zealand. Antenatal and intrapartum factors to 1 min of age were examined in 11 498 infants with gestational age >24 weeks. Risk and protective factors for mortality were derived from logistic regression models fitted to 1998-9 data and validated on 2000-1 data. RESULTS: For the whole cohort of infants born between 1998 and 2001, prematurity was the dominant risk factor, infants born at 25 weeks having 32 times greater odds of death than infants born at 31 weeks. Low birth weight for gestational age also had a dose-response effect: the more growth restricted the infant the greater the risk of mortality; infants below the 3rd centile had eight times greater odds of death than those between the 25th and 75th centiles. Male sex was also a significant risk factor (odds ratio (OR) 1.55, 95% confidence interval (CI) 1.31 to 1.82). Maternal hypertension in pregnancy was protective (OR 0.46, 95% CI 0.36 to 0.50). The predictive model for mortality had an area under the receiver operating characteristic curve of 0.82. CONCLUSIONS: Risk of mortality can be predicted with good accuracy with factors up to the 1 min Apgar score. By using gestation rather than birth weight as the main indicator of maturity, these data confirm that weight for gestational age is an independent risk factor for mortality.     

Impact of extremely immature infants on neonatal services.

The impact of very immature infants on neonatal services was examined within the United Kingdom. The Trent Health Region was used as a geographically defined population. Data were obtained on all infants weighing less than 1501 g at birth and all infants born before 32 weeks gestation between 1991-93. Information relating to length of stay, duration of ventilation, and survival was documented. Only one of 49 infants born before 24 weeks gestation survived. However, 75% of this group were ventilated. Most of the remaining infants died before 48 hours of age. A similar pattern was also seen in infants of 24 and 25 weeks gestation. Infants under 24 weeks gestation comprised 1.5% of all ventilated infants and consumed 2.14% of the total neonatal ventilator days for the region. It is concluded that the United Kingdom operates a conservative policy towards infants born before 24 weeks gestation and as a result resources expended on them are limited.     

The Swedish national prospective study on extremely low birthweight (ELBW) infants. Incidence, mortality, morbidity and survival in relation to level of care

In a 2-year (1990-92) prospective national investigation, comprising all stillborn and live-born ELBW infants with a birthweight of ≤1000 g born at 23 completed weeks of gestation or more, we examined the incidence, neonatal mortality, major morbidity and infant survival in relation to level of care and place of residence. A total of 633 ELBW infants were live-born, i.e. 0.26% of all live-born infants, and 298 were stillborn. The average neonatal mortality was 37% and 91% at 23 weeks, 70% at 24 weeks, and 40% at 25 weeks of gestation. Of neonatal survivors, 8% had intraventricular haemorrhage grade 3,10% retinopathy of prematurity of stage ≥3, 2% necrotizing enterocolitis, and 28% were oxygen-dependent at a time corresponding to 36 weeks of gestation. In all, 77% were treated with mechanical ventilation, whereas 19% survived without, almost all of them being CPAP treated. Infant mortality among infants born at level III (tertiary centres) was 30%, at level Ha (with full perinatal service) 46% and at level IIb (with basic neonatal service) 55 %. Only 1 % was born at hospital level I. Regarding the relation to place of residence, the mortality rates among infants residing in the areas served by levels III, IIa and lib hospitals were 36%, 45% and 41%, respectively. The referral system thus functioned well, but can be improved, and increased perinatal referral, at borderline perinatal viability, might provide a better quality of care and a better chance of survival.     

Ultrasound findings and clinical antecedents of cerebral palsy in very preterm infants.

OBJECTIVE: To investigate the incidence and timing of neonatal ultrasound lesions, and clinical details about pregnancy and the perinatal period, in a total population of extremely premature children with cerebral palsy, born to mothers who were resident in Oxfordshire. METHODS: Eighteen children born at less than 32 completed weeks of gestation were identified from a regional cerebral palsy register. Eighteen controls were matched for gestation, time, and place of birth. Perinatal records and ultrasound reports were systematically reviewed. Sequential neonatal ultrasound images stored on videotape were reanalysed, blind to the outcome of the infants. RESULTS: Sixteen (89%) of the cerebral palsy cases and one (6%) control had parenchymal cysts on neonatal brain scans. Of the cerebral palsy cases, none had cysts detectable on the first day. Six developed cysts within the first 10 days of life, and two of these had periventricular echodensities when first scanned postnatally. Antenatal complications were recorded in 16 cases and nine controls. The early postnatal appearance of cysts in a few babies with a history of severe antenatal complications suggested that antenatal factors may have contributed to the cerebral pathology. CONCLUSIONS: Intrauterine factors may have contributed to adverse neurological outcome, but 16/18 of the preterm cerebral palsy cases had an associated cerebral lesion which developed in the perinatal period.     

Epidemiology of necrotizing enterocolitis--Part II: Risks and susceptibility of premature infants during the surfactant era: a regional study

OBJECTIVES: We observed a reduced incidence of necrotizing enterocolitis (NEC) despite increased survival of extremely premature infants over the last two decades. A different susceptibility pattern to NEC according to gestation has been proposed. We aim to examine the influence of perinatal risk factors for NEC in infants less than 32 weeks gestation, in our region, in the post-surfactant era. METHODS: NEC incidence, perinatal risk factors and neonatal outcomes were examined in a cohort of 4649 infants of 24-31 weeks gestation from the Neonatal Intensive Care Unit Study (NICUS) database, admitted during 1994-99. RESULTS: A total of 178 (3.8%) infants developed NEC. More 24-27 weeks infants than 28-31 weeks infants had NEC (6.6% vs 2.6%, P < 0.001). Although low gestation infants had higher mortality and surgery need, post-operative survival (60%) was comparable to the higher gestation infants. NEC in the higher gestation group tended to be associated with perinatal risk factors, while risk factors were equally common in low gestation infants who developed NEC or not. Overall, gestation (P < 0.001), small for gestational age (P= 0.008), hyaline membrane disease (P < 0.001), placental abruption (P = 0.002) and earlier year of birth (P = 0.03) were independently associated with increased odds of NEC. Maternal hypertensive disease of pregnancy was associated with reduced NEC risk (P = 0.02). CONCLUSIONS: The incidence of NEC continues to decrease in the surfactant era and the pattern of susceptibility to NEC is based on gestational age grouping and risk factors. The reduced risk associated with hypertensive disease of pregnancy is unexplained.     

Predictive factors for survival for out‐born infants born between 23 and 24 weeks of gestation in the post‐surfactant era: Fourteen years’ experience in a single neonatal care unit, 1987–2000

Background: The purpose of the present paper was to identify the predictive factors for survival for out‐born infants born between 23 and 24 weeks of gestation. Methods: Ninety‐two infants born between 23 and 24 weeks’ gestation who were admitted to a level III neonatal intensive care unit from 1987 to 2000, were retrospectively studied. Survival was defined as discharge from the neonatal intensive care unit. Logistic regression was done to determine which clinical factors were most predictive of survival. The independent variables that were entered into the models were determined by preliminary univariate analysis. Results: Ninety‐two infants were enrolled in the present study, 49 of whom survived in the surfactant era. The four variables that were found to be most predictive for survival on logistic regression were systolic blood pressure at 6 h (odds ratio [OR], 1.3; 95% confidence interval [CI]: 1.11–1.44 1 mmHg), ventilatory index < 0.047 (OR, 4.8; 95%CI: 1.07–21.65), initial hemoglobin value (OR, 1.6; 95%CI: 1.09–2.34/1 g/dL), and base excess at 6 h (OR, 2.1; 95%CI: 1.08–1.84/5 mEq/L). Conclusions: A total of 53.2% of infants delivered between 23 and 24 weeks of gestation survived at discharge after introduction of surfactant replacement therapy. Early cardiopulmonary adaptation and initial hemoglobin value are key factors for survival in infants born at 23–24 weeks of gestation.     

Low gestational age and chronic lung disease are synergistic risk factors for retinopathy of prematurity

Aims

This retrospective, population based study was designed to investigate risk factors for development of retinopathy of prematurity (ROP) and their possible interrelationships, in neonates of gestational age (GA) < 32 weeks born in a well-defined geographical region.

Study design—subjects

The study population included all preterm infants born alive with GA 24–32 weeks in Northwestern Greece during a 9-year period and hospitalised in the regional neonatal intensive care unit (NICU).

Outcome measurements

The association was assessed of the presence of ROP with maternal factors: age, pathology of pregnancy, in-vitro fertilisation, multiple gestation, mode of delivery, perinatal factors: gender, antenatal steroids, transportation, resuscitation, GA, birth weight (BW), small for GA status and postnatal morbidity: chronic lung disease (CLD), intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC), respiratory distress syndrome (RDS), maximum O₂ needs, hypoxic/hyperoxic episodes, patent ductus arteriosus (PDA), sepsis, using multiple logistic regression analysis.

Results

Of 189 infants without congenital anomalies born at GA 24–32 weeks ROP was diagnosed in 24 (12.7%) (> grade 2: 6). Logistic regression analysis showed ROP to be strongly associated with GA, odds ratio (OR) 2.1, confidence interval (CI) 1.3–3.3, p < 0.01 and CLD, OR 10.2, CI 2.3–44, p < 0.01, respectively, independent of confounding factors. By estimating interaction on an additive scale it was shown that the combined risk effect of GA and CLD was larger than the sum of the individual risk effects, implying synergistic effect.

Conclusions

ROP was closely and independently related to both low GA and the diagnosis of CLD, which were interrelated in the development of ROP.     

Epidemiology of necrotizing enterocolitis--Part I: Changing regional trends in extremely preterm infants over 14 years

OBJECTIVES: Advances in perinatal care include exogenous surfactant, unequivocal acceptance of antenatal steroids and in utero and ex utero transfers to tertiary centres. Increased survival of extremely premature infants may change the incidence and outcome of necrotizing enterocolitis (NEC). Our aim was to examine the trends in the incidence of NEC, surgery and mortality in infants of 24-28 weeks gestation in a retrospective regional review of three epochs over a span of 14 years. METHODS: Radiologically or surgically proven NEC cases were determined from the New South Wales Neonatal Intensive Care Unit Study database. Three epochs were examined. A total of 360 infants were admitted in 1986-87 (Epoch 1), 622 in 1992-93 (Epoch 2) and 673 in 1998-99 (Epoch 3). RESULTS: There was an increase in neonatal intensive care unit admissions and a decrease in early and overall mortality of these very premature infants across the epochs. None of the early deaths was due to NEC. The incidence of NEC decreased in post day 5 survivors: 33 cases in Epoch 1 (12%), 60 cases in Epoch 2 (12%) and 34 cases in Epoch 3 (6%, P < 0.001). There was no change in surgical intervention (45%, 57% and 41%, respectively) or mortality due to NEC (37%, 27% and 32%). The reduced incidence of NEC was not singularly influenced by antenatal steroids, exogenous surfactant or outborn delivery. In a multivariate analysis, only later epoch of birth was independently associated with reduced NEC risk. CONCLUSIONS: With improved care and survival of extremely premature infants, the incidence of NEC has decreased, but it remains a disease of high mortality and morbidity.     

Longitudinal follow-up of height up to five years of age in infants born preterm small for gestational age; comparison to full-term small for gestational age infants

OBJECTIVE: This aims to conduct a comparative study of the height catch-up rate in preterm small for gestational age (SGA) infants during early childhood by gestational age and identify the factors affecting short stature in comparison to full-term SGA infants. METHODS: 449 SGA infants (214 full-term infants, 73 infants with gestation of less than 32 weeks, and 162 infants with gestation of more than 32 weeks but less than 37 weeks) from 25 institutions in Japan were assessed for catch-up (> or = -2SD) rate in growth by measuring for length/height at 1 year, 3 years and 5 years of age and the risk factors for no catch-up (< -2SD) at 5 years. RESULTS: The overall length/height catch-up rate was 68% at 1 year, 89% at 3 years and 88% at 5 years. The catch-up rate at 3 and 5 years of age in the group with gestation of less than 32 weeks had a rate of 74%, which was significantly less than the other two groups (approximately 90%). A significant factor associated with short stature at 5 years in the group with gestation of less than 32 weeks was the lower length SD score at time of birth, and for preterm infants born more than 32 weeks of gestation and full-term infants, significant factors were the lower maternal height and head circumference at birth. CONCLUSION: SGA infants born less than 32 weeks of gestation had a higher risk of no catch-up and different factors affecting catch-up compared to preterm SGA infants of gestation more than 32 weeks and full-term SGA infants.     

Duration of hospitalization in extremely preterm infants

This study reports the age at hospital discharge of 233 survivors and age at death of 209 infants who were born at 23-28 weeks gestation over a 10 year period, 1977-86. The mean duration of hospitalization of survivors was 95 days and was inversely related to maturity at birth; those born at 23-25 weeks remained in hospital on average 1-2 weeks beyond term while those born at 26-28 weeks went home on average at term or 1 week before term. The mean age at death was 12 days: 53% within 1 day, 23% between 2 and 7 days, 15% between 8 and 28 days and 9% between 28 days and 1 year. The proportions of death in the post-neonatal period for infants born at 23-24 weeks, 25-26 weeks and 27-28 weeks were 2, 9 and 16% respectively. There was no significant trend in prolonged hospitalization of survivors or postponement of neonatal deaths to the post-neonatal period over the 1977-86 period. Nevertheless, both neonatal and post-neonatal mortality should continually be monitored in this extremely preterm group.     

Postnatal age at time of death in infants born at 24-32 weeks' gestation

Medical records of all 483 infants live-born at 24-32 weeks' gestation in our hospital during the years 1982-86 were reviewed in order to determine postnatal age at time of death for those who died in the first year after birth. Twenty-seven died from immaturity without receiving intensive care and 11 died from lethal congenital malformations. Eighty (18%) of the remaining 445 who received intensive care died: 31% on day 1, 45% on days 2-7, 12% on days 8-28 and 11% on days 29-365. The neonatal mortality rate for those receiving intensive care was 160/1000, and the postneonatal mortality rate was 20/1000. Delayed mortality was most common in infants of 26-27 weeks' gestation, with 20% (five) of their deaths occurring after 28 days. In each gestational age range, the majority of hospital admission days were occupied by survivors (24-25 weeks = 62%; 26-27 weeks = 91%; 28-29 weeks = 91%; 30-32 weeks = 99%) rather than non-survivors. Whilst postneonatal mortality is a significant concern, these data suggest that if infants born at less than 33 weeks' gestation are offered intensive care and survive the early neonatal period, the long-term outcome is more likely to be survival rather than delayed death. Furthermore, the majority of hospital admission days invested in such infants involves those who will be discharged home rather than those who will not.     

Early neonatal hypocalcemia in extremely preterm infants. High incidence, early onset, and refractoriness to supraphysiologic doses of calcitriol

Nineteen preterm infants born at or before 32 weeks of gestation were studied to determine the dose of calcitriol that would be effective in the prophylaxis of early neonatal hypocalcemia (serum calcium level, less than 7.0 mg/dL [less than 1.75 mmol/L]). In these infants the course of early neonatal hypocalcemia was not modified by calcitriol administration. Serum 1,25-dihydroxyvitamin D level rose in response to intramuscular administration of calcitriol. The incidence of hypocalcemia in these infants was 37% by 12 hours, 83% by 24 hours, and 89% by 36 hours. Thus, in extremely preterm infants, the incidence of early neonatal hypocalcemia is higher and the onset earlier than in larger preterm infants; furthermore, in these infants the hypocalcemia is refractory even to high doses of calcitriol.     

The fate of ductus arteriosus in infants at 23-27 weeks of gestation: from spontaneous closure to ibuprofen resistance

BACKGROUND: Some extremely preterm infants experience spontaneous closure of the ductus arteriosus. On the other side, a high percentage (22-30%) of preterm infants born at the lower gestational age fail to respond to a single course of ibuprofen. AIM: To assess if there are clinical characteristics effective as predictive factors for spontaneous closure of the ductus arteriosus, development of patent ductus arteriosus (PDA) and ibuprofen-resistant PDA. METHODS: A cohort of inborn infants less than 28 weeks of gestation were prospectively studied. We distinguished infants who had spontaneous closure of ductus arteriosus, who developed PDA and who developed ibuprofen-resistant PDA. RESULTS: We studied 34 infants. Eight infants (24%) had spontaneous closure of PDA, 17 infants (50%) had a closure of PDA following the first ibuprofen course, while 9 infants (26%) failed to respond to the first ibuprofen course. Infants born at 23-25 weeks of gestation were found to have lower likelihood of PDA spontaneous closure, and higher risk of developing PDA refractory to ibuprofen therapy. Sepsis was found to increase significantly the risk of ibuprofen failure in closing PDA. CONCLUSION: An important percentage of extremely preterm infants exhibited spontaneous closure of PDA. Among clinical characteristics lowest gestational ages predict PDA and ibuprofen-resistant PDA, while sepsis predicts only ibuprofen-resistant PDA.