Prenatal or postnatal indomethacin exposure and neonatal gut injury associated with isolated intestinal perforation and necrotizing enterocolitis

To examine the role of indomethacin in neonatal gut injury.Infants born at gestational age ⩾23 weeks and with birth weights 400–1200 g were included in this prospective prevalence study of neonatal gut injury. Infants with isolated intestinal perforation (IIP) confirmed at laparotomy or at autopsy or with necrotizing enterocolitis (NEC) were identified. Data were abstracted bi-weekly.Among 992 study infants, 58 infants exposed solely to prenatal indomethacin did not show an increased rate of neonatal gut injury. Any postnatal indomethacin exposure (n=611) increased the odds of IIP (OR 4.17, CI, 1.24–14.08, P=0.02) but decreased the odds of NEC (OR 0.65, CI 0.43–0.97, P=0.04). There was a negative association between the timing of indomethacin-exposure and the odds of developing IIP (OR 0.30, CI 0.11–0.83, P=0.02). Compared with NEC, IIP occurred at an earlier age (P<0.05) and was more common (P<0.05) among infants who received early indomethacin (first dose at <12 h of age) to prevent intraventricular hemorrhage than among infants who were treated with late indomethacin for closure of a patent ductus arteriosus (PDA). Unlike the classic hemorrhagic ischemic lesions of NEC in which large areas of tissue were inflamed or necrotic, the IIP lesions were small and discrete.Early (<12 h) postnatal indomethacin exposure was associated with an increased odds of IIP in very low birth weight infants whereas its later use for closure of a PDA appeared to provide protection against NEC. The paradoxical effect of the timing of indomethacin on IIP versus on NEC may be related to the different pathogeneses of the two diseases. Our findings also suggest that PDA may contribute to NEC.

Related papers:

title: Necrotizing enterocolitis: recent scientific advances in pathophysiology and prevention.
abstract: Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among infants in the neonatal intensive care unit. Here we review the epidemiology and pathophysiology of NEC, with an emphasis on the latest research findings and potential areas for future research. NEC continues to be one of the most devastating and unpredictable diseases affecting premature infants. Despite decades of research, the pathogenesis of this disease remains unclear, and prevention and treatment strategies are limited. Hopefully, future studies aimed at understanding premature intestinal defenses, commensal or probiotic bacterial influences, and possible genetic predisposition will lead to the improvement of prevention and treatment strategies.

title: Neonatal outcome after exposure to indomethacin in utero: a retrospective case cohort study.
abstract: This study was undertaken to determine the clinical outcome for neonates who were exposed to indomethacin during gestation.



We identified 124 infants with in utero exposure to indomethacin and matched them to 124 infants whose mothers did not receive indomethacin. The two groups were matched for gestational age at birth, sex, and exposure to antenatal betamethasone. Sixty-two of the indomethacin-exposed infants were born within 48 hours of last exposure. These infants were also compared with their matched controls.



There were no significant differences between the indomethacin-exposed infants and control infants in birth weight, Apgar scores, frequency of cesarean section deliveries, and multiple gestation. The incidence of respiratory distress syndrome, need for surfactant treatment, patent ductus arteriosus, necrotizing enterocolitis, and intraventricular hemorrhage was similar between the indomethacin-exposed group and the control group. Indomethacin-exposed infants who were born within 48 hours of last exposure had similar incidence of respiratory distress syndrome but greater need for surfactant treatment (P=.02) compared with controls. All other complication rates were similar.



Indomethacin exposure in our study was not associated with increased neonatal complications for infants delivered within or beyond 48 hours of last exposure.

title: Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes.
abstract: The objective of the study was to determine whether indomethacin used as a tocolytic agent is associated with adverse neonatal outcomes.



We used published guidelines of the Metaanalysis of Observational Studies in Epidemiology Group (MOOSE) to perform the metaanalysis. The search strategy used included computerized bibliographic searches of MEDLINE (1966-2005), PubMed (1966-2005), abstracts published in Obstetrics and Gynecology (1991-2005), abstracts published in Pediatric Research (1991-2005), and references of published manuscripts. Study inclusion criteria were publication in English, more than 30 deliveries less than 37 weeks' gestation, and meeting diagnostic criteria for individual neonatal outcomes. Exclusion criteria included case reports, case series, and multiple publications from the same author. Metaanalysis was performed using random effects model if there were more than 2 observational studies for a specific outcome. Eggers test was performed to exclude publication bias. Sensitivity analysis was performed to evaluate the effect of antenatal steroid exposure, gestation, and recent antenatal indomethacin exposure (duration of 48 hours or more between the last dose and delivery).



Fifteen retrospective cohort studies and 6 case-controlled studies met inclusion criteria. Antenatal indomethacin was associated with an increased risk of periventricular leukomalacia (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.3-3.1). Recent exposure to antenatal indomethacin was associated with necrotizing enterocolitis (OR, 2.2; 95% CI; 1.1-4.2). Antenatal indomethacin was not associated with intraventricular hemorrhage, patent ductus arteriosus, respiratory distress syndrome, bronchopulmonary dysplasia, and mortality.



Antenatal indomethacin may be associated with an increased risk of periventricular leukomalacia and necrotizing enterocolitis in premature infants and therefore should be used judiciously for tocolysis.

title: Isolated small bowel perforation following intrauterine treatment with indomethacin.
abstract: Indomethacin, a prostaglandin synthetase inhibitor, is an effective tocolytic agent that may have adverse fetal side effects such as constriction of the ductus arteriosus, pulmonary hypertension, and reduced urine production. We describe an unusual neonatal complication following 6 days of tocolysis with indomethacin. A 22-year-old gravida 5, para 3104 was admitted at 25 weeks of gestation in labor. Attempts to stop labor using magnesium sulfate and terbutaline failed. The contractions stopped following the administration of indomethacin, which was continued for 6 days. On day 7, due to contractions and vaginal bleeding, she underwent a classic cesarean section. The female newborn, weighting 1044 g, did well for 2 days, when she developed pneumoperitoneum. On laparotomy, an isolated midileal perforation was found, with otherwise normal-appearing bowel. Isolated intestinal perforation has been described in premature neonates who were treated with indomethacin for patent ductus arteriosus. This complication is caused by splanchnic ischemia secondary to the loss of the vasodilatory effect of prostaglandins. This case indicates that this rare but serious complication may also follow intrauterine exposure to indomethacin.

title: Neonatal Necrotizing Enterocolitis With Intestinal Perforation in Extremely Premature Infants Receiving Early Indomethacin Treatment for Patent Ductus Arteriosus
abstract: Survival of extremely premature infants (<27 weeks' gestational age) has improved over the past two decades. Indomethacin prophylaxis was used in these infants, who have the highest mortality and morbidity rates, to reduce the incidence of intraventricular hemorrhage and patent ductus arteriosus (PDA). Medical records of 65 extremely premature infants born at our institution between 1995 and 2001 were reviewed retrospectively to determine whether treatment of PDA with indomethacin in the first 48 hours of life reduces the need for PDA ligation or increases neonatal morbidity, when compared to treatment begun later. Thirty infants in the early treatment group (ETG) were treated during the first 48 hours after birth, and 32 infants in the standard treatment group (STG) were managed expectantly for PDA. Three infants died in the first hours of life and were eliminated from further analysis. ETG infants were 24.9±1.1 (mean±SD) weeks' gestation with a birth weight of 678±143 g. STG infants were 25.3±1.1 weeks (NS) and 730±125 g (NS). Hemodynamically significant PDA was diagnosed or confirmed by echocardiography in 19 ETG patients and 17 STG patients. Of the patients with hemodynamically significant PDA, 1 (5%) ETG patient and 6 (35%) STG patients underwent surgical ligation (p=0.033). Necrotizing enterocolitis (NEC) with intestinal perforation was the most serious morbidity and occurred in 20% of infants in the ETG, but in no STG infant (p=0.011). Four of the six infants in the ETG with NEC and intestinal perforation died. The overall mortality rate for all infants studied was 28%. We conclude that in extremely premature infants, use of indomethacin during the first 48 hours of life was associated with a reduced need for PDA ligation, but an increased risk of NEC with intestinal perforation.

title: Predictors of Ductal Closure and Intestinal Complications in Very Low Birth Weight Infants Treated with Indomethacin
abstract: To describe factors associated with failure of patent ductus arteriosus closure and development of gastrointestinal complications in subjects treated with indomethacin.  Infants ≤30 weeks and <1,500 g delivered between 1997–2003 with patent ductus arteriosus treated with indomethacin were included in this single-center retrospective study. Risk factors for failed ductal closure rates and gastrointestinal complications were identified with uni- and multivariable analyses.  Among 210 subjects treated with indomethacin, ductal closure increased from 43% at 23 weeks to 87% at 27 weeks (OR 1.51 per week gestation, 95% CI 1.14–2.01, p = 0.004) and was unchanged thereafter. Gastrointestinal complications decreased with increasing gestational age (OR 0.67/week, 95% CI 0.52–0.84) but increased with male gender (OR 2.41, 95% CI 1.07–5.45). SNAP-II (Score for Neonatal Acute Physiology-II) scores at birth and at the time of first indomethacin therapy were not associated with likelihood of closure or with gastrointestinal complications. Duration of ductal patency was not associated with risk of necrotizing enterocolitis or intestinal perforation after adjusting for gestational age and gender.  Ductal closure with indomethacin is linearly associated with gestational age in infants ≤27 weeks. Illness severity at the time of treatment is not predictive of treatment outcome or gastrointestinal complications. The duration of ductal patency is not associated with an increase in adjusted risk of necrotizing enterocolitis or intestinal perforation in patients treated with indomethacin.

title: The controversy surrounding indomethacin for tocolysis.
abstract: Indomethacin is a prostaglandin synthetase inhibitor sometimes used for tocolysis. Several placebo-controlled trials and trials comparing indomethacin to other potential first-line tocolytic agents support its efficacy for delaying delivery for >48 hours. Recent observational studies, however, have raised concerns about the safety of indomethacin, implicating it with increased rates of intraventricular hemorrhage and necrotizing enterocolitis. Careful analysis of these observational studies suggests that these results should be viewed with caution, because of uncontrolled confounding by indication. A recent decision analysis supports the risk/benefit analysis of indomethacin in this setting. Still, the future of indomethacin in preterm labor should be guided by well-designed prospective clinical trials. Such studies are underway.

title: Indomethacin reduces the risks of severe intraventricular hemorrhage.
abstract: A prospective, random selection, double-blind clinical trial was carried out to determine the efficacy of indomethacin in preventing periventricular-intraventricular hemorrhage (PV-IVH). Babies who were born in our institution, had birth weights less than or equal to 1500 gm, and had no PV-IVH or grade 1 PV-IVH were given either placebo (n = 70) or indomethacin (n = 71), 0.2 mg/kg intravenously at 6 hours of age and 0.1 mg/kg at 18 and 30 hours. Two major outcomes were determined: the development of grades 2 to 4 PV-IVH and the development of severe PV-IVH (i.e., hemorrhages with blood filling greater than 50% of the ventricles and in some cases with associated parenchymal echodensities). Grades 2 to 4 PV-IVH occurred in 16 (23%) of the indomethacin group and 27 (39%) of the placebo group (p less than 0.03). The incidence of severe PV-IVH was 3% in the indomethacin-treated babies and 14% in the control group (p less than 0.02). The influence of other perinatal factors on the incidence of grades 2 to 4 or severe PV-IVH was determined by stepwise logistic regression. Placebo use, early grade 1 PV-IVH, lower birth weight, and higher fraction of inspired oxygen at 6 hours of life were associated with higher estimated odds of the development of grades 2 to 4 PV-IVH. Placebo use, male gender, lower 5-minute Apgar score, and a large base deficit were predictive of severe PV-IVH. Estimated odds ratios of severe PV-IVH with placebo use and male gender were 11.25:1 and 9:1, respectively. Thus indomethacin prophylaxis reduced the relative risk of grades 2 to 4 PV-IVH and severe PV-IVH, but other perinatal variables contributed significantly to the overall risk of PV-IVH.

title: Indomethacin-associated bowel perforations: a study of possible risk factors.
abstract: The association between indomethacin administration and bowel perforation in premature infants is well known. The goal of this study was to examine possible risk factors for this complication.



Fifteen cases of indomethacin-associated bowel perforation occurred from 1993 to 1996. All had a birth weight < or = 1,100 g. These patients were compared with a control group of 51 infants who were cared for contemporaneously, had birth weights < or = 1,100 g and received indomethacin.



Survival rate in the control group was 96%. For the group with perforations, it was 53%. Two types of perforation were seen, one occurring in the setting of necrotizing enterocolitis, and the other, a simple perforation in an otherwise normal-appearing bowel. For the latter group, the survival rate was 86%, and, when possible, primary repair was the procedure of choice. Use of aminophylline was greater in the control group. Otherwise, there were no significant differences between the two groups in any of the variables observed. However, when the simple perforations were observed separately, these patients had, on average, received indomethacin at a younger age than the controls (P < .05). The clustering of perforation cases from May through August suggests an infectious agent might be involved.



Earlier administration of indomethacin correlates with an increased risk of focal perforation. It is unclear, however, whether the risk factor is the drug itself or the earlier need for it. Aminophylline use was somewhat more in the control group, but this is not likely to reflect a protective role for that drug. The possible involvement of an infectious agent should be considered.

title: Gastrointestinal perforation in very low‐birthweight infants
abstract: Spontaneous isolated gastrointestinal perforation (SIP) in very low‐birthweight infants has been reported as a different disease entity from necrotizing enterocolitis (NEC). The objective of this study was to investigate the incidence and risk factors of NEC and SIP.

title: Increased risk of necrotizing enterocolitis in premature infants with patent ductus arteriosus treated with indomethacin.
abstract: The authors evaluated the risk of necrotizing enterocolitis (NEC) in very low birth weight infants receiving indomethacin (INDO) to close patent ductus arteriosus (PDA).



Controversy exists regarding the best method of managing very low birth weight infants with PDA and whether to employ medical management using INDO or surgical ligation of the ductus.



Two hundred fifty-two premature infants with symptomatic PDA were given intravenously INDO 0.2 mg/kg every 12 hours x 3 in an attempt to close the ductus. Patients were evaluated for sex, birth weight, gestational age, ductus closure, occurrence of NEC, bowel perforation, and mortality.



There were 135 boys and 117 girls. The PDA closed or became asymptomatic in 224 cases (89%), whereas 28 (11%) required surgical ligation. Ninety infants (35%) developed evidence of NEC after INDO therapy. Fifty-six were managed medically; surgical intervention was required in 34 of 90 cases (37.8%) or 13% of the entire PDA/INDO study group. Bowel perforation was noted in 27 cases (30%). Factors associated with the onset of NEC included gestational age < 28 weeks, birth weight < 1 kg, and prolonged ventilator support. The overall mortality rate was 25.5%, but was higher in infants with NEC versus those without. The highest mortality was noted in perforated NEC cases. The PDA/INDO patients were compared with a control group of 764 infants with similar sex distribution, birth weights, and gestational ages without PDA who did not receive INDO. Necrotizing enterocolitis occurred in 105 of 764 control patients (13.7%), including 13 (12.3%) with perforation. The overall mortality rate of controls was 25%, which was similar to the overall 25.5% mortality rate in the PDA/INDO study group.



These data indicate that there is increased risk of NEC and bowel perforation in premature infants with PDA receiving INDO. Mortality was higher in the PDA/INDO group with NEC than those PDA/INDO infants without NEC.

title: Neonatal Necrotizing Enterocolitis: Therapeutic Decisions Based upon Clinical Staging
abstract: A method of clinical staging for infants with necrotizing enterocolitis (NEC) is proposed. On the basis of assigned stage at the time of diagnosis, 48 infants were treated with graded intervention. For Stage I infants, vigorous diagnostic and supportive measures are appropriate. Stage II infants are treated medically, including parenteral and gavage aminoglycoside antibiotic, and Stage III patients require operation. All Stage I patients survived, and 32 of 38 Stage II and III patients (85%) survived the acute episode of NEC. Bacteriologic evaluation of the gastrointestinal microflora in these neonates has revealed a wide range of enteric organisms including anaerobes. Enteric organisms were cultured from the blood of four infants dying of NEC. Sequential cultures of enteric organisms reveal an alteration of flora during gavage antibiotic therapy. These studies support the use of combination antimicrobial therapy in the treatment of infants with NEC.

title: Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants.
abstract: Chronic lung disease (CLD) remains a major problem in neonatal intensive care units. Persistent inflammation in the lungs is the most likely underlying pathogenesis. Corticosteroids have been used to either prevent or treat CLD because of their potent anti-inflammatory effects.



To determine if postnatal corticosteroid treatment is of benefit in the prevention of chronic lung disease (CLD) in preterm infants. This review examines the outcome of trials where preterm infants at risk of CLD were given postnatal corticosteroids within the first seven days of life.


SEARCH STRATEGY
Randomised controlled trials (RCTs) of postnatal corticosteroid therapy were sought from the Cochrane Controlled Trials Register, MEDLINE (1966 - May 2008), hand searching paediatric and perinatal journals, examining previous review articles and information received from practising neonatologists. Authors of all studies were contacted, where possible, to confirm details of reported follow-up studies, or to obtain any information about long-term follow-up where none had been reported.



Randomised controlled trials of postnatal corticosteroid treatment within the first 7 days of life (early) in high risk preterm infants were selected for this review. Most studies evaluated the use of dexamethasone but we also included studies that assessed hydrocortisone, even if it was used to manage hypotension.



Data regarding clinical outcomes including mortality, CLD (including late rescue with corticosteroids, and need for home oxygen therapy), death or CLD, failure to extubate, complications during the primary hospitalisation (including infection, hyperglycaemia, hypertension, pulmonary air leak, patent ductus arteriosus (PDA), severe intraventricular haemorrhage (IVH), periventricular leucomalacia (PVL), necrotising enterocolitis (NEC), gastrointestinal bleeding, intestinal perforation, severe retinopathy of prematurity (ROP), and long-term outcome (including blindness, deafness, cerebral palsy and major neurosensory disability) were abstracted and analysed using RevMan 5.



Twenty-eight RCTs enrolling a total of 3740 participants were eligible for inclusion in this review. A meta-analysis of these trials demonstrated significant benefits as regards earlier extubation and decreased risks of CLD at both 28 days and 36 weeks' postmenstrual age (PMA), death or CLD at 28 days and 36 weeks' PMA, PDA and ROP, including severe ROP. There were no significant differences in the rates of neonatal or subsequent mortality, infection, severe IVH, PVL, NEC or pulmonary haemorrhage. Gastrointestinal bleeding and intestinal perforation were important adverse effects and the risks of hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure were also increased. In the twelve trials that reported late outcomes, several adverse neurological effects were found at follow-up examinations including developmental delay (not defined), cerebral palsy and abnormal neurological examination. However, major neurosensory disability was not significantly increased, either overall in the seven studies where this outcome could be determined, or in the two individual studies where the rates of cerebral palsy or abnormal neurological examination were significantly increased. Moreover, the rates of the combined outcomes of death or cerebral palsy, or of death or major neurosensory disability were not significantly increased. Dexamethasone was the drug used in most studies (n = 20); only eight studies used hydrocortisone. In subgroup analyses by type of corticosteroid, most of the beneficial and harmful effects were attributable to dexamethasone; hydrocortisone had little effect on any outcomes except for an increase in intestinal perforation and a borderline reduction in PDA.



The benefits of early postnatal corticosteroid treatment (</= 7 days), particularly dexamethasone, may not outweigh the known or potential adverse effects of this treatment. Although early corticosteroid treatment facilitates extubation and reduces the risk of chronic lung disease and patent ductus arteriosus, it causes short-term adverse effects including gastrointestinal bleeding, intestinal perforation, hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure. Long-term follow-up studies report an increased risk of abnormal neurological examination and cerebral palsy. However, the methodological quality of the studies determining long-term outcomes is limited in some cases; the surviving children have been assessed predominantly before school age, and no study has been sufficiently powered to detect important adverse long-term neurosensory outcomes. There is a compelling need for the long-term follow-up and reporting of late outcomes, especially neurological and developmental outcomes, among surviving infants who participated in all randomised trials of early postnatal corticosteroid treatment. Hydrocortisone in the doses and regimens used in the reported RCTs has few beneficial or harmful effects and cannot be recommended for prevention of CLD.

title: Recent indomethacin tocolysis is not associated with neonatal complications in preterm infants.
abstract: We sought to determine whether indomethacin tocolysis immediately before delivery is associated with any increased complications in neonates delivered between 24 and 32 weeks' gestation.



We performed a case-control analysis of neonates delivered between 24 and 32 weeks' gestation after maternal indomethacin treatment for preterm labor. All infants were delivered within 48 hours of indomethacin exposure. Seventy-five patients were matched with 150 control subjects in a patient/control ratio of 1:2. Matching variables in order of priority included gestational age at delivery, fetal number, betamethasone exposure >24 hours before delivery, magnesium sulfate use, mode of delivery, infant sex, and race. Data were analyzed by using the Student t test, chi(2) analysis, and the Fisher exact test and Yates' correction.



The gestational age at delivery (mean +/- SD) was 28.7 +/- 2.3 weeks in the indomethacin group and 28.3 +/- 2.1 weeks for the control subjects. Birth weights (mean +/- SD) were 1121 +/- 243 and 1141 +/- 287 g, respectively. All mothers received both magnesium sulfate and betamethasone before delivery. The median cumulative dose of indomethacin was 225 mg. The median interval from last dose of indomethacin until delivery was 12 hours. There were no significant differences between the groups in the incidence of necrotizing enterocolitis (odds ratio, 1.12; 95% confidence interval, 0.31-3.84), grade III/IV intraventricular hemorrhage (odds ratio, 0.37; 95% confidence interval, 0.10-1.19), patent ductus arteriosus (odds ratio, 0.85; 95% confidence interval, 0.44-1.64), bronchopulmonary dysplasia (odds ratio, 0.97; 95% confidence interval, 0.49-1.91), pulmonary hypertension (odds ratio, 0.49; 95% confidence interval, 0. 02-4.80), anuria (odds ration, 1.21; 95% confidence interval, 0.22-6. 01), thrombocytopenia (odds ratio, 1.14; 95% confidence interval, 0. 53-2.42), sepsis (odds ratio, 1.21; 95% confidence interval, 0.22-6. 01), or neonatal death (odds ratio, 1.34; 95% confidence interval, 0. 55-3.25).



Maternal indomethacin exposure immediately before delivery was not associated with increased neonatal complications for infants delivered between 24 and 32 weeks' gestation.

title: Indomethacin Tocolysis and Risk of Necrotizing Enterocolitis
abstract: To investigate the possible association of indomethacin tocolysis with neonatal necrotizing enterocolitis.  A case-control study was performed for the period November 1, 1997, through May 1, 1999. All cases of proven necrotizing enterocolitis were ascertained, and four controls for each case were randomly identified from all Special Care Nursery admissions before 37 weeks' gestation without necrotizing enterocolitis during that same period.  During the 18-month period there were 24 cases of necrotizing enterocolitis out of 10,200 deliveries. Infants with necrotizing enterocolitis were more preterm (29.7 ± 3.9 compared with 32.7 ± 6.0 weeks; P = .03) and had lower birth weights (1453 ± 777 compared with 1820 ± 678 g; P = .02) compared with controls (n = 96). Respiratory distress syndrome (RDS) and sepsis were both significantly associated with an increased risk of necrotizing enterocolitis: 16 of 24 cases compared with 40 of 96 controls had RDS (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.0, 8.3) and 14 of 24 cases compared with 11 of 96 controls were septic (OR 10.8, 3.4, 95% CI 34.2). Indomethacin as a single agent was not associated with necrotizing enterocolitis (OR 1.0, 95% CI 0.2, 4.8). Using a logistic regression model, necrotizing enterocolitis was strongly associated with sepsis (adjusted OR 8.5, 95% CI 2.2, 32.5). When sepsis was removed from the model, double-agent tocolytic therapy was significantly associated with necrotizing enterocolitis (adjusted OR 6.9, 95% CI 1.1, 43.6).  Tocolysis with indomethacin as a single agent was not associated with necrotizing enterocolitis in this case-control study. Combination tocolytic therapy may be a marker for subclinical infection and not causally related to necrotizing enterocolitis.

title: Neonatal Complications after the Administration of Indomethacin for Preterm Labor
abstract: The use of indomethacin as a tocolytic agent in pregnant women appears to be accompanied by a low incidence of neonatal complications. However, the neonatal effects of indomethacin have been studied primarily in infants born after 32 weeks' gestation. This study was designed to examine the incidence of neonatal complications in very premature infants.  We identified 57 infants delivered at or before 30 weeks' gestation whose mothers had been treated with indomethacin for preterm labor and matched them with 57 infants whose mothers had not received indomethacin. The infants in the two groups were matched for sex, gestational age at delivery (mean [±SD], 27.6 ±2.0 weeks), exposure to betamethasone for 24 hours or more before delivery, and rupture of membranes 24 hours or more before delivery.  There were no significant differences between the two groups in birth weight, Apgar scores, cord-blood gas values, frequency of multiple gestation, or incidence of respiratory distress syndrom...

title: Tocolysis with indomethacin increases the incidence of necrotizing enterocolitis in the low-birth-weight neonate.
abstract: The null hypothesis states that prolonged antenatal indomethacin exposure within 24 hours of delivery does not increase the incidence of necrotizing enterocolitis in the low-birth-weight neonate.



The neonates of patients receiving indomethacin tocolysis admitted in preterm labor (N = 56) were compared with the neonates of preterm labor patients who received no indomethacin tocolysis (N = 703). These neonatal groups were then compared with regard to gestational age at delivery, birth weight, mode of delivery, antenatal magnesium and steroid exposure, incidence of respiratory distress syndrome, perinatal depression, sepsis, umbilical catheterization, and feeding rates and volumes. The overall incidence of necrotizing enterocolitis, mortality secondary to necrotizing enterocolitis, and the intervals from delivery and feeding to necrotizing enterocolitis diagnosis were also compared. The association between necrotizing enterocolitis and the duration of indomethacin exposure and the interval from exposure to delivery for both the indomethacin and control groups was determined.



The incidence of necrotizing enterocolitis in neonates who were delivered within 24 hours of maternal indomethacin therapy was 20% compared with 9% in the control group (p = 0.005). The incidence of necrotizing enterocolitis in neonates with > 48 hours of antenatal indomethacin exposure was 26.4% compared with 4.1% in those with < 48 hours exposure (p = 0.042). The interval from first feeding to necrotizing enterocolitis development was significantly shorter in the indomethacin group versus the control group (2.1 +/- 3.0 vs 6.8 +/- 6.3 days) (p = 0.001), as was the mean interval from delivery to development of necrotizing enterocolitis (10.2 +/- 3.7 vs 15.2 +/- 3.8 days) (p = 0.019).



Antenatal indomethacin exposure occurring within < or = 24 hours of delivery and of at least 48 hours' duration is associated with a significant increase in the incidence of necrotizing enterocolitis in the low-birth-weight neonate.

title: Outcome of Very Low Birth Weight Infants Exposed to Antenatal Indomethacin for Tocolysis
abstract: Beginning in October 1995, and for several years thereafter, our institution used indomethacin as a first-line tocolytic drug. Our purpose is to compare the outcomes of very low birth weight infants who were exposed to antenatal indomethacin with those who were not exposed to this therapy.We used our center's component of the NICHD Neonatal Research Network's Generic Data Base which recorded the outcomes of all live born infants weighing less than 1500 g over a 5-year period. We abstracted data concerning neonatal morbidity (death, Grades III to IV intraventricular hemorrhage (IVH), necrotizing enterocolitis and patent ductus arteriosus), as well as other factors including gestational age, birth weight, antenatal corticosteroid treatment and maternal hypertension or pre-eclampsia. Univariate analysis was performed using Fisher's exact test. Multivariate analysis using logistic regression was performed to control for confounding factors.A total of 85 infants who were exposed to antenatal indomethacin were compared to 464 infants who were not exposed to the drug. In the univariate analysis, antenatal indomethacin exposure was not associated with a significant increase in the incidence of necrotizing enterocolitis or patent ductus arteriosus. The incidence of Grades III to IV IVH was 17.9% in those infants exposed to antenatal indomethacin compared to 7.1% in the nonexposed infants (p=0.008). The incidence of neonatal death in the exposed infants was 27.7 versus 16.4 in the nonexposed infants (p=0.02).After controlling for antenatal corticosteroids, maternal pre-eclampsia, gestational age and birth weight, antenatal indomethacin was significantly associated with an increased incidence of IVH, but not neonatal death.Antenatal indomethacin was associated with significantly higher rates of IVH. Additional studies assessing the potential risks of indomethacin tocolysis are needed before it is used as a first-line tocolytic therapy.

title: Effect of maternal tocolysis on the incidence of severe periventricular/intraventricular haemorrhage in very low birthweight infants
abstract: To examine the relation between grade III–IV periventricular/intraventricular haemorrhage (PVH/IVH) and antenatal exposure to tocolytic treatment in very low birthweight (VLBW) premature infants.  The study population consisted of 2794 infants from the Israel National VLBW Infant Database, of gestational age 24–32 weeks, who had a cranial ultrasound examination during the first 28 days of life. Infants of mothers with pregnancy induced hypertension or those exposed to more than one tocolytic drug were excluded. Of the 2794 infants, 2013 (72%) had not been exposed to tocolysis and 781 (28%) had been exposed to a single tocolytic agent. To evaluate the effect of tocolysis and confounding variables on grade III–IV PVH/IVH, the χ2test, univariate analysis, and a logistic regression model were used.  Of the 781 infants (28%) exposed to tocolysis, 341 (12.2%) were exposed to magnesium sulphate, 263 (9.4%) to ritodrine, and 177 (6.3%) to indomethacin. The overall incidence of grade III–IV PVH/IVH was 13.4%. In the multivariate logistic regression analysis, the following factors were related significantly and independently to grade III–IV PVH/IVH: no prenatal steroid treatment, low gestational age, one minute Apgar score 0–3, respiratory distress syndrome, patent ductus arteriosus, mechanical ventilation, and pneumothorax. Infants exposed to ritodrine tocolysis (but not to the other tocolytic drugs) were at significantly lower risk of grade III–IV PVH/IVH after adjustment for other variables (odds ratio = 0.3; 95% confidence interval 0.2 to 0.6).  This study suggests that antenatal exposure of VLBW infants to ritodrine tocolysis, in contrast with tocolysis induced by magnesium sulphate or indomethacin, was associated with a lower incidence of grade III–IV PVH/IVH.

title: Preterm delivery after indomethacin. A risk factor for neonatal complications?
abstract: To determine if tocolytic therapy with indomethacin is associated with an increased risk of neonatal complications in infants born prior to 32 weeks' gestation.



We performed a retrospective matched cohort study of infants born between 24 and 31(6)/7 weeks' gestation. The 62 cases (indomethacin treatment) and the 62 controls were matched by week of gestation, prenatal betamethasone exposure and multifetal gestation.



The mean gestational age of the two groups was 28.5 +/- SD weeks. The median total dose of indomethacin was 425 mg, the median treatment duration was three days, and the median interval from the last dose of indomethacin until delivery was one day. There was no significant difference between the groups in the incidence of necrotizing enterocolitis, intraventricular hemorrhage, patent ductus arteriosis, sepsis or neonatal death.



The use of indomethacin for tocolysis was not associated with an increased risk of neonatal complications in infants born between 24 and 31(6)/7 weeks' gestation.

title: Spontaneous localized intestinal perforation in very-low-birth-weight infants: a distinct clinical entity different from necrotizing enterocolitis.
abstract: Idiopathic spontaneous intestinal perforation (SIP), a distinct clinical entity different from necrotizing enterocolitis (NEC), has an increasing prevalence in very-low-birth-weight infants. The aims of our study were to define patient characteristics and potential risk factors for premature infants with SIP compared with infants subjected to surgical treatment for NEC.



The medical records of 29 premature infants with either SIP (n = 13) or NEC (n = 16) were reviewed retrospectively.



Infants who experienced SIP were smaller at birth, had lower Apgar scores, and required more intensive neonatal resuscitation. An increased rate of premature rupture of membranes in infants with SIP (8/13 versus 6/16) was not associated with a higher rate of infection in mothers or infants. The onset of illness in SIP was significantly earlier than in NEC (p = 0.022). In contrast to patients with NEC (7/16), 11 of 13 patients in the SIP group had received indomethacin (p = 0.02). Bluish discoloration of the abdomen (8/13), a gasless abdomen (8/13), and the absence of pneumatosis intestinalis (0/13) were further significant markers in infants with SIP. At operation, SIP was always located in the terminal ileum in an antimesenteric position (13/13), and the remaining bowel appeared grossly normal. In most cases of SIP (10/13), the histologic investigation revealed an area of hemorrhagic necrosis without the typical coagulation necrosis seen predominantly in NEC.



Based on clinical presentation and radiologic and intraoperative findings, SIP is a distinct pathologic entity in very-low-birth-weight infants and can be differentiated from classic NEC. Detected early, SIP can be treated by simple procedures (sutures, or resection and primary anastomosis) with a low rate of morbidity and mortality.

title: Impact of gestational age on the clinical presentation and surgical outcome of necrotizing enterocolitis
abstract: This investigation tests the hypothesis that the clinical presentation and the outcome of necrotizing enterocolitis (NEC) vary with gestational age (GA).Methods:All infants admitted to our center between October 1991 and September 2003 were evaluated weekly to identify confirmed cases of NEC. Based upon GA, these infants were divided into five groups: Extremely premature (EP, 23 to 26 weeks), very premature (VP, 27 to 29 weeks), moderately premature (MP, 30 to 34 weeks), near-term (NT, 35 to 36 weeks), and term (T, 37 to 42 weeks).Results:A total of 202 infants developed NEC. The most common sign of NEC among EP infants was ileus (77%), followed by abdominal distention (71%), emesis (58%), pneumoperitoneum (54%), fixed intestinal loop (52%), gasless abdomen (42%) and bloody stools (17%). Intramural gas was detected in 100% of T but was present in only 29% of EP infants (P<0.0001). Similarly, portal venous gas was common in T but infrequent in the EP infants (47 vs 10%, P<0.0001). Despite a higher peritoneal drain insertion rate (31 vs 5%, P<0.001) and a higher mortality rate (33 vs 10%, P=0.05) in EP compared to T infants, other clinical outcomes were not different.The clinical presentation of NEC is different in EP compared to more mature infants; however, outcome among NEC survivors is similar across all GA. Reliance solely on observation of intramural or on portal venous gas in EP infants may lead to a delay or failure in the diagnosis.

title: Adverse effects of early dexamethasone treatment in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network.
abstract: Early administration of high doses of dexamethasone may reduce the risk of chronic lung disease in premature infants but can cause complications. Whether moderate doses would be as effective but safer is not known.



We randomly assigned 220 infants with a birth weight of 501 to 1000 g who were treated with mechanical ventilation within 12 hours after birth to receive dexamethasone or placebo with either routine ventilatory support or permissive hypercapnia. The dexamethasone was administered within 24 hours after birth at a dose of 0.15 mg per kilogram of body weight per day for three days, followed by a tapering of the dose over a period of seven days. The primary outcome was death or chronic lung disease at 36 weeks' postmenstrual age.



The relative risk of death or chronic lung disease in the dexamethasone-treated infants, as compared with those who received placebo, was 0.9 (95 percent confidence interval, 0.8 to 1.1). Since the effect of dexamethasone treatment did not vary according to the ventilatory approach, the two dexamethasone groups and the two placebo groups were combined. The infants in the dexamethasone group were less likely than those in the placebo group to be receiving oxygen supplementation 28 days after birth (P=0.004) or open-label dexamethasone (P=0.01), were more likely to have hypertension (P<0.001), and were more likely to be receiving insulin treatment for hyperglycemia (P=0.02). During the first 14 days, spontaneous gastrointestinal perforation occurred in a larger proportion of infants in the dexamethasone group (13 percent, vs. 4 percent in the placebo group; P=0.02). The dexamethasone-treated infants had a lower weight (P=0.02) and a smaller head circumference (P=0.04) at 36 weeks' postmenstrual age.



In preterm infants, early administration of dexamethasone at a moderate dose has no effect on death or chronic lung disease and is associated with gastrointestinal perforation and decreased growth.

title: New insights into spontaneous intestinal perforation using a national data set (3): antenatal steroids have no adverse association with spontaneous intestinal perforation
abstract: To examine whether antenatal steroids (ANS), alone or with early indomethacin, are associated with spontaneous intestinal perforation (SIP). SIP is a known complication of concurrent post-natal administration of glucocorticoid and indomethacin in extremely low birth weight (ELBW) infants.A large de-identified national data set was retrospectively examined for infants with SIP without any report of other malformation or necrotizing entrocolitis. A control group was then derived matching for gender and birth weight (±20 g). Pre- and post-natal variables were tested by both univariate and multivariate analysis to identify associations with SIP.Results:From January 1996 to June 2004, there were 2 27 711 discharges from Pediatrix neonatal intensive care unit sites. From this population 388 infants with SIP associated with ELBW were compared to matched controls. Infants with SIP were more likely to have received early indomethacin and to have received a combination of early indomethacin with post-natal glucocorticoids (P<0.05 for both). When used alone (without subsequent indomethacin), ANS showed no association with SIP. When used in conjunction with indomethacin, ANS did not increase the rate of SIP beyond indomethacin alone.ELBW Infants that acquire SIP were more likely to have been exposed to early indomethacin and post-natal glucocorticoids. However, no association was found between SIP and ANS within a well-powered cohort.

title: Prophylactic indomethacin therapy in the first twenty-four hours of life for the prevention of patent ductus arteriosus in preterm infants treated prophylactically with surfactant in the delivery room.
abstract: To determine whether a course of low-dose indomethacin therapy, when initiated within 24 hours of birth, would decrease ductal shunting in premature infants who received prophylactic surfactant in the delivery room.



Ninety infants, with birth weights of 600 to 1250 gm, were entered into a prospective, randomized, controlled trial to receive either indomethacin, 0.1 mg/kg per dose, or placebo less than 24 hours and again every 24 hours for six doses. Echocardiography was performed on day 1 before treatment and on day 7, 24 hours after treatment. A hemodynamically significant patent ductus arteriosus (PDA) was confirmed with an out-of-study echocardiogram, and the nonresponders were treated with standard indomethacin or ligation.



Forty-three infants received indomethacin (birth weight, 915 +/- 209 gm; gestational age, 26.4 +/- 1.6 weeks; 25 boys), and 47 received placebo (birth weight, 879 +/- 202 gm; gestational age, 26.4 +/- 1.8 weeks; 22 boys) (P = not significant). Of 90 infants, 77 (86%) had a PDA by echocardiogram on the first day of life before study treatment; 84% of these PDAs were moderate or large in size in the indomethacin-treated group compared with 93% in the placebo group. Nine of forty indomethacin-treated infants (21%) were study-dose nonresponders compared with 22 (47%) of 47 placebo-treated infants (p < 0.018). There were no significant differences between both groups in any of the long-term outcome variables, including intraventricular hemorrhage, duration of oxygen therapy, endotracheal intubation, duration of stay in neonatal intensive care unit, time to regain birth weight or reach full caloric intake, incidence of bronchopulmonary dysplasia, and survival. No significant differences were noted in the incidence of oliguria, elevated plasma creatinine concentration, thrombocytopenia, pulmonary hemorrhage, or necrotizing enterocolitis.



The prophylactic use of low doses of indomethacin, when initiated in the first 24 hours of life in low birth weight infants who receive prophylactic surfactant in the delivery room, decreases the incidence of left-to-right shunting at the level of the ductus arteriosus.

title: Prophylactic indomethacin for prevention of intraventricular hemorrhage in premature infants.
abstract: The impact of early prophylactic use of intravenous indomethacin on the incidence and severity of periventricular-intraventricular hemorrhage and patent ductus arteriosus in 199 oxygen-requiring premature infants (less than or equal to 1300 g birth weight) was prospectively investigated. The trial was controlled, the infants were randomized, and the investigators were unaware of the group assignments. Patients with minimal (grade I) or no periventricular-intraventricular hemorrhage determined by prestudy echoencephalography were randomized within two birth weight subgroups (500 to 899 and 900 to 1300 g) to receive either prophylactic indomethacin (n = 99) or an equal volume of saline-vehicle placebo (n = 100). The first dose (0.2 mg/kg) was given within 12 hours of delivery and two subsequent doses (0.1 mg/kg) were administered at 12 hourly intervals. Prophylactic indomethacin significantly reduced the incidence of grades II to IV periventricular-intraventricular hemorrhage. Intraventricular hemorrhage was half as common in infants given prophylactic indomethacin as in control infants (23% v 46%, P less than .002). The reduction was manifested in both birth weight subgroups. Results of this study also confirmed a lower incidence of clinically significant patent ductus arteriosus in infants who received prophylactic indomethacin in contrast to those who received placebo (11% v 42%, P less than .001). No significant differences were found between treatment and control groups in the duration of oxygen therapy, mechanical ventilation, or hospitalization or in the incidence of pneumothorax, chronic lung disease, sepsis, necrotizing enterocolitis, retinopathy of prematurity, or death. Early prophylactic indomethacin initiated within 12 hours of delivery is effective in reducing the incidence of intraventricular hemorrhage as well as clinically significant patent ductus arteriosus in very low birth weight premature infants.

title: Patent Ductus Arteriosus, Indomethacin and Necrotizing Enterocolitis in Very Low Birth Weight Infants: A Population-Based Study
abstract: Patent ductus arteriosus is a risk factor for the development of necrotizing enterocolitis. The use of indomethacin to treat patent ductus arteriosus in preterm infants may either decrease the incidence of necrotizing enterocolitis by stabilizing or closing the ductus arteriosus or increase its incidence by a direct constricting effect on mesenteric blood vessels. The authors sought to evaluate the interrelationship between patent ductus arteriosus, treatment with indomethacin and the risk of necrotizing enterocolitis in very low birth weight infants.  The Israel National database includes prospectively collected data on 99% of all very low birth weight infants in Israel. The study population comprised 6146 infants of 24-34 weeks' gestation born between 1995 and 2000. The effect of patent ductus arteriosus on necrotizing enterocolitis was assessed using multiple regression analysis.  Necrotizing enterocolitis occurred in 5.5% (n = 343) of all infants, in 9.4% of infants with patent ductus arteriosus and in 8.9% of infants who received indomethacin. The occurrence of necrotizing enterocolitis was independently associated with the presence of patent ductus arteriosus among infants not treated with indomethacin (odds ratio, 1.85) and those who received indomethacin therapy (odds ratio, 1.53). Indomethacin therapy in absence of patent ductus arteriosus was not associated with an increased risk of necrotizing enterocolitis (odds ratio, 0.72).  Patent ductus arteriosus is an independent risk factor for the development of necrotizing enterocolitis in very low birth weight infants. Therapy with indomethacin did not have a significant effect on the risk for necrotizing enterocolitis.

title: A randomized, controlled trial of very early prophylactic ligation of the ductus arteriosus in babies who weighed 1000 g or less at birth.
abstract: We speculated that prophylactic ligation of the ductus arteriosus would reduce mortality and morbidity in very-low-birth-weight infants. To test this hypothesis, we randomly assigned 84 babies who weighed 1000 g or less at birth and required supplemental oxygen either to receive standard treatment (n = 44) or to undergo prophylactic surgical ligation of the ductus arteriosus on the day of birth (n = 40). The ductus was ligated in babies in the control group only if the shunt was hemodynamically important. All the babies were followed for one year. The incidence of necrotizing enterocolitis was reduced in the group that underwent prophylactic ligation (3 of 40 [8 percent]) as compared with the control group (13 of 44 [30 percent]; P = 0.002). The frequency of death, bronchopulmonary dysplasia, retinopathy of prematurity, and intraventricular hemorrhage was similar in both groups. Because early enteral feeding may have increased the incidence of necrotizing enterocolitis, we analyzed separately the babies who were fed early. Among the infants who were fed within 14 days of birth, those who underwent prophylactic ligation had a lower incidence of necrotizing enterocolitis (1 of 11 [9 percent]) than those who did not (13 of 24 [54 percent]; P = 0.001). Within the control group, the infants who were fed within 14 days of birth and whose ductus was ligated for medical reasons within 5 days of birth had a lower incidence of necrotizing enterocolitis (2 of 10  than those whose ductus was ligated later or not at all (11 of 14 [79 percent]; P = 0.004). We conclude that early surgical closure of the ductus arteriosus reduces the risk of necrotizing enterocolitis in infants of very low birth weight who require supplemental oxygen.

title: Patent Ductus Arteriosus, Indomethacin, and Intestinal Distension: Effects on Intestinal Blood Flow and Oxygen Consumption
abstract: To determine the relative importance of patent ductus arteriosus, indomethacin, and intestinal distension as factors that promote terminal ileum ischemia, eight near-term fetal lambs were surgically prepared by in situ cannulation of the proximal and distal ends of a loop of terminal ileum, formalin infiltration of the ductus arteriosus, and placement of a snare around the ductus arteriosus to control its patency. The incisions were closed; the lambs were delivered and mechanically ventilated. Terminal ileum blood flow and oxygen consumption were measured after the loop of ileum had been distended with 0.9% NaCl to luminal pressures of 1–2, 7, and 18 mm Hg (0.13–0.26, 0.93, and 2.38 kPa) (pressures observed in the intestinal lumen after feeding and during pathologic conditions). The effect of these pressures on terminal ileum blood flow and oxygen consumption was examined: 1) with ductus closed, 2) with ductus open, and 3) 1 h after administration of indomethacin (0.3 mg/kg; 0.8 μmol/kg) with ductus closed. Both open ductus and indomethacin produced a significant decrease in intestinal blood flow. This occurred over the entire range of luminal pressures examined. In all three study conditions, terminal ileum blood flow fell commensurate with a fall in perfusion pressure. Despite this absence of pressure-flow autoregulation, oxygen consumption was maintained when the ductus was closed or open. In contrast, indomethacin inhibited the ability of the terminal ileum to autoregulate its oxygen consumption. These findings suggest that both open ductus and indomethacin present an increased risk of intestinal ischemia. We hypothesize that indomethacin's beneficial effect on ductus closure may be counterbalanced by its negative effect on intestinal perfusion and metabolism.

title: Necrotizing Enterocolitis and Gastrointestinal Complications After Indomethacin Therapy and Surgical Ligation in Premature Infants With Patent Ductus Arteriosus
abstract: Indomethacin is the most frequently used pharmacological agent for closure of a patent ductus arteriosus (PDA) in premature infants. However, reports of complications, particularly, necrotizing enterocolitis (NEC) and isolated gastrointestinal perforation have generated concerns about the use of this medication. A retrospective study to compare the incidence of NEC, NEC-related gastrointestinal complications and isolated gastrointestinal perforation among premature infants treated for a PDA with either, indomethacin alone (I), surgical ligation alone (L), or indomethacin followed by surgical ligation (I–L).METHODS: The medical records of 224 infants that underwent treatment, either pharmacological or surgical, for a PDA, confirmed by echocardiography, over a 4-year period (1995 to 1998) were analyzed. Treatment history and gastrointestinal complications were reviewed. Of the 224 infants, 108 (48.2%) were treated with I, 50 (22.3%) by L, 66 (29.5%) with I–L. The clinical characteristics of the three treatment groups were similar and no differences in the incidence of NEC were observed between groups. NEC occurred in 14 (13%) of the I group, seven (14%) of the L group, and eight (12%) of the I–L group. The rate of NEC related gastrointestinal complications and isolated gastrointestinal perforation were also similar among groups. In this large retrospective study, indomethacin treatment for a significant PDA in premature infants was not associated with a greater risk for NEC or NEC-related gastrointestinal complications than surgical ligation.

title: Cerebral and splanchnic hemodynamics after duct ligation in very low birth weight infants.
abstract: To describe mesenteric and cerebral blood flow velocities after surgical patent ductus arteriosus (PDA) closure in premature infants.



We measured middle cerebral artery (MCA), celiac artery (CA), and superior mesenteric artery (SMA) Doppler ultrasound scanning blood flow velocity (BFV) preoperatively, 3 and 24 hours after ligation.



We studied 32 infants, with a mean (+/- SD) birthweight of 762 +/- 170 g and gestational age of 25.6 +/- 1.4 weeks at a mean age of 34 +/- 13 days. Significant changes in end-diastolic (EDV), average velocity (AV), and vascular resistance were measured in all 3 vessels by 3 hours. AV increased significantly in the CA and SMA within 3 hours; however, no significant increase in MCA AV was found until 24 hours after surgery.



PDA ligation significantly changes BFV in the MCA, CA, and SMA. In the MCA vascular tone is acutely modulated, with no change in AV at 3 hours. In the CA and SMA, AV increases acutely after ligation. These different patterns of change in BFV suggest region-specific adaptation to surgical PDA closure.

title: Effects of hypoxia and ischemia on autoregulation in postnatal intestine.
abstract: Pressure-flow autoregulation was quantified within in vitro intestine from 3- and 35-day-old swine before and after lowering arterial PO2 (hypoxia) or lowering baseline blood flow by means of norepinephrine infusion (ischemia). Autoregulation was elicited by reducing arterial pressure approximately 33% from an age-appropriate baseline pressure. In 3-day-old intestine, autoregulation was unaffected by hypoxia or ischemia: vascular resistance was unchanged after pressure reduction, while Gf averaged -0.33 +/- 0.15 vs. -0.26 +/- 0.05 under control vs. hypoxic conditions, and -0.48 +/- 0.15 vs. -0.46 +/- 0.11 under control vs. ischemic conditions, respectively. In 35-day-old intestine, autoregulation was enhanced by hypoxia and ischemia. Under both experimental conditions, vasodilation was noted in response to pressure reduction: Gf averaged -0.04 +/- 0.14 vs. 0.38 +/- 0.08 under control vs. hypoxic conditions, and -0.12 +/- 0.10 vs. 0.28 +/- 0.08 under control vs. ischemic conditions, respectively. Regression analysis revealed a significant inverse linear correlation between Gf and venous PO2 in older, but not younger, subjects. Significant relationships between Gf and blood flow were not demonstrated in either group under any experimental condition. We conclude that autoregulation is enhanced within in vitro intestine from 35-, but not 3-day-old, swine during hypoxia or ischemia, and that reduction of venous PO2 is the principal factor responsible for the effect noted in older subjects.

title: Age‐Dependent Changes in the Postnatal Intestinal Microcirculation
abstract: Significant changes occur in intestinal hemodynamics during the transition from fetal to newborn life and then again during the first postnatal month. Most importantly, basal vascular resistance substantially decreases following birth. It then decreases further between postnatal days 1 and 3, plateaus, and then begins a slow, progressive increase between postnatal days 12 and 30. The basal rate of intestinal blood flow mirrors the changes in vascular resistance in an inverse manner. The postnatal changes in vascular resistance appear to be mediated, in large part, by an increase in the constitutive and stimulated production of nitric oxide. Most importantly, the diameter of terminal mesenteric arteries (150–300 µm diameter) in newborn (i.e., 1 day old) swine is determined by three intrinsic vascular control systems: endothelial production of nitric oxide and endothelin, and the inherent myogenic response of vascular smooth muscle. In contrast, these vessels in older subjects (i.e., 35 days old) are primarily passive in nature and fail to demonstrate significant diameter change in response to blockade of endogenous nitric oxide production or endothelin receptors, or applied perturbations of pressure or flow rate. The circulatory physiology of the perinatal and newborn intestine is exceptional when compared to the adult condition inasmuch as several hemodynamic variables change quite dramatically between fetal and neonatal life and during the first postnatal month. The unique hemodynamic conditions that characterize the perinatal and newborn intestine appear to be part of the overall physiological transition that occurs as the fetus, once born, replaces the placenta with his gastrointestinal tract to obtain nutrition. The goal of this review is to describe the circulatory physiology of the perinatal and newborn intestine, with a particular emphasis on those portions of the intestinal microcirculation that have thus far been studied. First, however, it is important to discuss the age‐dependent changes that occur within the intestinal circulation during perinatal and early newborn life.

title: Surgical Therapy and Histological Abnormalities in Functional Isolated Small Bowel Obstruction and Idiopathic Gastrointestinal Perforation in the Very Low Birth Weight Infant
abstract: We examined surgical treatment, outcome, and histological findings in very low birth weight (VLBW) infants with functional isolated small bowel obstruction (FISBO) and idiopathic gastrointestinal perforation (IGIP). The files of 18 neonates (average gestational age 27.5 weeks; average birth weight 880 g), surgically treated for IGIP (n = 12) or FISBO (n = 6), were retrospectively reviewed. In both groups segmental or diffuse dilatation of the small bowel was seen. All but two perforations were localized in the small bowel. In half of the patients a discontinuous absence of the internal layer of the muscularis propria or muscularis mucosae was found. Signs of necrotizing enterocolitis (NEC) were absent. Most of the patients were treated with an enterostomy (IGIP: n = 11; FISBO: n = 4). Overall survival in both groups was 83%. Follow-up after enterostomy closure (mean 23 months) shows normal gastrointestinal function without failure to thrive in 67% of the survivors. Muscular wall abnormalities and small bowel distension are found in both FISBO and IGIP. Although the underlying etiology remains unclear, segmental muscular wall absence may be a major predisposing factor in both conditions. Creation of a temporary enterostomy is a valid surgical option in VLBW infants with minimal risk for recurrent obstruction and/or perforation. Survival and long-term gastrointestinal function is excellent. IGIP should be distinguished from NEC.

title: Are localized intestinal perforations distinct from necrotizing enterocolitis?
abstract: Localized intestinal perforation (LP) is thought to be a distinct entity when compared with perforation associated with necrotizing enterocolitis (NEC). Studies have indicated that LP is more amenable to percutaneous drainage and associated with a better outcome. We sought to determine whether LP and NEC could be distinguished based on clinical parameters alone.



A retrospective review of 40 neonates with gastrointestinal perforations between January 1990 and May 1998 was performed. All had undergone laparotomy and had histologic specimens available for evaluation.



Twenty-one neonates had necrotizing enterocolitis (NEC), and 19 had localized perforation (LP) based on histologic criteria. More neonates with LP were exposed to prenatal indomethacin (37% v 5%; P <.05), received intravenous dexamethasone (42% v 10%; P <.05), had umbilical artery catheters (63% v 14%; P <.05), and had a higher white blood cell (WBC) count (27.1 +/- 23.1 v 14.3 +/- 11.5; P <.05). More neonates with NEC had pneumatosis intestinalis (47% v 11%; P <.05). No significant differences existed in enteral feeding (16% LP v 38% NEC) or overall mortality rate (37% LP v 38% NEC). No statistical differences in the timing of perforation or clinical presentation were found.



NEC and LP are difficult to distinguish based on clinical parameters alone. The authors did find associations between LP and prenatal indomethacin, intravenous dexamethasone, umbilical artery catheters, and a higher WBC count. Mortality rate and clinical outcome were nearly identical in both groups. Pneumatosis intestinalis, thought to be pathognomonic for NEC, was seen on abdominal radiograph in 2 babies with histologically proven LP.

title: Spontaneous localized intestinal perforation and intestinal dilatation in very‐low‐birthweight infants
abstract: To elucidate how spontaneous localized intestinal perforation (SLIP) is related to intestinal morphological features such as dilatation in very‐low‐birthweight (VLBW) infants.  The medical records of 13 VLBW infants (<1500 g) undergoing laparotomy between 1983 and 2003 for presumed SLIP were retrospectively reviewed. Clinical findings including maternal, prenatal and perinatal factors were analysed, and the clinical and surgical findings upon laparotomy were compared.  Postnatal pathological conditions included patent ductus arteriosus (n= 7), sepsis (n= 2), respiratory distress syndrome (n= 7), intraventricular haemorrhage (n= 2), an indwelling catheter via the umbilical vein (n= 1) and pneumonia (n= 1). Indomethacin was used in seven neonates with patent ductus arteriosus, and dexamethasone preventive therapy was employed in one neonate for bronchopulmonary dysplasia. Operative findings revealed a localized small punched‐out perforation in the ileum. Five patients had intestinal dilatation: two with a perforation in the middle of the dilated intestine, and three with a perforation proximal to the region of dilatation. The muscularis propria was absent in the dilated intestine of four patients.

title: Understanding clinical literature relevant to spontaneous intestinal perforations.
abstract: Spontaneous intestinal perforation (SIP) has emerged as a disease of extremely low-birth-weight (ELBW) infants over the last two decades. Several risk factors have been associated with this disease including early postnatal steroids (EPS; use within the first week of life), early use of indomethacin (EUI; use within the first 3 postnatal days), and the synergistic combination of the two. These two risk factors are thought to play a causal role in the etiology of SIP through their effects on ileal trophism and motility. Two infectious agents ( Candida and Staphylococcus epidermidis) are commonly grown from peritoneal cultures of patients with SIP. It is less clear whether these infections play a causal role or if they represent comorbidities of perforation. Chorioamnionitis is thought to be a risk factor for SIP, as is the stress and elevated cortisol that accompanies it. Recent analyses suggest that antenatal indomethacin may also be a risk factor for SIP, particularly when given close to birth. These latter variables are more challenging to rank in importance compared with EPS and EUI, which have been repeatedly associated with SIP in both retrospective cohorts and randomized controlled trials. Because neonatal care of the ELBW infant is commonly standardized, the habitual combination of any of these risk factors potentially amplifies the risk of SIP. Many of these factors are medicines, thus SIP risk is exacerbated by select forms of polypharmacy. Our challenge lies in understanding how these drug interactions lead to harm.