Birth attendants as perinatal verbal autopsy respondents in low- and middle-income countries: a viable alternative?

OBJECTIVE: To assess the feasibility of using birth attendants instead of bereaved mothers as perinatal verbal autopsy respondents. METHODS: Verbal autopsy interviews for early neonatal deaths and stillbirths were conducted separately among mothers (reference standard) and birth attendants in 38 communities in four developing countries. Concordance between maternal and attendant responses was calculated for all questions, for categories of questions and for individual questions. The sensitivity and specificity of individual questions with the birth attendant as respondent were assessed. FINDINGS: For early neonatal deaths, concordance across all questions was 94%. Concordance was at least 95% for more than half the questions on maternal medical history, birth attendance and neonate characteristics. Concordance on any given question was never less than 80%. Sensitivity and specificity varied across individual questions, more than 80% of which had a sensitivity of at least 80% and a specificity of at least 90%. For stillbirths, concordance across all questions was 93%. Concordance was 95% or greater more than half the time for questions on birth attendance, site of delivery and stillborn characteristics. Sensitivity and specificity varied across individual questions. Over 60% of the questions had a sensitivity of at least 80% and over 80% of them had a specificity of at least 90%. Overall, the causes of death established through verbal autopsy were similar, regardless of respondent. CONCLUSION: Birth attendants can substitute for bereaved mothers as verbal autopsy respondents. The questions in existing harmonized verbal autopsy questionnaires need further refinement, as their sensitivity and specificity differ widely.

Causes of community stillbirths and early neonatal deaths in low-income countries using verbal autopsy: an International, Multicenter Study.

OBJECTIVE: Six million stillbirths (SB) and early neonatal deaths (END) occur annually worldwide, mostly in rural settings distant from health facilities. We used verbal autopsy (VA), to understand causes of non-hospital, community-based SB and END from four low-income countries. STUDY DESIGN: This prospective observational study utilized the train-the-trainer method. VA interviewers conducted standardized interviews; in each country data were reviewed by two local physicians who assigned an underlying causes of deaths (COD). RESULT: There were 252 perinatal deaths (118 END; 134 SB) studied from pooled data. Almost half (45%) the END occurred on postnatal day 1, 19% on the second day and 16% the third day. Major early neonatal COD were infections (49%), birth asphyxia (26%), prematurity (17%) and congenital malformations (3%). Major causes of SB were infection (37%), prolonged labor (11%), antepartum hemorrhage (10%), preterm delivery (7%), cord complications (6%) and accidents (5%). CONCLUSION: Many of these SB and END were from easily preventable causes. Over 80% of END occurred during the first 3 days of postnatal life, and >90% were due to infection, birth asphyxia and prematurity. The causes of SB were more varied, and maternal infections were the most common cause. Increased attention should be targeting at interventions that reduce maternal and neonatal infections and prevent END, particularly during the first 3 days of life.

An alternative strategy for perinatal verbal autopsy coding: single versus multiple coders.

OBJECTIVE: To determine the comparability between cause of death (COD) by a single physician coder and a two-physician panel, using verbal autopsy. METHODS: The study was conducted between May 2007 and June 2008. Within a week of a perinatal death in 38 rural remote communities in Guatemala, the Democratic Republic of Congo, Zambia and Pakistan, VA questionnaires were completed. Two independent physicians, unaware of the others decisions, assigned an underlying COD, in accordance with the causes listed in the chapter headings of the International classification diseases and related health problems, 10th revision (ICD-10). Cohen's kappa statistic was used to assess level of agreement between physician coders. RESULTS: There were 9461 births during the study period; 252 deaths met study enrolment criteria and underwent verbal autopsy. Physicians assigned the same COD for 75% of stillbirths (SB) (K = 0.69; 95% confidence interval: 0.61-0.78) and 82% early neonatal deaths (END) (K = 0.75; 95% confidence interval: 0.65-0.84). The patterns and proportion of SBs and ENDs determined by the physician coders were very similar compared to causes individually assigned by each physician. Similarly, rank order of the top five causes of SB and END was identical for each physician. CONCLUSION: This study raises important questions about the utility of a system of multiple coders that is currently widely accepted and speculates that a single physician coder may be an effective and economical alternative to VA programmes that use traditional two-physician panels to assign COD.

Detection and quantitation of gallid herpesvirus 1 in avian samples by 5' Taq nuclease assay utilizing Minor Groove Binder technology.

A 5' Taq nuclease assay utilizing Minor Groove Binder technology and targeting the thymidine kinase gene of gallid herpesvirus 1 (GaHV-1) was designed and optimized for use in diagnosing avian infectious laryngotracheitis. The assay was specific for GaHV-1 in that it did not react with other avian viral or bacterial pathogens. The detection limit was 1.0x10(-2) median tissue culture infectious dose per reaction or 90 target copies per reaction. Fifteen out of 41 diagnostic samples from sick birds reacted in the assay, five of which produced a typical alphaherpesvirus cytopathic effect (CPE) on chicken kidney (CK) cells. Sequencing, using amplicons generated by a polymerase chain reaction with primers flanking the 5' Taq nuclease amplicon, confirmed the presence of GaHV-1 in six samples (two producing alphaherpesvirus CPE on CK cells, three not producing alphaherpesvirus CPE, and one that was not inoculated onto CK cells). Tracheal swabs taken from 18 healthy broilers did not react in the assay. The ability of the assay to determine viral load in samples was demonstrated. Overall the assay is suitable for the rapid diagnosis of infectious laryngotracheitis.

Using verbal autopsy to ascertain perinatal cause of death: are trained non-physicians adequate?

OBJECTIVES: To develop a standardized verbal autopsy (VA) training program and evaluate whether its implementation resulted in comparable knowledge required to classify perinatal cause of death (COD) by physicians and non-physicians. METHODS: Training materials, case studies, and written and mock scenarios for this VA program were developed using conventional VA and ICD-10 guidelines. This program was used to instruct physicians and non-physicians in VA methodology using a train-the-trainer model. Written tests of cognitive and applied knowledge required to classify perinatal COD were administered before and after training to evaluate the effect of the VA training program. RESULTS: Fifty-three physicians and non-physicians (nurse-midwives/nurses and Community Health Workers [CHW]) from Pakistan, Zambia, the Democratic Republic of Congo, and Guatemala were trained. Cognitive and applied knowledge mean scores among all trainees improved significantly (12.8 and 28.8% respectively, P < 0.001). Cognitive and applied knowledge post-training test scores of nurse-midwives/nurses were comparable to those of physicians. CHW (high-school graduates with 15 months or less formal health/nursing training) had the largest improvements in post-training applied knowledge with scores comparable to those of physicians and nurse-midwives/nurses. However, CHW cognitive knowledge post-training scores were significantly lower than those of physicians and nurses. CONCLUSIONS: With appropriate training in VA, cognitive and applied knowledge required to determine perinatal COD is similar for physicians and nurses-midwives/nurses. This suggests that midwives and nurses may play a useful role in determining COD at the community level, which may be a practical way to improve the accuracy of COD data in rural, remote, geographic areas.

Birth asphyxia survivors in a developing country.

OBJECTIVE: Determine the baseline incidence of birth asphyxia in neonatal intensive care unit (NICU) survivors in a developing country and the early neurodevelopmental outcomes of such infants. STUDY DESIGN: This cross-sectional, prospective study collected diagnostic and examination findings on all infants seen in the University of Zambia NICU follow-up clinic over a 4-week period. RESULT: Of the 182 infants, 42 (23%) had a clinical diagnosis of birth asphyxia. Of 42 infants with birth asphyxia, 13 (31%) had an abnormal neurologic examination during the clinic visit; in contrast, 13 of 141 infants without birth asphyxia (9%) had an abnormal examination (odds ratio 4.4, 95% confidence interval: 1.8, 10.4). CONCLUSION: Birth asphyxia survivors account for almost a quarter of NICU survivors in a developing country and half of those with an abnormal neurologic examination. Studies are necessary to determine the percent of birth asphyxia survivors who have permanent motor and cognitive disabilities.

Periodontal disease and adverse birth outcomes: a study from Pakistan.

OBJECTIVE: Periodontal disease may increase the risk of adverse birth outcomes; however, results have been mixed. Few studies have examined periodontal disease in developing countries. We describe the relationship between periodontal disease and birth outcomes in a community setting in Pakistan. STUDY DESIGN: This was a prospective cohort study. Enrollment occurred at 20-26 weeks of gestation. A study dentist performed the periodontal examination to assess probing depth, clinical attachment level, gingival index, and plaque index. Outcomes included stillbirth, neonatal death, perinatal death, < 32 weeks preterm birth, 32-36 weeks preterm birth, and low birthweight and are presented for increasing periodontal disease severity by quartiles. RESULTS: Dental examinations and outcome data were completed for 1152 women: 81% of the women were multiparous, with a mean age of 27 years; 33% of the women had no education. Forty-seven percent of the women had dental caries; 27% of the women had missing teeth, and 91% of the women had had no dental care in the last year. Periodontal disease was common: 76% of the women had > or = 3 teeth with a probing depth of > or = 3 mm; 87% of the women had > or = 4 teeth with a clinical attachment level of > or = 3 mm; 56% of the women had > or = 4 teeth with a plaque index of 3; and 60% of the women had > or = 4 teeth with a gingival index of 3. As the measures of periodontal disease increased from the 1st to 4th quartile, stillbirth and neonatal and perinatal death also increased, with relative risks of approximately 1.3. Early preterm birth increased, but the results were not significant. Late preterm birth and low birthweight were not related to measures of periodontal disease. CONCLUSION: Pregnant Pakistani women have high levels of moderate-to-severe dental disease. Stillbirth and neonatal and perinatal deaths increased with the severity of periodontal disease.

Detection of Arcobacter spp. in piggery effluent and effluent-irrigated soils in southeast Queensland.

AIMS: To investigate the occurrence and levels of Arcobacter spp. in pig effluent ponds and effluent-treated soil. METHODS AND RESULTS: A Most Probable Number (MPN) method was developed to assess the levels of Arcobacter spp. in seven pig effluent ponds and six effluent-treated soils, immediately after effluent irrigation. Arcobacter spp. levels in the effluent ponds varied from 6.5 x 10(5) to 1.1 x 10(8) MPN 100 ml(-1) and in freshly irrigated soils from 9.5 x 10(2) to 2.8 x 10(4) MPN g(-1) in all piggery environments tested. Eighty-three Arcobacter isolates were subjected to an abbreviated phenotypic test scheme and examined using a multiplex polymerase chain reaction (PCR). The PCR identified 35% of these isolates as Arcobacter butzleri, 49% as Arcobacter cryaerophilus while 16% gave no band. All 13 nonreactive isolates were subjected to partial 16S rDNA sequencing and showed a high similarity (>99%) to Arcobacter cibarius. CONCLUSIONS: A. butzleri, A. cryaerophilus and A. cibarius were isolated from both piggery effluent and effluent-irrigated soil, at levels suggestive of good survival in the effluent pond. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study to provide quantitative information on Arcobacter spp. levels in piggery effluent and to associate A. cibarius with pigs and piggery effluent environments.

Evaluation of the educational impact of the WHO Essential Newborn Care course in Zambia.

OBJECTIVES: To evaluate the effectiveness of the World Health Organization (WHO) Essential Newborn Care (ENC) course in improving knowledge and skills of nurse midwives in low-risk delivery clinics in a developing country. METHODS: The investigators identified the content specifications of the training material, developed both written and performance evaluations and administered the evaluations both before and after training clinical nurse midwives in Zambia. FINDINGS: Based on these evaluations, both the knowledge and skills of the nurse midwives improved significantly following the course (from a mean of 65% correct pretraining to 84% correct post-training and from 65% to 77% correct on the performance and written evaluations, respectively). The ENC course written evaluation was validated and both tools allowed evaluation of the ENC course training. CONCLUSIONS: We found significant improvements in trainees' knowledge and skills in essential newborn care following the WHO ENC course; however, lack of basic resources may have limited the application of the ENC guidelines. Implementation of the ENC course should be undertaken in consideration with the local conditions available for newborn care.

Maternal and neonatal outcomes of hospital vaginal deliveries in Tibet.

INTRODUCTION: To determine the outcomes of vaginal deliveries in three study hospitals in Lhasa, Tibet Autonomous Region (TAR), People's Republic of China (PRC), at high altitude (3650 m). METHODS: Prospective observational study of 1121 vaginal deliveries. RESULTS: Pre-eclampsia/gestational hypertension (PE/GH) was the most common maternal complication 18.9% (n=212), followed by postpartum hemorrhage (blood loss > or = 500 ml) 13.4%. There were no maternal deaths. Neonatal complications included: low birth weight (10.2%), small for gestational age (13.7%), pre-term delivery (4.1%) and low Apgar (3.7%). There were 11 stillbirths (9.8/1000 live births) and 19 early neonatal deaths (17/1000 live births). CONCLUSION: This is the largest study of maternal and newborn outcomes in Tibet. It provides information on the outcomes of institutional vaginal births among women delivering infants at high altitude. There was a higher incidence of PE/GH and low birth weight; rates of PPH were not increased compared to those at lower altitudes.

Association between early postnatal weight loss and death or BPD in small and appropriate for gestational age extremely low-birth-weight infants.

OBJECTIVE: To examine the association between weight loss during the first 10 days of life and the incidence of death or bronchopulmonary dysplasia (BPD) in small for gestational age (SGA) and appropriate for gestational age (AGA) extremely low-birth-weight infants. DESIGN/METHODS: This is a retrospective analysis of a cohort of ELBW (birth weight <1000 g) infants from the NICHD Neonatal Research Network's database. The cohort consisted of 9461 ELBW infants with gestational age of 24-29 weeks, admitted to Network's participating centers during calendar years 1994-2002 and surviving at least 72 h after birth. The cohort was divided into two groups, 1248 SGA (with birth weight below 10th percentile for gestational age) and 8213 AGA (with birth weight between 10th and 90th percentile) infants. We identified infants with or without weight loss during the first 10 days of life, which we termed as 'early postnatal weight loss' (EPWL). Univariate analyses were used to predict whether EPWL was related to the primary outcome, death or BPD, within each birth weight/gestation category (SGA or AGA). BPD and death were also analyzed separately in relation to EPWL. Logistic regression analysis was done to evaluate the risk of death or BPD in SGA and AGA groups, controlling for maternal and neonatal demographic and clinical factors found to be significant by univariate analysis. RESULTS: SGA ELBW infants had a lower prevalence of EPWL as compared with AGA ELBW infants (81.2 vs 93.7%, respectively, P<0.001). In AGA infants, univariate analysis showed that death or BPD rate was lower in the group of infants with EPWL compared with infants without EPWL (53.4 vs 74.3%, respectively, P<0.001). The BPD (47.2 vs 64%, P<0.001) and death (13.8 vs 32.9%, P<0.001) rate were similarly lower in the EPWL group. The risk-adjusted odds ratios (ORs) showed that EPWL was associated with lower rate of death or BPD (OR 0.47, 95% CI: 0.37-0.60). In SGA infants, on univariate analysis, a similar association between EPWL and outcomes was seen as shown in AGA infants: death or BPD (55.9 vs 75.2%, P<0.001), BPD rate (48.3 vs 62.1%, P=0.002) and rate death (19 vs 40.8%, P<0.001) for those with or without EPWL, respectively. Multiple logistic regression showed that as in AGA ELBW infants, EPWL was associated with lower risk for death or BPD (OR 0.60, 95% CI: 0.41-0.89) among SGA infants. CONCLUSIONS: SGA infants experienced less EPWL when compared with their AGA counterparts. EPWL was associated with a lower risk of death or BPD in both ELBW AGA and SGA infants. These data suggest that clinicians who consider the association between EPWL and risk of death or BPD should do so independent of gestation/birth weight status.

The use of chlorhexidine to reduce maternal and neonatal mortality and morbidity in low-resource settings.

Of the 4 million neonatal deaths and 500,000 maternal deaths that occur annually worldwide, almost 99% are in developing countries and one-third are associated with infections. Implementation of proven interventions and targeted research on a select number of promising high-impact preventative and curative interventions are essential to achieve Millennium Development Goals for reduction of child and maternal mortality. Feasible, simple, low-cost interventions have the potential to significantly reduce the mortality and severe morbidity associated with infection in these settings. Studies of chlorhexidine in developing countries have focused on three primary uses: 1) intrapartum vaginal and neonatal wiping, 2) neonatal wiping alone, and 3) umbilical cord cleansing. A study of vaginal wiping and neonatal skin cleansing with chlorhexidine, conducted in Malawi in the 1990s suggested that chlorhexidine has potential to reduce neonatal infectious morbidity and mortality. A recent trial of cord cleansing conducted in Nepal also demonstrated benefit. Although studies have shown promise, widespread acceptance and implementation of chlorhexidine use has not yet occurred. This paper is derived in part from data presented at a conference on the use of chlorhexidine in developing countries and reviews the available evidence related to chlorhexidine use to reduce mortality and severe morbidity due to infections in mothers and neonates in low-resource settings. It also summarizes issues related to programmatic implementation.

Pasteurella multocida detection by 5' Taq nuclease assay: a new tool for use in diagnosing fowl cholera.

A 5' Taq nuclease assay utilising minor groove binder technology and targeting the 16S rRNA gene was designed to detect Pasteurella multocida (the causative agent of fowl cholera) in swabs collected from poultry. The assay was first evaluated using pure cultures. The assay correctly identified four P. multocida taxonomic type strains, 18 P. multocida serovar reference strains and 40 Australian field isolates (17 from poultry, 11 from pigs and 12 from cattle). Representatives of nine other Pasteurella species, 26 other bacterial species (18 being members of the family Pasteurellaceae) and four poultry virus isolates did not react in the assay. The assay detected a minimum of approximately 10 cfu of P. multocida per reaction. Of 79 poultry swabs submitted to the laboratory for routine bacteriological culture, 17 were positive in the 5' Taq nuclease assay, but only 10 were positive by culture. The other 62 swabs were negative for P. multocida by both 5' Taq nuclease assay and culture. The assay is suitable for use in diagnosing fowl cholera, is more rapid than bacteriological culture, and may also have application in diagnosing P. multocida infections in cattle and pigs.

Cocaine exposure is associated with subtle compromises of infants' and mothers' social-emotional behavior and dyadic features of their interaction in the face-to-face still-face paradigm.

Prenatal cocaine and opiate exposure are thought to subtly compromise social and emotional development. The authors observed a large sample of 236 cocaine-exposed and 459 nonexposed infants (49 were opiate exposed and 646 nonexposed) with their mothers in the face-to-face still-face paradigm. Infant and maternal behaviors were microanalytically coded. No opiate-exposure effects were detected. However, mothers of cocaine-exposed infants showed more negative engagement than other mothers. The cocaine-exposed dyads also showed higher overall levels of mismatched engagement states than other dyads, including more negative engagement when the infants were in states of neutral engagement. Infants exposed to heavier levels of cocaine showed more passive-withdrawn negative engagement and engaged in more negative affective matching with their mothers than other infants. Although effect sizes were small, cocaine exposure, especially heavy cocaine exposure, was associated with subtly negative interchanges, which may have a cumulative impact on infants' later development and their relationships with their mothers.

Changes in mortality and morbidities among infants born at less than 25 weeks during the post-surfactant era.

OBJECTIVES: To compare mortality and death or major morbidity (DOMM) among infants <25 weeks estimated gestational age (EGA) born during two post-surfactant era time periods. STUDY DESIGN AND PATIENTS: Comparative cohort study of very low birthweight (501-1500 g) infants <25 weeks EGA in the NICHD Neonatal Research Network born during two post-surfactant era time periods (group I, 1991-1994, n=1408; group II, 1995-1998, n=1348). Perinatal and neonatal factors were compared, and group related mortality and DOMM risk were evaluated. RESULTS: Mortality was higher for group I (63.1% v 56.7%; p=0.0006). Antenatal steroids (ANS) and antenatal antibiotics (AABX), surfactant (p<0.0001), and bronchopulmonary dysplasia (p=0.0008) were more prevalent in group II. In a regression model that controlled for basic and delivery factors only, mortality risk was greater for group I than for group II (odds ratio (OR) 1.4, 95% confidence interval (CI) 1.2 to 1.7); the addition of AABX and surfactant, or ANS (OR 0.97, 95% CI 0.79 to 1.2) to the model appeared to account for this difference. There was no difference in DOMM (86.8% v 88.4%; p=0.2), but risk was lower for group I in regression models that included ANS (OR 0.70, 95% CI 0.52 to 0.94). CONCLUSION: Survival to discharge was more likely during the more recent period because of group differences in ANS, AABX, and surfactant. However, this treatment shift may reflect an overall more aggressive management approach. More consistent application of treatment has led to improving survival of <25 week EGA infants during the post-surfactant era, but possibly at the cost of greater risk of major in-hospital morbidities.

Prenatal drug exposure and maternal and infant feeding behaviour.

OBJECTIVE: To evaluate feeding difficulties and maternal behaviour during a feeding session with 1 month old infants prenatally exposed to cocaine and/or opiates. METHODS: The study is part of the maternal lifestyle study, which recruited 11 811 subjects at four urban hospitals, then followed 1388 from 1 to 36 months of age. Exposure to cocaine and opiates was determined by maternal interview and meconium assay. At the 1 month clinic visit, biological mothers were videotaped while bottle feeding their infants. This sample included 364 exposed to cocaine, 45 exposed to opiates, 31 exposed to both drugs, and 588 matched comparison infants. Mothers were mostly black, high school educated, and on public assistance. Videotapes were coded without knowledge of exposure status for frequency, duration and quality of infant sucking, arousal, feeding problems, and maternal feeding activity and interaction. RESULTS: No cocaine effects were found on infant feeding measures, but cocaine-using mothers were less flexible (6.29 v 6.50), less engaged (5.77 v 6.22), and had shorter feeding sessions (638 v 683 seconds). Opiate exposed infants showed prolonged sucking bursts (29 v 20 seconds), fewer pauses (1.6 v 2.2 per minute), more feeding problems (0.55 v 0.38), and increased arousal (2.59 v 2.39). Their mothers showed increased activity (30 v 22), independent of their infants' feeding problems. CONCLUSIONS: Previous concerns about feeding behaviour in cocaine exposed infants may reflect the quality of the feeding interaction rather than infant feeding problems related to prenatal exposure. However, opiate exposed infants and their mothers both contributed to increased arousal and heightened feeding behaviour.

Central and autonomic system signs with in utero drug exposure.

AIMS: To determine risk for central nervous system/autonomic nervous system (CNS/ANS) signs following in utero cocaine and opiate exposure. METHODS: A multisite study was designed to determine outcomes of in utero cocaine and opiate exposure. A total of 11 811 maternal/infant dyads were enrolled. Drug exposed (EXP) infants were identified by maternal self report of cocaine or opiate use or by meconium testing. Of 1185 EXP, meconium analysis confirmed exposure in 717 to cocaine (CO) only, 100 to opiates (OP), and 92 to opiates plus cocaine (OP+CO); 276 had insufficient or no meconium to confirm maternal self report. Negative exposure history was confirmed in 7442 by meconium analysis and unconfirmed in 3184. Examiners masked to exposure status, assessed each enrolled infant. Using generalised estimating equations, adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated for manifesting a constellation of CNS/ANS outcomes and for each sign associated with cocaine and opiate exposure. RESULTS: Prevalence of CNS/ANS signs was low in CO, and highest in OP+CO. Signs were significantly related to one another. After controlling for confounders, CO was associated with increased risk of manifesting a constellation of CNS/ANS outcomes, OR (95% CI): 1.7 (1.2 to 2.2), independent of OP effect, OR (95% CI): 2.8 (2.1 to 3.7). OP+CO had additive effects, OR (95% CI): 4.8 (2.9 to 7.9). Smoking also increased the risk for the constellation of CNS/ANS signs, OR (95% CI) of 1.3 (1.04 to 1.55) and 1.4 (1.2 to 1.6), respectively, for use of less than half a pack per day and half a pack per day or more. CONCLUSION: Cocaine or opiate exposure increases the risk for manifesting a constellation of CNS/ANS outcomes.

Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial.

OBJECTIVES: Infants of

Changes in arterial oxygen tension when weaning neonates from inhaled nitric oxide.

We set out to evaluate changes in arterial oxygen tension (PaO(2)) when weaning neonates from inhaled nitric oxide (INO). We reviewed the records of 505 prospectively collected INO weaning attempts on 84 neonates with hypoxic respiratory failure. PaO(2) values before and 30 min after weaning attempts were recorded. Relationships between change in PaO(2) and decreases in INO concentrations were investigated using regression analysis and ANOVA. PaO(2) decreased (-18.7 +/- 1.8 torr; P < 0.001); when weaning INO. A stepwise decline in PaO(2) was observed weaning INO from 40 ppm. The greatest decline occurred when INO was discontinued (-42.1 +/- 4.1 torr). Forward stepwise multiple regression using variables with significant relationships to the decline in PaO(2) identified the specific dose reduction 7(P < 0.001), the prewean PaO(2) (P < 0.001), and surfactant therapy (P = 0.018) as the variables best describing the change in PaO(2)(P = 0.004, r = 0.51). In conclusion, a graded decline in PaO(2) occurs when reducing INO. INO should be weaned to less than 1 ppm before discontinuing its use. Prior surfactant treatment appears to enhance the oxygenation reserve when weaning INO.

Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants.

BACKGROUND: The prophylactic administration of indomethacin reduces the frequency of patent ductus arteriosus and severe intraventricular hemorrhage in very-low-birth-weight infants (those with birth weights below 1500 g). Whether prophylaxis with indomethacin confers any long-term benefits that outweigh the risks of drug-induced reductions in renal, intestinal, and cerebral blood flow is not known. METHODS: Soon after they were born, we randomly assigned 1202 infants with birth weights of 500 to 999 g (extremely low birth weight) to receive either indomethacin (0.1 mg per kilogram of body weight) or placebo intravenously once daily for three days. The primary outcome was a composite of death, cerebral palsy, cognitive delay, deafness, and blindness at a corrected age of 18 months. Secondary long-term outcomes were hydrocephalus necessitating the placement of a shunt, seizure disorder, and microcephaly within the same time frame. Secondary short-term outcomes were patent ductus arteriosus, pulmonary hemorrhage, chronic lung disease, ultrasonographic evidence of intracranial abnormalities, necrotizing enterocolitis, and retinopathy. RESULTS: Of the 574 infants with data on the primary outcome who were assigned to prophylaxis with indomethacin, 271 (47 percent) died or survived with impairments, as compared with 261 of the 569 infants (46 percent) assigned to placebo (odds ratio, 1.1; 95 percent confidence interval, 0.8 to 1.4; P=0.61). Indomethacin reduced the incidence of patent ductus arteriosus (24 percent vs. 50 percent in the placebo group; odds ratio, 0.3; P<0.001) and of severe periventricular and intraventricular hemorrhage (9 percent vs. 13 percent in the placebo group; odds ratio, 0.6; P=0.02). No other outcomes were altered by the prophylactic administration of indomethacin. CONCLUSIONS: In extremely-low-birth-weight infants, prophylaxis with indomethacin does not improve the rate of survival without neurosensory impairment at 18 months, despite the fact that it reduces the frequency of patent ductus arteriosus and severe periventricular and intraventricular hemorrhage.