Early exposures and inherent factors in premature newborns are associated with type 1 diabetes.

BACKGROUND: Pathophysiology of type 1 diabetes (T1D) involves immune responses that may be associated with early exposure to environmental factors among preterm newborns. The aim of this work was to evaluate for association between T1D and maternal, nutritional, and medical exposures during the neonatal period among premature newborns. METHODS: This is a multicenter, matched case-control study. Preterm newborns, who developed T1D before 18 years, were matched by sex, gestational age (GA), birth date, and medical center of birth with newborns who did not develop TID. Data included maternal medical history, birth weight (BW), length of hospitalization, enteral and parenteral medications, fluid administration, and feeding modalities during hospitalization. RESULTS: Fifty-two patients with T1D, 26 males, median age at T1D diagnosis 8.17 years (5.92-9.77), median GA 34 weeks (33-m36), and 132 matched controls, were included. Multivariate-conditional-regression demonstrated a significant association between T1D and any maternal illness (23.1% vs. 9.1%, OR = 4.99 (1.69-14.72), p = 0.004), higher BW-SDS (0.07 ± 0.95 vs. -0.27 ± 0.97, OR = 2.03 (1.19-3.49), p = 0.01), longer duration of glucose infusion (3 (1-5) days vs. 2 (0-4), OR = 1.23 (1.03-1.46), p = 0.02), and antibiotic therapy beyond the first week of life (19.2% vs. 6.9%, OR = 5.22 (1.32-20.70), p = 0.019). Antibiotic treatment during the first week of life was negatively associated with T1D (51.9% vs. 67.2%, OR 0.31 (0.11-0.88), p = 0.027). CONCLUSIONS: A novel association was demonstrated between the development of T1D and early interventions and exposures among preterm newborns. IMPACT: Type 1 diabetes mellitus during childhood may be associated with early exposures during the neonatal period, in addition to known maternal and neonatal metabolic parameters. Early exposure to intravenous antibiotics, differing between the first week of life and later, and longer parenteral glucose administration to preterm newborns were associated with childhood type 1 diabetes. This is in addition to familiar maternal risk factors. Future prospective studies should examine the microbial changes and immune system characteristics of preterm and term neonates exposed to parenteral antibiotics and glucose treatment, in order to validate our exploratory findings.

Neonatal morbidities and postnatal growth failure in very low birth weight, very preterm infants.

AIM: To assess postnatal growth in infants with and without major neonatal morbidities. METHODS: This study is based on analysis of data collected by the Israel Neonatal Network on VLBW infants (≤1500 g) born in Israel from 2009 to 2018. Postnatal growth was assessed in two 5 years epochs: 2009-2013 (n = 4583) and 2014-2018 (n = 4558). Outcome was considered as severe, mild and no postnatal growth failure (PNGF). Morbidities included respiratory distress syndrome, bronchopulmonary dysplasia, necrotising enterocolitis, patent ductus arteriosus and grades 3-4 intraventricular haemorrhage. Multinomial logistic regression analyses with the generalised estimating equation approach were applied. RESULTS: The study population composed 9141 infants. Of them, 2089 had at least one major morbidity and 7052 infants had none. In infants with no morbidities, 2.1% had severe PNGF, 23.7% mild PNGF and 74.2% had no PNGF, as compared to 13.6%, 43.9% and 42.5%, respectively, in infants with any major neonatal morbidity (p < 0.0001). CONCLUSION: Despite enormous advances in neonatal care, postnatal growth remains a challenge in VLBW infants, particularly in infants with major neonatal morbidities. Along with efforts to decrease morbidity, a more personalised plan and follow-up may be required in infants with major morbidities, given their high risk for diminished growth and potentially, adverse neurodevelopmental outcomes.

The Validity of Positive Coagulase-Negative Staphylococcus Cultures for the Diagnosis of Sepsis in the Neonatal Unit.

OBJECTIVE: Coagulase-negative Staphylococcus (CoNS) is the most frequent pathogen causing late-onset sepsis (LOS) in neonatal intensive care units (NICUs). Technical difficulties hinder blood culture (BC) collection and obtaining only one culture before initiating antibiotic therapy is a common practice. We sought to assess specific clinical information and CoNS cultures for the diagnosis of true bacteremia in the NICU. STUDY DESIGN: This historical cohort study was conducted in NICUs at the Hadassah-Hebrew University Medical Center of Jerusalem in Israel. Clinical and laboratory data in every CoNS bacteremia were collected and compared between bacteremia groups as follows: true positive, two positive BCs; contaminant, one positive BC out of two; undefined, one BC obtained and found positive. RESULTS: For 3.5 years, CoNS was isolated in 139 episodes. True positive was identified in 44 of 139 (31.7%), contaminant in 42 of 139 (30.2%), and the event was undefined in 53 of 139 (38.1%). Vancomycin treatment was more frequent in the true positive and undefined groups than the contaminant group (100, 90.6, and 73.8% respectively, p = 0.001); treatment was also prolonged in these two groups (p < 0.001). No clinical variables were associated with true bacteremia on multivariable analysis. CONCLUSION: Diagnosis should definitely be based on at least two positive BCs, despite objective difficulties in obtaining BCs in neonates. KEY POINTS: · CoNS is a frequent pathogen causing LOS in neonates.. · Due to technical difficulties, often only one culture is collected prior to antibiotic therapy.. · No clinical/laboratory variables were associated with the diagnosis of true CoNS bacteremia.. · Diagnosis should definitely be based on at least two positive BCs..

Eligibility for growth hormone therapy in children born small for gestational age is substantially lower than expected.

BACKGROUND: Growth hormone therapy is indicated for children who are both born 'small for gestational age' (SGA) and do not achieve adequate catch-up growth (ACUG). OBJECTIVE: To evaluate the actual incidence of infants born SGA and their actual ACUG. METHODS: Birth weight data from the newborn registry at two hospitals were analysed during four consecutive years. SGA was defined according to WHO parameters and the corresponding Israeli criteria. Follow-up measurements of height and weight were abstracted from either the Ministry of Health-child growth follow-up centres, or their paediatrician clinic. ACUG was declared when the height reached was above -2.5 or -2 standard deviations (SDS) from the mean for age and gender. RESULTS: Out of 43 307, only 524 babies in the cohort (1.2%) were SGA (52% of expected). This finding was consistent annually. Out of the 446 SGA born children with available growth data (85%) during 4-8 years, 405 children (90.8%) reached a height greater than -2SDS and 428 (96%!) reached a height greater than -2.5 SDS. Term children had higher rate of ACUG achievement as compared to preterm 97.2% vs 86.8% (P < .001). Birth week and birth weight were also related to achievement of ACUG (P < .001). CONCLUSION: This large representative, heterogeneous and Western Caucasian cohort indicates that the actual number of SGA newborns is nearly half of the expected and that the actual prevalence of ACUG is also significantly higher than previously reported. These findings may have an impact on morbidity, health cost planning and growth hormone requirements in SGA babies.

De novo variant in AMOTL1 in infant with cleft lip and palate, imperforate anus and dysmorphic features.

AMOTL1 belongs to the Motin family of proteins that are involved in organogenesis and tumorigenesis through regulation of cellular migration, tube formation, and angiogenesis. While involvement of all AMOTs in development or suppression of cancers is relatively well described, little is known about the congenital phenotype of pathogenic variants in these genes in humans. Recently, a heterozygous variant in AMOTL1 was published in association with orofacial clefts and cardiac abnormalities in an affected father and his daughter. However, studies in mice did not recapitulate the human phenotype and the case was summarized as inconclusive. We present a female infant with cleft lip and palate, imperforate anus and dysmorphic features, in whom trio exome sequencing revealed a de novo variant in AMOTL1 affecting a highly conserved amino acid (c.479C>T; p.[Pro160Leu]). Bioinformatic predictions and in silico modeling supported pathogenicity. This case reinforces the conjecture regarding the disruptive effect of pathogenic variants in AMOTL1 on organ formation in humans. Studies of additional families will reveal the full phenotypic spectrum associated with this multiple malformation syndrome.

Neonatal subgaleal hemorrhage unrelated to assisted vaginal delivery: clinical course and outcomes.

PURPOSE: The purpose of the study was to evaluate the occurrence of subgaleal hemorrhage (SGH) following non-assisted vaginal delivery (normal vaginal delivery or cesarean delivery), and to characterize associated factors, clinical course, and outcomes, compared to attempted assisted vaginal delivery (AVD)-associated SGH METHODS: A retrospective cohort study was conducted. All cases of SGH encountered following delivery of a singleton neonate at Hadassah, Hebrew University Medical Center during 2011-2018 were included. Maternal, fetal, intrapartum, and neonatal characteristics and outcomes were compared between AVD-related and non-AVD-related SGH groups. RESULTS: The overall incidence of SGH was 4.5/1000 (369/82,256) singleton deliveries. The incidences of AVD- and non-AVD-related SGH were 44.6/1000 (350/7852) and 0.3/1000 (19/74,404) singleton deliveries, respectively. Ten (53%) of the 19 non-AVD-related SGH were diagnosed after vaginal delivery and 9 (47%) after an urgent cesarean section. SGH severity was mild, moderate, and severe in 68%, 16%, and 16% of the cases, respectively. SGH severity did not differ between the attempted AVD group and the non-AVD-related SGH group. A higher proportion of neonates with non-AVD SGH required phototherapy treatment than did those diagnosed with AVD-related SGH (56% vs. 24%, P = 0.003). Other neonatal outcomes, including Apgar scores, maximal bilirubin level, length of stay, and the rate of composite adverse outcomes, did not differ between the groups. CONCLUSIONS: SGH, although rare, may be diagnosed after unassisted vaginal or cesarean delivery in the absence of an AVD attempt. We advocate continuing education for all medical staff who participate in peripartum and neonatal care, regarding the possible occurrence of non-AVD-related SGH.

[APNEA OF PREMATURITY - PATHOPHYSIOLOGY, TREATMENT & PROGNOSIS].

INTRODUCTION: Apnea of prematurity affects the majority of infants born before 34 weeks of complete gestation. Significant recurrent apnea of prematurity is associated with both short and long term complications and is a risk factor for increased mortality and neurodevelopmental disability. The current review discusses the recent advances in the understanding of the pathophysiology of apnea of prematurity, as well as the clinical questions relevant to physicians and staff treating infants with apnea of prematurity. Finally, we discuss monitoring and discharge decisions, and present recommendations following discharge from the neonatal intensive care unit.

Saliva Real-Time Polymerase Chain Reaction for Targeted Screening of Congenital Cytomegalovirus Infection.

BACKGROUND: Saliva real-time polymerase chain reaction (PCR) was shown to be sensitive and specific for the detection of congenital cytomegalovirus (cCMV) in universal screening studies. In the current study, we assessed the performance of saliva real-time PCR in newborns undergoing targeted cCMV screening. METHODS: Saliva real-time PCR results were prospectively correlated with reference-standard urine detection in newborns undergoing targeted cCMV screening over a 3-year period, in successive validation (concurrent testing of all saliva and urine specimens) and routine-screening (confirmatory urine testing of positive saliva results) implementation phases. RESULTS: The sensitivity, specificity, and positive and negative predictive values of saliva real-time PCR were 98.3% (95% confidence interval, 90.8%-99.9%), 91.5% (89.3%-93.3%), 45.6% (36.7%-54.7%), and 99.9% (99.2%-99.9%), respectively, in 856 concurrently tested newborns. True-positive saliva real-time PCR detection (defined in relation to urine detection) was associated with earlier saliva sampling (P = .002) and a higher saliva viral load (P < .001). We further identified a saliva viral load cutoff value that reliably distinguished between true-positive and false-positive saliva results. CONCLUSIONS: In newborns undergoing targeted screening for cCMV, saliva real-time PCR is highly sensitive yet has a low positive predictive value, necessitating confirmatory testing. Early sampling and application of a validated viral load cutoff could improve the assay performance and support its large-scale implementation in this growing clinical setting.

Homozygous variants in MAPRE2 and CDON in individual with skin folds, growth delay, retinal coloboma, and pyloric stenosis.

Cases with multiple molecular diagnoses are challenging to diagnose clinically, yet may be resolved by unbiased exome sequencing analysis. We report an infant with developmental delay, severe growth delay, dysmorphic features, and multiple congenital anomalies including retinal coloboma, congenital pyloric stenosis, and circumferential skin creases. Exome sequencing identified a homozygous missense variant in MAPRE2 and a homozygous stopgain (nonsense) variant in CDON. Variants in MAPRE2, encoding a regulator of microtubule dynamics, lead to congenital symmetric circumferential skin creases type 2, with associated dysmorphism, small growth parameters, and congenital cardiac and genital anomalies. Monoallelic variants in CDON, encoding a coreceptor for sonic hedgehog, have been associated with autosomal dominant pituitary stalk interruption syndrome and holoprosencephaly. Cdon-/- mice have multiple eye defects including coloboma, consistent with the observed human phenotype. Thus, the complex phenotypic presentation of the infant may potentially be attributed to a dual molecular diagnosis. Furthermore, we present CDON as a candidate gene for coloboma formation in addition to the known holoprosencephaly phenotype, and propose to expand the allelic spectrum of CDON to variants associated with autosomal recessive inheritance in addition to dominant inheritance.

Determining gestational age using genome methylation profile: A novel approach for fetal medicine.

Gestational age determination by traditional tools (last menstrual period, ultrasonography measurements and Ballard Maturational Assessment in newborns) has major limitations and therefore there is a need to find different approaches. In this study, we looked for a molecular marker that can be used to determine the accurate gestational age of the newborn. To this end, we performed reduced representation bisulfite sequencing (RRBS) on 41 cord blood and matching placenta samples from women between 25 and 40 weeks of gestation and generated an epigenetic clock based on the methylation level at different loci in the genome. We identified a set of 332 differentially methylated regions (DMRs) that undergo demethylation in late gestational age in cord blood cells and can predict the gestational age (r = -.7, P = 2E-05). Once the set of 411 DMRs that undergo de novo methylation in late gestational age was used in combination with the first set, it generated a more accurate clock (R = .77, P = 1.87E-05). We have compared gestational age determined by Ballard score assessment with our epigenetic clock and found high concordance. Taken together, this study demonstrates that DNA methylation can accurately predict gestational age and thus may serve as a good clinical predictor.

Risk factors associated with subgaleal hemorrhage in neonates exposed to vacuum extraction.

INTRODUCTION: Subgaleal hemorrhage (SGH) is a life-threatening neonatal condition that is strongly associated with vacuum assisted delivery (VAD). The factors associated with the development of SGH following VAD are not well-established. We aimed to evaluate the factors associated with the development of SGH following attempted VAD. MATERIAL AND METHODS: A retrospective case-control study of women who delivered at a tertiary university-affiliated medical center in Jerusalem, Israel, during 2009-2018. Cases comprised all parturients with singleton pregnancies for whom attempted VAD resulted in neonatal SGH. A control group of VAD attempts was established by matching one-to-one according to gestational age at delivery, parity and year of delivery. Fetal, intrapartum and vacuum procedure characteristics were compared between the groups. RESULTS: In all, 313 (89.5%) of the 350 attempted VAD were nulliparous. Baseline maternal and fetal characteristics were similar between the groups except for higher neonatal birthweight in the SGH group. In multivariate logistic regression analysis, only six independent risk factors were significantly associated with the development of SGH: second-stage duration (for each 30-minute increase, adjusted odds ratio [OR] 1.13; 95% confidence intervals [CI] 1.04-1.25; P = .006), presence of meconium-stained amniotic fluid (adjusted OR 2.61; 95% CI 1.52-4.48; P = .001), presence of caput succedaneum (adjusted OR 1.79; 95% CI 1.11-2.88; P = .01), duration of VAD (for each 3-minute increase, adjusted OR 2.04; 95% CI 1.72, 2.38; P < .001), number of dislodgments (adjusted OR 2.38; 95% CI 1.66-3.44; P < .001), and fetal head station (adjusted OR 3.57; 95% CI 1.42-8.33; P = .006). Receiver operating characteristic curves showed that VAD duration of ≥15 minutes had a 96.7% sensitivity and 75.0% specificity in predicting SGH formation, with an area under the curve equal to .849. CONCLUSIONS: Vacuum duration, the number of dislodgments, the duration of second stage of delivery, fetal head station, the presence of caput succedaneum and the presence of meconium were found to be independently associated with SGH formation.

Questionnaire-based study showed that neonatal chest radiographs could be reliably interpreted using the WhatsApp messaging application.

AIM: We surveyed whether clinicians used the WhatsApp messaging application to view neonatal chest radiographs and asked a sub-sample to compare them with computer screen viewings. METHODS: The study was conducted at three university-affiliated medical centres in Israel from June-December 2016. Questionnaires on using smartphones for professional purposes were completed by 68/71 paediatric residents and 20/28 neonatologists. In addition, 11 neonatologists viewed 20 chest radiographs on a computer screen followed by a smartphone and 10 viewed the same radiographs in the opposite order, separated by a washout period of 2 months. After another 2 months, five from each group viewed the same radiographs on a computer screen. Different interpretations between viewing modes were assessed. RESULTS: Most respondents used WhatsApp to send chest radiographs for consultation: 82% of the paediatric residents and 80% of the neonatologists. The mean number of inconsistencies in diagnosis was 3.7/20 between two computer views and 2.9/20 between computer and smartphone views (p = 0.88) and the disease severity means were 3.7/20 and 2.85/20, respectively (p = 0.94). Neonatologists using WhatsApp only determined umbilical line placement in 80% of cases. CONCLUSION: WhatsApp was reliable for preliminary interpretation of neonatal chest radiographs, but caution was needed when assessing umbilical lines.

Using anaerobic blood cultures for infants younger than 90 days rarely showed anaerobic infections but increased yields of bacterial growth.

AIM: The use of anaerobic blood cultures in infants suspected of bacteraemia is controversial. Our children's hospital uses both aerobic and anaerobic media, regardless of the risk of anaerobic infection, and the aim of this study was to re-evaluate the use of anaerobic cultures in infants. METHODS: We collected retrospective data from 2002 to 2016 on all blood cultures taken from infants younger than 90 days in the Hadassah-Hebrew University Medical Centre, Jerusalem, Israel. The incidence and characteristics of infants with positive anaerobic blood cultures were assessed. RESULTS: During the study period, 51 035 blood cultures were drawn from 44 304 infants. Of these, 1496 (2.9%) were clinically significant positive cultures. Pathogenic obligatory anaerobic bacteraemia was extremely rare, with only 37 positive cultures (0.07%) from all of the cultures drawn. No specific risk factors for obligatory anaerobic bacteraemia could be defined, but as many as 174 (11.6%) clinically significant isolates were only detected in the anaerobic culture bottle. CONCLUSION: True anaerobic bacteraemia was extremely rare in neonates. Nevertheless, using anaerobic culture media may increase the overall yield of bacterial culture growth by isolating anaerobic-facultative bacteria. This should be weighed up against increasing the volume of blood used for the aerobic culture.

[ADVANCES IN FETAL THERAPY IN COMPLICATED MONOCHORIONIC PREGNANCIES AND IN SEVERE CONGENITAL DIAPHRAGMATIC HERNIA: FIVE YEARS EXPERIENCE].

INTRODUCTION: : Minimally invasive fetal therapeutic procedures reduce the morbidity and mortality in monochorionic (MC) twins and in fetuses with congenital diaphragmatic hernia (CDH). MC pregnancies share their blood systems due to communicating vessels over their single placenta and may develop specific complications: Twin-to-Twin transfusion syndrome (TTTS), Selective intrauterine growth restriction (sIUGR), Twin Anemia-Polycythemia Sequence (TAPS), Twin Reverse Arterial Perfusion Syndrome (TRAP) or anomalies in one. Half of complicated MC require intrauterine interventions. Severe CDH is linked to a high rate of neonatal death due to pulmonary hypoplasia. Fetoscopic tracheal occlusion (FETO) with a balloon improves postnatal outcome. AIMS: A fetal therapy center was established in the Hadassah Medical Centers, Jerusalem in 2011 for intrauterine interventions. We report our 5 years' experience. METHODS: This prospective cohort follows the outcome of MC pregnancies and cases of severe CDH which underwent therapeutic fetal procedures in Hadassah between the years 2011-16. RESULTS: Out of 114 procedures, 95 were in MC: 84 monochorionic diamniotic twins, 7 monochorionic monoamniotic twins, 2 dichorionic triamniotic triplets and 2 monochorionic triplets. We treated 65 TTTS cases with fetoscopy and laser ablation of communicating vessels. The survival rate of both twins was 58.5% and at least one survived in 81.5% of the cases. In 2nd/3rd trimesters selective termination of 15 cases the survival rate of the remaining twin was 87%. In 11 cases of TRAP sequence treated with laser ablation of the feeding vessel the survival of the remaining twin was 91%. In 19 fetoscopies in severe CDH, 12 were for balloon insertion and 7 for removal. Endotracheal balloon was successfully placed in 11 of 12 cases (10 left-sided, 1 right-sided CDH). Balloon removal was prenatally performed by elective fetoscopy (n=7) or by intrapartum urgent puncture. There were no intrauterine fetal deaths. In isolated left-sided CDH the survival was 57%, whereas none survived in non-isolated left-sided CDH and right sided CDH. CONCLUSIONS: In-utero procedures are safe for the mother and increase newborn survival in MC pregnancies, thus specialized clinics are life-saving. FETO is a therapeutic option for severe CDH. Our results meet similar achievements reported by other leading world centers.

Maternal resolution of preterm birth from 1 to 18 months.

Preterm birth can be traumatic for some mothers, involving feelings of grief over the hoped-for full-term pregnancy. In this longitudinal study, we interviewed 50 mothers of preterm infants, using the reaction to diagnosis interview when their child was 1 month and 18 months old. We examined change and stability in resolution status over time. Additionally, we explored possible predictors of resolution trajectories between 1 and 18 months. Findings indicated that resolution at 1 month was not yet common. The rate of resolution at 18 months was 62.6%, compared with 38.2% at 1 month. Prenatal precursors of preterm birth, lower medical neonatal risk, and lower maternal stress at 1 month significantly differentiated mothers who attained resolution as early as at 1 month from those who were unresolved at 1 and 18 months. Lower maternal stress at 1 month was the only predictor that significantly differentiated initially unresolved mothers who later attained resolution from those who remained unresolved at 18 months. Discussion focuses on maternal stress, which may mark a subgroup of mothers of preterm infants who are at risk of being unresolved through the first 18 months, and who may benefit from resolution-focused intervention.

[CONTROLLING AN OUTBREAK OF RESPIRATORY SYNCYTIAL VIRUS (RSV AMONG NICU PATIENTS AND THE MEDICAL TEAM].

Respiratory Syncytial Virus (RSV is the most common cause of respiratory infections in infants, causing bronchiolitis and pneumonia. Premature infants have an increased risk for developing severe illness and even death. A monoclonal antibody vaccination named Palivizumab is available for preventing RSV infection. We describe an outbreak and control of RSV infections in one of our neonatal intensive care units, involving three patients and two medical team members.

The association of maternal intrapartum subfebrile temperature and adverse obstetric and neonatal outcomes.

BACKGROUND: Subfebrile intrapartum maternal temperature is very common, yet there is sparse evidence regarding its causes or its effects on perinatal outcomes. We examined whether mild temperature elevation during labour is a risk marker for adverse obstetric and neonatal outcomes. METHODS: A retrospective cohort analysis including 42 601 term, singleton live-births in two medical centres between 2003 and 2010 was performed. This study compared women who experienced a maximal intrapartum temperature of ≤37°C with women who experienced subfebrile intrapartum temperature (37.1-37.9°C). Adjusted risks for adverse obstetric and neonatal outcomes were calculated by using multivariable logistic regression models. RESULTS: Compared with maternal temperature ≤ 37°C, subfebrile temperature was associated with higher rates of primary caesarean deliveries {adjusted odds ratios [aOR] = 1.36 [95% confidence interval (CI) 1.25, 1.49])} and assisted vaginal deliveries (aOR = 1.20 [95% CI 1.11, 1.30]), as well as with greater risks of early neonatal sepsis (aOR = 2.66 [95% CI 1.88, 3.77]), neonatal intensive care unit admissions (aOR = 1.40 [95% CI 1.08, 1.83]), and neonatal asphyxia or seizures (aOR = 3.18 [95% CI 1.51, 6.70]). Mildly elevated maternal intrapartum temperature (37.1-37.5°C) was also associated with adverse outcomes. CONCLUSIONS: Maternal intrapartum subfebrile temperature may be an indicator of operative delivery and neonatal morbidity. Further research is needed to confirm these findings and to reveal underlying mechanisms.

A randomized controlled trial of the efficacy and respiratory effects of patient-controlled intravenous remifentanil analgesia and patient-controlled epidural analgesia in laboring women.

BACKGROUND: Safe and effective alternatives are required in labor when epidural analgesia is not appropriate. We hypothesized that patient-controlled IV remifentanil labor analgesia would not be inferior to patient-controlled epidural labor analgesia. METHODS: This randomized nonblinded controlled noninferiority study in healthy women with a singleton fetus and vertex presentation was performed at 1 site. Women were randomized to receive patient-controlled IV analgesia titrated from 20 mcg up to a maximum bolus dose of 60 mcg with a lockout interval of 1 to 2 minutes, or patient-controlled epidural analgesia 0.1% bupivacaine with 2 mcg/mL fentanyl (initiation bolus 15 mL; maintenance bolus 10 mL, lockout interval 20 minutes, basal infusion 5 mL/h). Crossover was permitted after 30 minutes. The primary study outcome was efficacy (assessed as hourly numerical rating scale [NRS] pain score [11-point NRS] and maternal satisfaction [11-point NRS]); the secondary outcome was safety (maternal apnea). Supplementary oxygen was administered continuously during the respiratory monitoring period. During the first hour of analgesia, the heart rate, respiratory rate, pulse oximetry (SpO2), and end-tidal CO2, as an indication of apnea, were compared. Apnea lasting >40 seconds was managed by light stimulation by the attending anesthesiologist. RESULTS: Forty women were recruited to the following groups: remifentanil n = 19 (1 exclusion), epidural n = 20. Four crossed over: 3 from the remifentanil to epidural group and 1 from the epidural to remifentanil group. Mean (± SD) baseline NRS pain scores were similar, 8.4 ± 1.5 for remifentanil and 8.7 ± 1.2 for epidural analgesia, P = 0.52. Baseline adjusted mean NRS reduction at 30 minutes for remifentanil was -4.5 (± 0.6) vs -7.1(± 0.6) for epidural analgesia, P < 0.0001 for both. Pain score at 30 minutes was 3.7 ± 2.8 for remifentanil and 1.5 ± 2.2 for epidural analgesia, P = 0.009. Remifentanil was inferior to epidural analgesia with respect to the NRS at all time points, because the observed difference in NRS was greater than the expected -1.5 units. Maternal satisfaction was 8.6 ± 1.4 for the remifentanil group and 9.1 ± 1.5 for epidural group, P = 0.26. Mean respiratory rate was lower in the remifentanil group, 18 ± 4 vs 21 ± 4 breaths/min in the epidural group, P = 0.03. Mean SpO2 was lower in the remifentanil group 96.8% ± 1.4 vs 98.4 ± 1.2 for epidural group, P < 0.0001. There were 9 apnea events; all occurred in 5 women receiving remifentanil (5/19 [26.3%], P = 0.046). Apgar scores and neonatal respiratory outcomes were similar. CONCLUSION: IV remifentanil is inferior to epidural analgesia for provision of labor analgesia; however, remifentanil does provide a satisfactory level of labor analgesia. Laboring women receiving remifentanil require suitable monitoring to detect and alert for apnea.