The Impact of Parental Presence Restrictions on Canadian Parents in the NICU During COVID-19: A National Survey.

The purpose of this research was to explore parental perspectives on the impact of parent restrictions imposed in response to the COVID-19 pandemic across Canadian Neonatal Intensive Care Units (NICUs). A co-designed online survey was conducted targeting parents (n = 235) of infants admitted to a Canadian NICU from March 1, 2020, until March 5, 2021. Parents completed the survey from 38 Canadian NICUs. Large variation in the severity of policies regarding parental presence was reported. Most respondents (68.9%) were classified as experiencing high restrictions, with one or no support people allowed in the NICU, and felt that policies were less easy to understand, felt less valued and respected, and found it more challenging to access medicine or health care. Parents reported gaps in care related to self-care, accessibility, and mental health outcomes. There is significant variation in parental restrictions implemented across Canadian NICUs. National guidelines are needed to support consistent and equitable care practices.

Parental perspectives on technology use to enhance communication and closeness during the COVID-19 parental presence restrictions.

Objective: To explore parental perspectives on the use of technology in neonatal intensive care units (NICU), and its impact during COVID-19 parental presence restrictions. Methods: Co-designed online survey targeting parents of infants admitted to a Canadian NICU from March 1st, 2020 until March 5th, 2021. Results: Parents (n = 117) completed the survey from 38 NICUs. Large variation in policies regarding parental permission to use technology across sites was reported. Restrictive use of technology was reported as a source of parental stress. While families felt that technology helped them feel close to their infant when they could not be in the NICU, it did not replace being in-person. Conclusion: Large variation in policies were reported. Despite concerns about devices in NICUs, evidence on how to mitigate these concerns exists. Benefits of using technology to enhance parental experiences appear substantial. Future study is needed to inform recommendations on technology use in the NICU.

Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants.

BACKGROUND: Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited. METHODS: We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy. RESULTS: Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P = 0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16). CONCLUSIONS: There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425.).

Postdischarge Iron Status in Very Preterm Infants Receiving Prophylactic Iron Supplementation after Birth.

OBJECTIVE: To determine postdischarge iron status and associated factors in very preterm infants. STUDY DESIGN: A retrospective cohort study was conducted through a provincial database on all very preterm infants born in Nova Scotia between 2005 and 2018. As a standard of care, all infants received prophylactic iron supplements starting at 2-4 weeks of chronological age and were tested for iron deficiency at 4 or 6 months corrected age. Iron deficiency was defined as serum ferritin <20 g/L at 4 months or <12 g/L at 6 months. Multivariate logistic regression analysis identified factors associated with iron deficiency. RESULTS: Among 411 infants, 132 (32.1%) had iron deficiency and 11 (2.7%) had iron deficiency anemia. The prevalence of iron deficiency decreased over time, from 37.6% in 2005-2011 to 25.8% in 2012-2018. Gestational hypertension in the mother (P = .01) and gestational age <27 weeks (P = .02) were independent risk factors for iron deficiency. In addition, the odds of iron deficiency were lower in the mixed-fed group (ie, with breast milk and formula combined) compared with the exclusive formula-fed group (P = .01). CONCLUSIONS: Iron deficiency was prevalent in 32% of the very preterm infants despite early iron prophylaxis. These results demonstrate the importance of monitoring iron stores during preterm follow-up. Information about risk factors is important to mitigate iron deficiency in very preterm infants.

Prophylactic cyclo-oxygenase inhibitor drugs for the prevention of morbidity and mortality in preterm infants: a network meta-analysis.

BACKGROUND: Patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. Cyclooxygenase inhibitors (COX-I) may prevent PDA-related complications. Controversy exists on which COX-I drug is the most effective and has the best safety profile in preterm infants. OBJECTIVES: To compare the effectiveness and safety of prophylactic COX-I drugs and 'no COXI prophylaxis' in preterm infants using a Bayesian network meta-analysis (NMA). SEARCH METHODS: Searches of Cochrane CENTRAL via Wiley, OVID MEDLINE and Embase via Elsevier were conducted on 9 December 2021. We conducted independent searches of clinical trial registries and conference abstracts; and scanned the reference lists of included trials and related systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that enrolled preterm or low birth weight infants within the first 72 hours of birth without a prior clinical or echocardiographic diagnosis of PDA and compared prophylactic administration of indomethacin or ibuprofen or acetaminophen versus each other, placebo or no treatment. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal. We used the GRADE NMA approach to assess the certainty of evidence derived from the NMA for the following outcomes: severe intraventricular haemorrhage (IVH), mortality, surgical or interventional PDA closure, necrotizing enterocolitis (NEC), gastrointestinal perforation, chronic lung disease (CLD) and cerebral palsy (CP). MAIN RESULTS: We included 28 RCTs (3999 preterm infants). Nineteen RCTs (n = 2877) compared prophylactic indomethacin versus placebo/no treatment, 7 RCTs (n = 914) compared prophylactic ibuprofen versus placebo/no treatment and 2 RCTs (n = 208) compared prophylactic acetaminophen versus placebo/no treatment. Nine RCTs were judged to have high risk of bias in one or more domains.We identified two ongoing trials on prophylactic acetaminophen. Bayesian random-effects NMA demonstrated that prophylactic indomethacin probably led to a small reduction in severe IVH (network RR 0.66, 95% Credible Intervals [CrI] 0.49 to 0.87; absolute risk difference [ARD] 43 fewer [95% CrI, 65 fewer to 16 fewer] per 1000; median rank 2, 95% CrI 1-3; moderate-certainty), a moderate reduction in mortality (network RR 0.85, 95% CrI 0.64 to 1.1; ARD 24 fewer [95% CrI, 58 fewer to 16 more] per 1000; median rank 2, 95% CrI 1-4; moderate-certainty) and surgical PDA closure (network RR 0.40, 95% CrI 0.14 to 0.66; ARD 52 fewer [95% CrI, 75 fewer to 30 fewer] per 1000; median rank 2, 95% CrI 1-2; moderate-certainty) compared to placebo. Prophylactic indomethacin resulted in trivial difference in NEC (network RR 0.76, 95% CrI 0.35 to 1.2; ARD 16 fewer [95% CrI, 42 fewer to 13 more] per 1000; median rank 2, 95% CrI 1-3; high-certainty), gastrointestinal perforation (network RR 0.92, 95% CrI 0.11 to 3.9; ARD 4 fewer [95% CrI, 42 fewer to 137 more] per 1000; median rank 1, 95% CrI 1-3; moderate-certainty) or CP (network RR 0.97, 95% CrI 0.44 to 2.1; ARD 3 fewer [95% CrI, 62 fewer to 121 more] per 1000; median rank 2, 95% CrI 1-3; low-certainty) and may result in a small increase in CLD (network RR 1.10, 95% CrI 0.93 to 1.3; ARD 36 more [95% CrI, 25 fewer to 108 more] per 1000; median rank 3, 95% CrI 1-3; low-certainty). Prophylactic ibuprofen probably led to a small reduction in severe IVH (network RR 0.69, 95% CrI 0.41 to 1.14; ARD 39 fewer [95% CrI, 75 fewer to 18 more] per 1000; median rank 2, 95% CrI 1-4; moderate-certainty) and moderate reduction in surgical PDA closure (network RR 0.24, 95% CrI 0.06 to 0.64; ARD 66 fewer [95% CrI, from 82 fewer to 31 fewer] per 1000; median rank 1, 95% CrI 1-2; moderate-certainty) compared to placebo. Prophylactic ibuprofen may result in moderate reduction in mortality (network RR 0.83, 95% CrI 0.57 to 1.2; ARD 27 fewer [95% CrI, from 69 fewer to 32 more] per 1000; median rank 2, 95% CrI 1-4; low-certainty) and leads to trivial difference in NEC (network RR 0.73, 95% CrI 0.31 to 1.4; ARD 18 fewer [95% CrI, from 45 fewer to 26 more] per 1000; median rank 1, 95% CrI 1-3; high-certainty), or CLD (network RR 1.00, 95% CrI 0.83 to 1.3; ARD 0 fewer [95% CrI, from 61 fewer to 108 more] per 1000; median rank 2, 95% CrI 1-3; low-certainty). The evidence is very uncertain on effect of ibuprofen on gastrointestinal perforation (network RR 2.6, 95% CrI 0.42 to 20.0; ARD 76 more [95% CrI, from 27 fewer to 897 more] per 1000; median rank 3, 95% CrI 1-3; very low-certainty). The evidence is very uncertain on the effect of prophylactic acetaminophen on severe IVH (network RR 1.17, 95% CrI 0.04 to 55.2; ARD 22 more [95% CrI, from 122 fewer to 1000 more] per 1000; median rank 4, 95% CrI 1-4; very low-certainty), mortality (network RR 0.49, 95% CrI 0.16 to 1.4; ARD 82 fewer [95% CrI, from 135 fewer to 64 more] per 1000; median rank 1, 95% CrI 1-4; very low-certainty), or CP (network RR 0.36, 95% CrI 0.01 to 6.3; ARD 70 fewer [95% CrI, from 109 fewer to 583 more] per 1000; median rank 1, 95% CrI 1-3; very low-certainty). In summary, based on ranking statistics, both indomethacin and ibuprofen were equally effective (median ranks 2 respectively) in reducing severe IVH and mortality. Ibuprofen (median rank 1) was more effective than indomethacin in reducing surgical PDA ligation (median rank 2). However, no statistically-significant differences were observed between the COX-I drugs for any of the relevant outcomes. AUTHORS' CONCLUSIONS: Prophylactic indomethacin probably results in a small reduction in severe IVH and moderate reduction in mortality and surgical PDA closure (moderate-certainty), may result in a small increase in CLD (low-certainty) and results in trivial differences in NEC (high-certainty), gastrointestinal perforation (moderate-certainty) and cerebral palsy (low-certainty). Prophylactic ibuprofen probably results in a small reduction in severe IVH and moderate reduction in surgical PDA closure (moderate-certainty), may result in a moderate reduction in mortality (low-certainty) and trivial differences in CLD (low-certainty) and NEC (high-certainty). The evidence is very uncertain about the effect of acetaminophen on any of the clinically-relevant outcomes.

Association of 24-Hour In-house Neonatologist Coverage with Outcomes of Extremely Preterm Infants.

OBJECTIVE: This study aimed to assess if 24-hour in-house neonatologist (NN) coverage is associated with delivery room (DR) resuscitation/stabilization and outcomes among inborn infants <29 weeks' gestational age (GA). STUDY DESIGN: Survey-linked cohort study of 2,476 inborn infants of 23 to 28 weeks' gestation, admitted between 2014 and 2015 to Canadian Neonatal Network Level-3 neonatal intensive care units (NICUs) with a maternity unit. Exposures were classified using survey responses based on the most senior provider offering 24-hour in-house coverage: NN, fellow, and no NN/fellow. Primary outcome was death and/or major morbidity (bronchopulmonary dysplasia, severe neurological injury, late-onset sepsis, necrotizing enterocolitis, and retinopathy of prematurity). Multivariable logistic regression analysis was used to assess the association between exposures and outcomes and adjust for confounders. RESULTS: Among the 28 participating NICUs, most senior providers ensuring 24-hour in-house coverage were NN (32%, 9/28), fellows (39%, 11/28), and no NN/fellow (29%, 8/28). No NN/fellow coverage and 24-hour fellow coverage were associated with higher odds of infants receiving DR chest compressions/epinephrine compared with 24-hour NN coverage (adjusted odds ratio [aOR] = 4.72, 95% confidence interval [CI]: 2.12-10.6 and aOR = 3.33, 95% CI: 1.44-7.70, respectively). Rates of mortality/major morbidity did not differ significantly among the three groups: NN, 63% (249/395 infants); fellow, 64% (1092/1700 infants); no NN/fellow, 70% (266/381 infants). CONCLUSION: 24-hour in-house NN coverage was associated with lower rates of DR chest compressions/epinephrine. There was no difference in neonatal outcomes based on type of coverage; however, further studies are needed as ecological fallacy cannot be ruled out. KEY POINTS: · Lower rates of DR cardiopulmonary resuscitation with 24h in-house NN coverage. · The type of 24h in-house coverage was not associated with mortality and/or major morbidity.. · High-volume centers more often have 24h in-house neonatal fellow coverage.

Development and validation of a risk prediction model of preterm birth for women with preterm labour symptoms (the QUIDS study): A prospective cohort study and individual participant data meta-analysis.

BACKGROUND: Timely interventions in women presenting with preterm labour can substantially improve health outcomes for preterm babies. However, establishing such a diagnosis is very challenging, as signs and symptoms of preterm labour are common and can be nonspecific. We aimed to develop and externally validate a risk prediction model using concentration of vaginal fluid fetal fibronectin (quantitative fFN), in combination with clinical risk factors, for the prediction of spontaneous preterm birth and assessed its cost-effectiveness. METHODS AND FINDINGS: Pregnant women included in the analyses were 22+0 to 34+6 weeks gestation with signs and symptoms of preterm labour. The primary outcome was spontaneous preterm birth within 7 days of quantitative fFN test. The risk prediction model was developed and internally validated in an individual participant data (IPD) meta-analysis of 5 European prospective cohort studies (2009 to 2016; 1,783 women; mean age 29.7 years; median BMI 24.8 kg/m2; 67.6% White; 11.7% smokers; 51.8% nulliparous; 10.4% with multiple pregnancy; 139 [7.8%] with spontaneous preterm birth within 7 days). The model was then externally validated in a prospective cohort study in 26 United Kingdom centres (2016 to 2018; 2,924 women; mean age 28.2 years; median BMI 25.4 kg/m2; 88.2% White; 21% smokers; 35.2% nulliparous; 3.5% with multiple pregnancy; 85 [2.9%] with spontaneous preterm birth within 7 days). The developed risk prediction model for spontaneous preterm birth within 7 days included quantitative fFN, current smoking, not White ethnicity, nulliparity, and multiple pregnancy. After internal validation, the optimism adjusted area under the curve was 0.89 (95% CI 0.86 to 0.92), and the optimism adjusted Nagelkerke R2 was 35% (95% CI 33% to 37%). On external validation in the prospective UK cohort population, the area under the curve was 0.89 (95% CI 0.84 to 0.94), and Nagelkerke R2 of 36% (95% CI: 34% to 38%). Recalibration of the model's intercept was required to ensure overall calibration-in-the-large. A calibration curve suggested close agreement between predicted and observed risks in the range of predictions 0% to 10%, but some miscalibration (underprediction) at higher risks (slope 1.24 (95% CI 1.23 to 1.26)). Despite any miscalibration, the net benefit of the model was higher than "treat all" or "treat none" strategies for thresholds up to about 15% risk. The economic analysis found the prognostic model was cost effective, compared to using qualitative fFN, at a threshold for hospital admission and treatment of ≥2% risk of preterm birth within 7 days. Study limitations include the limited number of participants who are not White and levels of missing data for certain variables in the development dataset. CONCLUSIONS: In this study, we found that a risk prediction model including vaginal fFN concentration and clinical risk factors showed promising performance in the prediction of spontaneous preterm birth within 7 days of test and has potential to inform management decisions for women with threatened preterm labour. Further evaluation of the risk prediction model in clinical practice is required to determine whether the risk prediction model improves clinical outcomes if used in practice. TRIAL REGISTRATION: The study was approved by the West of Scotland Research Ethics Committee (16/WS/0068). The study was registered with ISRCTN Registry (ISRCTN 41598423) and NIHR Portfolio (CPMS: 31277).

Association of Co-Exposure of Antenatal Steroid and Prophylactic Indomethacin with Spontaneous Intestinal Perforation.

OBJECTIVE: To evaluate the association of a combined exposure to antenatal steroids and prophylactic indomethacin with the outcome of spontaneous intestinal perforation (SIP) among neonates born at <26 weeks of gestation or <750 g birth weight. STUDY DESIGN: We conducted a retrospective study of preterm infants admitted to Canadian Neonatal Network units between 2010 and 2018. Infants were classified into 2 groups based on receipt of antenatal steroids; the latter subgrouped as recent (≤7 days before birth) or latent (>7 days before birth) exposures. The co-exposure was prophylactic indomethacin. The primary outcome was SIP. Multivariable logistic regression analysis was used to calculate aORs. RESULTS: Among 4720 eligible infants, 4121 (87%) received antenatal steroids and 1045 (22.1%) received prophylactic indomethacin. Among infants exposed to antenatal steroids, those who received prophylactic indomethacin had higher odds of SIP (aOR 1.61, 95% CI 1.14-2.28) compared with no prophylactic indomethacin. Subgroup analyses revealed recent antenatal steroids exposure with prophylactic indomethacin had higher odds of SIP (aOR 1.67, 95% CI 1.15-2.43), but latent antenatal steroids exposure with prophylactic indomethacin did not (aOR 1.24, 95% CI 0.48-3.21), compared with the respective groups with no prophylactic indomethacin. Among those not exposed to antenatal steroids, mortality was lower among those who received prophylactic indomethacin (aOR 0.45, 95% CI 0.28-0.73) compared with no prophylactic indomethacin. CONCLUSIONS: In preterm neonates of <26 weeks of gestation or birth weight <750 g, co-exposure of antenatal steroids and prophylactic indomethacin was associated with SIP, especially if antenatal steroids was received within 7 days before birth. Among those unexposed to antenatal steroids, prophylactic indomethacin was associated with lower odds of mortality.

Caregiver Presence and Involvement in a Canadian Neonatal Intensive Care Unit: An Observational Cohort Study.

BACKGROUND: Presence in the neonatal intensive care unit (NICU) is a vital step for caregivers initiating involvement, such as skin-to-skin contact, holding or singing/reading to their newborn. Little is known about caregiver presence and involvement in Canadian NICU's context by caregiver type (mother, father, other), and the association between maternal presence and key maternal and newborn characteristics. PURPOSE: The primary objective was to examine the presence and involvement of family caregivers in the NICU. The secondary objective was to examine the relationship between maternal presence and maternal and newborn characteristics. DESIGN AND METHODS: A prospective observational cohort study in an open bay setting of an Eastern Canadian NICU. Presence (physically present at the newborn's bedside) and involvement (e.g., skin-to-skin, singing/reading) were tracked daily by families in the NICU until discharge. Demographic information was also collected. RESULTS: Participants included 142 mothers and their newborns. Mothers were present 8.7 h/day, fathers were present 4.1 h/day, and other caregivers were present 1.8 h/day in the NICU in the first 34 days. Mothers were involved in care activities 50% of the time they were present in the NICU, whereas fathers and other caregivers were spending 20% and 6% of their time respectively. Regression identified maternal age, distance to home, parity, birthweight, and length of stay to be statistically significant variables related to maternal presence. CONCLUSIONS: There is variation in presence and involvement by caregiver type. Targeted interventions to maintain and increase mothers, fathers and other caregivers' presence and involvement in care throughout their stay in the NICU are recommended.

Do Single-Family Rooms Increase Parental Presence, Involvement, and Maternal Well-Being in Neonatal Intensive Care?

Objectives of this study were to determine whether single-family room (SFR) design enhances parental presence, involvement, and maternal well-being during neonatal intensive care hospitalization. An observational cohort including mothers of infants was randomly assigned to receive care in a tertiary-level open-bay (OB) (n = 35) or SFR (n = 36). Mothers were asked to complete daily diaries documenting parental presence, involvement in care, and questionnaires examining maternal well-being. Mother and father mean presence (standard deviation) was significantly higher in the SFR-17.4 (5.2) and 13.6 (6.8)-compared to OB-11.9 (6.3) and 4.6 (3.7) hours/day. Total time spent in care activities did not differ for mothers, except SFR mothers spent more time expressing breast milk (EBM). SFR fathers had greater involvement with care activities. There were no other significant differences. The SFR was associated with greater maternal presence, but not greater involvement in care activities except for EBM, nor improved maternal well-being. The SFR appears to have greater impact on fathers' involvement in care and comforting activities, although the amount of time involved remained quite low compared with mothers. Further studies examining ways to enhance parental involvement in the neonatal intensive care unit are warranted.

A co-design of clinical virtual care pathways to engage and support families requiring neonatal intensive care in response to the COVID-19 pandemic (COVES study).

BACKGROUND: In response to the COVID-19 pandemic, family presence restrictions in neonatal intensive care units (NICU) were enacted to limit disease transmission. This has resulted in communication challenges, negatively impacting family integrated care. AIM: To develop clinical care pathways to ensure optimal neonatal care to support families in response to parental presence restrictions imposed during the COVID-19 pandemic. METHODS: An agile, co-design process utilizing expert consensus of a large interdisciplinary team and focus groups and semi-structured interviews with families and HCPs were used to co-design clinical virtual care pathways. RESULTS: Three clinical virtual care pathways were co-designed: (1) building and maintaining relationships between family and healthcare providers; (2) awareness of resources; and (3) standardized COVID-19 messaging. Modifications were made to optimize uptake and utilization in the clinical areas. CONCLUSION: Clinical care virtual pathways were successfully co-designed to meet these needs to ensure more equitable family centered care.

Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial.

BACKGROUND: Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and increased serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth, and neonatal unit admission. Ursodeoxycholic acid is widely used as a treatment without an adequate evidence base. We aimed to evaluate whether ursodeoxycholic acid reduces adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. METHODS: We did a double-blind, multicentre, randomised placebo-controlled trial at 33 hospital maternity units in England and Wales. We recruited women with intrahepatic cholestasis of pregnancy, who were aged 18 years or older and with a gestational age between 20 weeks and 40 weeks and 6 days, with a singleton or twin pregnancy and no known lethal fetal anomaly. Participants were randomly assigned 1:1 to ursodeoxycholic acid or placebo, given as two oral tablets a day at an equivalent dose of 500 mg twice a day. The dose could be increased or decreased at the clinician's discretion, to a maximum of four tablets and a minimum of one tablet a day. We recommended that treatment should be continued from enrolment until the infant's birth. The primary outcome was a composite of perinatal death (in-utero fetal death after randomisation or known neonatal death up to 7 days after birth), preterm delivery (<37 weeks' gestation), or neonatal unit admission for at least 4 h (from birth until hospital discharge). Each infant was counted once within this composite. All analyses were done according to the intention-to-treat principle. The trial was prospectively registered with the ISRCTN registry, number 91918806. FINDINGS: Between Dec 23, 2015, and Aug 7, 2018, 605 women were enrolled and randomly allocated to receive ursodeoxycholic acid (n=305) or placebo (n=300). The primary outcome analysis included 304 women and 322 infants in the ursodeoxycholic acid group, and 300 women and 318 infants in the placebo group (consent to use data was withdrawn for 1 woman and 2 infants). The primary composite outcome occurred in 74 (23%) of 322 infants in the ursodeoxycholic acid group and 85 (27%) of 318 infants in the placebo group (adjusted risk ratio 0·85 [95% CI 0·62-1·15]). Two serious adverse events were reported in the ursodeoxycholic acid group and six serious adverse events were reported in the placebo group; no serious adverse events were regarded as being related to treatment. INTERPRETATION: Treatment with ursodeoxycholic acid does not reduce adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Therefore, its routine use for this condition should be reconsidered. FUNDING: National Institute for Health Research Efficacy and Mechanism Evaluation Programme.

A Comparison of Strategies for Managing the Umbilical Cord at Birth in Preterm Infants.

OBJECTIVE: To evaluate the rates of practice, and the associations between different cord management strategies at birth (delayed cord clamping [DCC], umbilical cord milking [UCM], and early cord clamping [ECC]) and mortality or major morbidity, rates of blood transfusion, and peak serum bilirubin in a large national cohort of very preterm infants. STUDY DESIGN: We retrospectively studied preterm infants <33 weeks of gestation admitted to the Canadian Neonatal Network between January 2015 and December 2017. Patients who received ECC (<30 seconds), UCM, or DCC (≥30 seconds) were compared. Multiple generalized linear/quantile logistic regression models were used. RESULTS: Of 12 749 admitted infants, 9729 were included; 4916 (50.5%) received ECC, 394 (4.1%) UCM, and 4419 (45.4%) DCC. After adjustment for potential confounders identified between groups in univariate analyses, the odds of mortality or major morbidity were higher in the ECC group when compared with UCM group (aOR, 1.18; 95% CI, 1.03-1.35). Mortality and intraventricular hemorrhage were associated with ECC as compared with DCC (aOR, 1.6 [95% CI, 1.22-2.1] and aOR, 1.29 [95% CI, 1.19-1.41], respectively). The odds of severe intraventricular hemorrhage were higher with UCM compared with DCC (aOR, 1.38; 95% CI, 1.05-1.81). Rates of blood transfusion were higher with ECC compared with UCM and DCC (aOR, 1.67 [95% CI, 1.31-2.14] and aOR, 1.68 [95% CI, 1.35-2.09], respectively), although peak serum bilirubin levels were not significantly different. CONCLUSIONS: Both DCC and UCM were associated with better short-term outcomes than ECC; however, the odds of severe intraventricular hemorrhage were higher with UCM compared with DCC.

Education of family members to support weaning to solids and nutrition in later infancy in term-born infants.

BACKGROUND: Education of family members about infant weaning practices could affect nutrition, growth, and development of children in different settings across the world. OBJECTIVES: To compare effects of family nutrition educational interventions for infant weaning with conventional management on growth and neurodevelopment in childhood. SEARCH METHODS: We used the standard strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 5), MEDLINE via PubMed (1966 to 26 June 2018), Embase (1980 to 26 June 2018), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 26 June 2018). We searched clinical trials databases, conference proceedings, and references of retrieved articles. We ran an updated search from 1 January 2018 to 12 December 2019 in the following databases: CENTRAL via CRS Web, MEDLINE via Ovid, and CINAHL via EBSCOhost. SELECTION CRITERIA: We included randomised controlled trials that examined effects of nutrition education for weaning practices delivered to families of infants born at term compared to conventional management (standard care in the population) up to one year of age. DATA COLLECTION AND ANALYSIS: Two review authors independently identified eligible trial reports from the literature search and performed data extraction and quality assessments for each included trial. We synthesised effect estimates using risk ratios (RRs), risk differences (RDs), and mean differences (MDs), with 95% confidence intervals (CIs). We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 21 trials, recruiting 14,241 infants. Five of the trials were conducted in high-income countries and the remaining 16 were conducted in middle- and low-income countries. Meta-analysis showed that nutrition education targeted at improving weaning-related feeding practices probably increases both weight-for-age z scores (WAZ) (MD 0.15 standard deviations, 95% CI 0.07 to 0.22; 6 studies; 2551 infants; I² = 32%; moderate-certainty evidence) and height-for-age z scores (0.12 standard deviations, 95% CI 0.05 to 0.19; 7 studies; 3620 infants; I² = 49%; moderate-certainty evidence) by 12 months of age. Meta-analysis of outcomes at 18 months of age was heterogeneous and inconsistent in the magnitude of effects of nutrition education on WAZ and weight-for-height z score across studies. One trial that assessed effects of nutrition education on growth at six years reported an uncertain effect on change in height and body mass index z score. Two studies investigated effects of nutrition education on neurodevelopment at 12 to 24 months of age with conflicting results. No trials assessed effects of nutrition education on long-term neurodevelopmental outcomes. AUTHORS' CONCLUSIONS: Nutrition education for families of infants may reduce the risk of undernutrition in term-born infants (evidence of low to moderate certainty due to limitations in study design and substantial heterogeneity of included studies). Modest effects on growth during infancy may not be of clinical significance. However, it is unclear whether these small improvements in growth parameters in the first two years of life affect long-term childhood growth and development. Further studies are needed to resolve this question.

Education of family members to support weaning to solids and nutrition in infants born preterm.

BACKGROUND: Weaning refers to the period of introduction of solid food to complement breast milk or formula milk. Preterm infants are known to acquire extrauterine growth restriction by the time of discharge from neonatal units. Hence, the postdischarge and weaning period are crucial for optimal growth. Optimisation of nutrition during weaning may have long-term impacts on outcomes in preterm infants. Family members of preterm infants may require nutrition education to promote ideal nutrition practices surrounding weaning in preterm infants who are at high risk of nutritional deficit. OBJECTIVES: To investigate the role of nutrition education of family members in supporting weaning in preterm infants with respect to their growth and neurodevelopment compared with conventional management. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE via PubMed (1966 to 26 June 2018), Embase (1980 to 26 June 2018), and CINAHL (1982 to 26 June 2018). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs. SELECTION CRITERIA: RCTs and quasi-RCTs were eligible for inclusion if they examined the effects of nutrition education of family members as compared to conventional management for weaning of preterm infants up to one year of corrected gestational age. We defined prematurity as less than 37 completed weeks of gestation. DATA COLLECTION AND ANALYSIS: At least two review authors independently screened potential studies for inclusion and planned to identify, extract data, and assess the quality of eligible studies. We resolved any differences in opinion through discussion with a third review author and consensus among all three review authors. MAIN RESULTS: No eligible trials looking at the impact of nutrition education of family members in weaning of preterm infants fulfilled the inclusion criteria of this systematic review. Two studies investigating the ideal timing for weaning in premature infants reported conflicting results, AUTHORS' CONCLUSIONS: We were unable to assess the impact of nutrition education of family members in weaning of preterm infants as there were no eligible studies. This may be due to the lack of evidence to determine the ideal weaning strategies for preterm infants with regards to the time of initiating weaning and type of solids to introduce. Trials are needed to assess the many aspects of infant weaning in preterm infants. Long-term neurodevelopment and metabolic outcomes should also be assessed in addition to growth parameters.

Risk of Severe Intraventricular Hemorrhage in the First Week of Life in Preterm Infants Transported Before 72 Hours of Age.

OBJECTIVES: Evaluate the risk of severe intraventricular hemorrhage, in the first week of life, in preterm infants undergoing early interhospital transport. DESIGN: Retrospective cohort study. SETTING: Tertiary neonatal centers of the Trent Perinatal Network in the United Kingdom. PATIENTS: Preterm infants less than 32 weeks gestation, who were either born within and remained at the tertiary neonatal center (inborn), or were transferred (transported) between centers in the first 72 hours of life. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Multivariable logistic regression models adjusting for key confounders were used to calculate odds ratios for intraventricular hemorrhage with 95% CIs for comparison of inborn and transported infants. Cranial ultrasound findings on day 7 of life. Secondary analyses were performed for antenatal steroid course and gestational age subgroups. A total of 1,047 preterm infants were included in the main analysis. Transported infants (n = 391) had a significantly higher risk of severe (grade III/IV) intraventricular hemorrhage compared with inborns (n = 656) (9.7% vs 5.8%; adjusted odds ratio, 1.69; 95% CI, 1.04-2.76), especially for infants born at less than 28 weeks gestation (adjusted odds ratio, 1.83; 95% CI, 1.03-3.21). Transported infants were less likely to receive a full antenatal steroid course (47.8% vs 64.3%; p < 0.001). A full antenatal steroid course significantly decreased the risk of severe intraventricular hemorrhage irrespective of transport status (odds ratio, 0.33; 95% CI, 0.2-0.55). However, transported infants less than 28 weeks gestation remained significantly more likely to develop a severe intraventricular hemorrhage despite a full antenatal steroid course (adjusted odds ratio, 2.84; 95% CI, 1.08-7.47). CONCLUSIONS: Preterm infants transported in the first 72 hours of life have an increased risk of early-life severe intraventricular hemorrhage even when maternal antenatal steroids are given. The additional burden of postnatal transport could be an important component in the pathway to severe intraventricular hemorrhage. As timely in-utero transfer is not always possible, we need to focus research on improving the transport pathway to reduce this additional risk.

Gastric Residual Volume Measurement in U.K. PICUs: A Survey of Practice.

OBJECTIVES: Despite little evidence, the practice of routine measurement of gastric residual volume to guide both the initiation and delivery of enteral feeding in PICUs is widespread internationally. In light of increased scrutiny of the evidence surrounding this practice, and as part of a trial feasibility study, we aimed to determine enteral feeding and gastric residual volume measurement practices in U.K. PICUs. DESIGN: An online survey to 27 U.K. PICUs. SETTING: U.K. PICUs. SUBJECTS: A clinical nurse, senior doctor, and dietician were invited to collaboratively complete one survey per PICU and send a copy of their unit guidelines on enteral feeding and gastric residual volume. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Twenty-four of 27 units (89%) approached completed the survey. Twenty-three units (95.8%; 23/24) had written feeding guidelines, and 19 units (19/23; 83%) sent their guidelines for review. More units fed continuously (15/24; 62%) than intermittently (9/24; 37%) via the gastric route as their primary feeding method. All but one PICU routinely measured gastric residual volume, regardless of the method of feeding. Eighteen units had an agreed definition of feed tolerance, and all these included gastric residual volume. Gastric residual volume thresholds for feed tolerance were either volume based (mL/kg body weight) (11/21; 52%) or a percentage of the volume of feed administered (6/21; 29%). Yet only a third of units provided guidance about the technique of gastric residual volume measurement. CONCLUSIONS: Routine gastric residual volume measurement is part of standard practice in U.K. PICUs, with little guidance provided about the technique which may impact the accuracy of gastric residual volume. All PICUs that defined feed tolerance included gastric residual volume in the definition. This is important to know when proposing a standard practice arm of any future trial of no-routine gastric residual volume measurement in critically ill children.

WITHDRAWN: Time to move on from early cord clamping in preterm infants.

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Oropharyngeal colostrum in preventing mortality and morbidity in preterm infants.

BACKGROUND: Placing a small volume of colostrum directly onto the buccal mucosa of preterm infants during the early neonatal period may provide immunological and growth factors that stimulate the immune system and enhance intestinal growth. These benefits could potentially reduce the risk of infection and necrotising enterocolitis (NEC) and improve survival and long-term outcome. OBJECTIVES: To determine if early (within the first 48 hours of life) oropharyngeal administration of mother's own fresh or frozen/thawed colostrum can reduce rates of NEC, late-onset invasive infection, and/or mortality in preterm infants compared with controls. To assess trials for evidence of safety and harm (e.g. aspiration pneumonia). To compare effects of early oropharyngeal colostrum (OPC) versus no OPC, placebo, late OPC, and nasogastric colostrum. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 8), MEDLINE via PubMed (1966 to August 2017), Embase (1980 to August 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to August 2017). We also searched clinical trials registries for ongoing and recently completed trials (clinicaltrials.gov; the World Health Organization International Trials Registry (www.whoint/ictrp/search/en/), and the ISRCTN Registry), conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We performed the last search in August 2017. We contacted trial investigators regarding unpublished studies and data. SELECTION CRITERIA: We searched for published and unpublished randomised controlled trials comparing early administration of oropharyngeal colostrum (OPC) versus sham administration of water, oral formula, or donor breast milk, or versus no intervention. We also searched for studies comparing early OPC versus early nasogastric or nasojejunal administration of colostrum. We considered only trials that included preterm infants at < 37 weeks' gestation. We did not limit the review to any particular region or language. DATA COLLECTION AND ANALYSIS: Two review authors independently screened retrieved articles for inclusion and independently conducted data extraction, data analysis, and assessments of 'Risk of bias' and quality of evidence. We graded evidence quality using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We contacted study authors for additional information or clarification when necessary. MAIN RESULTS: We included six studies that compared early oropharyngeal colostrum versus water, saline, placebo, or donor, or versus no intervention, enrolling 335 preterm infants with gestational ages ranging from 25 to 32 weeks' gestation and birth weights of 410 to 2500 grams. Researchers found no significant differences between OPC and control for primary outcomes - incidence of NEC (typical risk ratio (RR) 1.42, 95% confidence interval (CI) 0.50 to 4.02; six studies, 335 infants; P = 0.51; I² = 0%; very low-quality evidence), incidence of late-onset infection (typical RR 0.86, 95% CI 0.56 to 1.33; six studies, 335 infants; P = 0.50; I² = 0%; very low-quality evidence), and death before hospital discharge (typical RR 0.76, 95% CI 0.34 to 1.71; six studies, 335 infants; P = 0.51; I² = 0%; very low-quality evidence). Similarly, meta-analysis showed no difference in length of hospital stay between OPC and control groups (mean difference (MD) 0.81, 95% CI -5.87 to 7.5; four studies, 293 infants; P = 0.65; I² = 49%). Days to full enteral feeds were reduced in the OPC group with MD of -2.58 days (95% CI -4.01 to -1.14; six studies, 335 infants; P = 0.0004; I² = 28%; very low-quality evidence).The effect of OPC was uncertain because of small sample sizes and imprecision in study results (very low-quality evidence).No adverse effects were associated with OPC; however, data on adverse effects were insufficient, and no numerical data were available from the included studies.Overall the quality of included studies was low to very low across all outcomes. We downgraded GRADE outcomes because of concerns about allocation concealment and blinding, reporting bias, small sample sizes with few events, and wide confidence intervals. AUTHORS' CONCLUSIONS: Large, well-designed trials would be required to evaluate more precisely and reliably the effects of oropharyngeal colostrum on important outcomes for preterm infants.

Feed thickener for infants up to six months of age with gastro-oesophageal reflux.

BACKGROUND: Gastro-oesophageal reflux (GOR) is common in infants, and feed thickeners are often used to manage it in infants as they are simple to use and perceived to be harmless. However, conflicting evidence exists to support the use of feed thickeners. OBJECTIVES: To evaluate the use of feed thickeners in infants up to six months of age with GOR in terms of reduction in a) signs and symptoms of GOR, b) reflux episodes on pH probe monitoring or intraluminal impedance or a combination of both, or c) histological evidence of oesophagitis. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 2), MEDLINE via PubMed (1966 to 22 November 2016), Embase (1980 to 22 November 2016), and CINAHL (1982 to 22 November 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials. SELECTION CRITERIA: We included randomised controlled trials if they examined the effects of feed thickeners as compared to unthickened feeds (no treatment or placebo) in treating GOR in term infants up to six months of age or six months of corrected gestational age for those born preterm. DATA COLLECTION AND ANALYSIS: Two review authors independently identified eligible studies from the literature search. Two review authors independently performed data extraction and quality assessments of the eligible studies. Differences in opinion were resolved by discussion with a third review author, and consensus was reached among all three review authors. We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS: Eight trials recruiting a total of 637 infants met the inclusion criteria for the systematic review. The infants included in the review were mainly formula-fed term infants. The trials were of variable methodological quality. Formula-fed term infants with GOR on feed thickeners had nearly two fewer episodes of regurgitation per day (mean difference -1.97 episodes per day, 95% confidence interval (CI) -2.32 to -1.61; 6 studies, 442 infants, moderate-certainty evidence) and were 2.5 times more likely to be asymptomatic from regurgitation at the end of the intervention period (risk ratio 2.50, 95% CI 1.38 to 4.51; number needed to treat for an additional beneficial outcome 5, 95% CI 4 to 13; 2 studies, 186 infants, low-certainty evidence) when compared to infants with GOR on unthickened feeds. No studies reported failure to thrive as an outcome. We found low-certainty evidence based on 2 studies recruiting 116 infants that use of feed thickeners improved the oesophageal pH probe parameters of reflux index (i.e. percentage of time pH < 4), number of reflux episodes lasting longer than 5 minutes, and duration of longest reflux episode. No major side effects were reported with the use of feed thickeners. Information was insufficient to conclude which type of feed thickener is superior. AUTHORS' CONCLUSIONS: Gastro-oesophageal reflux is a physiological self resolving phenomenon in infants that does not necessarily require any treatment. However, we found moderate-certainty evidence that feed thickeners should be considered if regurgitation symptoms persist in term bottle-fed infants. The reduction of two episodes of regurgitation per day is likely to be of clinical significance to caregivers. Due to the limited information available, we were unable to assess the use of feed thickeners in infants who are breastfeeding or preterm nor could we conclude which type of feed thickener is superior.