Does the use of higher versus lower oxygen concentration improve neurodevelopmental outcomes at 18-24 months in very low birthweight infants?

BACKGROUND: Immediately after birth, the oxygen saturation is between 30 and 50%, which then increases to 85-95% within the first 10 min. Over the last 10 years, recommendations regarding the ideal level of the initial fraction of inspired oxygen (FiO2) for resuscitation in preterm infants have changed from 1.0, to room air to low levels of oxygen (< 0.3), up to moderate concentrations (0.3-0.65). This leaves clinicians in a challenging position, and a large multi-center international trial of sufficient sample size that is powered to look at safety outcomes such as mortality and adverse neurodevelopmental outcomes is required to provide the necessary evidence to guide clinical practice with confidence. METHODS: An international cluster, cross-over randomized trial of initial FiO2 of 0.3 or 0.6 during neonatal resuscitation in preterm infants at birth to increase survival free of major neurodevelopmental outcomes at 18 and 24 months corrected age will be conducted. Preterm infants born between 230/7 and 286/7 weeks' gestation will be eligible. Each participating hospital will be randomized to either an initial FiO2 concentration of either 0.3 or 0.6 to recruit for up to 12 months' and then crossed over to the other concentration for up to 12 months. The intervention will be initial FiO2 of 0.6, and the comparator will be initial FiO2 of 0.3 during respiratory support in the delivery room. The sample size will be 1200 preterm infants. This will yield 80% power, assuming a type 1 error of 5% to detect a 25% reduction in relative risk of the primary outcome from 35 to 26.5%. The primary outcome will be a composite of all-cause mortality or the presence of a major neurodevelopmental outcome between 18 and 24 months corrected age. Secondary outcomes will include the components of the primary outcome (death, cerebral palsy, major developmental delay involving cognition, speech, visual, or hearing impairment) in addition to neonatal morbidities (severe brain injury, bronchopulmonary dysplasia; and severe retinopathy of prematurity). DISCUSSION: The use of supplementary oxygen may be crucial but also potentially detrimental to preterm infants at birth. The HiLo trial is powered for the primary outcome and will address gaps in the evidence due to its pragmatic and inclusive design, targeting all extremely preterm infants. Should 60% initial oxygen concertation increase survival free of major neurodevelopmental outcomes at 18-24 months corrected age, without severe adverse effects, this readily available intervention could be introduced immediately into clinical practice. TRIAL REGISTRATION: The trial was registered on January 31, 2019, at ClinicalTrials.gov with the Identifier: NCT03825835.

Long-Term Outcomes of Multiple versus a Single Course of Antenatal Steroids: A Systematic Review.

Multiple courses versus a single course of antenatal corticosteroids (ACS) have been associated with mild respiratory benefits but also adverse outcomes like smaller head circumference and birth weight. Long-term effects warrant study. We systematically reviewed long-term outcomes (≥1 year) in both preterm and term birth after exposure to preterm multiple courses (including a rescue dose or course) versus a single course. We searched seven databases from January 2000 to October 2021. We included follow-up studies of randomized controlled trials (RCTs) and cohort studies with births occurring in/after the year 2000, given advances in perinatal care. Two reviewers assessed titles/abstracts, articles, quality, and outcomes including psychological disorders, neurodevelopment, and anthropometry. Six follow-up studies of three RCTs and two cohort studies (over 2,860 children total) met inclusion criteria. Among children born preterm, randomization to multiple courses versus a single course of ACS was not associated with adjusted beneficial or adverse neurodevelopmental/psychological or other outcomes, but data are scant after a rescue dose (120 and 139 children, respectively, low certainty) and nonexistent after a rescue course. For children born at term (i.e., 27% of the multiple courses of ACS 5-year follow-up study of 1,728 preterm/term born children), preterm randomization to multiple courses (at least one additional course) versus a single course was significantly associated with elevated odds of neurosensory impairment (adjusted odds ratio = 3.70, 95% confidence interval: 1.57-8.75; 212 and 247 children, respectively, moderate certainty). In this systematic review of long-term outcomes after multiple courses versus a single course of ACS, there were no significant benefits or risks regarding neurodevelopment in children born preterm but little data after one rescue dose and none after a rescue course. However, multiple courses (i.e., at least one additional course) should be considered cautiously: after term birth, there are no long-term benefits but neurosensory harms. KEY POINTS: · We systematically reviewed the long-term impact of multiple versus a single course of ACS.. · Long-term follow-up data were scant after a rescue dose and absent after one rescue course of ACS.. · In children born preterm, multiple courses of ACS were not associated with long-term benefits/harms.. · In children born at term, multiple courses of ACS were associated with neurosensory impairment.. · Preterm administration of multiple courses of ACS should be considered cautiously..

The Impact of Infant Sex on Multiple Courses versus a Single Course of Antenatal Corticosteroids: A Secondary Analysis of a Randomized Controlled Trial.

OBJECTIVE: Animal literature has suggested that the impact of antenatal corticosteroids (ACS) may vary by infant sex. Our objective was to assess the impact of infant sex on the use of multiple courses versus a single course of ACS and perinatal outcomes. STUDY DESIGN: We conducted a secondary analysis of the Multiple Courses of Antenatal Corticosteroids for Preterm Birth trial, which randomly allocated pregnant people to multiple courses versus a single course of ACS. Our primary outcome was a composite of perinatal mortality or clinically significant neonatal morbidity (including neonatal death, stillbirth, severe respiratory distress syndrome, intraventricular hemorrhage [grade III or IV], cystic periventricular leukomalacia, and necrotizing enterocolitis [stage II or III]). Secondary outcomes included individual components of the primary outcome as well as anthropometric measures. Baseline characteristics were compared between participants who received multiple courses versus a single course of ACS. An interaction between exposure to ACS and infant sex was assessed for significance and multivariable regression analyses were conducted with adjustment for predefined covariates, when feasible. RESULTS: Data on 2,300 infants were analyzed. The interaction term between treatment status (multiple courses vs. a single course of ACS) and infant sex was not significant for the primary outcome (p = 0.86), nor for any of the secondary outcomes (p > 0.05). CONCLUSION: Infant sex did not modify the association between exposure to ACS and perinatal outcomes including perinatal mortality or neonatal morbidity or anthropometric outcomes. However, animal literature indicates that sex-specific differences after exposure to ACS may emerge over time and thus investigating long-term sex-specific outcomes warrants further attention. KEY POINTS: · We explored the impact of infant sex on perinatal outcomes after multiple versus a single course of ACS.. · Infant sex was not a significant effect modifier of ACS exposure and perinatal outcomes.. · Animal literature indicates that sex-specific differences after ACS exposure may emerge over time.. · Further investigation of long-term sex-specific outcomes is warranted..

The proportions of term or late preterm births after exposure to early antenatal corticosteroids, and outcomes: systematic review and meta-analysis of 1.6 million infants.

OBJECTIVE: To systematically review the proportions of infants with early exposure to antenatal corticosteroids but born at term or late preterm, and short term and long term outcomes. DESIGN: Systematic review and meta-analyses. DATA SOURCES: Eight databases searched from 1 January 2000 to 1 February 2023, reflecting recent perinatal care, and references of screened articles. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials and population based cohort studies with data on infants with early exposure to antenatal corticosteroids (<34 weeks) but born at term (≥37 weeks), late preterm (34-36 weeks), or term/late preterm combined. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently screened titles, abstracts, and full text articles and assessed risk of bias (Cochrane risk of bias tool for randomised controlled trials and Newcastle-Ottawa scale for population based studies). Reviewers extracted data on populations, exposure to antenatal corticosteroids, and outcomes. The authors analysed randomised and cohort data separately, using random effects meta-analyses. MAIN OUTCOME MEASURES: The primary outcome was the proportion of infants with early exposure to antenatal corticosteroids but born at term. Secondary outcomes included the proportions of infants born late preterm or term/late preterm combined after early exposure to antenatal corticosteroids and short term and long term outcomes versus non-exposure for the three gestational time points (term, late preterm, term/late preterm combined). RESULTS: Of 14 799 records, the reviewers screened 8815 non-duplicate titles and abstracts and assessed 713 full text articles. Seven randomised controlled trials and 10 population based cohort studies (1.6 million infants total) were included. In randomised controlled trials and population based data, ∼40% of infants with early exposure to antenatal corticosteroids were born at term (low or very low certainty). Among children born at term, early exposure to antenatal corticosteroids versus no exposure was associated with increased risks of admission to neonatal intensive care (adjusted odds ratio 1.49, 95% confidence interval 1.19 to 1.86, one study, 5330 infants, very low certainty; unadjusted relative risk 1.69, 95% confidence interval 1.51 to 1.89, three studies, 1 176 022 infants, I2=58%, τ2=0.01, low certainty), intubation (unadjusted relative risk 2.59, 1.39 to 4.81, absolute effect 7 more per 1000, 95% confidence interval from 2 more to 16 more, one study, 8076 infants, very low certainty, one study, 8076 infants, very low certainty), reduced head circumference (adjusted mean difference -0.21, 95% confidence interval -0.29 to -0.13, one study, 183 325 infants, low certainty), and any long term neurodevelopmental or behavioural disorder in population based studies (eg, any neurodevelopmental or behavioural disorder in children born at term, adjusted hazard ratio 1.47, 95% confidence interval 1.36 to 1.60, one study, 641 487 children, low certainty). CONCLUSIONS: About 40% of infants exposed to early antenatal corticosteroids were born at term, with associated adverse short term and long term outcomes (low or very low certainty), highlighting the need for caution when considering antenatal corticosteroids. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022360079.

Early Breast Milk Volumes and Response to Galactogogue Treatment.

The aim of this study was to evaluate the effect of galactogogue management in mothers of very preterm infants with varying breast milk volumes prior to initiating this treatment. Data were utilized from 90 women who participated in a trial employing domperidone. Three groups were formed according to their breast milk volumes (based on their infants' birth weight) at the time of randomization and study entry to the trial protocol: (1) ≤100 mL/kg/d; (2) 101-200 mL/kg/d; and (3) ≥201 mL/kg/d. Breast milk volumes were evaluated at the 14- and 28-day study treatment periods. All three groups showed a significant volume increase and volume percent increase both at the 14-day measure and also the 28-day measure. Mothers who started in the two lower volume groups showed the greatest % volume change overall, with 356.2% in the ≤100 mL/kg/d and 106.1% in the 101-200 mL/kg/d groups, compared to those mothers in the higher group of ≥201 mL/kg/d, showing a change of 45.2%, where p = 0.001. Mothers producing varying low volumes were able to demonstrate an effect from the use of domperidone and increase their volumes as much as three-hundred-fold over 14- and 28-day study periods. However, those mothers whose volumes were ≤100 mL/kg/d continued to maintain low absolute milk volumes, putting these mothers at ongoing risk of ceasing lactation.

Evaluation of Long-term Outcomes Associated With Preterm Exposure to Antenatal Corticosteroids: A Systematic Review and Meta-analysis.

Importance: Animal studies have found that antenatal corticosteroids affect many organs across multiple stages of life. However, the long-term outcomes in human children are not well understood. Objective: To conduct a systematic review and meta-analysis of long-term outcomes associated with preterm exposure to antenatal corticosteroids compared with no exposure in all children as well as children with preterm and full-term birth. Data Sources: Academic databases were searched for articles published from January 1, 2000, to October 29, 2021, including Ovid MEDLINE, Ovid Embase, PsycInfo, CINAHL (Cumulative Index of Nursing and Allied Health Literature), Web of Science, ClinicalTrials.gov, and Google Scholar. References of articles were also searched for relevant studies. Study Selection: Randomized clinical trials (RCTs), quasi-RCTs, and cohort studies that assessed long-term neurodevelopmental, psychological, or other outcomes at 1 year or older in those who had preterm exposure to antenatal corticosteroids were included. No language restrictions were set. Data Extraction and Synthesis: Two reviewers independently extracted data using a piloted data extraction form. Data on study population, pregnancy characteristics, exposure to antenatal corticosteroids, and outcomes were collected. Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guidelines were followed, and random-effects models were used for the meta-analysis. Main Outcomes and Measures: The primary outcome was an author-defined composite of any adverse neurodevelopmental and/or psychological disorder. The secondary outcomes included specific measures of psychological disorders; neurodevelopmental delay; and anthropometric, metabolic, and cardiorespiratory outcomes. Results: A total of 30 studies met the inclusion criteria, and involved more than 1.25 million children who were at least 1 year of age when the outcomes were assessed. Exposure to a single course of antenatal corticosteroids for children with extremely preterm birth was associated with a significant reduction in risk of neurodevelopmental impairment (adjusted odds ratio, 0.69 [95% CI, 0.57-0.84]; I2 = 0%; low certainty). For children with late-preterm birth, exposure to antenatal corticosteroids was associated with a higher risk of investigation for neurocognitive disorders (n = 25 668 children; adjusted hazard ratio [aHR], 1.12 [95% CI, 1.05-1.20]; low certainty). For children with full-term birth, exposure to antenatal corticosteroids was associated with a higher risk of mental or behavioral disorders (n = 641 487 children; aHR, 1.47 [95% CI, 1.36-1.60]; low certainty) as well as proven or suspected neurocognitive disorders (n = 529 205 children; aHR, 1.16 [95% CI, 1.10-1.21]; low certainty). Conclusions and Relevance: Results of this study showed that exposure to a single course of antenatal corticosteroids was associated with a significantly lower risk of neurodevelopmental impairment in children with extremely preterm birth but a significantly higher risk of adverse neurocognitive and/or psychological outcomes in children with late-preterm and full-term birth, who made up approximately half of those with exposure to antenatal corticosteroids. The findings suggest a need for caution in administering antenatal corticosteroids.

A Growing Dilemma: Antenatal Corticosteroids and Long-Term Consequences.

OBJECTIVE: A single course of synthetic antenatal corticosteroids is standard care for women considered to be at risk for preterm birth before 34 weeks of gestation. While the intended target is the fetal lung, the fetal brain contains remarkably high levels of glucocorticoid receptors in structures critical in the regulation of behavior and endocrine function. Negative programming signals may occur which can lead to permanent maladaptive changes and predispose the infant/child to an increased risk in physical, mental, and developmental disorders. METHODS: Framed around these areas of concerns for physical, mental, and developmental disorders, this narrative review drew on studies (animal and clinical), evaluating the long-term effects of antenatal corticosteroids to present the case that a more targeted approach to the use of antenatal corticosteroids for the betterment of the fetus urgently needed. RESULTS: Studies raised concerns about the potential negative long-term consequences, especially for the exposed fetus who was born beyond the period of the greatest benefit from antenatal corticosteroids. The long-term consequences are more subtle in nature and usually manifest later in life, often beyond the scope of most clinical trials. CONCLUSION: Continued research is needed to identify sufficient safety data, both short term and long term. Caution in the use of antenatal corticosteroids should be exercised while additional work is undertaken to optimize dosing strategies and better identify women at risk of preterm birth prior to administration of antenatal corticosteroids. KEY POINTS: · A single-course ACS is a remarkable therapy with substantial benefits.. · There is a potential of long-term neurodevelopmental consequences in the ACS-exposed fetus.. · There is a need to improve dosing strategies and identification of appropriate at risk women..

Delivery of monochorionic twins: lessons learned from the Twin Birth Study.

BACKGROUND: The current literature regarding the recommended mode of delivery of monochorionic-diamniotic twins is limited to small numbers, retrospective studies, and comparisons of outcomes of monochorionic-diamniotic twin pregnancies with those of dichorionic-diamniotic twin pregnancies instead of outcomes of trial of labor vs elective cesarean delivery of monochorionic-diamniotic twins. OBJECTIVE: This study aimed to compare perinatal and maternal outcomes of planned cesarean delivery and planned vaginal delivery of monochorionic-diamniotic twins using the Twin Birth Study data. STUDY DESIGN: This study is a secondary analysis of the Twin Birth Study. Women were randomized from 32 weeks and 0 days gestation to 38 weeks and 6 days gestation to planned cesarean delivery or planned vaginal delivery. Twin A in the cephalic presentation and estimated weight of each twin between 1500 and 4000 grams were the inclusion criteria. Pregnancies complicated by fetal reduction after 13 weeks of gestation, lethal fetal anomaly, or contraindication to vaginal delivery were excluded. Elective delivery was planned between 37 weeks and 5 to 7 days of gestation and 38 weeks and 6 to 7 days of gestation. Perinatal and maternal outcomes of monochorionic-diamniotic twin pregnancies were compared between those randomized for planned cesarean delivery and those randomized for planned vaginal delivery. In addition, outcomes of monochorionic-diamniotic twin pregnancies were compared with those of dichorionic-diamniotic twin pregnancies. RESULTS: Out of the 1393 women in each arm, 346 (24.9%) women in the planned cesarean delivery arm and 324 (23.3%) women in the planned vaginal delivery arm had monochorionic-diamniotic twin pregnancies and were eligible for the first analysis. The rate of cesarean delivery was 39.2% in the planned vaginal delivery arm and was 91.3% in the planned cesarean delivery arm. There was no significant difference in gestational age at delivery between the groups (34.4±1.8 weeks vs 34.5±1.8 weeks; P=.78). No difference was found in maternal outcomes. As for perinatal outcomes, the rate of the primary adverse neonatal composite outcomes in twins A or twins B was similar in both the planned vaginal delivery and the planned cesarean delivery arms (twins A, 1.2% vs 1.2% [P=.92]; twins B, 1.2% vs 3.2% [P=.09]). Within the planned cesarean delivery arm, the rate of primary adverse neonatal composite outcome was higher in twins B than twins A (3.2% vs 1.2%; P=.03). There was no difference in the primary adverse neonatal composite outcome between twins A in the monochorionic-diamniotic group and the dichorionic-diamniotic group (1.2% vs 1.3%; P=.89) or between twins B in similar groups (2.3% vs 2.7%; P=.47). CONCLUSION: In monochorionic-diamniotic twin pregnancy between 32 weeks and 0 to 7 days of gestation and 38 weeks and 6 to 7 days of gestation, with twin A in a cephalic presentation, planned cesarean delivery did not decrease or increase the risk of fetal or neonatal death or serious neonatal morbidity, as compared with planned vaginal delivery.

Lactoferrin infant feeding trial_Canada (LIFT_Canada): protocol for a randomized trial of adding lactoferrin to feeds of very-low-birth-weight preterm infants.

BACKGROUND: In Canada alone, almost 3000 VLBW infants are born and treated annually with almost 1200 going onto death or survival with severe brain injury, chronic lung disorders, aggressive retinopathy of prematurity, late-onset sepsis, or significant necrotizing enterocolitis. Lactoferrin is an antimicrobial, antioxidant, anti-inflammatory iron-carrying, bifidogenic glycoprotein found in all vertebrates and in mammalian milk, leukocytes and exocrine secretions. Lactoferrin aids in creating an environment for growth of beneficial bacteria in the gut, thus reducing colonization with pathogenic bacteria. It is hypothesized that oral bovine lactoferrin (bLF), through its antimicrobial, antioxidant and anti-inflammatory properties, will reduce the rate of mortality or major morbidity in very low birth weight preterm infants. METHOD: Lactoferrin Infant Feeding Trial_Canada (LIFT_Canada) is a multi-centre, double-masked, randomized controlled trial with the aim to enroll 500 infants whose data will be combined with the data of the 1542 infants enrolled from Lactoferrin Infant Feeding Trial_Australia/New Zealand (LIFT_ANZ) in a pooled intention-to-treat analysis. Eligible infants will be randomized and allocated to one of two treatment groups: 1) a daily dose of 200 mg/kg bLF in breast/donor human milk or formula milk until 34 weeks corrected gestation or for a minimum of 2 weeks, whichever is longer, or until discharge home or transfer, if earlier; 2) no bLF with daily feeds. The primary outcome will be determined at 36 weeks corrected gestation for the presence of neonatal morbidity and at discharge for survival and treated retinopathy of prematurity. The duration of the trial is expected to be 36 months. DISCUSSION: Currently, there continues to be no clear answer related to the benefit of bLF in reducing mortality or any or all of the significant neonatal morbidities in very low birth weight infants. LIFT_Canada is designed with the hope that the pooled results from Australia, New Zealand, and Canada may help to clarify the situation. TRIAL REGISTRATION: Clinical Trials.Gov, Identifier: NCT03367013, Registered December 8, 2017.

The worst of both worlds-combined deliveries in twin gestations: a subanalysis of the Twin Birth Study, a randomized, controlled, prospective study.

OBJECTIVE: The reported incidence of combined twin delivery (vaginal delivery of twin A followed by cesarean delivery for twin B) ranges between 5% and 10%. These estimates are based mostly on small studies or retrospective data. We aimed to evaluate to incidence and risk factors for and outcomes of combined twin deliveries, using a subanalysis of the Twin Birth Study, a randomized, controlled, prospective study. STUDY DESIGN: The Twin Birth Study included women with twin gestation between 32+0 and 38+6 weeks, with the first twin in vertex presentation at randomization. Women were randomized to planned cesarean delivery or planned vaginal delivery. For the purpose of this subanalysis, we included women who had a vaginal delivery of twin A. Women who had a combined delivery (cesarean delivery for twin B) were compared with women who had a vaginal delivery of both twins. Our primary objective was to identify risk factors for combined twin deliveries. Our secondary objective was to assess the rate of fetal/neonatal death or serious neonatal morbidity in combined deliveries. RESULTS: Of the 2786 women included in the original study, 842 women delivered twin A by a vaginal delivery and were included in the current analysis, of whom 59 (7%) had a combined delivery. Women in the combined delivery group had a lower rate of nulliparity (22.0% vs 34.7%, P = 0.047) and higher rates of noncephalic presentation of twin B at delivery (61.0% vs 27.3%, P < 0.001) and spontaneous version from presentation at randomization of twin B (72.9% vs 44.3%, P < 0.0001). In a multivariable model, the only risk factor significantly associated with a combined delivery was transverse/oblique lie of twin B following delivery of twin A (adjusted odds ratio, 47.7; 95% confidence interval, 15.4-124.5). Twins B in the combined delivery group had a higher rate of fetal/neonatal death or serious neonatal morbidity (13.6% vs 2.3%, P < 0.001), 5-minute Apgar score <7, neonatal intensive care unit admission, abnormal level of consciousness, and assisted ventilation. CONCLUSION: Transverse/oblique lie of twin B following vaginal delivery of twin A is a risk factor for combined delivery. Combined delivery is associated with higher risk of adverse neonatal outcomes of twin B. These data may be used to better counsel women with twin gestation who consider a trial of labor.

Role of days postdelivery on breast milk production: a secondary analysis from the EMPOWER trial.

Background: With an increasing demand for mother's own milk to be viewed as a primary source of nutritional support in the care of very small and preterm infants, mothers of preterm infants may be at risk of expressing suboptimal amounts of milk. The use of a galactogogue is often considered when these mothers are still having challenges in breast milk production. Methods: For this analysis, the study participants were the 90 mothers who participated in the EMPOWER trial and, at the time of randomization, were stratified by days post-delivery, 8-14 days and 15-21 days. The primary outcome measure was the proportion of mothers in each of the days post-delivery groups who achieved a 50% increase in breast milk volume on day 14 of the study treatment period. Results: There was no significant difference in the proportion of mothers in the 8-14 days group (75.0%) who achieved a 50% increase in breast milk volume on day 14 of the study treatment period.compared to those in the 15-21 days group (60.9%), OR 1.93 (95% CI 0.78, 4.76; p = 0.15). Because comorbidities and exposure to antenatal corticosteroids between the groups of mothers were viewed as potential confounders, a logistic regression was performed after controlling for these two variables with the adjusted OR being 1.84 (0.73, 4.64; p = 0.19). Conclusions: This secondary analysis was able to demonstrate that mothers of very preterm infants, < 30 weeks gestation at birth, were able to respond to the study treatment in a similar fashion regardless of timing of entry and exposure to domperidone. In the presence of a suboptimal breast milk production by the end of the first week postpartum, below 250 ml/kg/d based on infant birth weight, a 14 day treatment of domperidone could be considered to augment breast milk production. Trial registration: EMPOWER has been registered at http://www.clinicaltrials.gov (identifier NCT01512225) on January 10, 2012.

Effects of repeat prenatal corticosteroids given to women at risk of preterm birth: An individual participant data meta-analysis.

BACKGROUND: Infants born preterm compared with infants born at term are at an increased risk of dying and of serious morbidities in early life, and those who survive have higher rates of neurological impairments. It remains unclear whether exposure to repeat courses of prenatal corticosteroids can reduce these risks. This individual participant data (IPD) meta-analysis (MA) assessed whether repeat prenatal corticosteroid treatment given to women at ongoing risk of preterm birth in order to benefit their infants is modified by participant or treatment factors. METHODS AND FINDINGS: Trials were eligible for inclusion if they randomised women considered at risk of preterm birth who had already received an initial, single course of prenatal corticosteroid seven or more days previously and in which corticosteroids were compared with either placebo or no placebo. The primary outcomes for the infants were serious outcome, use of respiratory support, and birth weight z-scores; for the children, they were death or any neurosensory disability; and for the women, maternal sepsis. Studies were identified using the Cochrane Pregnancy and Childbirth search strategy. Date of last search was 20 January 2015. IPD were sought from investigators with eligible trials. Risk of bias was assessed using criteria from the Cochrane Collaboration. IPD were analysed using a one-stage approach. Eleven trials, conducted between 2002 and 2010, were identified as eligible, with five trials being from the United States, two from Canada, and one each from Australia and New Zealand, Finland, India, and the United Kingdom. All 11 trials were included, with 4,857 women and 5,915 infants contributing data. The mean gestational age at trial entry for the trials was between 27.4 weeks and 30.2 weeks. There was no significant difference in the proportion of infants with a serious outcome (relative risk [RR] 0.92, 95% confidence interval [CI] 0.82 to 1.04, 5,893 infants, 11 trials, p = 0.33 for heterogeneity). There was a reduction in the use of respiratory support in infants exposed to repeat prenatal corticosteroids compared with infants not exposed (RR 0.91, 95% CI 0.85 to 0.97, 5,791 infants, 10 trials, p = 0.64 for heterogeneity). The number needed to treat (NNT) to benefit was 21 (95% CI 14 to 41) women/fetus to prevent one infant from needing respiratory support. Birth weight z-scores were lower in the repeat corticosteroid group (mean difference -0.12, 95%CI -0.18 to -0.06, 5,902 infants, 11 trials, p = 0.80 for heterogeneity). No statistically significant differences were seen for any of the primary outcomes for the child (death or any neurosensory disability) or for the woman (maternal sepsis). The treatment effect varied little by reason the woman was considered to be at risk of preterm birth, the number of fetuses in utero, the gestational age when first trial treatment course was given, or the time prior to birth that the last dose was given. Infants exposed to between 2-5 courses of repeat corticosteroids showed a reduction in both serious outcome and the use of respiratory support compared with infants exposed to only a single repeat course. However, increasing numbers of repeat courses of corticosteroids were associated with larger reductions in birth z-scores for weight, length, and head circumference. Not all trials could provide data for all of the prespecified subgroups, so this limited the power to detect differences because event rates are low for some important maternal, infant, and childhood outcomes. CONCLUSIONS: In this study, we found that repeat prenatal corticosteroids given to women at ongoing risk of preterm birth after an initial course reduced the likelihood of their infant needing respiratory support after birth and led to neonatal benefits. Body size measures at birth were lower in infants exposed to repeat prenatal corticosteroids. Our findings suggest that to provide clinical benefit with the least effect on growth, the number of repeat treatment courses should be limited to a maximum of three and the total dose to between 24 mg and 48 mg.

Planned cesarean or vaginal delivery for women in spontaneous labor with a twin pregnancy: A secondary analysis of the Twin Birth Study.

BACKGROUND: The Twin Birth Study, a multicenter randomized controlled trial, found no differences in neonatal outcomes in women with twins randomized to planned cesarean or vaginal delivery. Nevertheless, women who present in spontaneous labor might expect a better outcome following a trial of vaginal delivery than undergoing cesarean delivery. In this secondary analysis, we aimed to compare neonatal outcomes of women who presented in spontaneous labor in the two arms of the Twin Birth Study. METHODS: Women in whom the first twin was in the cephalic presentation were randomized between 32 + 0 and 38 + 6 weeks to planned vaginal delivery or cesarean. The primary outcome was a composite of fetal or neonatal death or serious neonatal morbidity. RESULTS: Of the 2804 women included in the Twin Birth Study, 823 women in the planned vaginal delivery arm and 612 in the planned cesarean arm presented in spontaneous labor. Although the odds ratio favored planned vaginal delivery, there was no statistically significant difference in the rate of primary outcome between the vaginal delivery and cesarean arms (1.8% vs 2.7%, respectively; P = 0.16; OR 1.49; 95% CI, 0.87-2.55). Similarly, the rates of the individual components of the primary outcome and of maternal adverse outcome were similar between the two arms. CONCLUSION: In women with twins who present in spontaneous labor between 32 + 0 and 38 + 6 weeks' gestation, where the first twin is cephalic, a policy of planned vaginal delivery or cesarean is not associated with significant differences in neonatal or maternal outcomes.

Evaluating the Effect of a 14-Day Course of Domperidone on Breast Milk Production: A Per-Protocol Analysis from the EMPOWER Trial.

BACKGROUND: Galactogogues are often considered when mothers of very preterm infants experience challenges in producing adequate amounts of breast milk. We conducted a per-protocol analysis of those mothers who completed a 14-day course of domperidone during the EMPOWER trial. Our primary aim was to evaluate the response to a completed course of domperidone and whether the response was affected by the timing of the initiation of intervention. METHODS: For this analysis, 83 mothers of infants ≤29 weeks gestation were included: 45 mothers who received domperidone from days 1 to 14 of the trial study treatment period and 38 mothers who received domperidone from days 15 to 28. Domperidone was given at a dose of 10 mg thrice daily for 14 days. The primary outcome was the proportion of mothers who achieved a modest 50% increase in breast milk volume from the volume at the end of the 2-week period of treatment of domperidone. RESULTS: When adjusted for the initiation of domperidone treatment, the proportion of mothers in the days 1-14 group (77.8%) was similar compared to those in the days 15-28 group (65.8%), OR 1.96 (95% CI 0.72-5.32; p = 0.19). CONCLUSION: Taking into consideration potential limitations in power, this secondary analysis was able to show that the mothers in the EMPOWER study who were identified as actually completing a 14-day treatment course responded irrespective of the timing of their initiation of domperidone and demonstrated a modest increase in breast milk volume.

Pregnancy gestation at delivery and breast milk production: a secondary analysis from the EMPOWER trial.

BACKGROUND: Preterm birth alters the normal sequence of lactogenesis. Lactogenesis I may not yet have started when mothers of very preterm infants (≤ 29 weeks gestation) have given birth. Preterm infants are too small or too ill to initiate suckling in the immediate postpartum period thus altering the normal cascade of event for lactogenesis II. With an increasing demand for mother's own milk as a primary source of nutritional support in the care of very small and preterm infants, mothers of these infants are often at risk of expressing inadequate amounts of milk. The use of galactogogues is often considered when mothers of preterm infants are still having challenges in breast milk production. What is not clear in the literature is the role that pregnancy gestation at birth plays in successful response to galactogogues. Our objective for this study was to evaluate the role of pregnancy gestation at birth on a mother's response to the treatment interventions in the EMPOWER trial. METHODS: For this analysis, the study participants are the 90 mothers who participated in the EMPOWER trial and were in the stratified in two gestational age groups, 230/7-266/7 weeks and 270/7-296/7 weeks at the time of randomization. The primary outcome measures were the proportion of mothers in each of the gestational age groupings who achieved a 50% increase in breast milk volume on day 14 and day 28 of the study treatment period. RESULTS: On day 14 of the study treatment, there was no significant difference in the proportion of mothers in the 23-26 weeks gestation group (72.9%) compared to those in the 27-29 weeks gestation group (64.2%), OR 1.51 (95% CI 0.60, 3.78; p = 0.38). Similarly, there was no difference in the proportion of mothers between the two gestational age groupings on day 28 of the study treatment, 70.3% compared to 62.3%, OR 1.43 (95% CI 0.58, 3.51; p = 0.43). CONCLUSION: This secondary analysis was able to demonstrate that mothers of very preterm infants, < 30 weeks gestation at birth, were able to respond to the study treatment in a similar fashion regardless of gestation at birth. If non-pharmacologic approaches are unsuccessful, then a 14-day treatment of domperidone may be considered to enhance breast milk production, even in the lowest gestational ages at delivery. TRIAL REGISTRATION: EMPOWER has been registered at www.clinicaltrials.gov (identifier NCT 01512225) on January 10, 2012.

Supporting Mothers of Very Preterm Infants and Breast Milk Production: A Review of the Role of Galactogogues.

Human milk, either mother’s own milk or donor human milk, is recommended as the primary source of nutrition for very preterm infants. Initiatives should be in place in neonatal units to provide support to the mother as she strives to initiate and maintain a supply of breast milk for her infant. The use of galactogogues are considered when these initiatives alone may not be successful in supporting mothers in this endeavor. Although there are non-pharmacologic compounds, this review will focus on the pharmacologic galactogogues currently available and the literature related to their use in mothers of very preterm infants.

Neurobehavioral Outcomes 11 Years After Neonatal Caffeine Therapy for Apnea of Prematurity.

BACKGROUND AND OBJECTIVES: Caffeine is effective in the treatment of apnea of prematurity. Although caffeine therapy has a benefit on gross motor skills in school-aged children, effects on neurobehavioral outcomes are not fully understood. We aimed to investigate effects of neonatal caffeine therapy in very low birth weight (500-1250 g) infants on neurobehavioral outcomes in 11-year-old participants of the Caffeine for Apnea of Prematurity trial. METHODS: Thirteen academic hospitals in Canada, Australia, Great Britain, and Sweden participated in this part of the 11-year follow-up of the double-blind, randomized, placebo-controlled trial. Measures of general intelligence, attention, executive function, visuomotor integration and perception, and behavior were obtained in up to 870 children. The effects of caffeine therapy were assessed by using regression models. RESULTS: Neurobehavioral outcomes were generally similar for both the caffeine and placebo group. The caffeine group performed better than the placebo group in fine motor coordination (mean difference [MD] = 2.9; 95% confidence interval [CI]: 0.7 to 5.1; P = .01), visuomotor integration (MD = 1.8; 95% CI: 0.0 to 3.7; P < .05), visual perception (MD = 2.0; 95% CI: 0.3 to 3.8; P = .02), and visuospatial organization (MD = 1.2; 95% CI: 0.4 to 2.0; P = .003). CONCLUSIONS: Neonatal caffeine therapy for apnea of prematurity improved visuomotor, visuoperceptual, and visuospatial abilities at age 11 years. General intelligence, attention, and behavior were not adversely affected by caffeine, which highlights the long-term safety of caffeine therapy for apnea of prematurity in very low birth weight neonates.

Academic Performance, Motor Function, and Behavior 11 Years After Neonatal Caffeine Citrate Therapy for Apnea of Prematurity: An 11-Year Follow-up of the CAP Randomized Clinical Trial.

Importance: Caffeine citrate therapy for apnea of prematurity reduces the rates of bronchopulmonary dysplasia, severe retinopathy, and neurodevelopmental disability at 18 months and may improve motor function at 5 years. Objective: To evaluate whether neonatal caffeine therapy is associated with improved functional outcomes 11 years later. Design, Setting, and Participants: A follow-up study was conducted at 14 academic hospitals in Canada, Australia, and the United Kingdom from May 7, 2011, to May 27, 2016, of English- or French-speaking children who had been enrolled in the randomized, placebo-controlled Caffeine for Apnea of Prematurity trial between October 11, 1999, and October 22, 2004. A total of 1202 children with birth weights of 500 to 1250 g were eligible for this study; 920 (76.5%) had adequate data for the main outcome. Interventions: Caffeine citrate or placebo until drug therapy for apnea of prematurity was no longer needed. Main Outcomes and Measures: Functional impairment was a composite of poor academic performance (defined as at least 1 standard score greater than 2 SD below the mean on the Wide Range Achievement Test-4), motor impairment (defined as a percentile rank of ≤5 on the Movement Assessment Battery for Children-Second Edition), and behavior problems (defined as a Total Problem T score ≥2 SD above the mean on the Child Behavior Checklist). Results: Among the 920 children (444 females and 476 males; median age, 11.4 years [interquartile range, 11.1-11.8 years]), the combined rates of functional impairment were not significantly different between the 457 children assigned to receive caffeine compared with the 463 children assigned to receive placebo (145 [31.7%] vs 174 [37.6%]; adjusted odds ratio, 0.78; 95% CI, 0.59-1.02; P = .07). With all available data, including those from up to 24 Swedish trial participants, the rates of poor academic performance on 1 or more of 4 subtests (66 of 458 [14.4%] vs 61 of 462 [13.2%]; adjusted odds ratio, 1.11; 95% CI, 0.77-1.61; P = .58) and behavior problems (52 of 476 [10.9%] vs 40 of 481 [8.3%]; adjusted odds ratio, 1.32; 95% CI, 0.85-2.07; P = .22) were broadly similar between the group that received caffeine and the group that received placebo. However, caffeine therapy was associated with a reduced risk of motor impairment compared with placebo (90 of 457 [19.7%] vs 130 of 473 [27.5%]; adjusted odds ratio, 0.66; 95% CI, 0.48-0.90; P = .009). Conclusions and Relevance: Caffeine therapy for apnea of prematurity did not significantly reduce the combined rate of academic, motor, and behavioral impairments but was associated with a reduced risk of motor impairment in 11-year-old children with very low birth weight. At the doses used in this trial, neonatal caffeine therapy is effective and safe into middle school age. Trial Registration: clinicaltrials.gov Identifier: NCT00182312; isrctn.org Identifier: ISRCTN44364365.

Enhancing Human Milk Production With Domperidone in Mothers of Preterm Infants.

BACKGROUND: Mothers of preterm infants often are at risk of expressing an inadequate amount of milk for their infants and the use of galactogogues is often considered. Domperidone is a widely used galactogogue with little information available to guide clinicians regarding initiation, timing, and duration of treatment. Research aim: The primary objective of this study was to determine whether administration of domperidone within the first 21 days after delivery would lead to a higher proportion of mothers achieving a 50% increase in the volume of milk at the end of 14 days of treatment compared with mothers receiving placebo. METHODS: Eligible mothers were randomized to one of two treatment arms: Group A-domperidone 10 mg orally three times daily for 28 days; or Group B-placebo 10 mg orally three times daily for 14 days followed by domperidone 10 mg orally three times daily for 14 days. RESULTS: A total of 90 mothers of infants ≤ 29 weeks gestation were randomized. Mean milk volumes at entry were similar for both groups. More mothers achieved a 50% increase in milk volume after 14 days in Group A (77.8%) compared with Group B (57.8%), odds ratio = 2.56, 95% confidence interval [1.02, 6.25], p = .04. CONCLUSION: A greater number of mothers experienced a 50% or more increase in human milk volume, but the absolute increase in milk volume was modest.