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..

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.

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.

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.

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.

The effect of induction method in twin pregnancies: a secondary analysis for the twin birth study.

BACKGROUND: This secondary analysis for the Twin Birth Study, an international, multicenter trial, aimed to compare the cesarean section rates and safety between methods of induction of labor in twin pregnancies. METHODS: Women with twin pregnancies where the first twin was in a cephalic presentation and who presented for labor induction, were non-randomly assigned to receive prostaglandin or amniotomy and/or oxytocin. Main outcome measures were the rates of unplanned cesarean section and neonatal and maternal mortality or serious morbidity. RESULTS: 153 (41.5%) were induced by prostaglandin (prostaglandin group) and 215 (58.5%) were induced by amniotomy and/or oxytocin alone (no prostaglandin group). Induction using prostaglandin was more common in countries with a low perinatal mortality rate <10/1000 (45.7 versus 32.5%, p = 0.02). Cesarean section rates were similar in the two groups: 62/153 (40.5%) in the prostaglandin group and 87/215 (40.5%) in the no prostaglandin group (odds ratio 1, 95% CI 0.65-1.5). Nulliparity, late maternal age, non-cephalic presentation of twin B and high country's perinatal mortality rate were found to be independently associated with the induction to end with an unplanned cesarean section. There were no significant differences between groups with respect to maternal or neonatal adverse outcomes. CONCLUSIONS: The need for cervical ripening by prostaglandin had no effect on the incidence of cesarean delivery or an abnormal outcome. There is a significant risk of unplanned cesarean section independent of chosen induction method. TRIAL REGISTRATION: This trial was registered at the International Standard Randomized Controlled Trial Register (identifier ISRCTN74420086 ; December 9, 2003) and retrospectively registered at the www.clinicaltrials.gov (identifier NCT 00187369 ; September 12, 2005).

Association between Primary Caregiver Education and Cognitive and Language Development of Preterm Neonates.

Objective This study aims to explore the association between primary caregiver education and cognitive and language composite scores of the Bayley Scales of Infant and Toddler Development, 3rd ed. (Bayley-III) in preterm infants at 18 to 21 months corrected age. Design An observational study was performed on preterm infants born before 29 weeks' gestation between 2010 and 2011. Primary caregivers were categorized by their highest education level and cognitive and language composite scores of the Bayley-III were compared among infants between these groups with adjustment for perinatal and neonatal factors. Results In total, 1,525 infants/caregivers were included in the multivariate analysis. Compared with those with less than a high school education, infants with primary caregivers who received partial college/specialized training displayed higher cognitive (adjusted difference [AD]: 4.6, 95% confidence interval [CI]: 1.8-7.4) and language scores (AD: 4.0, 95% CI: 0.8-7.1); infants with primary caregivers with university graduate education or above also demonstrated higher cognitive (AD: 6.4, 95% CI: 2.6-10.1) and language scores (AD: 9.9, 95% CI: 5.7-14.1). Conclusion Higher levels of education of the primary caregiver were associated with increased cognitive and language composite scores at 18 to 21 months corrected age in preterm infants.

Neonatal Factors Associated with a Good Neurodevelopmental Outcome in Very Preterm Infants.

Objective This study aims to examine the association between the absence of neonatal comorbidities, as well as the presence of indicators of clinical progress with good neurodevelopmental (ND) outcomes, at 18 months corrected age in a national cohort of preterm infants of < 29 weeks' gestation. Design Study subjects included preterm infants (< 29 weeks' gestation) born in 2010 and 2011. Univariate analyses were conducted and regression estimates were calculated for variables where odds of a good ND outcome, composite scores ≥ 100 in three domains (cognitive, language, and motor) in the Bayley Scales of Infant and Toddler Development, 3rd ed. (Bayley-III), were estimated. Results In total, 2,069 infants were included in the analyses. For all three domains evaluated on the Bayley-III, cognition, language, motor, respectively, the absence of three major morbidities was associated with a score ≥ 100: bronchopulmonary dysplasia, necrotizing enterocolitis, and severe neurological injury. Less time spent on positive pressure support and on total parenteral nutrition administration were associated with a positive motor outcome and showed a positive trend for both cognition and language scores. Conclusion The absence of neonatal comorbidities was associated with good ND outcome. Less time spent on positive pressure support and parenteral nutrition may also contribute to a good ND outcome.

A randomized trial of planned cesarean or vaginal delivery for twin pregnancy.

BACKGROUND: Twin birth is associated with a higher risk of adverse perinatal outcomes than singleton birth. It is unclear whether planned cesarean section results in a lower risk of adverse outcomes than planned vaginal delivery in twin pregnancy. METHODS: We randomly assigned women between 32 weeks 0 days and 38 weeks 6 days of gestation with twin pregnancy and with the first twin in the cephalic presentation to planned cesarean section or planned vaginal delivery with cesarean only if indicated. Elective delivery was planned between 37 weeks 5 days and 38 weeks 6 days of gestation. The primary outcome was a composite of fetal or neonatal death or serious neonatal morbidity, with the fetus or infant as the unit of analysis for the statistical comparison. RESULTS: A total of 1398 women (2795 fetuses) were randomly assigned to planned cesarean delivery and 1406 women (2812 fetuses) to planned vaginal delivery. The rate of cesarean delivery was 90.7% in the planned-cesarean-delivery group and 43.8% in the planned-vaginal-delivery group. Women in the planned-cesarean-delivery group delivered earlier than did those in the planned-vaginal-delivery group (mean number of days from randomization to delivery, 12.4 vs. 13.3; P=0.04). There was no significant difference in the composite primary outcome between the planned-cesarean-delivery group and the planned-vaginal-delivery group (2.2% and 1.9%, respectively; odds ratio with planned cesarean delivery, 1.16; 95% confidence interval, 0.77 to 1.74; P=0.49). CONCLUSIONS: In twin pregnancy between 32 weeks 0 days and 38 weeks 6 days of gestation, with the first twin in the cephalic presentation, planned cesarean delivery did not significantly decrease or increase the risk of fetal or neonatal death or serious neonatal morbidity, as compared with planned vaginal delivery. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00187369; Current Controlled Trials number, ISRCTN74420086.).

Twin Birth Study: 2-year neurodevelopmental follow-up of the randomized trial of planned cesarean or planned vaginal delivery for twin pregnancy.

BACKGROUND: The Twin Birth Study randomized women with uncomplicated pregnancies, between 32(0/7)-38(6/7) weeks' gestation where the first twin was in cephalic presentation, to a policy of either a planned cesarean or planned vaginal delivery. The primary analysis showed that planned cesarean delivery did not increase or decrease the risk of fetal/neonatal death or serious neonatal morbidity as compared with planned vaginal delivery. OBJECTIVE: This study presents the secondary outcome of death or neurodevelopmental delay at 2 years of age. STUDY DESIGN: A total of 4603 children from the initial cohort of 5565 fetuses/infants (83%) contributed to the outcome of death or neurodevelopmental delay. Surviving children were screened using the Ages and Stages Questionnaire with abnormal scores validated by a clinical neurodevelopmental assessment. The effect of planned cesarean vs planned vaginal delivery on death or neurodevelopmental delay was quantified using a logistic model to control for stratification variables and using generalized estimating equations to account for the nonindependence of twin births. RESULTS: Baseline maternal, pregnancy, and infant characteristics were similar. Mean age at assessment was 26 months. There was no significant difference in the outcome of death or neurodevelopmental delay: 5.99% in the planned cesarean vs 5.83% in the planned vaginal delivery group (odds ratio, 1.04; 95% confidence interval, 0.77-1.41; P = .79). CONCLUSION: A policy of planned cesarean delivery provides no benefit to children at 2 years of age compared with a policy of planned vaginal delivery in uncomplicated twin pregnancies between 32(0/7)-38(6/7)weeks' gestation where the first twin is in cephalic presentation.

Prediction of Late Death or Disability at Age 5 Years Using a Count of 3 Neonatal Morbidities in Very Low Birth Weight Infants.

OBJECTIVE: To evaluate bronchopulmonary dysplasia (BPD), serious brain injury, and severe retinopathy of prematurity (ROP) as predictors of poor long-term outcome in very low birth weight infants. STUDY DESIGN: We examined the associations between counts of the 3 morbidities and long-term outcomes in 1514 of 1791 (85%) infants with birth weights of 500-1250 g who were enrolled in the Caffeine for Apnea of Prematurity trial from October 1999, to October 2004, had complete morbidity data, and were alive at 36 weeks postmenstrual age (PMA). BPD was defined as use of supplemental oxygen at 36 weeks PMA. Serious brain injury on cranial ultrasound included grade 3 and 4 hemorrhage, cystic periventricular leucomalacia, porencephalic cysts, or ventriculomegaly of any cause. Poor long-term outcome was death after 36 weeks PMA or survival to 5 years with 1 or more of the following disabilities: motor impairment, cognitive impairment, behavior problems, poor general health, deafness, and blindness. RESULTS: BPD, serious brain injury, and severe ROP occurred in 43%, 13%, and 6% of the infants, respectively. Each of the 3 morbidities was similarly and independently correlated with poor 5-year outcome. Rates of death or disability (95% CI) in children with none, any 1, any 2, and all 3 morbidities were 11.2% (9.0%-13.7%), 22.9% (19.6%-26.5%), 43.9% (35.5%-52.6%), and 61.5% (40.6%-79.8%), respectively. CONCLUSIONS: In very low birth weight infants who survive to 36 weeks PMA, a count of BPD, serious brain injury, and severe ROP predicts the risk of a late death or survival with disability at 5 years.

Association Between Intermittent Hypoxemia or Bradycardia and Late Death or Disability in Extremely Preterm Infants.

IMPORTANCE: Extremely preterm infants may experience intermittent hypoxemia or bradycardia for many weeks after birth. The prognosis of these events is uncertain. OBJECTIVE: To determine the association between intermittent hypoxemia or bradycardia and late death or disability. DESIGN, SETTING, AND PARTICIPANTS: Post hoc analysis of data from the inception cohort assembled for the Canadian Oxygen Trial in 25 hospitals in Canada, the United States, Argentina, Finland, Germany, and Israel, including 1019 infants with gestational ages of 23 weeks 0 days through 27 weeks 6 days who were born between December 2006 and August 2010 and survived to a postmenstrual age of 36 weeks. Follow-up assessments occurred between October 2008 and August 2012. EXPOSURES: Episodes of hypoxemia (pulse oximeter oxygen saturation <80%) or bradycardia (pulse rate <80/min) for 10 seconds or longer. Values were sampled every 10 seconds within 24 hours after birth until at least 36 weeks' postmenstrual age. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of death after 36 weeks' postmenstrual age, motor impairment, cognitive or language delay, severe hearing loss, or bilateral blindness at 18 months' corrected age. Secondary outcomes were motor impairment, cognitive or language delay, and severe retinopathy of prematurity. RESULTS: Downloaded saturation and pulse rate data were available for a median of 68.3 days (interquartile range, 56.8-86.0 days). Mean percentages of recorded time with hypoxemia for the least and most affected 10% of infants were 0.4% and 13.5%, respectively. Corresponding values for bradycardia were 0.1% and 0.3%. The primary outcome was ascertained for 972 infants and present in 414 (42.6%). Hypoxemic episodes were associated with an estimated increased risk of late death or disability at 18 months of 56.5% in the highest decile of hypoxemic exposure vs 36.9% in the lowest decile (modeled relative risk, 1.53; 95% CI, 1.21-1.94). This association was significant only for prolonged hypoxemic episodes lasting at least 1 minute (relative risk, 1.66; 95% CI, 1.35-2.05 vs for shorter episodes, relative risk, 1.01; 95% CI, 0.77-1.32). Relative risks for all secondary outcomes were similarly increased after prolonged hypoxemia. Bradycardia did not alter the prognostic value of hypoxemia. CONCLUSIONS AND RELEVANCE: Among extremely preterm infants who survived to 36 weeks' postmenstrual age, prolonged hypoxemic episodes during the first 2 to 3 months after birth were associated with adverse 18-month outcomes. If confirmed in future studies, further research on the prevention of such episodes is needed.

Impact of study oximeter masking algorithm on titration of oxygen therapy in the Canadian oxygen trial.

OBJECTIVE: To compare oxygen saturations as displayed to caregivers on offset pulse oximeters in the 2 groups of the Canadian Oxygen Trial. STUDY DESIGN: In 5 double-blind randomized trials of oxygen saturation targeting, displayed saturations between 88% and 92% were offset by 3% above or below the true values but returned to true values below 84% and above 96%. During the transition, displayed values remained static at 96% in the lower and at 84% in the higher target group during a 3% change in true saturations. In contrast, displayed values changed rapidly from 88% to 84% in the lower and from 92% to 96% in the higher target group during a 1% change in true saturations. We plotted the distributions of median displayed saturations on days with >12 hours of supplemental oxygen in 1075 Canadian Oxygen Trial participants to reconstruct what caregivers observed at the bedside. RESULTS: The oximeter masking algorithm was associated with an increase in both stability and instability of displayed saturations that occurred during the transition between offset and true displayed values at opposite ends of the 2 target ranges. Caregivers maintained saturations at lower displayed values in the higher than in the lower target group. This differential management reduced the separation between the median true saturations in the 2 groups by approximately 3.5%. CONCLUSIONS: The design of the oximeter masking algorithm may have contributed to the smaller-than-expected separation between true saturations in the 2 study groups of recent saturation targeting trials in extremely preterm infants.

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.

Effects of targeting higher vs lower arterial oxygen saturations on death or disability in extremely preterm infants: a randomized clinical trial.

IMPORTANCE: The goal of oxygen therapy is to deliver sufficient oxygen to the tissues while minimizing oxygen toxicity and oxidative stress. It remains uncertain what values of arterial oxygen saturations achieve this balance in preterm infants. OBJECTIVE: To compare the effects of targeting lower or higher arterial oxygen saturations on the rate of death or disability in extremely preterm infants. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind trial in 25 hospitals in Canada, the United States, Argentina, Finland, Germany, and Israel in which 1201 infants with gestational ages of 23 weeks 0 days through 27 weeks 6 days were enrolled within 24 hours after birth between December 2006 and August 2010. Follow-up assessments began in October 2008 and ended in August 2012. INTERVENTIONS: Study participants were monitored until postmenstrual ages of 36 to 40 weeks with pulse oximeters that displayed saturations of either 3% above or below the true values. Caregivers adjusted the concentration of oxygen to achieve saturations between 88% and 92%, which produced 2 treatment groups with true target saturations of 85% to 89% (n = 602) or 91% to 95% (n = 599). Alarms were triggered when displayed saturations decreased to 86% or increased to 94%. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of death, gross motor disability, cognitive or language delay, severe hearing loss, or bilateral blindness at a corrected age of 18 months. Secondary outcomes included retinopathy of prematurity and brain injury. RESULTS: Of the 578 infants with adequate data for the primary outcome who were assigned to the lower target range, 298 (51.6%) died or survived with disability compared with 283 of the 569 infants (49.7%) assigned to the higher target range (odds ratio adjusted for center, 1.08; 95% CI, 0.85 to 1.37; P = .52). The rates of death were 16.6% for those in the 85% to 89% group and 15.3% for those in the 91% to 95% group (adjusted odds ratio, 1.11; 95% CI, 0.80 to 1.54; P = .54). Targeting lower saturations reduced the postmenstrual age at last use of oxygen therapy (adjusted mean difference, -0.8 weeks; 95% CI, -1.5 to -0.1; P = .03) but did not alter any other outcomes. CONCLUSION AND RELEVANCE: In extremely preterm infants, targeting oxygen saturations of 85% to 89% compared with 91% to 95% had no significant effect on the rate of death or disability at 18 months. These results may help determine the optimal target oxygen saturation. TRIAL REGISTRATIONS: ISRCTN Identifier: 62491227; ClinicalTrials.gov Identifier: NCT00637169.

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.

Enhancing breast milk production with Domperidone in mothers of preterm neonates (EMPOWER trial).

BACKGROUND: The use of mother's own breast milk during initial hospitalization has a positive impact not only in reducing potential serious neonatal morbidities but also contribute to improvements in neurodevelopmental outcomes. Mothers of very preterm infants struggle to maintain a supply of breast milk during their infants' prolonged hospitalization. Galactogogues are medications that induce lactation by exerting its effects through oxytocin or prolactin enhancement. Domperidone is a potent dopamine D2 receptor antagonist which stimulates the release of prolactin. Small trials have established its ability in enhancing breast milk production. EMPOWER was designed to determine the safety and efficacy of domperidone in mothers experiencing an inadequate milk supply. METHODS/DESIGN: EMPOWER is a multicenter, double masked, randomized controlled phase-II trial to evaluate the safety and effectiveness of domperidone in those mothers identified as having difficulty in breast milk production. Eligible mothers will be randomized to one of two allocated groups: Group A: domperidone 10 mg orally three times daily for 28 days; and Group B: identical placebo 10 mg orally three times daily for 14 days followed by domperidone 10 mg orally three times daily for 14 days. The primary outcome will be determined at the completion of the first 2-week period; the second 2-week period will facilitate answering the secondary questions regarding timing and duration of treatment. To detect an estimated 30% change between the two groups (from 40% to 28%, corresponding to an odds ratio of 0.6), a total sample size of 488 mothers would be required at 80% power and alpha=0.05. To account for a 15% dropout, this number is increased to 560 (280 per group). The duration of the trial is expected to be 36-40 months. DISCUSSION: The use of a galactogogue often becomes the measure of choice for mothers in the presence of insufficient breast milk production, particularly when the other techniques are unsuccessful. EMPOWER is designed to provide valuable information in guiding the practices for this high-risk group of infants and mothers. The results of this trial will also inform both mothers and clinicians about the choices available to increase and maintain sufficient breast milk. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT01512225.