Prenatal exposure to PFAS and the association with neurobehavioral and social development during childhood.

Exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous and may be associated with neurodevelopmental toxicity. However, epidemiological studies report mixed results on the risks of gestational PFAS exposure for children's neurobehavioral impairment. We aimed to examine the associations between prenatal PFAS exposure and children's neurobehavioral and social problems. We measured plasma concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), and perfluorohexane sulphonate (PFHxS) in first-trimester blood from 757 women from the Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study. Children were assessed at 3-4 years with the Behavior Assessment System for Children-2 (BASC-2) and the Social Responsiveness Scale-2 (SRS-2) (n = 756 and 496, respectively). We used multivariable linear regression to examine associations between individual and summed log2-transformed PFAS and scores on these assessments. Effect modification by sex was evaluated through interaction terms and stratified analyses. In the sample combining both sexes, a doubling of maternal PFOA was significantly associated with lower T-scores on the following SRS-2 scales: Social Motivation, DSM-Social Communication, and SRS Total score (B ranging from -1.08 to -0.78), suggesting lesser impairments with higher exposure. In sex-stratified analysis, PFOA was related to significantly lower T-scores in boys for these BASC-2 scales: Behavioral Symptoms Index, Externalizing Problems, Aggression, and Hyperactivity (B ranging from -1.32 to -1.03). In girls, however, PFAS were associated more problem behaviors, but most associations were small and the CIs included the null, with the exception of PFOA being significantly associated with higher T-scores for the BASC-2Anxiety scale (B = 1.84, 95% CI: 0.36, 3.32). In conclusion, we did not observe strong associations between prenatal exposure to the PFAS evaluated and children's neurobehavioral and social development in this population with low exposure levels. The results show mixed findings, depending on children's sex, neurodevelopmental outcome, and specific PFAS.

Growth and Neurodevelopmental Outcomes of Preterm Infants Born < 26 Weeks Gestation before and after Implementation of a Nutrition-Care Bundle.

BACKGROUND: This study aimed to assess the impact of a nutrition-care bundle on growth and neurodevelopmental outcomes of micro-preterm infants born in a level III neonatal intensive care unit (NICU) by two years corrected age. METHODS: A nutrition-care bundle emphasizing the prompt initiation of parenteral nutrition at birth, initiation of enteral feeds within 6 h after birth, and early addition of human milk fortifiers was implemented in 2015 for infants born < 26 weeks gestation. This before-and-after study evaluated growth and neurodevelopmental outcomes in infants born between 2012-2013 (before-nutrition-bundle, BNB) and 2016-2017 (after-nutrition-bundle, ANB). RESULTS: A total of 145 infants were included in the study. Infants in the ANB group (n = 73) were smaller (birthweight and gestational age), and there were more male infants and multiples included compared to the BNB group (n = 72). Enteral feeds and fortifiers started earlier in the ANB group. Growth velocity and weight z-score changes were similar in both groups during NICU stay and post-discharge. Systemic steroid use, but not cohort, was linked to lower Bayley scores across all domains. CONCLUSIONS: Implementing a nutrition-care bundle was not consistently associated with improved weight gain and neurodevelopmental outcomes in the micro-preterm infant population, possibly due to ongoing high-quality nutritional care by the clinical team.

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.

Association of low hemoglobin at birth and neurodevelopmental outcomes in preterm neonates ≤28 weeks' gestation: a retrospective cohort study.

OBJECTIVE: To compare neurodevelopmental outcomes at 18-24 months corrected age (CA) for preterm infants who had hemoglobin levels <120 g/l versus those with hemoglobin level ≥120 g/l at birth. METHODS: We included infants of ≤28 weeks gestational age (GA) born between January 2009 and June 2018. The primary outcome was neurodevelopmental impairment (NDI) at 18-24 months. Multivariable logistic regression was applied to determine the association. RESULTS: Of the 2351 eligible neonates, 351 (14.9%) had hemoglobin levels <120 g/L at birth. Of the 2113 surviving infants, 1534 (72.5%) underwent developmental follow-up at 18-24 months CA. There was no statistically significant difference in ND outcomes between the two groups. The composite outcome of death or NDI was significantly higher in the low hemoglobin group. CONCLUSION: In preterm infants ≤28 weeks GA, initial hemoglobin <120 g/L at birth was not associated with neurodevelopmental impairment at 18-24 months CA among survivors.

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..

Cohort profile update: The Canadian Maternal-Infant Research on Environmental Chemicals Child Development study (MIREC-CD PLUS).

BACKGROUND: The pan-Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study was established to determine whether maternal environmental chemical exposures were associated with adverse pregnancy outcomes in 2001 pregnant women. OBJECTIVES: The MIREC-Child Development (CD PLUS) study followed this cohort with the goal of assessing the potential effects of prenatal exposures on anthropometry and neurodevelopment in early childhood. POPULATION: MIREC families with children between the ages of 15 months and 5 years who had agreed to be contacted for future research (n = 1459) were invited to participate in MIREC-CD PLUS which combines data collected from an online Maternal Self-Administered Questionnaire with biomonitoring and neurodevelopment data collected from two in-person visits. PRELIMINARY RESULTS: Between April 2013 and March 2015, 803 children participated in the Biomonitoring visit where we collected anthropometric measures, blood, and urine from the children. The Behavioural Assessment System for Children-2, Behaviour Rating Inventory of Executive Function, MacArthur-Bates Communicative Development Inventories and the Communication subscale of the Adaptive Behaviour Scale from the Bayley Scales of Infant and Toddler Development-III are available on close to 900 children. There were 610 singleton children who completed in-person visits for neurodevelopment assessments including the Social Responsiveness Scale, Wechsler Preschool Primary Scale of Intelligence-III and NEuroPSYchological assessments (NEPSY). Currently, we are following the cohort into early adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). CONCLUSIONS: Data collection for the MIREC-CD PLUS study is complete and analysis of the data continues. We are now extending the follow-up of the cohort into adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). MIREC-CD PLUS is limited by loss to follow-up and the fact that mothers are predominately of higher socioeconomic status and 'White' ethnicity, which limits our generalizability. However, the depth of biomonitoring and clinical measures in MIREC provides a platform to examine associations of prenatal, infancy and childhood exposures with child growth and development.

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.

Prenatal and concurrent blood mercury concentrations and associations with IQ in canadian preschool children.

BACKGROUND: Prenatal and childhood mercury (Hg) exposures have been associated with negative impacts on child neurodevelopment. It is unclear if associations persist at the low Hg exposures typical in Western countries. OBJECTIVE: To examine associations between prenatal/childhood blood Hg concentrations and child IQ in Canadian male and female children while considering the potential modifying role of prenatal fish consumption. METHODS: We analyzed data from the Maternal-Infant Research on Environmental Chemicals study. Hg was measured in first trimester (n = 527), cord (n = 430), and child (at 3-4 years of age, n = 355) blood and examined sex-stratified associations between blood Hg and children's Full Scale IQ (FSIQ), Verbal IQ (VIQ), Performance IQ (PIQ), and General Language Composite (GLC) scores (assessed with WPPSI-III). Prenatal Hg analyses were further stratified by prenatal fish consumption (low: 0-2, moderate: 3-7, or high: ≥8 times/month). RESULTS: Higher cord blood Hg concentrations were associated with lower PIQ (ß = -3.27; 95%CI: 6.44, -0.09) in male children with the lowest prenatal fish consumption. Progressively stronger positive associations were observed with PIQ in male children for moderate (ß = 1.08; 95%CI: 0.10, 2.26) and high (ß = 3.07; 95%CI: 1.95, 4.19) prenatal fish consumption. Cord blood Hg concentrations were positively associated with female children's FSIQ (ß = 1.29; 95% CI: 0.77, 1.81) and PIQ (ß = 2.01; 95% CI: 1.19, 2.83); however, when stratified only in the highest fish consumption subgroup. Among female children, higher child blood Hg concentrations were associated with an approximately 1-point increase in FSIQ, VIQ, and GLC. CONCLUSIONS: Prenatal exposure to low levels of Hg was associated with lower PIQ scores in male children with low prenatal fish intake. Positive associations between cord and child blood Hg concentrations and IQ were primarily observed in female children and may be due to beneficial effects of prenatal fish intake.

One vs 2 courses of antenatal corticosteroids in pregnancies at risk of preterm birth: a secondary analysis of the MACS trial.

BACKGROUND: Birth is unpredictable and many patients who receive antenatal corticosteroids for preterm birth remain pregnant. Some professional societies recommend rescue antenatal corticosteroids for those who remain pregnant ≥14 days following the initial course. OBJECTIVE: This study aimed to explore a single vs a second course of antenatal corticosteroids in terms of severe neonatal morbidity and mortality. STUDY DESIGN: This is a secondary analysis of the Multiple Courses of Antenatal Corticosteroids for Preterm Birth (MACS) trial. The MACS study was a randomized clinical trial conducted in 80 centers in 20 different countries from 2001 to 2006. Participants who received only 1 course of intervention (ie, either a second course of antenatal corticosteroids or placebo) were included in this study. The primary outcome was a composite of stillbirth, neonatal mortality in the first 28 days of life or before discharge, severe respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage stage III and IV, periventricular leukomalacia, and necrotizing enterocolitis. Two subgroup analyses were planned to address the effect of a second course of antenatal corticosteroids on infants born before 32 weeks or within 7 days from the intervention. Moreover, a sensitivity analysis was performed to assess the effect of intervention on singleton pregnancies. Baseline characteristics were compared between the groups using chi-square and Student t tests. Multivariable regression analysis was performed to adjust for confounding variables. RESULTS: There were 385 and 365 participants included in the antenatal corticosteroid and placebo groups, respectively. The composite primary outcome occurred in 24% and 20% of participants in the antenatal corticosteroid and placebo groups, respectively (adjusted odds ratio, 1.09; 95% confidence interval, 0.76-1.57). Moreover, severe respiratory distress syndrome rate was similar between the 2 groups (adjusted odds ratio, 0.98; 95% confidence interval, 0.65-1.48). Newborns exposed to antenatal corticosteroids were more likely to be small for gestational age (14.9% vs 10.6%; adjusted odds ratio, 1.63; 95% confidence interval, 1.07-2.47). These findings remained true among singleton pregnancies for the primary composite outcome and birthweight <10th percentile (adjusted odds ratio, 1.29 [0.82-2.01]; and adjusted odds ratio, 1.74 [1.06-2.87]; respectively). Subgroup analyses of infants born before 32 weeks or within 7 days from the intervention did not show any benefits in terms of the composite primary outcome with antenatal corticosteroids vs placebo (50.5% vs 41.8% [adjusted odds ratio, 1.16; 95% confidence interval, 0.78-1.72]; and 42.3% vs 37.1% [adjusted odds ratio, 1.02; 95% confidence interval, 0.67-1.57]; respectively). CONCLUSION: Neonatal mortality and severe morbidities, including severe respiratory distress syndrome, were not improved by a second course of antenatal corticosteroids. Policy makers need to be thoughtful when recommending a second course of antenatal corticosteroids and consider whether not only short-term but also long-term benefits can be gained from such administration.

Mild neonatal morbidity in twins by planned mode of delivery: a secondary analysis of the Twin Birth Study.

BACKGROUND: The Twin Birth Study showed no differences in major severe adverse neonatal outcomes between those with planned vaginal delivery and those with planned cesarean delivery. OBJECTIVE: This was a secondary analysis of the Twin Birth Study in which mild neonatal morbidities, not previously reported, were compared between parturients with planned cesarean deliveries and those with planned vaginal delivery in twin births. STUDY DESIGN: This was a secondary analysis of the Twin Birth Study. In this study, women with a twin pregnancy at 32+0/7 to 38+6/7 weeks of gestation with the first twin in cephalic presentation and with an estimated weight between 1500 and 4000 g were randomized to either planned cesarean delivery or planned vaginal delivery. The primary outcome of this study was a composite mild neonatal outcome of respiratory and neurologic morbidities and neonatal intensive care unit admission that were not reported in the original Twin Birth Study at 34+0/7 to 38+6/7 weeks of gestation. A multivariable logistic regression analysis was used to identify factors associated with the composite adverse neonatal outcomes. Neonatal outcomes were further stratified by gestational age at delivery and by actual mode of delivery. RESULTS: A total of 1304 women and 1326 women were randomly assigned to planned cesarean delivery and planned vaginal delivery, respectively. Demographic and obstetrical characteristics were similar between the study groups. The rate of cesarean delivery was 90.1% in the planned cesarean delivery group and 40.1% in the planned vaginal delivery group. There was no significant difference in the primary composite outcome between the groups (10.6% vs 11.3%; P=.45) neither by planned mode of delivery nor by actual mode of delivery. Stratification by gestational age found a lower rate of the primary outcomes at ≥38+0/7 weeks of gestation in the planned cesarean delivery group when compared with the planned vaginal delivery group (4.8% vs 10.8%, respectively; P=.02). Furthermore, a lower risk for some individual outcomes was reported in the planned cesarean delivery group when compared with the planned vaginal delivery group, including intraventricular hemorrhage stage 1 to 2 (0.2% vs 0.6%; P<.05), low Apgar scores (0.8% vs 2.3%; P<.05), pH <7.0 (0.3 vs 1%; P<.05), and assisted ventilation needed at delivery (0.4% vs 0.9%; P<.05). CONCLUSION: In twin deliveries, with the first twin in the cephalic presentation, composite mild neonatal morbidity was not affected by the planned mode of delivery. These findings reinforce the original results of the Twin Birth Study. Nevertheless, an increased composite outcome after 38 weeks' gestation and a higher risk for some individual morbidities in the planned vaginal delivery group might be viewed as a concerning signal for the safety of vaginal delivery in twin deliveries and requires further research.

Outcomes in children of women with type 2 diabetes exposed to metformin versus placebo during pregnancy (MiTy Kids): a 24-month follow-up of the MiTy randomised controlled trial.

BACKGROUND: Metformin is increasingly being used during pregnancy, with potentially adverse long-term effects on children. We aimed to examine adiposity in children of women with type 2 diabetes from the Metformin in Women with Type 2 Diabetes in Pregnancy (MiTy) trial, with and without in-utero exposure to metformin, up to 24 months of age. METHODS: MiTy Kids is a follow-up study that included infants of women who participated in the MiTy randomised controlled trial, receiving either oral 1000 mg metformin twice daily or placebo. Caregivers and researchers remained masked to the type of medication (metformin or placebo) mothers received during their pregnancy. Anthropometric measurements, including weight, height, and skinfold thicknesses, were taken at 3, 6, 12, 18, and 24 months. At 24 months, linear regression was used to compare the BMI Z score and sum of skinfolds in the metformin versus placebo groups, adjusted for confounders. Fractional polynomials were used to assess growth trajectories. This study is registered with ClinicalTrials.gov, NCT01832181. FINDINGS: Of the 465 eligible children, 283 (61%) were included from 19 centres in Canada and Australia. At 24 months, there was no difference between groups in mean BMI Z score (0·84 [SD 1·52] with metformin vs 0·91 [1·38] with placebo; mean difference 0·07 [95% CI -0·31 to 0·45], p=0·72) or mean sum of skinfolds (23·0 mm [5·2] vs 23·8 mm [5·4]; mean difference 0·8 mm [-0·7 to 2·3], p=0·31). Metformin was not a predictor of BMI Z score at 24 months of age (mean difference -0·01 [95% CI -0·42 to 0·37], p=0·92). There was no overall difference in BMI trajectory but, in males, trajectories were significantly different by treatment (p=0·048); BMI in the metformin group was higher between 6 and 24 months. Children of women with type 2 diabetes were approximately 1 SD heavier than the WHO reference population. INTERPRETATION: Anthropometrics were similar in children exposed and those not exposed to metformin in utero; hence, overall, data are reassuring with regard to the use of metformin during pregnancy in women with type 2 diabetes and the long-term health of their children. FUNDING: Canadian Institute for Health Research.

PROspective Meta-analysis Of Trials of Initial Oxygen in preterm Newborns (PROMOTION): Protocol for a systematic review and prospective meta-analysis with individual participant data on initial oxygen concentration for resuscitation of preterm infants.

BACKGROUND: Clinicians favour low oxygen concentrations when resuscitating preterm infants immediately after birth despite inconclusive evidence to support this practice. Prospective meta-analysis (PMA) is a novel approach where studies are identified as eligible for inclusion in the meta-analysis before their results are known. AIMS: To explore whether high (60%) or low (30%) oxygen is associated with greater efficacy and safety for the initial resuscitation (immediately after birth) of preterm infants born at <29 weeks' gestation. METHODS: We will conduct a prospective meta-analysis (PMA) with individual participant data (IPD). We will perform a systematic search to identify ongoing RCTs including infants <29 weeks' gestation randomised to high (60%) or low (30%) oxygen for initial resuscitation after birth. IPD will be sought for all infants randomised for the purpose of meta-analysis. We will employ a one-stage random-effects approach to IPD meta-analysis. Potential heterogeneity and the differential effect of high or low oxygen will be explored through subgroup and interaction analyses. The primary outcome of this study is all-cause mortality prior to hospital discharge. There will be a follow-up analysis of neurodevelopmental outcomes once available. RESULTS/CONCLUSION: The results of neonatal outcomes at hospital discharge are expected by 2025, and neurodevelopmental outcomes by 2027.

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.

Optimizing Care for the Preterm Infant.

Preterm birth remains an ongoing global health issue with over 15 million infants born preterm annually [...].

Determinants of Small for Gestational Age in Women With Type 2 Diabetes in Pregnancy: Who Should Receive Metformin?

OBJECTIVE: In the MiTy (Metformin in Women With Type 2 Diabetes in Pregnancy) randomized trial of metformin versus placebo added to insulin, we found numerous benefits with metformin but identified an increased proportion of infants who were small for gestational age (SGA). We aimed to determine the predictors of SGA in order to individualize care. RESEARCH DESIGN AND METHODS: Using logistic regression, we assessed baseline maternal characteristics as predictors of SGA. We compared maternal/neonatal outcomes in SGA metformin and placebo groups using the t, χ2, or Fisher exact test, as appropriate. RESULTS: Among the 502 mothers, 460 infants were eligible for this study. There were 30 infants with SGA in the metformin group (12.9%) and 15 in the placebo group (6.6%) (P = 0.026). Among SGA infants, those in the metformin group were delivered significantly later than those in the placebo group (37.2 vs. 35.3 weeks; P = 0.038). In adjusted analyses, presence of a comorbidity (chronic hypertension and/or nephropathy) (odds ratio [OR] 3.05; 95% CI 1.58-5.81) and metformin use (OR 2.26; 95% CI 1.19-4.74) were predictive of SGA. The absolute risk of SGA was much higher in women receiving metformin with comorbidity compared with women receiving metformin without comorbidity (25.0% vs. 9.8%). CONCLUSIONS: In this study, we observed a high percentage of SGA births among women with type 2 diabetes and chronic hypertension and/or nephropathy who were treated with metformin. Therefore, with the aim of reducing SGA, it is reasonable to be cautious in our use of metformin in those with type 2 diabetes and chronic hypertension or nephropathy in pregnancy.

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.

Individualized treatment of preterm premature rupture of membranes to prolong the latency period, reduce the rate of preterm birth, and improve neonatal outcomes.

BACKGROUND: Preterm premature rupture of membranes complicates approximately 3% of pregnancies. Currently, in the absence of chorioamnionitis or placental abruption, expectant management, including antenatal steroids for lung maturation and prophylactic antibiotic treatment, is recommended. The benefits of individualized management have not been adequately explored. OBJECTIVE: This study aimed to compare the impact of 2 different management strategies of preterm premature rupture of membranes in 2 tertiary obstetrical centers on latency of >7 days, latency to birth, chorioamnionitis, funisitis, and short-term adverse maternal and neonatal outcomes. STUDY DESIGN: This was a multicenter retrospective study of women with singleton pregnancies with preterm premature rupture of membranes from 23 0/7 to 33 6/7 weeks of gestation between 2014 and 2018 and undelivered within 24 hours after hospital admission managed at Sunnybrook Health Sciences Center, Toronto, Canada (standard management group), and BCNatal (Hospital Clínic of Barcelona and Hospital Sant Joan de Déu Barcelona), Barcelona, Spain (individualized management group), following local protocols. The standard management group received similar management for all patients, which included a standard antibiotic regimen and routine maternal and fetal surveillance, whereas the individualized management group received personalized management on the basis of amniocentesis at hospital admission (if possible), to rule out microbial invasion of the amniotic cavity and targeted treatment. The exclusion criteria were cervical dilatation >2 cm, active labor, contraindications to expectant management (acute chorioamnionitis, placental abruption, or abnormal fetal tracing), and major fetal anomalies. The primary outcome was latency of >7 days, and the secondary outcomes included latency to birth, chorioamnionitis, and short-term adverse maternal and neonatal outcomes. Statistical comparisons between groups were conducted with propensity score weighting. RESULTS: A total of 513 pregnancies with preterm premature rupture of membranes were included in this study: 324 patients received standard management, and 189 patients received individualized management, wherein amniocentesis was performed in 112 cases (59.3%). After propensity score weighting, patients receiving individualized management had a higher latency of >7 days (76.0% vs 41.6%; P<.001) and latency to birth (18.1±14.7 vs 9.7±9.7 days; P<.001). Although a higher rate of clinical chorioamnionitis was suspected in the individualized management group than the standard group (34.5% vs 22.0%; P<.01), there was no difference between the groups in terms of histologic chorioamnionitis (67.2% vs 73.4%; P=.16), funisitis (57.6% vs 58.1%; P=.92), or composite infectious maternal outcomes (9.1% vs 7.9%; P=.64). Prolonged latency in the individualized management group was associated with a significant reduction of preterm birth at <32 weeks of gestation (72.1% vs 90.5%; P<.001), neonatal intensive care unit admission (75.6% vs 83.0%; P=.046), and neonatal respiratory support at 28 days of life (16.1% vs 26.1%; P<.01) compared with that in the standard management group. Moreover, prolonged latency was not associated with neonatal severe morbidity at discharge (survival without severe morbidity, 80.4% vs 73.5%; P=.09). CONCLUSION: Individualized management of preterm premature rupture of membranes may prolong pregnancy and reduce preterm birth at <32 weeks of gestation, the need for neonatal support, and neonatal intensive care unit admissions, without an increase in histologic chorioamnionitis, funisitis, neonatal infection-related morbidity, and short-term adverse maternal and neonatal outcomes.