Mid-Childhood Outcomes of Repeat Antenatal Corticosteroids: A Randomized Controlled Trial.

OBJECTIVE: To assess if exposure to repeat dose(s) of antenatal corticosteroids has beneficial effects on neurodevelopment and general health in mid-childhood, at 6 to 8 years' corrected age. METHODS: Women at risk for very preterm birth, who had received a course of corticosteroids ≥7 days previously, were randomized to intramuscular betamethasone (11.4 mg Celestone Chronodose) or saline placebo, repeated weekly if risk of very preterm birth remained. Mid-childhood assessments included neurocognitive function, behavior, growth, lung function, blood pressure, health-related quality of life, and health service utilization. The primary outcome was survival free of neurosensory disability. RESULTS: Of the 1059 eligible long-term survivors, 963 (91%) were included in the primary outcome; 479 (91%) in the repeat corticosteroid group and 484 (91%) in the placebo group. The rate of survival free of neurosensory disability was similar in both groups (78.3% repeat versus 77.3% placebo; risk ratio 1.00, 95% confidence interval, 0.94-1.08). Neurodevelopment, including cognitive function, and behavior, body size, blood pressure, spirometry, and health-related quality of life were similar in both groups, as was the use of health services. CONCLUSIONS: Treatment with repeat dose(s) of antenatal corticosteroids was associated with neither benefit nor harm in mid-childhood. Our finding of long-term safety supports the use of repeat dose(s) of antenatal corticosteroids, in view of the related neonatal benefits. For women at risk for preterm birth before 32 weeks' gestation, ≥7 days after an initial course of antenatal corticosteroids, clinicians could consider using a single injection of betamethasone, repeated weekly if risk remains.

Thyrotropin-releasing hormone added to corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease.

BACKGROUND: Thyrotropin-releasing hormones (TRH) added to prenatal corticosteroids has been suggested as a way to further reduce breathing problems and neonatal lung disease in infants born preterm. OBJECTIVES: To assess the effects of giving prenatal TRH in addition to corticosteroids to women at risk of preterm birth for the prevention of neonatal respiratory disease. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 June 2013) and reference lists of retrieved studies. We also contacted trial authors. SELECTION CRITERIA: Randomised controlled trials in women at sufficient risk of preterm birth to warrant the use of prenatal corticosteroids to promote lung maturity. TRH and corticosteroids were compared with corticosteroids, with or without placebo. DATA COLLECTION AND ANALYSIS: All assessments of trial eligibility, risk of bias and data extractions were independently carried out by at least two review authors. MAIN RESULTS: Over 4600 women were recruited into the 15 trials included in the review, however two trials did not contribute any outcome data to the review. The trials had a moderate risk of bias. Overall, prenatal TRH, in addition to corticosteroids, did not reduce the risk of death prior to hospital discharge (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.86 to 1.27, six trials, 3694 infants), neonatal respiratory distress syndrome (average RR 1.05, 95% CI 0.91 to 1.22, nine trials, 3833 infants), or chronic lung disease (RR 1.01, 95% CI 0.85 to 1.19, five trials, 2511 infants), and did not improve any of the secondary fetal, neonatal or childhood outcomes assessed by intention-to-treat analyses.Indeed, the data showed prenatal TRH to have adverse effects for women and their infants. All side effects reported (nausea, vomiting, light headedness, urgency of micturition, facial flushing) were significantly more likely to occur in women receiving TRH. In the infants, prenatal TRH increased the risk of needing respiratory support (RR 1.16, 95% CI 1.03 to 1.29, three trials, 1969 infants), and of having a low Apgar score at five minutes (RR 1.48, 95% CI 1.14 to 1.92, three trials, 1969 infants). Only three trials provided data on childhood follow-up, and while one trial suggested poorer outcomes for infants who were exposed to prenatal TRH, the other two trials, that assessed infants using an established developmental instrument, showed no clear differences between groups in follow-up outcomes.Sensitivity analyses by trial quality, or subgroups with differing times from entry to birth, or different dose regimens of TRH, did not change these findings. AUTHORS' CONCLUSIONS: Prenatal TRH in addition to corticosteroids, given to women at risk of preterm birth, does not improve infant outcomes and can cause maternal side effects.

Reduced corticomotor excitability and motor skills development in children born preterm.

The mechanisms underlying the altered neurodevelopment commonly experienced by children born preterm, but without brain lesions, remain unknown. While individuals born the earliest are at most risk, late preterm children also experience significant motor, cognitive and behavioural dysfunction from school age, and reduced income and educational attainment in adulthood. We used transcranial magnetic stimulation and functional assessments to examine corticomotor development in 151 children without cerebral palsy, aged 10-13 years and born after gestations of 25-41 completed weeks. We hypothesized that motor cortex and corticospinal development are altered in preterm children, which underpins at least some of their motor dysfunction. We report for the first time that every week of reduced gestation is associated with a reduction in corticomotor excitability that remains evident in late childhood. This reduced excitability was associated with poorer motor skill development, particularly manual dexterity. However, child adiposity, sex and socio-economic factors regarding the child's home environment soon after birth were also powerful influences on development of motor skills. Preterm birth was also associated with reduced left hemisphere lateralization, but without increasing the likelihood of being left handed per se. These corticomotor findings have implications for normal motor development, but also raise questions regarding possible longer term consequences of preterm birth on motor function.

Planned vaginal birth or elective repeat caesarean: patient preference restricted cohort with nested randomised trial.

BACKGROUND: Uncertainty exists about benefits and harms of a planned vaginal birth after caesarean (VBAC) compared with elective repeat caesarean (ERC). We conducted a prospective restricted cohort study consisting of a patient preference cohort study, and a small nested randomised trial to compare benefits and risks of a planned ERC with planned VBAC. METHODS AND FINDINGS: 2,345 women with one prior caesarean, eligible for VBAC at term, were recruited from 14 Australian maternity hospitals. Women were assigned by patient preference (n = 2,323) or randomisation (n = 22) to planned VBAC (1,225 patient preference, 12 randomised) or planned ERC (1,098 patient preference, ten randomised). The primary outcome was risk of fetal death or death of liveborn infant before discharge or serious infant outcome. Data were analysed for the 2,345 women (100%) and infants enrolled. The risk of fetal death or liveborn infant death prior to discharge or serious infant outcome was significantly lower for infants born in the planned ERC group compared with infants in the planned VBAC group (0.9% versus 2.4%; relative risk [RR] 0.39; 95% CI 0.19-0.80; number needed to treat to benefit 66; 95% CI 40-200). Fewer women in the planned ERC group compared with women in the planned VBAC had a major haemorrhage (blood loss ≥ 1,500 ml and/or blood transfusion), (0.8% [9/1,108] versus 2.3% [29/1,237]; RR 0.37; 95% CI 0.17-0.80). CONCLUSIONS: Among women with one prior caesarean, planned ERC compared with planned VBAC was associated with a lower risk of fetal and infant death or serious infant outcome. The risk of major maternal haemorrhage was reduced with no increase in maternal or perinatal complications to time of hospital discharge. Women, clinicians, and policy makers can use this information to develop health advice and make decisions about care for women who have had a previous caesarean. TRIAL REGISTRATION: Current Controlled Trials ISRCTN53974531

Timing of birth for women with a twin pregnancy at term: a randomised controlled trial.

BACKGROUND: There is a well recognized risk of complications for both women and infants of a twin pregnancy, increasing beyond 37 weeks gestation. Preterm birth prior to 37 weeks gestation is a recognized complication of a twin pregnancy, however, up to 50% of twins will be born after this time. The aims of this randomised trial are to assess whether elective birth at 37 weeks gestation compared with standard care in women with a twin pregnancy affects the risk of perinatal death, and serious infant complications. DESIGN: Multicentred randomised trial. INCLUSION CRITERIA: women with a twin pregnancy at 366 weeks or more without contraindication to continuation of pregnancy. Trial Entry & Randomisation: Following written informed consent, eligible women will be randomised from 36+6 weeks gestation. The randomisation schedule uses balanced variable blocks, with stratification for centre of birth and planned mode of birth. Women will be randomised to either elective birth or standard care. Treatment Schedules: Women allocated to the elective birth group will be planned for elective birth from 37 weeks gestation. Where the plan is for vaginal birth, this will involve induction of labour. Where the plan is for caesarean birth, this will involve elective caesarean section. For women allocated to standard care, birth will be planned for 38 weeks gestation or later. Where the plan is for vaginal birth, this will involve either awaiting the spontaneous onset of labour, or induction of labour if required. Where the plan is for caesarean birth, this will involve elective caesarean section (after 38 and as close to 39 weeks as possible). Primary Study Outcome: A composite of perinatal mortality or serious neonatal morbidity. SAMPLE SIZE: 460 women with a twin pregnancy to show a reduction in the composite outcome from 16.3% to 6.7% with adjustment for the clustering of twin infants within mothers (p = 0.05, 80% power). DISCUSSION: This is a protocol for a randomised trial, the findings of which will contribute information about the optimal time of birth for women with an uncomplicated multiple pregnancy at and beyond 37 weeks gestation.

Outcomes at 2 years of age after repeat doses of antenatal corticosteroids.

BACKGROUND: We previously reported the results of a randomized, controlled trial showing that repeat doses of antenatal corticosteroids reduced the risk of respiratory distress syndrome and serious neonatal morbidity. However, data have not been available regarding longer-term effects of this treatment. METHODS: Women who had received an initial course of corticosteroid treatment 7 or more days previously were randomly assigned to receive an intramuscular injection of corticosteroid (11.4 mg of betamethasone) or saline placebo; the dose was repeated weekly if the mother was still considered to be at risk for preterm delivery and the duration of gestation was less than 32 weeks. We assessed survival free of major neurosensory disability and body size of the children at 2 years of corrected age. RESULTS: Of the 1085 children who were alive at 2 years of age, 1047 (96.5%) were seen for assessment (521 exposed to repeat-corticosteroid treatment and 526 exposed to placebo). The rate of survival free of major disability was similar in the repeat-corticosteroid and placebo groups (84.4% and 81.0%, respectively; adjusted relative risk, 1.04, 95% confidence interval, 0.98 to 1.10; adjusted P=0.20). There were no significant differences between the groups in body size, blood pressure, use of health services, respiratory morbidity, or child behavior scores, although children exposed to repeat doses of corticosteroids were more likely than those exposed to placebo to warrant assessment for attention problems (P=0.04). CONCLUSIONS: Administration of repeat doses of antenatal corticosteroids reduces neonatal morbidity without changing either survival free of major neurosensory disability or body size at 2 years of age. (Current Controlled Trials number, ISRCTN48656428 [controlled-trials.com].).

Birth after caesarean study--planned vaginal birth or planned elective repeat caesarean for women at term with a single previous caesarean birth: protocol for a patient preference study and randomised trial.

BACKGROUND: For women who have a caesarean section in their preceding pregnancy, two care policies for birth are considered standard: planned vaginal birth and planned elective repeat caesarean. Currently available information about the benefits and harms of both forms of care are derived from retrospective and prospective cohort studies. There have been no randomised trials, and recognising the deficiencies in the literature, there have been calls for methodologically rigorous studies to assess maternal and infant health outcomes associated with both care policies. The aims of our study are to assess in women with a previous caesarean birth, who are eligible in the subsequent pregnancy for a vaginal birth, whether a policy of planned vaginal birth after caesarean compared with a policy of planned repeat caesarean affects the risk of serious complications for the woman and her infant. DESIGN: Multicentered patient preference study and a randomised clinical trial. INCLUSION CRITERIA: Women with a single prior caesarean presenting in their next pregnancy with a single, live fetus in cephalic presentation, who have reached 37 weeks gestation, and who do not have a contraindication to a planned VBAC. Trial Entry & Randomisation: Eligible women will be given an information sheet during pregnancy, and will be recruited to the study from 37 weeks gestation after an obstetrician has confirmed eligibility for a planned vaginal birth. Written informed consent will be obtained. Women who consent to the patient preference study will be allocated their preference for either planned VBAC or planned, elective repeat caesarean. Women who consent to the randomised trial will be randomly allocated to either the planned vaginal birth after caesarean or planned elective repeat caesarean group. Treatment Groups: Women in the planned vaginal birth group will await spontaneous onset of labour whilst appropriate. Women in the elective repeat caesarean group will have this scheduled for between 38 and 40 weeks. Primary Study Outcome: Serious adverse infant outcome (death or serious morbidity). SAMPLE SIZE: 2314 women in the patient preference study to show a difference in adverse neonatal outcome from 1.6% to 3.6% (p = 0.05, 80% power).

Effect of omeprazole on acid gastroesophageal reflux and gastric acidity in preterm infants with pathological acid reflux.

INTRODUCTION: Proton pump inhibitor (PPI) therapy is increasingly being used to treat premature infants with gastroesophageal reflux disease (GERD); however, the efficacy of PPI on acid production in this population has yet to be assessed in this patient group. The aim of this study was to determine the effect of 0.7 mg/kg/d omeprazole on gastric acidity and acid gastroesophageal reflux in preterm infants with reflux symptoms and pathological acid reflux on 24-h pH probe. METHODS: A randomized, double blind, placebo-controlled, crossover design trial of omeprazole therapy was performed in 10 preterm infants (34-40 weeks postmenstrual age). Infants were given omeprazole for 7 d and then placebo for 7 d in randomized order. Twenty-four-hour esophageal and gastric pH monitoring was performed on days 7 and 14 of the trial. RESULTS: Compared to placebo, omeprazole therapy significantly reduced gastric acidity (%time pH <4, 54% vs 14%, P < 0.0005), esophageal acid exposure (%time pH <4, 19% vs 5%, P < 0.01) and number of acid GER episodes (119 vs 60 episodes, P < 0.05). CONCLUSIONS: Omeprazole is effective in reducing esophageal acid exposure in premature infants with pathological acid reflux on 24-h pH probe; however, the far more complex issues of safety and efficacy have yet to be addressed.

Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.

BACKGROUND: The efficacy and safety of repeat doses of prenatal corticosteroids remains uncertain. Our aim was to establish whether repeat prenatal corticosteroids given to women at risk of preterm birth can reduce neonatal morbidity without harm. METHODS: In this hospital-based study, 982 women who remained at risk of preterm birth at less than 32 weeks' gestation, 7 or more days after receiving a first course of prenatal corticosteroids, were randomly assigned to receive a repeat intramuscular dose of either 11.4 mg betamethasone (as Celestone Chronodose), or saline placebo. This was repeated every week the woman remained undelivered, at less than 32 weeks' gestation, and at risk of preterm birth. Primary outcomes were occurrence and severity of neonatal respiratory distress syndrome, use and duration of oxygen and mechanical ventilation, and weight, length, and head circumference at birth and hospital discharge. Statistical analyses were on an intention to treat basis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN48656428. FINDINGS: Fewer babies exposed to repeat corticosteroids had respiratory distress syndrome (33%vs 41%; relative risk 0.82, 95% CI 0.71-0.95, p=0.01) and fewer had severe lung disease (12%vs 20%; relative risk 0.60, 95% CI 0.46-0.79, p=0.0003) than those in the placebo group. In keeping with these benefits, babies exposed to repeat corticosteroids needed less oxygen therapy (p=0.03), and shorter duration of mechanical ventilation (p=0.01). Mean weight, length, and head circumference at birth and hospital discharge did not differ between treatment groups. Z-scores for weight (p=0.04) and head circumference (p=0.03) at birth were lower in the babies who received repeat corticosteroids although at the time of hospital discharge Z-scores did not differ between treatment groups (p=0.29 for weight, p=0.48 for head circumference). INTERPRETATION: Exposure to repeat doses of antenatal corticosteroids reduces neonatal morbidity. Pending long-term outcome results, the short-term benefits for the babies in our study support the use of repeat doses of corticosteroids in women who remain at risk of very preterm birth 7 or more days after an initial course.

Vitamins C and E and the risks of preeclampsia and perinatal complications.

BACKGROUND: Supplementation with antioxidant vitamins has been proposed to reduce the risk of preeclampsia and perinatal complications, but the effects of this intervention are uncertain. METHODS: We conducted a multicenter, randomized trial of nulliparous women between 14 and 22 weeks of gestation. Women were assigned to daily supplementation with 1000 mg of vitamin C and 400 IU of vitamin E or placebo (microcrystalline cellulose) until delivery. Primary outcomes were the risks of maternal preeclampsia, death or serious outcomes in the infants (on the basis of definitions used by the Australian and New Zealand Neonatal Network), and delivering an infant whose birth weight was below the 10th percentile for gestational age. RESULTS: Of the 1877 women enrolled in the study, 935 were randomly assigned to the vitamin group and 942 to the placebo group. Baseline characteristics of the two groups were similar. There were no significant differences between the vitamin and placebo groups in the risk of preeclampsia (6.0 percent and 5.0 percent, respectively; relative risk, 1.20; 95 percent confidence interval, 0.82 to 1.75), death or serious outcomes in the infant (9.5 percent and 12.1 percent; relative risk, 0.79; 95 percent confidence interval, 0.61 to 1.02), or having an infant with a birth weight below the 10th percentile for gestational age (8.7 percent and 9.9 percent; relative risk, 0.87; 95 percent confidence interval, 0.66 to 1.16). CONCLUSIONS: Supplementation with vitamins C and E during pregnancy does not reduce the risk of preeclampsia in nulliparous women, the risk of intrauterine growth restriction, or the risk of death or other serious outcomes in their infants. (Controlledtrials.com number, ISRCTN00416244.).

Neonatal adrenal function after repeat dose prenatal corticosteroids: a randomized controlled trial.

OBJECTIVE: Do repeat prenatal corticosteroids suppress neonatal cortisol concentrations? STUDY DESIGN: Randomized controlled trial of women given weekly repeat corticosteroids or saline placebo, while at risk of preterm birth, until 32 weeks' gestation. RESULTS: Cord serum cortisol concentrations in infants exposed to repeat corticosteroids were similar compared with infants exposed to a single course of corticosteroids (mean difference -26 nmol/L (95% CI -57, 5 nmol/L, P = .10), as were prestress salivary cortisol concentrations on day 3 (median 16.5 vs 15.3 nmol/L, P = .96). The adrenal response to a stressor on day 3 was lower in the repeat corticosteroid group compared with the single course group (median 11.9 vs 21.4 nmol/L, P = .02). Cortisol concentrations were lower in the repeat corticosteroid group on day 7 (median 11.7 vs 18.2 nmol/L, P = .04), but not on days 14 and 21. CONCLUSION: The short- or long-term clinical impact, if any, of these changes in adrenal function needs to be determined.

Paradoxical impact of body positioning on gastroesophageal reflux and gastric emptying in the premature neonate.

OBJECTIVES: To combine manometry and impedance to characterize the mechanisms of gastroesophageal reflux (GER) and to explore their relation to the rate of gastric emptying (GE) and body position. STUDY DESIGN: Ten healthy preterm infants (35 to 37 weeks' postmenstrual age) were studied with the use of a micromanometric/impedance assembly. Episodes of GER were identified by impedance, and the mechanism(s) of GER triggering and GER clearance were characterized. GE was determined with a C13Na-octanoate breath test. RESULTS: Gastroesophageal reflux episodes (n=89) were recorded, consisting of 74% liquid, 14% gas, and 12% mixed. Transient lower esophageal sphincter relaxation (TLESR) was the predominant mechanism of reflux, triggering 83% of GER. Of 92 TLESRs recorded, 27% were not associated with reflux. Infants studied in the right lateral position had significantly (P <.01) more GER, a higher proportion of liquid GER (P <.05), and faster GE (P <.005) when compared with infants studied in the left lateral position. CONCLUSIONS: In healthy preterm infants, GER is predominantly liquid in nature. Right-side positioning is associated with increased triggering of TLESR and GER despite accelerating GE.

Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial.

CONTEXT: Prenatal magnesium sulfate may reduce the risk of cerebral palsy or death in very preterm infants. OBJECTIVE: To determine the effectiveness of magnesium sulfate given for neuroprotection to women at risk of preterm birth before 30 weeks' gestation in preventing pediatric mortality and cerebral palsy. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial at 16 tertiary hospitals in Australia and New Zealand with stratification by center and multiple pregnancy. A total of 1062 women with fetuses younger than 30 weeks' gestation for whom birth was planned or expected within 24 hours were enrolled from February 1996 to September 2000 with follow-up of surviving children at a corrected age of 2 years. INTERVENTIONS: Women were randomly assigned to receive a loading infusion of 8 mL (4 g [16 mmol] of 0.5 g/mL of magnesium sulfate solution or isotonic sodium chloride solution [0.9%]) for 20 minutes followed by a maintenance infusion of 2 mL/h for up to 24 hours. MAIN OUTCOME MEASURES: Rates of total pediatric mortality, cerebral palsy, and the combined outcome of death or cerebral palsy at a corrected age of 2 years. RESULTS: Data were analyzed for 1047 (99%) 2-year survivors. Total pediatric mortality (13.8% vs 17.1%; relative risk [RR], 0.83; 95% confidence interval [CI], 0.64-1.09), cerebral palsy in survivors (6.8% vs 8.2%; RR, 0.83; 95% CI, 0.54-1.27), and combined death or cerebral palsy (19.8% vs 24.0%; RR, 0.83; 95% CI, 0.66-1.03) were less frequent for infants exposed to magnesium sulfate, but none of the differences were statistically significant. Substantial gross motor dysfunction (3.4% vs 6.6%; RR, 0.51; 95% CI, 0.29-0.91) and combined death or substantial gross motor dysfunction (17.0% vs 22.7%; RR, 0.75; 95% CI, 0.59-0.96) were significantly reduced in the magnesium group. CONCLUSIONS: Magnesium sulfate given to women immediately before very preterm birth may improve important pediatric outcomes. No serious harmful effects were seen.