A treatment strategy with nifedipine versus labetalol for women with pregnancy hypertension: study protocol for a randomised controlled trial (Giant PANDA).

BACKGROUND: Approximately one in ten women have high blood pressure during pregnancy. Hypertension is associated with adverse maternal and perinatal outcomes, and as treatment improves maternal outcomes, antihypertensive treatment is recommended. Previous trials have been unable to provide a definitive answer on which antihypertensive treatment is associated with optimal maternal and neonatal outcomes and the need for robust evidence evaluating maternal and infant benefits and risks remains an important, unanswered question for research and clinical communities. METHODS: The Giant PANDA study is a pragmatic, open-label, multicentre, randomised controlled trial of a treatment initiation strategy with nifedipine (calcium channel blocker), versus labetalol (mixed alpha/beta blocker) in 2300 women with pregnancy hypertension. The primary objective is to evaluate if treatment with nifedipine compared to labetalol in women with pregnancy hypertension reduces severe maternal hypertension without increasing fetal or neonatal death or neonatal unit admission. Subgroup analyses will be undertaken by hypertension type (chronic, gestational, pre-eclampsia), diabetes (yes, no), singleton (yes, no), self-reported ethnicity (Black, all other), and gestational age at randomisation categories (11 + 0 to 19 + 6, 20 + 0 to 27 + 6, 28 + 0 to 34 + 6 weeks). A cost-effectiveness analysis using an NHS perspective will be undertaken using a cost-consequence analysis up to postnatal hospital discharge and an extrapolation exercise with a lifetime horizon conditional on the results of the cost-consequence analysis. DISCUSSION: This trial aims to address the uncertainty of which antihypertensive treatment is associated with optimal maternal and neonatal outcomes. The trial results are intended to provide definitive evidence to inform guidelines and linked, shared decision-making tools, thus influencing clinical practice. TRIAL REGISTRATION: EudraCT number: 2020-003410-12, ISRCTN: 12,792,616 registered on 18 November 2020.

Nutritional management in newborn babies receiving therapeutic hypothermia: two retrospective observational studies using propensity score matching.

BACKGROUND: Therapeutic hypothermia is standard of care for babies with moderate to severe hypoxic-ischaemic encephalopathy. There is limited evidence to inform provision of nutrition during hypothermia. OBJECTIVES: To assess the association during therapeutic hypothermia between (1) enteral feeding and outcomes, such as necrotising enterocolitis and (2) parenteral nutrition and outcomes, such as late-onset bloodstream infection. DESIGN: A retrospective cohort study using data held in the National Neonatal Research Database and applying propensity score methodology to form matched groups for analysis. SETTING: NHS neonatal units in England, Wales and Scotland. PARTICIPANTS: Babies born at ≥ 36 gestational weeks between 1 January 2010 and 31 December 2017 who received therapeutic hypothermia for 72 hours or who died during treatment. INTERVENTIONS: Enteral feeding analysis - babies who were enterally fed during therapeutic hypothermia (intervention) compared with babies who received no enteral feeds during therapeutic hypothermia (control). Parenteral nutrition analysis - babies who received parenteral nutrition during therapeutic hypothermia (intervention) compared with babies who received no parenteral nutrition during therapeutic hypothermia (control). OUTCOME MEASURES: Primary outcomes were severe and pragmatically defined necrotising enterocolitis (enteral feeding analysis) and late-onset bloodstream infection (parenteral nutrition analysis). Secondary outcomes were survival at neonatal discharge, length of neonatal stay, breastfeeding at discharge, onset of breastfeeding, time to first maternal breast milk, hypoglycaemia, number of days with a central line in situ, duration of parenteral nutrition, time to full enteral feeds and growth. RESULTS: A total of 6030 babies received therapeutic hypothermia. Thirty-one per cent of babies received enteral feeds and 25% received parenteral nutrition. Seven babies (0.1%) were diagnosed with severe necrotising enterocolitis, and further comparative analyses were not conducted on this outcome. A total of 3236 babies were included in the matched enteral feeding analysis. Pragmatically defined necrotising enterocolitis was rare in both groups (0.5% vs. 1.1%) and was lower in babies who were fed during hypothermia (rate difference -0.5%, 95% confidence interval -1.0% to -0.1%; p = 0.03). Higher survival to discharge (96.0% vs. 90.8%, rate difference 5.2%, 95% confidence interval 3.9% to 6.6%; p < 0.001) and higher breastfeeding at discharge (54.6% vs. 46.7%, rate difference 8.0%, 95% confidence interval 5.1% to 10.8%; p < 0.001) rates were observed in enterally fed babies who also had a shorter neonatal stay (mean difference -2.2 days, 95% confidence interval -3.0 to -1.2 days). A total of 2480 babies were included in the matched parenteral nutrition analysis. Higher levels of late-onset bloodstream infection were seen in babies who received parenteral nutrition (0.3% vs. 0.9%, rate difference 0.6%, 95% confidence interval 0.1% to 1.2%; p = 0.03). Survival was lower in babies who did not receive parenteral nutrition (90.0% vs. 93.1%, rate difference 3.1%, 95% confidence interval 1.5% to 4.7%; p < 0.001). LIMITATIONS: Propensity score methodology can address imbalances in observed confounders only. Residual confounding by unmeasured or poorly recorded variables cannot be ruled out. We did not analyse by type or volume of enteral or parenteral nutrition. CONCLUSIONS: Necrotising enterocolitis is rare in babies receiving therapeutic hypothermia, and the introduction of enteral feeding is associated with a lower risk of pragmatically defined necrotising enterocolitis and other beneficial outcomes, including rates of higher survival and breastfeeding at discharge. Receipt of parenteral nutrition during therapeutic hypothermia is associated with a higher rate of late-onset infection but lower mortality. These results support introduction of enteral feeding during therapeutic hypothermia. FUTURE WORK: Randomised trials to assess parenteral nutrition during therapeutic hypothermia. TRIAL REGISTRATION: Current Controlled Trials ISRCTN474042962. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 36. See the NIHR Journals Library website for further project information.

Every year, approximately 1200 babies in the UK suffer a lack of oxygen to the brain around birth. This is called hypoxic­ischaemic encephalopathy and can lead to brain injury or death. To treat hypoxic­ischaemic encephalopathy, babies receive cooling treatment in which their body temperature is lowered. Doctors do not know the best way to give nutrition to babies receiving cooling treatment. Babies can either be fed milk into their stomach (enteral nutrition) or be given nutrients through their veins (parenteral nutrition). We compared babies who were fed milk while they were being cooled with babies from whom milk was withheld while they were being cooled to see if there was a difference in the frequency of necrotising enterocolitis, a severe gut disease. In addition, we compared babies who received parenteral nutrition while they were being cooled with babies who did not to see if there was a difference in infections. Finally, we looked at other outcomes, including survival and breastfeeding. We used the National Neonatal Research Database, which holds de-identified (i.e. no baby can be identified) information on all babies who have received NHS neonatal care. We used a statistical approach to match babies in each group (i.e. fed babies and not fed babies) as closely as possible so that any difference in outcomes was because of different nutrition and not because of other differences. We included > 6000 babies with hypoxic­ischaemic encephalopathy. Approximately one in three babies received milk feeds and one in four babies received parenteral nutrition during cooling. Necrotising enterocolitis was very rare. More babies who were fed milk during cooling had good outcomes (e.g. being breastfed at discharge) and fewer had necrotising enterocolitis. Most of these babies received only a small amount of milk in the first 3 days. More babies given parenteral nutrition had infections, but also more survived. This suggests that it is probably safe and may be beneficial to feed babies milk during cooling. More research should look at milk feeding and parenteral nutrition during cooling.

Administration of parenteral nutrition during therapeutic hypothermia: a population level observational study using routinely collected data held in the National Neonatal Research Database.

BACKGROUND: Parenteral nutrition is commonly administered during therapeutic hypothermia. Randomised trials in critically ill children indicate that parenteral nutrition may be harmful. OBJECTIVE: To examine the association between parenteral nutrition during therapeutic hypothermia and clinically important outcomes. DESIGN: Retrospective, population-based cohort study using the National Neonatal Research Database; propensity scores were used to create matched groups for comparison. SETTING: National Health Service neonatal units in England, Scotland and Wales. PARTICIPANTS: 6030 term and near-term babies, born 1/1/2010 and 31/12/2017, who received therapeutic hypothermia; 2480 babies in the matched analysis. EXPOSURE: We compared babies that received any parenteral nutrition during therapeutic hypothermia with babies that did not. MAIN OUTCOME MEASURES: Primary outcome: blood culture confirmed late-onset infection; secondary outcomes: treatment for late onset infection, necrotising enterocolitis, survival, length of stay, measures of breast feeding, hypoglycaemia, central line days, time to full enteral feeds, discharge weight. RESULTS: 1475/6030 babies (25%) received parenteral nutrition. In comparative matched analyses, the rate of culture positive late onset infection was higher in babies that received parenteral nutrition (0.3% vs 0.9%; difference 0.6; 95% CI 0.1, 1.2; p=0.03), but treatment for presumed infection was not (difference 0.8%, 95% CI -2.1 to 3.6, p=0.61). Survival was higher in babies that received parenteral nutrition (93.1% vs 90.0%; rate difference 3.1, 95% CI 1.5, 4.7; p<0.001). CONCLUSIONS: Receipt of parenteral nutrition during therapeutic hypothermia is associated with higher late-onset infection but lower mortality. This finding may be explained by residual confounding. Research should address the risks and benefits of parenteral nutrition in this population.

Study protocol: optimising newborn nutrition during and after neonatal therapeutic hypothermia in the United Kingdom: observational study of routinely collected data using propensity matching.

INTRODUCTION: Therapeutic hypothermia is standard of care for infants born ≥36 weeks gestation with hypoxic ischaemic encephalopathy (HIE); consensus on optimum nutrition during therapeutic hypothermia is lacking. This results in variation in enteral feeding and parenteral nutrition (PN) for these infants. In this study, we aim to determine the optimum enteral nutrition and PN strategy for newborns with HIE during therapeutic hypothermia. METHODS AND ANALYSIS: We will undertake a retrospective cohort study using routinely recorded electronic patient data held on the United Kingdom (UK) National Neonatal Research Database (NNRD). We will extract data from infants born ≥36 weeks gestational age between 1 January 2008 and 31 December 2016, who received therapeutic hypothermia for at least 72 hours or died during therapeutic hypothermia, in neonatal units in England, Wales and Scotland. We will form matched groups in order to perform two comparisons examining: (1) the risk of NEC between infants enterally fed and infants not enterally fed, during therapeutic hypothermia; (2) the risk of late-onset blood stream infections between infants who received intravenous dextrose without any PN and infants who received PN, during therapeutic hypothermia. The following secondary outcomes will also be examined: survival, length of stay, breast feeding at discharge, hypoglycaemia, time to full enteral feeds and growth. Comparison groups will be matched on demographic, maternal, infant and organisational factors using propensity score matching. ETHICS AND DISSEMINATION: In this study, we will use deidentifed data held in the NNRD, an established national population database; parents can opt out of their baby's data being held in the NNRD. This study holds study-specific Research Ethics Committee approval (East Midlands Leicester Central, 17/EM/0307). These results will help inform optimum nutritional management in infants with HIE receiving therapeutic hypothermia; results will be disseminated through conferences, scientific publications and parent-centred information produced in partnership with parents. TRIAL REGISTRATION NUMBER: NCT03278847; pre-results, ISRCTN47404296; pre-results.

Term admissions to neonatal units in England: a role for transitional care? A retrospective cohort study.

OBJECTIVE: To identify the primary reasons for term admissions to neonatal units in England, to determine risk factors for admissions for jaundice and to estimate the proportion who can be cared for in a transitional setting without separation of mother and baby. DESIGN: Retrospective observational study using neonatal unit admission data from the National Neonatal Research Database and data of live births in England from the Office for National Statistics. SETTING: All 163 neonatal units in England 2011-2013. PARTICIPANTS: 133 691 term babies born ≥37 weeks gestational age and admitted to neonatal units in England. PRIMARY AND SECONDARY OUTCOMES: Primary reasons for admission, term babies admitted for the primary reason of jaundice, patient characteristics, postnatal age at admission, total length of stay, phototherapy, intravenous fluids, exchange transfusion and kernicterus. RESULTS: Respiratory disease was the most common reason for admission overall, although jaundice was the most common reason for admission from home (22% home vs 5% hospital). Risk factors for admission for jaundice include male, born at 37 weeks gestation, Asian ethnicity and multiple birth. The majority of babies received only a brief period of phototherapy, and only a third received intravenous fluids, suggesting that some may be appropriately managed without separation of mother and baby. Admission from home was significantly later (3.9 days) compared with those admitted from elsewhere in the hospital (1.7 days) (p<0.001). CONCLUSION: Around two-thirds of term admissions for jaundice may be appropriately managed in a transitional care setting, avoiding separation of mother and baby. Babies with risk factors may benefit from a community midwife postnatal visit around the third day of life to enable early referral if necessary. We recommend further work at the national level to examine provision and barriers to transitional care, referral pathways between primary and secondary care, and community postnatal care.