Research projects currently recruiting at The Rotunda

MINT- The use of Milrinone in neonates with persistent pulmonary hypertension of the newborn.

Principal investigator- Dr.Afif El- Khuffash()

Persistant pulmonary hypertension (PPHN) is a relatively common condition occurring in 0.5-7 per 1000 live births and results in mortality ranging between 4%-33%. Inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation (ECMO) are the only current therapeutic options that have been systemically evaluated in clinical trial. The widespread use of iNO has resulted in a reduction in the need for ECMO however mortality and long-term morbidity remain unchanged. In addition, up to 40% of infants treated with iNO either has transient response or fail to demonstrate an improvement in oxygenation. There is a lack of consensus regarding alternative therapies in the setting of PPHN when there is a slow or lack of response to iNO.

The use of milirinone (a cardiac medication) in the setting of PPHN is limited to case series demonstrating an improvement in oxygenation when used in infants failing to respond to iNO. It’s inotropic and vasodilator properties make it ideal agent to use and may improve response to therapy and reduce mortality associated with the disease.

The purpose of the pilot study is to assess the feasibility of performing a pivotal trial to obtain preliminary data to calculate a sample size for definitive multicentre trial of milrinone therapy in PPHN. We aim to recruit a total of 30 infants of a period of 1 year.

We hypothesis that infants > 34 weeks gestation with PPHN, intravenous milrinone used in conjunction with iNO will result in a reduction in the time spent on iNO and invasive ventilation and that milrinone treatment will lead to an improvement in myocardial performance and global hemodynamics when compared to iNO alone.

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IRELAND - Aspirin for Optimising Pregnancy Outcome in Pre-gestational Diabetes

Principal Investigator – Professor Fionnuala Breathnach()

Pre-gestational diabetes represents a high-risk for the development of preeclampsia, with rates of preeclampsia within this group of approximately 20%. Women who have pre-gestational diabetes are at higher risk for pre-eclampsia and fetal growth restriction due to kidney damage associated with diabetes. The combination of diabetes and preeclampsia places the pregnancy at increased risk for stillbirth. Studies on the role of low-dose aspirin in the prevention of preeclampsia in high-risk women have yielded conflicting results.

Pre-eclampsia is caused by an imbalance between prostacyclin and thromboxane which are fat molecules in the body. This imbalance results from shallow placental invasion and restricted blood flow to body tissue (ischaemia) occurring shortly after implantation in the first trimester of pregnancy.

For this pilot study, 24 diabetic patients were recruited at two hospitals (The Rotunda Hospital and The Coombe Women and Infants University Hospital). 12 patients were randomised to receive aspirin and 12 were controls (did not receive aspirin).

The aims of this study were to:

  • determine patient participation rates, compliance with taking aspirin and perinatal outcomes.
  • logistical issues relating to recruitment, data collection and procurement, transport and storage of serum samples will be tested in this pilot study.
  • develop a multi-centre study in a large group of diabetic patients

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TEST-An Open-Label Randomized-Controlled Trial of Low dose Aspirin with an Early Screening Test For Pre-eclampsia and Growth restriction.

Principal Investigator- Professor Fionnuala McAuliffe (National Maternity Hospital) ()

Pre-eclampsia is a condition that affects 2-8% of pregnancies. It causes increased blood pressure in pregnancy (hypertension) and protein in the urine (proteinuria), which can cause eclampsia (seizures). Internationally it is a major cause of poor outcome in pregnancy for both mother and baby.

Previous studies have shown that low dose of Aspirin (LDA) can reduce the chance of developing pre-eclampsia in women with known risk factors. However, there is a lack of information regarding low risk populations.

The study was designed to assess the effectiveness of routine prescription of LDA to low risk women in their first pregnancy versus women who were prescribed aspirin on the basis of a positive early pregnancy screening test for pre-eclampsia and fetal growth restriction.

The effectiveness was measured by the following outcomes:

  • The number of eligible women who agree to participate in the study.
  • How well the protocol for the study is followed
  • The number of women in whom it was possible to get first trimester abdominal uterine artery Doppler examination (ultrasound test of blood flow to the uterus)
  • The number of women with a completed screening test who are issued the screening result on time
  • The acceptability of undergoing a screening test and or of taking aspirin to women in their first pregnancy

In this study, 500 first time mothers with low risk pregnancies were recruited and randomised to a group. Group 1 received 75mg of aspirin, group 2 did not receive aspirin and group 3 received aspirin until 36 weeks if they had positive early screening.

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HIP trial- Management of Hypotension In the Preterm Extremely Low Gestational Age Newborn.

Principal Investigator – Dr. David Corcoran()

Hypotension remains a significant problem in the preterm infant and is statistically associated with adverse short-term and long-term outcomes. Currently no uniform criteria exist to define hypotension and the evidence to support our current management strategies is limited.

HIP stands for: Management of Hypotension In the Preterm Extremely Low Gestational Age Newborn. The HIP Trial is an EU FP7 funded project that will be the largest multicentered European study in Extremely Low Gestational Age Newborns (ELGANs).

The aim of the HIP Trial is to develop an effective treatment of hypotension in the extremely low gestational age newborn.

Hypotension cannot only lead to mortality of preterm infants but also to brain injury and impaired neurosensory development. Preterm brain injury has far reaching implications and makes it necessary to perform an appropriate trial to determine whether the infusion of inotropic agents leads to improved outcome.

Short-term clinical outcomes will be closely monitored. The efficacy and safety of each treatment will be rigorously assessed. This will include objective assessment of cardiac output with echocardiography, cerebral oxygenation with NIRS and continuous EEG as an indirect measure of cerebral activity. The protocol includes neurodevelopmental follow-up of the cohort of babies at 12 and 24 months. This is one of the strengths of the study and will provide accurate data on the long-term safety of dopamine in Extremely Low Birth Weights (<1000g) (ELBW). This data does not exist and is urgently needed.

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ANSeR: The Algorithm for Neonatal Seizure Recognition

Principal investigator: Dr. Adrienne Foran ()

ANSeR is a multi-centre clinical investigation of an automated computer system (algorithm) that can detect seizures in newborn babies. ANSeR was developed by the Neonatal Brain Research Group at University College Cork in collaboration with University College London and has been funded by the Wellcome Trust. The Rotunda Hospital is one of 8 European sites involved in the ANSeR clinical investigation.

Seizures are the most common neurological emergency encountered in the neonatal intensive care unit and are frequently caused by problems such as hypoxia-ischaemia, haemorrhage, meningitis, infection or stroke. Seizures can put newborn babies at risk of serious complications. Early and accurate detection is therefore crucial to allow for appropriate treatment. Despite this, accurate diagnosis of seizures can be very challenging in newborns. The gold standard for seizure diagnosis is electroencephalography (EEG), which allows for continuous monitoring of brain activity. However, the specific expertise required for interpretation of the EEG is not readily available in most neonatal intensive care units. ANSeR aims to help with this issue by providing a computer-based decision support tool that will alert healthcare professionals to potential seizures. ANSeR works by analysing EEG data which is collected as normal standard of care and generating real-time automated analysis that is similar to a human expert.

ANSeR is 10 years in the making and extensive research has already been performed to develop, validate and test the algorithm. The current ANSeR investigation is testing the algorithm in real-time in the neonatal intensive care setting.

To learn more about the newborn seizures and the ANSeR clinical investigation please visit:

HIGHLOW

Principal Investigator: Dr. Fionnuala Ni Ainle()

The HIGHLOW trial assesses the efficacy and safety of heparin treatment in pregnant women who have previously had a form of thrombosis, such as deep vein thrombosis or a pulmonary embolism (VTE, venous thromboembolism). Women who have had a VTE in the past have a higher risk of reccurence. Heparin is an anticoagulant (“blood thinner”) which has been proven to decrease the chance of a new VTE. The most common form is a low-molecular-weight heparin (LMWH). In most hospitals LMWH is used during the pregnancy and in the 6 weeks following delivery as a precaution for pregnant women who have a history of VTE.

There has not yet been sufficient research on the most effective and at the same time safe dosage. This is the reason that the dosage of LMWH differs in different hospitals. In this trial we want to compare the effect of an often used low dosage to a higher dosage of LMWH. We want to test if the higher dosage decreases the risk of a VTE even more, without the treatment becoming less safe (ie with more bleeding).

In this trial we use the LMWH Tinzaparin. Tinzaparin is a drug which has already been used for many years in the prevention or treatment of VTE, also in pregnant women. It is given once daily via a subcutaneous injection.

Approximately 850 to 1100 patients will be taking part in this trial, receiving various different types of LMWH.

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Prospective practical evaluation of intrapartum screening for maternal GBS carriage.

Principal investigator - Dr. Maeve Eogan()

Women, men and children of all ages can be colonized with Group B streptococcus (GBS) bacteria without having any symptoms. GBS is particularly found in the gastrointestinal tract (‘gut’), vagina and urethra (‘water passage’). GBS occurs in both developed and developing countries.

Between 1 in every 5-10 pregnant women carry this bacterium and, unfortunately, a small number of their babies will become unwell. Between 0.5 and 3 newborn babies in every 1000 develop GBS bacterial infections, usually evident as respiratory disease, general sepsis, or meningitis within the first week. This can have devastating effects on the baby, including cerebral palsy and death so anything we can do to reduce this incidence must be explored.

Because the baby contracts the infection from the mother during labour, giving the mother an antibiotic directly into a vein during labour causes bacterial counts to fall rapidly and reduces the incidence of severe disease in the baby. The crux of the issue, however, is who should receive these antibiotics, and this pilot study aims to tease that out further, with a view to changing how we decide which women need antibiotics in labour.

  • It is not appropriate to routinely give antibiotics to all pregnant women at the start of labour.
  • Therefore, many countries screen all pregnant women for GBS late in pregnancy, the problem with this is that GBS carriage can be transient or intermittent – so a woman can screen positive at 37 weeks but be negative at delivery or vice versa.
  • In other countries (including Ireland and UK) therefore, a risk based approach is adopted. Women who have risk factors for GBS disease are treated with antibiotics during labour – risk factors include the following: mothers who have previously had a baby with GBS infection, mothers who have GBS detected on a urine or vaginal swab sample, mothers with high temperature in labour, mothers who’s waters have broken for more than 18 hours. This strategy does not however prevent all GBS infections as some affected babies will be born to mothers without any of these risk factors.

Very few of the women in labour who are GBS positive give birth to babies who are infected with GBS, and antibiotics can have harmful effects such as severe maternal allergic reactions, increase in drug-resistant organisms and exposure of newborn infants to resistant bacteria, and postnatal maternal and neonatal yeast infections.

Therefore, here at the Rotunda we are undertaking a study assessing whether it is feasible and effective use a rapid test to screen all women for GBS at onset of labour and whether such a strategy would better inform who should receive antibiotics and thus improve maternal and fetal outcomes.

AFFIRM- Can promoting awareness of fetal movements and focusing on interventions reduce fetal mortality a stepped wedge cluster randomised trial

Principal Investigator: Professor Fionnuala Breathnach
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Rates of stillbirth in Scotland and Ireland remain high. The majority of stillbirths occur in normally formed infants, with (retrospective) evidence of placental insufficiency being the commonest clinical finding.

Maternal perception of decreased fetal movements appears to be an early indication both of placental insufficiency and subsequent stillbirth.

The Affirm study will test the hypothesis that the rates of stillbirth will be reduced through the introduction of a package of care consisting of strategies for increasing pregnant women's awareness of the need for prompt reporting of decreased fetal movements, followed by a management plan for identification of placental insufficiency with timely delivery in confirmed cases. The odds of stillbirth fell by 30% after the introduction of a similar package of care in Norway but the efficacy of this intervention (and possible adverse effects and implications for service delivery) have not been tested in a randomized trial.

We plan a stepped wedge cluster design trial, in which hospitals in Scotland and Ireland will be randomized to the timing of introduction of the care package. Outcomes (including the primary outcome of stillbirth) will be derived from detailed routinely collected maternity data, allowing us to robustly test our hypothesis. In addition a nested qualitative study will examine the acceptability of the intervention to patients and health care providers and identify barriers to implementation.

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HANDLE- Haemodynamic Assessment iNpregnancy anDneonataL Echocardiography

Principal Investigator: Dr.Afif El-Khuffash()

A study identifying Abnormal Haemodynamic Profiles in Pregnancy as a Predictor of Adverse Obstetric Outcome and Characterisation of Neonatal Myocardial Performance in Infants.

Hypothesis and Aims of the Study

We hypothesise that serial evaluation of maternal Hemodynamic variables using NICOM can identify different hemodynamic patterns associated with IUGR and PET, when compared with normal pregnancies.

We also hypothesise that infants born to mothers with PET and IUGR have impaired myocardial performance.

Relevance and Importance

Management of pregnancies complicated by PET and/or IUGR remains one of the greatest challenges in obstetrics. The morbidity, both maternal and fetal, associated with these conditions is considerable. While there are identifiable clinical risk factors for the development of these disorders of uteroplacental origin, the majority of cases are encountered in the apparent ‘low-risk’ population. Provision of antenatal care is centred on regular maternal and fetal surveillance in order to enable timely identification of these complications. Frequently, however, clinical evidence of underlying uteroplacental dysfunction only emerges at a late stage in the disease process. With advanced disease the only therapeutic intervention is delivery of the fetus and placenta. Prolonging the pregnancy is associated with the risk of increasing maternal morbidity, maternal mortality and inuterofetal demise. As PET frequently occurs at very preterm gestations these risks must be balanced against the risks associated with delivery of a preterm infant. Identifying mothers at risk of developing disease early in the pregnancy, before clinical disease becomes apparent, has several advantages.

If this hypothesis is proven, the potential exists to use this test on a global scale in pregnancy. There is also evidence supporting increased long-term cardiovascular risk for women who have had a pregnancy complicated by diseases of uteroplacental origin. Underlying Hemodynamic aberrations in these patients may be a factor in this increased long-term risk. Assessing the maternal Hemodynamic profile in the postnatal period will enable us to study whether or not Hemodynamic changes identified during pregnancy persist following delivery. This may further our understanding of the enhanced cardiovascular risk seen in these women.

The characterisation of the myocardial performance of infants born to mothers with PET will help direct the care of those infants and also guide the use of cardiotropic agents. The myocardial performance of infants born to mothers with PET and IUGR may be different to those born to healthy pregnancies. The use of newer echocardiographic techniques has not been applied to those infants. Establishing reference ranges for these new echocardiographic markers of ventricular function in the neonatal population will pave the way for further research and clinical care in this field. Knowing the expected measurements of a relatively steady state will allow further research into the effects of diseases (such as sepsis, asphyxia, and respiratory distress) and the impact of therapeutic interventions (such as mechanical ventilation, inotropes and surfactant administration) on myocardial function. In addition, these markers may be used in the future to detect early myocardial compromise, determine the appropriate treatment strategy, and monitor treatment response.