DR.BERCOVICH: MCG en Diabeticas Tipo 1 Embarazadas

La monitorización glucémica continua en el embarazo reduce las complicaciones

Este mes se ha dado a conocer en Lisboa, con motivo de la EASD, una nuevo ensayo publicado en la prestigiosa revista The Lancet, en la que los autores de la misma señalan que la monitorización continua de glucosa debe ser ofrecida a todas las mujeres embarazadas con diabetes tipo 1 para reducir el riesgo de complicaciones para los recién nacidos.

Para las mujeres con diabetes tipo 1, monitorizar los niveles de azúcar en la sangre continuamente durante el embarazo a través de un dispositivo implantado ayuda a manejar mejor la enfermedad y mejora los resultados del parto en comparación con las pruebas tradicionales de pinchazos.

Uno de cada dos recién nacidos de mujeres con diabetes tipo 1 puede sufrir complicaciones como resultado de estar expuesta a niveles elevados de azúcar en la sangre materna. Las complicaciones pueden incluir anomalía congénita, parto prematuro, muerte fetal, necesidad de cuidados intensivos después del nacimiento, y mayores tasas de pre-eclampsia y cesárea para la madre.

Los autores del ensayo internacional dicen que, como resultado de estos hallazgos, este tipo de monitorización continua de glucosa debería ser ofrecido a todas las mujeres embarazadas con diabetes tipo 1 para ayudar a mejorar los resultados de los recién nacidos, y de las propias madres.

En el estudio, los investigadores ensayaron con un dispositivo de monitorización continua de glucosa (CGM) implantado que proporciona 288 registros de glucosa al día, lo que permite a los usuarios reconocer y responder los cambios en los niveles de azúcar en la sangre a medida que ocurren. Compararon esto con la monitorización tradicional, usado 4-8 veces al día, que consiste en pinchar el dedo y poner la sangre en una tira de prueba para medir los niveles de azúcar en la sangre.

El estudio incluyó a 214 mujeres embarazadas con diabetes tipo 1 de 18 a 40 años que manejaban su condición con insulina diaria (bombas de insulina o inyecciones diarias múltiples). La mitad fueron asignados al azar para usar el dispositivo CGM, y la otra mitad para usar el método de monitorización tradicional. El dispositivo se usó durante aproximadamente 24 semanas. El estudio se llevó a cabo en 31 hospitales de Canadá, Inglaterra, Escocia, España, Irlanda, Italia y Estados Unidos.

El dispositivo de monitorización continua de glucosa ayudó a reducir los niveles de azúcar en la sangre en una pequeña cantidad [0,2% (-0,34 a -0,03)]. En comparación con la monitorización tradicional, las mujeres que usaron el dispositivo pasaron más tiempo en el rango normal de niveles de azúcar en la sangre (68% vs 61% – equivalente a 100 minutos más por día) y pasaron menos tiempo con altos niveles de azúcar en la sangre (27% % – equivalente a 1 hora menos por día). El número de episodios de hipoglucemia grave y el tiempo de hipoglucemia fue comparable en los dos grupos (18 vs 21 y 3% vs 4% respectivamente).

Es importante destacar que los resultados del parto mejoraron para aquellas mujeres con diabetes que usaron monitorización continua de glucosa, reduciendo el número de bebés que nacen más grande que el promedio (53% vs 69%), el número de bebés admitidos a cuidados intensivos por más de 24 horas (27% vs 43% , y el número de bebés nacidos con niveles bajos de azúcar en sangre (15% vs 28%). En promedio, los bebés cuyas madres habían utilizado el dispositivo de monitorización continua de glucosa también salieron del hospital un día antes que los bebés cuyas madres usaron el control tradicional (3,1 vs 4 días).

“Durante mucho tiempo ha habido un progreso limitado en la mejora de los resultados de parto para las mujeres con diabetes tipo 1, por lo que estamos contentos de que nuestro estudio ofrece una nueva opción para ayudar a las mujeres embarazadas con diabetes y sus hijos”, dice el Dr. Denice Feig, Universidad de Toronto y Sistema de Salud de Sinaí, Canadá. “Mantener los niveles de azúcar en la sangre dentro del rango normal durante el embarazo para las mujeres con diabetes tipo 1 es crucial para reducir los riesgos para la madre y el niño. Sin embargo, con el proceso tradicional, esto puede ser difícil ya que la sensibilidad a la insulina fluctúa durante el embarazo, lo que significa que el ajuste exacto de las dosis de insulina es complejo. Como resultado de nuestros hallazgos, creemos que este tipo de monitorización debe ser ofrecido a todas las mujeres embarazadas con diabetes tipo 1.

La profesora Helen Murphy, de la Universidad de East Anglia, Reino Unido, agrega: “Aunque la monitorización continua de glucosa es costosa, los costes adicionales probablemente serán compensados ​​por las estancias hospitalarias más cortas para los bebés y la reducción en las admisiones de la unidad de cuidados intensivos neonatales. Sólo necesitamos tratar a seis mujeres embarazadas para evitar que un bebé pesa más de lo normal al nacer y una unidad de cuidados intensivos neonatales “.

El estudio también analizó los efectos del dispositivo sobre los niveles de azúcar en la sangre para las mujeres que planeaban el embarazo, pero no encontró el mismo grado de beneficio para estas mujeres.

CONCEPTT: Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial: A multi-center, multi-national, randomized controlled trial - Study protocol

·         Denice S. Feig

·         Elizabeth Asztalos,

·         Rosa Corcoy,

·         Alberto De Leiva,

·         Lois Donovan,

·         Moshe Hod,

·         Lois Jovanovic,

·         Erin Keely,

·         Craig Kollman,

·         Ruth McManus,

·         Kellie Murphy,

·         Katrina Ruedy,

·         J. Johanna Sanchez,

·         George Tomlinson,

·         Helen R. Murphy and

·         on behalf of the CONCEPTT Collaborative Group

Abstract

Background

Women with type 1 diabetes strive for optimal glycemic control before and during pregnancy to avoid adverse obstetric and perinatal outcomes. For most women, optimal glycemic control is challenging to achieve and maintain. The aim of this study is to determine whether the use of real-time continuous glucose monitoring (RT-CGM) will improve glycemic control in women with type 1 diabetes who are pregnant or planning pregnancy.

Methods/design

A multi-center, open label, randomized, controlled trial of women with type 1 diabetes who are either planning pregnancy with an HbA1c of 7.0 % to ≤10.0 % (53 to ≤ 86 mmol/mol) or are in early pregnancy (<13 weeks 6 days) with an HbA1c of 6.5 % to ≤10.0 % (48 to ≤ 86 mmol/mol). Participants will be randomized to either RT-CGM alongside conventional intermittent home glucose monitoring (HGM), or HGM alone. Eligible women will wear a CGM which does not display the glucose result for 6 days during the run-in phase. To be eligible for randomization, a minimum of 4 HGM measurements per day and a minimum of 96 hours total with 24 hours overnight (11 pm-7 am) of CGM glucose values are required. Those meeting these criteria are randomized to RT- CGM or HGM. A total of 324 women will be recruited (110 planning pregnancy, 214 pregnant). This takes into account 15 and 20 % attrition rates for the planning pregnancy and pregnant cohorts and will detect a clinically relevant 0.5 % difference between groups at 90 % power with 5 % significance. Randomization will stratify for type of insulin treatment (pump or multiple daily injections) and baseline HbA1c. Analyses will be performed according to intention to treat. The primary outcome is the change in glycemic control as measured by HbA1c from baseline to 24 weeks or conception in women planning pregnancy, and from baseline to 34 weeks gestation during pregnancy. Secondary outcomes include maternal hypoglycemia, CGM time in, above and below target (3.5–7.8 mmol/l), glucose variability measures, maternal and neonatal outcomes.

Discussion

This will be the first international multicenter randomized controlled trial to evaluate the impact of RT- CGM before and during pregnancy in women with type 1 diabetes.

Trial registration:ClinicalTrials.gov Identifier: NCT01788527 Registration Date: December 19, 2012.

Keywords

Diabetes mellitus type 1 Pregnancy Preconception Continuous glucose monitoring Randomized controlled trial

Background

Despite all efforts, women with type 1 diabetes in pregnancy continue to have increased rates of adverse pregnancy outcomes. Women aiming for optimal glycemic control are at substantially increased risk of severe hypoglycemia (episode of low blood glucose requiring third party assistance) as well as pregnancy related complications of gestational hypertension, preeclampsia and delivery by caesarean section. Infants of mothers with diabetes face increased risk of preterm delivery, macrosomia, neonatal hypoglycemia, hyperbilirubinemia, respiratory distress and neonatal intensive care unit admissions. Macrosomia itself is associated with shoulder dystocia, birth injury, asphyxia and death. In a study of over 1,000,000 deliveries in Ontario, Canada, the rates of perinatal mortality and congenital anomalies among women with pre-existing diabetes in pregnancy were found to be approximately twice the rates of women without diabetes [1].

Numerous studies have shown that adverse pregnancy outcomes can be reduced with improved glycemic control. Pre-pregnancy care has been shown to assist women to improve glycemic control during the crucial period of organogenesis, and has been associated with reduced rates of adverse pregnancy outcomes including major congenital malformation, stillbirth and neonatal death. However, even motivated women who attend pre-pregnancy clinics still struggle to achieve and maintain optimal glycemic control [2].

CGM systems contain a subcutaneous glucose-sensing device which measures interstitial glucose and provide detailed information about the frequency and duration of glucose excursions, which is either unavailable to the user at the time of collection but available after (masked CGM) or available at the time (RT-CGM). One study comparing conventional home glucose monitoring (HGM) with masked CGM, found that CGM detected substantial hyperglycemia (>3 hours/day) and overnight hypoglycemia (1–4 hours) missed by conventional glucose monitoring [3]. Another study demonstrated that pregnant women with type 1 diabetes are still far from achieving the recommended glucose control target range of 3.9–7.8 mmol/l [4]. During the first trimester, masked CGM demonstrated that women spent 10–12 h per day hyperglycemic (>7.8 mmol/L) and 2–3 h hypoglycemic (<3.9 mmol/l). By the third trimester maternal hyperglycemia improved only slightly even with frequent antenatal clinic visits.

RT- CGM use provides additional information for the user to consider when adjusting diet, activity and insulin doses. A systematic review in non-pregnant adults, demonstrated that RT- CGM use is associated with modest improvements in glycemic control (a mean HbA1c reduction of 0.3 %), with maximal impact (up to 1.0 % reduction in HbA1c) in those with poor glycaemic control who use CGM at least 6 days per week [5]. However data from two randomized trials in pregnancy are conflicting. In a UK trial of 71 women with type 1 and type 2 diabetes, randomized to wearing a masked CGM every 4–6 weeks compared to standard care with HGM, the use of the CGM was associated with both reduced HbA1c (0.6 %) and reduced risk of macrosomia (OR 0.36, 95 % CI 0.13-0.98) [6]. A subsequent Danish trial of 154 women, randomized to use RT-CGM intermittently (six days x five times) or standard care with HGM found no difference in glycemic control or neonatal outcomes [7]. This may have been because women had good glycaemic control at baseline and were not particularly compliant with RT- CGM, with only 60 % of women using it intermittently. A systematic review thus concluded that more research is needed to identify the most effective techniques of blood glucose monitoring in pregnant women [8].

The aim of this study is to determine whether the use of continuous RT- CGM will improve glycemic control in women with type 1 diabetes who are a) planning pregnancy and b) in early in pregnancy, without substantially increasing the rate of hypoglycemia.

Methods/design

Overall study design

CONCEPTT is a multicenter, randomized, open label, controlled trial with an intention-to-treat analysis of two parallel trials: one trial in women planning pregnancy, and one in women in early pregnancy. Thirty trial centers are located across six countries: Canada (11), UK (15), Spain (1), Italy (1), USA (1) and Ireland (1). Women with type 1 diabetes in pregnancy who are ≤13 weeks 6 days gestation with an HbA1c of 6.5 % to ≤10.0 % (48 to ≤86 mmol/mol), and women with type 1 diabetes planning pregnancy with an HbA1c of 7.0 % to ≤10.0 % (53 to ≤86 mmol/mol), will be eligible for the run-in phase (see Fig. 1). The run-in incorporates a 6-day period during which women wear a masked CGM (Medtronic iPro®2 Professional CGM with Enlite2 sensor) to ensure that they can tolerate wearing a CGM device. Women who pass the run-in (>96 hours total with ≥24 hours overnight [11 pm-7 am] of CGM data and at least 4 HGM measurements per day) are eligible for randomization. Eligible women are randomized to CGM (Medtronic MiniMed Guardian®, Medtronic MiniMed Paradigm® Veo™ or Medtronic MiniMed® 640G system as per participant insulin delivery method) along with usual HGM, or continue HGM without CGM. The primary outcome is the change in HbA1c from baseline to 24 weeks or conception in women planning pregnancy, and from baseline to 34 weeks gestation in women who are pregnant.

 Primary outcome

Pre-pregnant cohort

The primary outcome is glycemic control as measured by a change in HbA1c from randomization to 24 weeks. If the participant becomes pregnant before 24 weeks, her final HbA1c is measured post-confirmation of a positive pregnancy test.

Pregnant cohort

The primary outcome is glycemic control as measured by a change in HbA1c from randomization to 34 weeks gestation. In women who do not progress to 34 weeks gestation, the latest measured HbA1c is used to contribute to the primary outcome.

Secondary outcomes

Pre-pregnant cohort

·         CGM time in target at baseline, 12 and 24 weeks.

·         HbA1c at baseline, 12 and 24 weeks.

Pregnant cohort

·         CGM time in target at baseline, 24 and 34 weeks gestation.

·         HbA1c at baseline, 24 and 34 weeks gestation

·         Incidence of gestational hypertension/preeclampsia

·         Caesarean section: pre-labour and intrapartum

·         Gestational weight gain (randomization to 36 weeks)

Pre-pregnant and pregnant cohorts

·         Hypoglycemia

o    Episodes of ‘severe hypoglycemia’ requiring third party assistance

o    Mild-moderate episodes of hypoglycemia from CGM data <3.5 mmol/L (mild) and <2.8 mmol/L (moderate) for 20 min duration

o    Nocturnal hypoglycemia: CGM glucose <3.5 mmol/L (mild) and <2.8 mmol/L (moderate) for 20 min duration between 23.00–07:00 h

·         Measures of glucose variability:

o    Mean amplitude of glycemic excursions

o    SD of CGM measurements

o    Mean absolute rate of change of CGM based on one week of sensor values

·         Length of hospital stay associated with delivery

·         Questionnaires

·         Insulin requirements

·         Safety outcome:

o    A substantial increase in hypoglycemia will be defined as >10 % increase in hypoglycemic episodes (<3.5 mmol/L for at least 20 min duration) over and above the HGM group.

Infant Outcomes.

·         Birth weight:

o    Infant birth weight >90th centile using national growth curves

o    Infant birth weight >90th centile using customized centiles

o    Infant birth weight <10th centile, using national growth curves

o    Infant birth weight <10th centile using customized centiles

o    Infant birth weight ≥4 kg

·         Pregnancy loss: miscarriage, stillbirth, neonatal death (death ≤28 days of life)

·         Preterm birth (<37 weeks and early preterm <34 weeks)

·         Birth injury

·         Shoulder dystocia

·         Neonatal hypoglycemia

·         Hyperbilirubinemia

·         Respiratory distress

·         High level neonatal care > 24 h

·         Cord blood gas pH < 7.0

·         Hyperinsulinemia (using cord c-peptide)

·         Composite fetal outcome: Pregnancy loss: miscarriage, stillbirth, neonatal death (death ≤28 days of life), birth injury, neonatal hypoglycemia, hyperbilirubinemia, respiratory distress, high level neonatal care > 24 h.

·         Sum of skin-folds >90th percentile for gestational age – triceps, sub scapular, biceps and suprailiac skin-folds

·         Anthropometric measures - infant birth weight, head circumference, chest circumference, abdominal circumference, left and right upper-arm circumference, crown-heel length, crown-rump length

·         Length of hospital stay until first discharge home

Statistical analysis

Primary Outcome: The primary analysis will compare the treatment groups on the 24-week HbA1c for the pre-pregnant cohort and on the 34-week HbA1c for the pregnant cohort, controlling for baseline HbA1c in an analysis of covariance that includes the treatment modality (pump/MDI) and strata used in randomization as covariates. We will obtain point and interval estimates of the treatment effect (the mean adjusted difference in follow-up HbA1c between treated and control groups) and also test the null hypothesis that the treatment effect is zero. The primary analysis will follow the intention-to-treat principle with all participants analyzed in the group to which they were randomized, regardless of actual sensor wear. In the analysis of the pre-pregnant cohort, in women who become pregnant before 24 weeks, the final outcome will be a measurement of HbA1c taken post-confirmation of pregnancy. In the analysis of the pregnant cohort, in women who do not reach 34 weeks gestation, the last HbA1c taken prior to 34-weeks will be used for the primary outcome. If important covariates remain imbalanced between treatment groups despite the stratified randomization, these covariates will be added to the regression model and the difference between adjusted and unadjusted estimates will be examined to assess the impact of this imbalance. Multiple imputation using earlier HbA1c measurements will be used to deal with HbA1c values that are missing at the final assessment.

Sample size estimation

The trial will include 324 participants, with 110 in the pre-pregnant cohort (women planning pregnancy), and 214 in the pregnant cohort.

In both cohorts, the sample size is based on a clinically relevant difference in HbA1c of 0.5 %. For pregnant women, a cross-sectional standard deviation (SD) of 1.1 was used, as it is towards the upper limit of published HbA1c SD values ([9, 10, 11]. In pre-pregnant women, a SD value of 0.8 was used, based on reported SD values in a trial of CGM in young adults [12]. As this latter study also reported the SD of change over 26 weeks, it was possible to compute the correlation between repeated measurements. In the various study groups, these correlations ranged from 0.4 to 0.7. To be conservative, we used the lower value of 0.4 in our sample size calculations. In both cohorts (pre-pregnant and pregnant), sample size was computed for an analysis of covariance with the final HbA1c as the outcome and baseline HbA1c and treatment group as predictors. Power was set at 90 % and the two-tailed significance level was set at 5 %.

Data management

The continuous glucose monitoring data management and analyses will be handled by the Jaeb Center for Health Research, Tampa, Florida. All other data and statistical aspects will be handled by the Clinical Trials Services/Centre for Mother, Infant and Child Research, Toronto, Ontario, and the trial statistician.

Trial steering committee

A trial steering committee will be responsible for the conduct of the trial. They will meet by teleconference on a quarterly basis to review the progress of the trial or on an ad hoc basis should the need arise.

Safety considerations

A Data Safety Monitoring Board (DSMB) will be established and will include experts in or representatives of the fields of endocrinology, obstetrics, epidemiology, and clinical trials methodology. They will meet after the initial safety analysis is completed, which will be done after 50 % of the pregnant group has been recruited. Serious unanticipated adverse events will be reported to the DSMB should the need arise.

Discussion

Implications of the findings

We aim to evaluate the impact of RT- CGM on glycemic control in two groups of women, those who are planning pregnancy and women in early pregnancy. If we find an improvement, the use of the RT-CGM will be encouraged and potentially reimbursed. We may also be able to determine if RT-CGM is more helpful in certain subsets of participants (e.g. those using pump or MDI), and whether the use of RT-CGM will affect maternal and neonatal outcomes. If we do not find that RT-CGM is beneficial, then other technologies such as closed-loop insulin delivery, may be indicated to facilitate optimal glycemic control in type 1 diabetes pregnancies.

Dissemination

A report will be written for the funding bodies and for peer-reviewed publication and will be disseminated to international lay and scientific audiences.

Conclusion

Results from studies in non-pregnant populations suggest that CGM improves glycemic control. Results from two randomized studies performed during pregnancy are conflicting, one with and one without improved glycemic control. This is the first study to look at continuous use of RT- CGM both in women planning pregnancy and in women during early pregnancy. It will inform patients, caregivers, and funding agencies regarding the use of CGM in the pregnant woman with type 1 diabetes.

Abbreviations

AUC, Area under the curve; DSMB, Data Safety Monitoring Board; HbA1c, Glycated haemoglobin; HGM, Home glucose monitoring; MDI, Multiple daily injections; RT-CGM, Real-time Continuous glucose monitoring; SD, Standard deviation.

Acknowledgements: The authors would like to thank the Clinical Trials Services team in particular Jon Barrett, Keitha McMurray, and Tamara Birkenheier at the Centre for Mother, Infant and Child Research, Sunnybrook Research Institute, Toronto, Canada. We would also like to thank Olivia Lou and Marlon Pragnell of the JDRF for their invaluable advice. For assistance with the complex legal and contractual issues we sincerely thank Frances Farnworth Ipswich Hospital NHS Trust and Mary Kasanicki Cambridge University Hospitals NHS Foundation Trust.

CONCEPTT Collaborative Group: Stephanie Amiel, Katharine Hunt, Louisa Green, Helen Rogers, Benedetta Rossi and, Ben Stodhart, King’s College Hospital, London, UK. Matteo Bonomo, Federico Bertuzzi, Giuseppina D. Corica, Silvana Fazio, Roberto Giro, Elena Mion, Andrea Moletta, Basilio Pintaudi and Rosa Sorrentino, Niguarda ca’ Granda Hospital, Milano, Italy. Rosa Corcoy, Ana Isabel Chico, Mª José Martínez, Mireia Sánchez, Diana Tundidor and, Alberto De Leiva, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain & CIBER-BBN, Zaragoza, Spain. John Booth, Natalia McInnes, Adelle Nykamp, Rose Otto, Ada Smith, Irene Stanton and, Tracy Tazzeo, McMaster University, Hamilton, Canada. Lois Donovan, Carolyn Oldford, Catherine Young and Claire Gougeon Alberta Health Services, University of Calgary, Calgary, Canada. Denice Feig, Barbara Cleave, Diane Donat, Shital Gandhi and, Michelle Strom, Mount Sinai Hospital, Toronto, Canada. Robyn Houlden and, Adriana Breen Kingston General Hospital, Queen’s University, Kingston, Canada. Kristin Castorino, William Sansum Diabetes Center, Santa Barbara, USA. Erin Keely, Heather Clark, Laura Gaudet, Alan Karovitch and, Janine Malcolm, The Ottawa Hospital General Campus, Ottawa, Canada. Julia Lowe and, Anna Rogowsky, The Ottawa Hospital General Campus, Ottawa, Canada. Ruth McManus, Anne Kudirka and, Margaret Watson, St. Joseph’s Health Centre, London, Canada. Damian Morris, Frances Farnworth, Duncan Fowler, Sue Mitchell and, Josephine Rosier, Ipswich Hospital NHS Trust, Ipswich, UK. Helen Murphy, Caroline Byrne, Katy Davenport, Jeannie Grisoni, Sandra Mulrennan, Sandra Neoh, Esther O’Sullivan, David Simmons, Zoe Stewart, Heike Templin, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. Helen Murphy, Jeremy Turner, Gioia Canciani, Niranjala (Nilu) Hewapathirana, Louise Jones, Leanne Piper, Rosemary Temple and, Tara Wallace, Norfolk and Norwich University Hospital, Norwich, UK. Rahat Maitland, Anita Banerjee, Annette Briley, Anna Brackenridge, Pam Gilby, Carolyn Gill, Anna Reid, Claire Singh and, Sara White, Guys and St Thomas’ NHS Foundation Trust, London, UK. Maria Wolfs St. Michael’s Hospital, Toronto, Canada. Eleanor Scott, Del Endersby, Leeds Teaching Hospitals NHS Trust, Leeds, UK. Michael Maresh, Gretta Kearney, Juliet Morris, Susan Quinn and, Prasanna Rao-Balakrishna, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK. Malcolm MacDougall, Royal Victoria Infirmary, Newcastle Upon Tyne, Newcastle, UK. Rudy Bilous, Mary Bilous, Shilpa Mahadissu, Deepika Menini and, Rasha Mukhtar, South Tees Hospitals, NHS Foundation Trust, Middlesbrough, UK. Richard Holt, Jane Forbes, Nicki Martin, and, Fiona Walbridge, Southampton General Hospital, Southampton, UK. Peter Mansell, Gayna Babington, George Bugg, Tasso Gazis, Nia Jones and, Dawn Spick, Queen’s Medical Centre, Nottingham, UK. Simon Heller, Rebecca Bustani, Val Gordon, Priya Madhuvrata, Sue Hudson, Chloe Nisbet, Peter Novodvorsky, Alexandra Solomon and, Karen Towse, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. Sam Philip, Anne Booth, Ann Cadzow, Martyna Chlost, Lynne Murray, Karen Norris and, Katrina Shearer, Grampian Diabetes Centre, Aberdeen, UK. Anna Dover, Frances Dougherty, Susan Johnston, Jill Little and, Liz McKay, Royal Infirmary of Edinburgh, Edinburgh, UK. Robert Lindsay, David Carty, Isobel Crawford, Fiona Mackenzie and, Therese McSorley, Glasgow Royal Infirmary, Glasgow, UK. Fidelma Dunne, Elizabeth Brosnan, Sharon Conway, Michelle Courcy Byrnes, Linda Duane, Niamh Duffy, Aoife Egan, Geraldine Gaffney, Grainne Higgins, Caroline Kelly, Collette Kirwan, Aaron Liew, Kevin Normoyle, Christina Roarty and, Mairead Waldron, Galway University Hospitals, Galway, Ireland. John Weisnagel, Christyne Allen, Martin D’Amours, Marie-Christine Dubé and, Valérie-Eve Julien, Centre hospitalier universitaire de Québec, Quebec City, Canada. Ariane Godbout, Sylvie Daigle. Centre Hospitalier de Université de Montréal, Hôpital St. Luc, Montreal, Canada. Thomas Ransom, Jill Coolen and Darlene Baxendale. Izaak Walton Killam Health Sciences Centre (IWK), Halifax, Canada. Jill Newstead-Angel, Royal University Hospital, Saskatoon, Canada. Alexandra L. Soloman, Karen Gorton, Margaret Jackson, Kirsty Miller and, Julie Taylor, The Dudley Group NHS FT, Russells Hall Hospital, Dudley, UK. Sonya Mergler, Asma Qureshi, Adriana Rodriguez, Kathryn Mangoff,  The Centre for Mother, Infant and Child Research (CMICR), Toronto, Canada.