Do women have to come off DAFNE when pregnant? Dr Helen R Murphy hm386@medschl.cam.ac.uk DAFNE Manchester June 26 2015
Topics for discussion Current practice in T1D pregnancy Reflect on current DAFNE guidelines Advantages of DAFNE (pre-pregnancy, antenatal and post pregnancy) Discuss limitations of DAFNE Top tips for advanced management DAFNE bucket list
Fetal development at 5 weeks 5 week human fetus
Early Cardiac Development Srivastava D, Nature 2000
Early neural tube development
400,00 singleton pregnancies, 1677 diabetes 9,488 1 malformation, 129 diabetes HbA1c % (mmol/mol) 1000 Pregnancy 6.5 (48) 30.3 1 in 33 7.0 (53) 38.4 1 in 26 7.5 (58) 50.6 1 in 20 8.0 (64) 60.1 1 in 17 9.5 (80) 95.3 1 in 10 71.6/1,000 pregnancies, RR 3.8 OR 1.3 per 1% HbA1c >6.3% (11>45mmol/mol) Bell R Diabetologia 2012
Risk of congenital malformation/perinatal mortality <8% With PPC this falls to <1.5% PPC (n=181) No PPC (n=499) p Pre-pregnancy 7.2% 8.1% <0.0001 1 st trimester 6.9% 7.4% <0.0001 2 nd trimester 6.4% 6.5% 0.001 3 rd trimester 6.4% 6.5% 0.05 HbA1c <7.0% (53mmol/mol) HbA1c < 6.1% (43 mmol/mol) 53% 38% <0.0001 18% 10% <0.0001 Murphy HR Diab Care 2010
National Pregnancy in Diabetes Audit 1700 pregnancies 128 NHS Trusts 55% T1D 45%T2D Type 1D Pregnancy 50% PPC LGA/macrosomia 53% Preterm delivery 37% Neonatal care admission 40% Type 2D pregnancy 33% PPC LGA/Macrosomia 25% Preterm delivery 20% NPID Headlines Improvements in T2D pregnancy - access to PPC T1D outcomes unchanged need to optimise day-to-day BG control
Does DAFNE do enough re PPC? Diabetes and Pregnancy Project
HbA1c goals Diabetes and Pregnancy Project HbA1c 6.5%(48)= 1:33 HbA1c 7% (53) = 1:25 HbA1c> 8% (64) = 1:15 HbA1c >10% (86)- pregnancy NOT recommended.
Folic Acid Diabetes and Pregnancy Project Reduces primary NTD 60%; May reduce risk of congenital heart defects; May reduce the risk of orofacial clefts; May increase multiple births??
Medications Diabetes and Pregnancy Project Stop statins midline CNS/limb defects (pravastatin preferred) Stop ACE/AII inhibitors Switch to Nifedipine +/- Labetalol (rarely Me Dopa) Continue antidepressants as required
Has DAFNE kept up with new Technologies? Retrospective/Professional CGMS Real-time/Personal CGM Sensor augmented pump (SAP)/LGS Closed Loop/Artificial Pancreas
7 day CGM profile T1D pregnancy
Time with BGL 3.9-7.8 (%) CGM profiles in T1 & T2D pregnancy 100 80 60 40 20 Type 1 DM Type 2 DM p=0.0001 T1 vs T2 DM p<0.0001 increase over time 0 4 8 12 16 20 24 28 32 36 40 Gestation (weeks) Murphy HR Diab Care 07
Time with BGL <3.5 (%) Hypoglycaemia in T1 & T2D pregnancy 35 30 Type 1 DM Type 2 DM 25 20 15 10 5 p=0.03 T1 vs T2 DM 0 4 8 12 16 20 24 28 32 36 40 Gestation (weeks) Hewapathiraana N Curr Diab Rep 2012
Mean HbA1c (%) CGMS as Educational tool Mean HbA1c 6.4+/-0.7% Standard Care vs. 5.8%+/-0.6 CGMS (p=0.007) 8.5 8.0 7.5 7.0 Std care CGMS 6.5 6.0 p=0.007 5.5 5.0 8 12 16 20 24 28 32 36 Gestational age (weeks)
Impact of CGMS on infant birth weight Median birth weight percentile 93 Standard Care vs. 69 CGM, p=0.02 100 80 60 40 20 0 Standard care CGM Reduced risk of LGA: Odds ratio 0.36 (95% CI 0.13 0.98; p = 0.05) Murphy HR et al, BMJ 2008
EFFICIENCY OF REAL-TIME CGM IN PREGNANT WOMEN WITH DIABETES A RANDOMIZED CONTROLLED TRIAL To assess whether intermittent real-time CGM, as part of routine pregnancy care, improves glycaemic control and pregnancy outcome in women with pregestational diabetes AL Secher, L Ringholm, HU Andersen, P Damm, ER Mathiesen, Diabetes Care, Epub Jan 24 2013
SUBGROUP ANALYSES RT-CGM Controls Type 1 diabetes (60 vs. 59) LGA infant Preterm delivery and/or severe neonatal hypoglycaemia Per-protocol (49 vs. 73) LGA infant Preterm delivery and/or severe neonatal hypoglycaemia 50% (30) 32% (18) 49% (25) 24% (11) 36% (21) 27% (16) 34% (22) 22% (16)
Matching insulin to food in real-life? Casey et al, BMC Public Health 2011 Lawton et al, Diab Res & Clin Pract 2011
Conclusions/Lessons Learned 1. Intermittent RT-CGM not helpful in this cohort (good baseline HbA1c & poor compliance) 2. CGM limited impact on hypoglycaemia exposure 3. Sensor discrepancy, discomfort, alarms annoying. CGM is burdensome; takes time, effort approx 1hr /day! 4. Qualitative data helped but CGM implementation is very variable
Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial D Feig (Co-PI), H Murphy (Co-PI), R Corcoy, M Hod, L Jovanovic,
International multi-centre, open label, intention-to-treat RCT n=324 2 parallel randomized controlled trials ( 110 prepregnant, 214 pregnant) Stratified by Mode of insulin therapy (Pump or MDI) Baseline HbA1c (>8.0 prepregnant, >7.5% pregnant) Focus on reducing maternal hyperglycaemia using CGM to deliver personalised education & insulin dose adjustment, pre-meal algorithms and adjustment for trends Will RT-CGM improve glycaemic control in women who are pregnant with T1D, or planning pregnancy, as measured by the change in HbA1c at 24/34 weeks clinicaltrials.gov NCT01788527
Circadian changes in CGM glucose from UK and Danish cohorts Glucose levels with 95% pointwise confidence intervals Data Graham Law, George Ellison & Eleanor Scott University of Leeds (TIME research group) Diab Care Feb 2015
CSII rationale Pickup J NEJM 2012
CSII stable basal insulin replacement
Mean postprandial glucose excursions from 0 to 300 min for 33 subjects after test meals of LF/LP ( ), LF/HP ( ), HF/LP ( ), and HF/HP ( ) content. Carmel E.M. Smart et al. Dia Care 2013;36:3897-3902 2013 by American Diabetes Association
Carbohydrate metabolism in T1D pregnancy 50 dinner & prandial bolus Murphy HR et al, Diabetologia 2012 breakfast & prandial bolus early gestation late gestation 40 Ra ( mol/kg/min) 30 20 10 0 18:00 20:00 22:00 00:00 02:00 04:00 06:00 08:00 10:00 12:00 Time (hh:mm) No changes in postprandial Ra in early vs. late pregnancy; p=0.61 Ra t50% 109±24 vs. 97±39min dinner and 58±18 vs. 52±33min breakfast
Delayed postprandial glucose disposal 50 dinner & prandial bolus breakfast & prandial bolus Rd ( mol/kg/min) 40 30 20 early gestation late gestation 10 0 18:00 20:00 22:00 00:00 02:00 04:00 06:00 08:00 10:00 12:00 Time (hh:mm) Postprandial Rd significantly reduced late pregnancy; P=0.003 Rd t50% 112 ± 22 vs. 142 ± 34 dinner and 103 ± 17 vs. 125 ± 21 breakfast
Insulin pharmacokinetics in T1D pregnancy Plasma insulin concentration (pmol/l) 500 400 300 200 100 0 dinner & prandial bolus 14:00 16:00 18:00 20:00 22:00 00:00 02:00 04:00 06:00 08:00 10:00 12:00 Time (hh:mm) breakfast & prandial bolus early gestation late gestation Tmax 53±13 vs. 79±33min dinner; 46±10 vs. 78±34min breakfast; p=0.0002
Structured Diet and Exercise 14 Structured Exercise Free Living 12 Sensor glucose (mmol/l) 10 8 6 4 2 0 14:00 16:00 18:00 20:00 22:00 00:00 02:00 04:00 06:00 08:00 10:00 12:00 Time (hh:mm) Overnight MBG 7.5±3.1 vs. 5.2±1.5mmol/l; p=0.05 Kumareswaran K, Diab Care Epub Feb 2013
Clinical Practice Dietary attention (20-30g CHO breakfast, 40-50g lunch, 50-60 dinner) Pre-meal boluses required (15 10 minutes early, 45 15mins late pregnancy) Post-meal exercise 15-20 mins walking
DAFNE bucket list PPC most important intervention in T1 pregnancy targeted information all women 16-45 years Pregnancy modules DAFNE grads & Novices (on-line, Face-2-Face, group) Huge variability CHO metabolism/insulin kinetics Impact of maternal diet & physical activity Integration of CGM & CSII into DAFNE curriculum before & during pregnancy
Thanks to all participating women
Acknowledgments AP Team at Cambridge Roman Hovorka Lalantha Leelarathna David B Dunger Janet M Allen Daniela Elleri Kavita Kumareswaran Zoe Stewart Nilu Hewapathiraana Julie Harris Josephine Hayes Marianna Nodale Angie Watts Malgorzata E Wilinska Kings College London Stephanie Amiel Funders JDRF AP Consortium (Aaron Kowalski) Diabetes UK/NIHR Abbott Diabetes Care/Animas (Johnsons & Johnsons)/Medtronic Key collaborators Health Psychology Prof TC Skinner Gerry Rayman/Jonathan Roland/Rosemary Temple