Do women have to come off DAFNE when pregnant?

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1 Do women have to come off DAFNE when pregnant? Dr Helen R Murphy hm386@medschl.cam.ac.uk DAFNE Manchester June

2 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

3 Fetal development at 5 weeks 5 week human fetus

4 Early Cardiac Development Srivastava D, Nature 2000

5 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.

6 400,00 singleton pregnancies, 1677 diabetes 9,488 1 malformation, 129 diabetes HbA1c % (mmol/mol) 1000 Pregnancy 6.5 (48) in (53) in (58) in (64) in (80) in /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.

7 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% < st trimester 6.9% 7.4% < nd trimester 6.4% 6.5% rd trimester 6.4% 6.5% 0.05 HbA1c <7.0% (53mmol/mol) HbA1c < 6.1% (43 mmol/mol) 53% 38% < % 10% < 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

8 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

9 Does DAFNE do enough re PPC? Diabetes and Pregnancy Project

10 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.

11 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??

12 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

14 Has DAFNE kept up with new Technologies? Retrospective/Professional CGMS Real-time/Personal CGM Sensor augmented pump (SAP)/LGS Closed Loop/Artificial Pancreas

15 7 day CGM profile T1D pregnancy

16 Time with BGL (%) CGM profiles in T1 & T2D pregnancy Type 1 DM Type 2 DM p= T1 vs T2 DM p< increase over time Gestation (weeks) Murphy HR Diab Care 07

17 Time with BGL <3.5 (%) Hypoglycaemia in T1 & T2D pregnancy Type 1 DM Type 2 DM p=0.03 T1 vs T2 DM Gestation (weeks) Hewapathiraana N Curr Diab Rep 2012

18 Mean HbA1c (%) CGMS as Educational tool Mean HbA1c 6.4+/-0.7% Standard Care vs. 5.8%+/-0.6 CGMS (p=0.007) Std care CGMS p= Gestational age (weeks)

Impact of CGMS on infant birth weight Median birth weight percentile 93 Standard Care vs. 69 CGM, p=0.

19 Impact of CGMS on infant birth weight Median birth weight percentile 93 Standard Care vs. 69 CGM, p= Standard care CGM Reduced risk of LGA: Odds ratio 0.36 (95% CI ; 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,

20 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

21 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)

22 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.

23 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

24 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,

25 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 NCT

26 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

27 CSII rationale Pickup J NEJM 2012

28 CSII stable basal insulin replacement

29 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: by American Diabetes Association

30 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) :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

31 Delayed postprandial glucose disposal 50 dinner & prandial bolus breakfast & prandial bolus Rd ( mol/kg/min) early gestation late gestation :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

32 Insulin pharmacokinetics in T1D pregnancy Plasma insulin concentration (pmol/l) 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

33 Structured Diet and Exercise 14 Structured Exercise Free Living 12 Sensor glucose (mmol/l) :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

34 Clinical Practice Dietary attention (20-30g CHO breakfast, 40-50g lunch, dinner) Pre-meal boluses required (15 10 minutes early, 45 15mins late pregnancy) Post-meal exercise mins walking

35 DAFNE bucket list PPC most important intervention in T1 pregnancy targeted information all women 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

36 Thanks to all participating women

Acknowledgments AP Team at Cambridge Roman Hovorka Lalantha Leelarathna David B

Hewapathiraana Julie Harris Josephine Hayes Marianna Nodale Angie Watts Malgorzata

Kowalski) Diabetes UK/NIHR Abbott Diabetes Care/Animas (Johnsons &

37 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

Maternal and Fetal Complications in Diabetes Pregnancy

Maternal and Fetal Complications in Diabetes Pregnancy Helen R Murphy Professor of Medicine (Diabetes & Antenatal Care), UEA Professor of Women s Health, Kings College London hm386@medschl.cam.ac.uk 1